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Doctoral Thesis

Novel approach to spiro-pyrrolidine-oxindoles and its applicationto the synthesis of (±)-horsfiline and (-)-spirotryprostatin B

Author(s): Marti, Christiane

Publication Date: 2003

Permanent Link: https://doi.org/10.3929/ethz-a-004489068

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Diss. ETH No. 15001

Novel Approach to Spiro-Pyrrolidine-Oxindoles and its Application to the Synthesis

of (±)-Horsfiline and (–)-Spirotryprostatin B

A dissertation submitted to the

SWISS FEDERAL INSTITUTE OF TECHNOLOGY ZÜRICH

for the degree of

Doctor of Natural Sciences

Presented by

Christiane MARTI

Dipl. Ing. ECPM Strasbourg

born 25. August 1972 in Stuttgart, Germany

Accepted on the recommendation of

Prof. Dr. Erick M. Carreira, examiner

Prof. Dr. Hans-Jürg Borschberg, co-examiner

Karin, Gerhard und Thomas

in grosser Dankbarkeit gewidmet

Und ist schon jemals ein Ziegel so vom Dach

gefallen, wie es das Gesetz vorschreibt? Niemals!

Nicht einmal im Laboratorium zeigen sich die

Dinge so wie sie sollen. Sie weichen regellos nach

allen Richtungen davon ab, und es ist einigermaβen

eine Fiktion, daβ wir das als Fehler der Ausführung

ansehen und in der Mitte einen wahren Wert

vermuten.

Robert Musil

Acknowledgements

My dissertation at ETH was a real learning experience that was enjoyable most of the

time. Any successes during this time are also due to substantial support from others. I

therefore express my deepest thanks to:

Prof. Dr. Erick M. Carreira ― I benefited his guidance and support throughout the

course of my thesis. He was always open for scientific discussions, has an endless supply

of ideas, and allowed me the freedom to decide the direction of the project. At times

when I was willing to give up; he somehow found a way of motivating me to reach the

final goal.

Prof. Dr. Hans-Jürg Borschberg ― He accepted the co-examination of my thesis and his

interest in this work led to a thoroughly corrected manuscript.

Alec Fettes ― He read and corrected my manuscript and thereby substantially improved

this thesis not only in grammar and spelling, but also with clever suggestions on the

presentation of the content.

Christian Fischer ― His diploma work presents a noteworthy contribution to this thesis.

His enthusiastic working attitude and his conscientious but efficient preparative work

impressed me deeply.

Brigitte Brandenberg, Philipp Zumbrunnen and Prof. Dr. Bernhard Jaun ― The spectra

from the NMR-service had always a wonderful appearance, even when I only submitted

the tiniest amounts. Without help interpreting some of the spectral data, I would have

been lost.

Rolf Häflinger, Oswald Greter, Oliver Scheidegger and Dr. Walter Amrein ― They

measured my MS spectra and answered all associated questions.

Volker Gramlich and Paul Seiler ― They both solved X-ray crystal structures relevant to

this project and had the time to discuss their results with me in detail.

The members of the ETH staff responsible for ‘Schalter’, ‘Glaswäscherei’, ‘Entsorgung’

are gratefully acknowledged for prompt service always accompanied with a smile and a

friendly word.

The students in the OCP1 synthesized multigram quantities of my starting material.

The Carreira group is acknowledged for creating an overall pleasant working

atmosphere. My special thanks go to:

Claudia Dörfler and Franziska Peyer ― They solved every administrative problem and

did all the paperwork. Also they always had an open ear for problems of the group and its

individuals.

Jeffrey Bode, Alec Fettes, Dieter Muri, Tobias Ritter ― They have all been more than

just co-workers, lab-mates or ‘Settlers’ but real friends. Jeff is a wonderful person and a

brilliant chemist. His suggestions on my project were always very helpful. Alec and I

went a long way together (St Gallen-Zürich, Sola Duo, 8 h 15 min). His suggestions on

my chemistry decided the success of this project. Didi and Tobi are real sportsman and I

enjoyed playing volley and squash with them or having them chase me though the forest

(jogging), up the mountains (hiking in summer) und down the hills (skiing in winter).

Roger Fässler, Patrick Aschwanden, Jürg Oetiker and Stephan Schnidrig ― They where

always in a good mood and made the atmosphere in the lab an enjoyable one. Aschi is the

best PC-expert and was always solving my problems with ‘this stupid computer’.

My friends outside of the Carreira group also contributed significantly to this thesis by

encouraging me whenever it was necessary. My special thanks go to Anja Schürch,

Sibylle Steimen and Ulee Speicher, but also to my friends back in Germany and France

and from Volley KSOe.

Many thanks go also to my family for their support and love.

Last but not least: Thomas, I thank you very much for you support and love and for

standing at my side all the time. Without you, I would not have made it.

Publications and Presentations

Alec Fettes, Christiane Marti and Erick M. Carreira “Catalytic Asymmetric Aldol Reactions” Org. Reactions, manuscript in preparation. Christiane Marti and Erick M. Carreira “Total Synthesis of (–)-Spirotryprostatin B, Synthesis and Related Studies” manuscript in preparation. Christiane Marti and Erick M. Carreira “Construction of Spiro[Pyrrolidine-3,3’-Oxindoles] ― Recent Applications to the Synthesis of Oxindole Alkaloids” Eur. J. Org. Chem. manuscript submitted. Christiane Meyers and Erick M. Carreira “Total Synthesis of (–)-Spirotryprostatin B” Angew. Chem. Int. Ed. in press. Christian Fischer, Christiane Meyers and Erick M. Carreira “Efficient Synthesis of (±)-Horsfiline through the MgI2-Catalysed Ring-Expansion Reaction of a Spiro[cyclopropane-1,3’-indol]-2’-one” Helv. Chim. Acta 2000, 83, 1175. Phil B. Alper, Christiane Meyers, Andreas Lerchner, Dionicio R. Siegel and Erick M. Carreira ”Facile, Novel Methodology for the Synthesis of Spiro[pyrrolidin-3,3’-oxindoles]: Catalyzed Ring-Expansion Reactions of Cyclopropanes by Aldimines” Angew. Chem. Int. Ed. 1999, 38, 3186. Christiane Meyers, Phil B. Alper, Christian Fischer and Erick M. Carreira “Novel Methodology for the Synthesis of Spiro-Oxindoles” Poster presentation; Bayer Informationstage, Bayer AG (Germany), July 2000. Christiane Meyers, Phil B. Alper and Erick M. Carreira “Novel Methodology for the Synthesis of Pyrrolidine-spiro-Oxindole Ring Systems” Poster presentation; Drug Discovery, Pfizer (UK), September 1999

Abstract

The spiro-pyrrolidine-oxindole ring system is a recurring structural element that has been

identified in a number of cytostatic alkaloids. These spiro-fused ring systems embody

stereochemical and structural complexities that continue to challenge the synthetic

chemist. In this thesis the development of a novel approach to spiro-pyrrolidine-oxindoles

by MgI2-catalyzed ring-expansion reaction of spiro-cyclopropyl-oxindole I and a number

of N-alkyl- as well as N-aryl-sulfonyl aldimines II is presented (Scheme A).

NBn

O NBn

O

N R'MgI2 (10-20 mol%),THF

R

N

R

R'

III

IIImajor diastereomer

ca. 80:20

NBn

OMg

I

I

activation byLewis acid

nucleophilicactivation

MgI2 acts as a bifunctional catalyst:

Scheme A: Ring expansion of spiro-cyclopropyl-oxindole I with aldimines II catalyzed by MgI2.

MgI2 acts as a bifunctional catalyst wherein the Lewis-acidic metal and the nucleophilic

counterion operate in synergy. The resulting spiro-pyrrolidine-oxindole ring systems III

were obtained in good yields and with high diastereoselectivities.

NBn

MeO

O NBn

MeO

O

NMe

NH

MeO

O

NMe

83 %

IVMeN NMe

MeN

MgI2 (5.5 mol%), THF

41 %overall

horsfiline

V

Scheme B: Synthesis of (±)-horsfiline.

Our interest in the class of spiro-pyrrolidine-oxindole natural products as well as the

scope of the ring-expansion reaction led us to apply this method in the synthesis of

horsfiline and spirotryprostatin B. The synthetic route to (±)-horsfiline demonstrates the

use of 1,3,5-trimethyl-1,3,5-triazine (V) as an equivalent for N-methylmethanimine under

the conditions of the ring-expansion reaction. The synthesis afforded (±)-horsfiline in

41% yield over 5 steps via N-benzyl-spiro-cyclopropyl-oxindole (IV) (Scheme B).

In order to access the spirotryprostatin B core in a straightforward fashion, we could

establish that C9-substituted (spirotryprostatin numbering) spiro-pyrrolidine-oxindole

derivative VIII can be obtained in good yield from substituted cyclopropane VI and

imine VII.

The diastereomer distribution favors VIII possessing the required C3–C18 anti-

relationship (6:1). The corresponding syn-diastereomers were found to be converted to

VIII by refluxing in acetic acid. Resolution is achieved by peptide coupling with N-Boc-

L-proline chloride to furnish IX.

NH

O

VI

MgI2, THF

MeHC

N

TIPS

+

VII

N

NO

OH

Me

Me

spirotryprostatin B

HN

O

N

BocN

OH

HN

O

TIPS

N

BocN

OH

HN

O

CO2Me

Me

Me

+ isomers

MeHC

AcOH, ∆

18

3 N

BocN

OH

HN

O

CO2Me

O

Julia-Kocienskyolefination

VIII IX

XXI

NHN

O

MeHC

TIPS

9

183

Scheme C: Total synthesis of (–)-spirotryprostatin B.

Introduction of the prenyl side chain was accomplished by olefination of aldehyde XII by

Julia–Kocieńsky reaction to give XI, although similar transformations proved difficult in

earlier syntheses. Intermediate XI was then converted to spirotryprostatin B (Scheme C).

The synthetic sequence was performed in 16 steps (3.4% overall yield) and is a powerful

demonstration of the utility of the ring-expansion method.

Zusammenfassung

Das Spiro-Pyrrolidin-Oxindol Ringsystem ist ein Strukturelement, welches in einigen

zytostatisch wirkenden Alkaloiden identifiziert wurde. Die stereochemische und

strukturelle Komplexität dieser Systeme machen Spiro-Pyrrolidin-Oxindole zu

attraktiven Zielmolekülen für den organischen Synthetiker. Diese Abhandlung beschreibt

die Entwicklung einer neuartigen Methode, die über eine MgI2-katalysierte Ring-

Erweiterungs-Reaktion von Spiro-Cyclopropyl-Oxindol I mit verschiedenen N-Alkyl-

bzw N-Aryl-Sulfonyl-Aldiminen II zu Spiro-Pyrrolidin-Oxindolen führt (Schema A).

NBn

O NBn

O

N R'MgI2 (10-20 mol%),THF

R

N

R

R'

III

IIIbevorzugtes

Diastereomerca. (80:20)

NBn

OMg

I

I

Lewis SäureAktivierung

nucleophileAktivierung

MgI2, ein Katalysator mitsynergetischem Aktivierungsmuster:

Schema A: MgI2-katalysierte Ring-Erweiterung von Spiro-Cyclopropyl-Oxindol I mit Aldiminen II.

MgI2 konnte als wirksamer Katalysator identifiziert werden, in dem die Lewis-Acidität

des Metallzentrums (MgII) und die Nukleophilie des Gegenions (I−) synergetisch zu

wirken scheinen. Die Spiro-Pyrrolidin-Oxindole III wurden in guten Ausbeuten und mit

hoher Diastereoselektivität erhalten.

NBn

MeO

O NBn

MeO

O

NMe

NH

MeO

O

NMe

83%

IVMeN NMe

MeN

MgI2 (5.5 mol%), THF

41 %Gesamt-ausbeute

Horsfiline

V

Schema B: Synthese von (±)-Horsfilin.

Unser allgemeines Interesse an Naturstoffen aus der Klasse der Spiro-Pyrrolidin-

Oxindole, sowie die Anwendungsbreite der von uns entwickelten Methode führten zur

Verwendung der MgI2-katalysierten Ringerweiterungsreaktion in den Synthesen der

Alkaloide Horsfilin und Spirotryprostatin B.

In der Synthese von (±)-Horsfilin konnte die Eignung von 1,3,5-Trimethyl-1,3,5-triazin

(V) als synthetisches Äquivalent für N-Methyl-Methanimin unter den Bedingungen der

Ringerweiterungsreaktion bewiesen werden. (±)-Horsfilin wurde in 41% Ausbeute in 5

Stufen über N-Benzyl-Spiro-Cyclopropyl-Oxindol (IV) als Zwischenstufe erhalten

(Schema B).

Um das Gerüst von Spirotryprostatin B in effizienter Weise aufzubauen, muss ein Spiro-

Pyrrolidin-Oxindol mit einem Substituent in der 9-Position (Spirotryprostatin

Nummerierung) zugänglich sein. Wir konnten zeigen, dass das Spiro-Pyrrolidin-Oxindol-

Derivat VIII in guter Ausbeute durch Verknüpfung von Cyclopropan VI und Imin VII

erhalten werden kann.

Das Diastereomerenverhältnis begünstigt VIII (Verhältnis 6:1) mit der benötigten

relativen anti-Orientierung an den Zentren C3 und C18. Die entsprechenden syn-

Diastereomere konnten durch Behandlung mit kochender Essigsäure in VIII überführt

werden. Die Umsetzung mit N-Boc geschütztem L-Prolin-Chlorid erlaubt eine Trennung

der Diastereomere und führt zu IX.

NH

O

VI

MgI2, THF

MeHC

N

TIPS

+

VII

N

NO

OH

Me

Me

spirotryprostatin B

HN

O

NHN

O

MeHC

TIPS

N

BocN

OH

HN

O

TIPS

N

BocN

OH

HN

O

CO2Me

Me

Me

+ Isomere

MeHC

AcOH, ∆

18

3 N

BocN

OH

HN

O

CO2Me

O

Julia-KocienskyOlefinierung

VIII IX

XXI

9

183

Schema C: Totalsynthese von (–)-Spirotryprostatin B.

Die Prenyl-Seitenkette konnte durch eine Julia–Kocieńsky Reaktion des Aldehyds X

eingeführt werden, obwohl ähnliche Olefinierungsreaktionen in früheren Synthesen

Probleme bereiteten. Aus der Zwischenstufe XI wurde Spirotryprostatin B erhalten

(Schema C). Spirotryprostatin B wurde in 16 Stufen und 3.4% Gesamtausbeute erhalten.

Diese Synthese ist Beweis für die Eignung unserer Ring-Erweiterungs-Reaktion zur

Synthese komplexer Naturstoffe.

Abbreviation List

[α]DT specific rotation at the sodium D line at temperature T

Å angström Ac acetyl AIBN 2,2’-azo-iso-butyronitrile aq aqueous atm atmosphere Bn benzyl bp boiling point Boc tert-butyl carbamate BOP

benzotriazol-1-yloxitris(dimethylamino)phosphonium hexafluoro- phosphate

BOP-Cl bis(2-oxo-3-oxazolidinyl)phosphinic chloride br broad Bu butyl c concentration °C degree centigrade ca. circa calcd calculated cat. catalytic Cbz carbobenzyloxycarbonyl cm centimeter COSY correlated spectroscopy Cp cyclopentadiene δ NMR chemical shift in ppm downfield from a standard d day d doublet dba (E,E)-dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DEAD diethyl azodicarboxylate decomp. decomposition DEI desorption electron impact ionization DHQ-CLB dihydrochinine-(4-chlorobenzoylether) (DHQ)2PHAL dihydrochinine-(1,4-phthalazinediether) DMA N,N-dimethyl acetamide DMAP 4-N,N-dimethylamino pyridine DMDO dimethyl dioxirane DME 1,2-dimethoxyethane DMF N,N-dimethyl formamide DMSO dimethyl sulfoxide DNBA 1,3-dimethyl barbituric acid

DPPA diphenylphosphoryl azide ∆ reflux ∆∆E difference in heat of formation EI electron impact ionization equiv equivalent Et ethyl EWG electron withdrawing group FAB fast atom bombardment ionization g gram Glu glutamic acid h hour HMBC heteronuclear multiple-bond correlation HMDS 1,1,1,3,3,3-hexamethyldisilazane HMQC heteronuclear multiple quantum coherence HPLC high-performance liquid chromatography HR high resolution Hz herz IC50 incapacitating concentration 50 IR infrared spectrum J coupling constant J joule kcal kilocalorie L liter LDA lithium di-iso-propyl amide LHMDS lithium 1,1,1,3,3,3-hexamethyldisilazane m meta m multiplet m milli M molarity M mega MALDI matrix assisted laser desorption ionization mCPBA 3-chloroperbenzoic acid Me methyl MIC maximum inhibitory concentration min minute mol moles mp melting point MS mass spectrometry MS molecular sieves µ micro N normality NBS N-bromosuccine imide NCS N-chlorosuccine imide NMO N-methylmorpholine N-oxide NOE nuclear Overhauser effect

o ortho org. organic p para PFG pulse field gradient PG protecting group Ph phenyl PMP 1,2,2,6,6-pentamethylpiperidine ppm parts per million Pr propyl psi pounds per square inch Py pyridine q quartet quint quintett R substituent Rf retention factor RT room temperature s singlet s second s sec sat. saturated SEM 2-(trimethylsilyl)ethoxymethyl t triplet TBAF tetra-n-butylammonium fluoride TBS tert-butyldimethylsilyl TDA-1 tris[2-(2-methoxyethoxy)-ethyl]amine Tf trifluoromethanesulfonyl TFA trifluoroacetic acid THF tetrahydrofuran TIPS tri-iso-propyl TLC thin layer chromatography TMS trimethylsilyl Tol tolyl Troc 2,2,2-trichloroethoxycarbonyl Ts 4-methylphenylsulfonyl UV ultraviolet vs. versus WSC 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride

Table of Contents

1

I. Table of Contents

II. Introduction........................................................................................................... 5

1. Alkaloids ................................................................................................................. 5

2. Oxindole Alkaloids ................................................................................................. 7

III. Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles.......... 11

1. Existing Methods for the Synthesis of Spiro-Pyrrolidine-Oxindoles ................... 11

1.1. Oxidative Rearrangement Reactions..................................................................... 11

1.2. Intramolecular Mannich Reactions ....................................................................... 18

1.3. Dipolar Cycloaddition Reactions.......................................................................... 19

1.4. Intramolecular Heck Reactions............................................................................. 21

1.5. Radical Cyclization Reactions .............................................................................. 23

1.6. Asymmetric Nitroolefination ................................................................................ 25

1.7. Rearrangement of [(N-Aziridinomethylthiomethylene]-2-oxindoles ................... 25

2. Novel Approach to the Synthesis of Spiro-Pyrrolidine-Oxindoles....................... 26

2.1. Retrosynthetic Analysis ........................................................................................ 26

2.2. MgI2-Catalyzed Ring-Expansion Reaction of Spiro-Cyclopropyl-Oxindoles with

Aldimines.............................................................................................................. 29

2.2.1. Initial Results ........................................................................................................ 29

2 Table of Contents

2.2.2. Optimization and Scope of the Ring-Expansion Reaction ................................... 31

2.2.3. Mechanistic Aspects ............................................................................................. 38

2.2.4. Conclusion ............................................................................................................ 41

IV. The Synthesis of (±)-Horsfiline .......................................................................... 42

1. Introduction........................................................................................................... 42

1.1. Isolation................................................................................................................. 42

1.2. Synthetic Approaches ........................................................................................... 43

1.2.1. Jones’ and Wilkinson’s Synthesis of (±)-Horsfiline............................................. 43

1.2.2. Laronze’s Syntheses of (±)-Horsfiline.................................................................. 44

1.2.3. Borschberg’s Approach to (+)- and (–)-Horsfiline ............................................... 45

1.2.4. Palmisano’s Route to (–)-Horsfiline ..................................................................... 46

1.2.5. Fuji’s Synthesis of (–)-Horsfiline ......................................................................... 48

2. Synthesis of (±)-Horsfiline by MgI2-Catalyzed Ring-Expansion Reaction of

Spiro-Cyclopropyl-Oxindole and 1,3,5-Trimethyl-1,3,5-Triazinane .................. 49

3. Conclusion ............................................................................................................ 51

V. The Total Synthesis of (–)-Spirotryprostatin B................................................ 52

1. Introduction........................................................................................................... 52

1.1. Isolation and Biological Activity .......................................................................... 52

1.2. Synthetic Approaches ........................................................................................... 55

1.2.1. Danishefsky’s Route to Spirotryprostatin A ......................................................... 55

Table of Contents

3

1.2.2. Williams’s Synthesis of Spirotryprostatin B......................................................... 58

1.2.3. Ganesan’s Approach to Spirotryprostatin B ......................................................... 60

1.2.4. Danishefsky’s Synthesis of Spirotryprostatin B ................................................... 62

1.2.5. Overman’s Approach to Spirotryprostatin B ........................................................ 63

1.2.6. Fuji’s Route to Spirotryprostatin B....................................................................... 65

2. Synthesis of (–)-Spirotryprostatin B Employing the MgI2-Catalyzed Ring-

Expansion Reaction .............................................................................................. 67

2.1. Retrosynthetic Analysis ........................................................................................ 67

2.2. Initial Studies ........................................................................................................ 69

2.2.1. Regioselectivity..................................................................................................... 69

2.2.2. Substituent at the Spiro-Cyclopropyl-Oxindole Suitable for Ring Expansion ..... 71

2.2.3. Identification of a Suitable Imine for the Ring Expansion ................................... 77

2.2.4. Optimization of the Key Step ............................................................................... 78

2.3. Synthesis of Spirotryprostatin B from Intermediate 323 ...................................... 83



3. Conclusion .......................................................................................................... 101

VI. Conclusion and Outlook ................................................................................... 103

VII. Experimental Part............................................................................................. 105

1. General methods ................................................................................................. 105

4 Table of Contents

2. Preparation of Useful Reagents and Buffers....................................................... 108

3. MgI2-Catalyzed Ring-Expansion Reaction of Spiro-Cyclopropyl-Oxindoles with

Aldimines............................................................................................................ 110

4. Synthesis of (±)-Horsfiline by MgI2-Catalyzed Ring-Expansion Reaction of

Spiro-Cyclopropyl-Oxindole and 1,3,5-Trimethyl-1,3,5-Triazinane ................. 136

5. Synthesis of (–)-Spirotryprostatin B Employing the MgI2-Catalyzed Ring-

Expansion Reaction ............................................................................................ 141

5.1. Synthesis of Spirotryprostatin B from Intermediate 323 .................................... 165



Curriculum Vitae .......................................................................................................... 195

Introduction

5

II. Introduction

1. Alkaloids

The first alkaloid obtained in pure form was morphine, which was isolated from opium

by Sertürner in 1806. The product was commercialized by Merck and was the first

medicine sold with a purity guaranty in 1822. In 1819, Meissner introduced the term

alkaloid for nitrogen-containing substances of vegetable origin as a description of their

basic (alkaline) character. Soon enough, the definition had to be adjusted, as alkaloids

were also discovered in animals, for example in insects and amphibians. Today, alkaloids

are defined as nitrogen-containing substances originating from vegetable and animal

origin. Some classes of compounds that match this definition are not considered

alkaloids, namely amino acids, peptides and nucleotides.1

amino acidsglutamic acidornithinlysinphenylalaninetyrosinetryptophanehistidine

biogenic aminesGABAputrescinecadaverinephenylethylaminetyraminetryptaminehistamine

secondary metabolitespolyketidesshikimate metabolitesterpenes/steroids

NH3

alkaloids pseudo alkaloids

Figure 1: Biogenesis of alkaloids in plants

[1] Hesse, M. Alkaloidchemie; Thieme: Stuttgart, 1978; Vol. B9.

6 Introduction

Plants produce alkaloids from amino acids by enzymatic decarboxylation to the

corresponding biogenic amines, which subsequently undergo condensation with

secondary metabolites such as polyketides, shikimate metabolites, terpenes and steroids

to form alkaloids. The condensation products of secondary metabolites with ammonia as

nitrogen source instead of an amine are referred to as pseudo alkaloids.

The classification of alkaloids is rather difficult because of their enormous structural

diversity and, according to the context, a different mode of classification can be useful,

for example biogenesis, structural relationship, botanical origin or spectroscopic criteria

(chromophore for UV spectroscopy, ring skeleton for MS). These classification systems

are generally not exclusive. The most useful classification for the organic chemist is

made on the basis of the nitrogen containing substructure: 2

- heterocyclic alkaloids

- alkaloids with exocyclic nitrogen and aliphatic amines

- putrescin, spermidin and spermine alkaloids

- peptide alkaloids

- terpene and steroid alkaloids

[2] Hesse, M. Alkaloide, Fluch oder Segen der Natur?; Verlag Helvetica Chimia Acta, Wiley-VCH: Weinheim, 2000.

Introduction

7

2. Oxindole Alkaloids

The oxindole alkaloids are a subclass of the indole alkaloids, a family of heterocyclic

alkaloids. Indole alkaloids comprise alkaloids that contain the indole chromophor (1)

itself, or a structural element derived from indole like 2-8 (Figure 2).

NR

NR

NR

NR

NR

NR

NR

N

O

O

NN

indole (1) dihydroindole (2) indolenine (3)

3-oxindole pseudoindoxyl (4)

2-oxindole (5) carbazole (6)

β-carboline (7) γ-carboline (8)

Figure 2: Structural motifs of some indole alkaloids.

Historically, the first four oxindole alkaloids (9-12) were found in the roots of Gelsemium

sempervirens, and are classified as Gelsemium species. Additional oxindoles were

isolated from Aspidosperma, Mitragyna, Ourouparia, Rauwolfia and Vinca.3 These

alkaloids possess the same basic framework derived from tryptamine and secologanine

(13), a C10 unit of terpenoid origin, and can be further classified into two substructural

classes: the tetracyclic secoyohimbane (or corynantheidine) type (e.g. rhynchophylline

(14)) and the pentacyclic heteroyohimbane (or ajmalicine) type (e.g. formosanine (15)).

Other types of oxindole alkaloids could be isolated, exemplified by (–)-horsfiline (16)4,

spirotryprostatin B (17)5, strychnofoline (18)6 and (+)-paraherquamide B (19)7,8

[3] Bindra, J. S. In The Alkaloids; Manske, R. H. F., Ed.; Academic Press: New York, 1973; Vol. 14, pp 84-121. [4] Jossang, A.; Jossang, P.; Hadi, H. A.; Sevenet, T.; Bodo, B. J. Org. Chem. 1991, 56, 6527-6530. [5] Cui, C. B.; Kakeya, H.; Osada, H. J. Antibiot. 1996, 49, 832-835. [6] Angenot, L. Plantes médicales et phytothérapie 1978, 12, 123. [7] Ondeyka, J. G.; Goegelman, R. T.; Schaeffer, J. M.; Kelemen, L.; Zitano, L. J. Antibiot. 1990, 43, 1375-1379. [8] Banks, R. M.; Blanchflower, S. E.; Everett, J. R.; Manger, B. R.; Reading, C. J. Antibiot. 1997, 50, 840-846.

8 Introduction

NH

N R'

OMeO2CH

7 OMe20

3R

C D

A B

(Figure 3). The secoyohimbane and heteroyohimbane alkaloids, that comprise a large

group of natural products, can be classified as normal, pseudo, allo and epiallo on the

basis of their configuration at C3 relative to C20 (numbering of heteroyohimboid

alkaloids). Additional classification is based on the configuration at C7 of the spiro-

pyrrolidine-oxindole moiety and comprises the two possible isomers A and B (Table 1).8

RNO

NMe

O

R = H: gelsemine (9)R = OMe: gelsevirine (10)

NO

HN

O

Et

R

R = H: gelsemicine (11)R = OMe: gelsedine (12)

NH

N

O NH

N

O

O

Me

rychnophylline (14)secoyohimbane sceletton

tetracyclic oxindol alkaloids

MeO2C

Me

CO2Me

formosanine (15)heteroyohimbane sceletton

pentacyclic oxindol alkaloids

MeOO

CHO

MeO2C

secologanine (13)

H

HOGlu

NH

MeO

MeN

O

(-)-horsfiline (16)

N

NO

OH

Me

Me

spirotryprostatin B (17)

N

MeNHN

H H

strychnofoline (18)

H

H

H

R ROMe

H

HHH

MeMe

NO

Me

N

(+)-paraherquamide B (19)

HNO

O

O

MeMe

HN

O

HN

O

OH

Figure 3: Some oxindole alkaloids.

Table 1: Configuration terminology for oxindole alkaloids: α: H below C/D plane, β: H above C/D plane, A = (S), B = (R).

In the normal/pseudo series, no oxindole alkaloid with pseudo configuration has been

isolated so far. In the allo/epiallo series, the allo configuration is more abundant than its

Configuration C3-H C20-H C7 normal α β A or B pseudo β β A or B

allo α α A or B epiallo β α A or B

Introduction

9

epiallo counterpart. Biogenetic studies suggest that the biosynthesis of spiro-pyrrolidine-

oxindoles occurs via oxidation of the corresponding tetrahydro-β-carboline 20. The

thereby created spiro-center possesses either (R)- (B-series, 22) or (S)- (A-series, 21)

configuration. Both forms can be equilibrated in vitro through the ring-opened form 23

(Scheme 1).9

NH

NR

OR'

NH

NR

R'

[O]

NH

NR

OR'

[O]

NH

NR

OR'

R

S

20 21

22 23

Scheme 1: Biosynthesis of oxindoles from tetrahydro-β-carbolines and isomerization.

In nature, oxindole alkaloids often occur as pairs of interconvertible isomers (e.g.

rhynchophylline (14) and isorychnophylline, which is 7-epi-rhynchophylline). This

observation can be explained by the same isomerization mechanism, which was noticed

as early as 1959 and independently elucidated by two research groups. Wenkert and

Marion both proposed a retro-Mannich reaction involving the open-ring intermediate

23.10,11 Kinetic studies of the isomerization in the series of tetracyclic oxindole alkaloids

were performed by Laus and revealed that the reaction is a pseudo-first-order process.12 It

could be shown that refluxing each of the isomers independently in pyridine or acetic

anhydride led to the same equilibrium mixture wherein one of the isomers is favored.11

Hendrickson noted that the predominant isomer is also the less basic one. In equilibration

studies with yohimbine oxindoles, the stronger base was predominant after treatment with

[9] Brown, R. T. In Heterocyclic Compounds; Saxon, J. E., Ed.; Wiley Interscience: New York, 1983; Vol. 25, Part 4, pp 85-97. [10] Wenkert, E.; Udelhofen, J. H.; Bhattacharyya, N. K. J. Am. Chem. Soc. 1959, 81, 3763-3768. [11] Seaton, J. C.; Nair, M. D.; Edwards, O. E.; Marion, L. Can. J. Chem. 1960, 38, 1035-1042. [12] Laus, G. J. Chem. Soc. Perkin Trans. 2 1998, 315-317.

10 Introduction

acid, whereas the weaker base predominated after refluxing in pyridine. Only in one

structure could the conjugate acid be stabilized by hydrogen bonding to the oxindole

carbonyl. The free base is apparently destabilized by electrostatic repulsion of the

carbonyl group and the lone pair of Nb (Figure 4).13

HNN

O

NHNO

possiblility ofhydrogen bonding

minimal electrostaticrepulsion

predominant in acidic media predominant in basic media

H

Figure 4: Stabilization of yohimbine oxindoles in different media.

[13] Yeoh, G. B.; Chan, K. C.; Morsingh, F. Rev. Pure and Appl. Chem. 1967, 49-66.

Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles

11

III. Novel Methodology for the Synthesis of Spiro-

Pyrrolidine-Oxindoles

1. Existing Methods for the Synthesis of Spiro-Pyrrolidine-

Oxindoles

1.1. Oxidative Rearrangement Reactions

First studies in the oxindole series were based on the structural relationship of oxindoles

and their tetrahydro-β-carboline counterpart. An early study by Taylor revealed that

rhynchophylline (14) can be obtained from dihydrocorynantheine (24) by a three-step

procedure by oxidative rearrangement (Scheme 2),14 and a general relationship between

indole alkaloids and their oxindole analogues was postulated by Shavel and Zinnes.15

NH

N Et

O

14

MeO2CH

H

H

OMeNH

N

Et

MeO2C

H H

HOMe

24

a - c

Scheme 2: a) tBuOCl; b) KOH/MeOH; c) H2O/AcOH.

Later experiments showed that the chloro-indolenine intermediate 26, upon heating in

acetic acid, undergoes rearrangement to a C3 (indole numbering) epimeric mixture 27/28,

without pronounced preference for either of the two epimers.

Furthermore, it was found that chlorination of the indole ring yielded a mixture of α- and

β-chloro derivatives 26, obtained from tetrahydro-β-carboline 25, and that only the major

α-chloro-isomer undergoes rearrangement in refluxing methanol to provide a rapidly

[14] Finch, N.; Taylor, W. I. J. Am. Chem. Soc. 1962, 84, 3871-3877. [15] Shavel, J.; Zinnes, H. J. Am. Chem. Soc. 1962, 84, 1320-1321.

12 Novel Methodology for the Synthesis of Spiro-Pyrrolidine-Oxindoles

equilibrating mixture of 29 and 30 (Scheme 3).16 Extensive studies and computational

analyses by Borschberg and Acklin on the oxidative rearrangement of yohimbane-type

alkaloids suggest that the α-chloro-isomers undergo rearrangement much faster than the

β-chloro-isomers and are thus to a great extent protected from side-reactions observed

with the β-chloro compounds.17,18

NH

N

R

R' NN

R

R'

ClNH

N

O

R'

R NH

N

O

R'

R

N

N

OMe

R'

RN

N

OMe

R'

R

+

+

b

c25 26

27 28

29 30

a

3 3

3 3

Scheme 3: a) tBuOCl, RT; b) H2O/AcOH; ∆ c) MeOH, ∆.

Martin expanded the method to the oxidation of indoles, where Nb is incorporated in a

D-ring lactam. The critical ring contraction was achieved by addition of silver perchlorate

and led ultimately to pteropodine (34) (Scheme 4).19

NH

N

NH

N

O

O

Me

CO2Me

H

HHNH

N

O

O

Me

CO2Me

H

HH

O

OH

H

Me

MeO2C

H

X

a, b e

32: X = O33: X = H2

c, d3134

A B C

D

Scheme 4: a) tBuOCl, RT; b) AgClO4, aq MeOH/HClO4, RT; c) AlH3, RT; d) NaBH4, RT; e) AcOH, ∆.

[16] Awang, D. V. C.; Vincent, A.; Kindack, D. Can. J. Chem. 1984, 62, 2667-2675. [17] Stahl, R.; Borschberg, H. J.; Acklin, P. Helv. Chim. Acta 1996, 79, 1361-1378. [18] Another approach to intermediates of the general structure 26 from 1,2,3,4-tetrahydro-9-hydroxy-β-carboline is described by Somei: Somei, M.; Noguchi, K.; Yamagami, R.; Kawada, Y.; Yamada, K.; Yamada, F. Heterocycles 2000, 53, 7-10. [19] Martin, S. F.; Mortimore, M. Tetrahedron Lett. 1990, 31, 4557-4560.


13

Cook and co-workers discovered that tetracycle 36 and its N-benzyl-protected derivative

35 led to two isomeric oxindole products 37 and 38 stereospecifically upon reaction with

tBuOCl/NEt3, followed by treatment with acetic acid. Simply the absence or presence of

the N-benzyl protecting group allows access alsonisine- or voachalotine- related oxindole

alkaloids respectively. It is believed that the diastereoselection is of steric origin (Scheme

5).20 The starting material 35 is accessible from D-(+)-tryptophane by asymmetric Pictet–

Spengler reaction.21,22

NH

NBn

H

H

O

NH

NH

H

H

O

lesshindered

NH

BnN O

O

NH

O

NH

O

35

36

37

38

alstonisine seriesalkaloids

voachalotineoxindole

a

b, c

b, c

N

ONH

morehindered

HN

ONH

Ph

HH

Scheme 5: a) 5% HCl in EtOH, H2, Pd/C, RT; b) tBuOCl/NEt3, RT; c) AcOH, MeOH, ∆.

Among the possible strategies for assembly of the oxindole core, the use of the Pictet–

Spengler reaction (Scheme 6) later followed by an oxidation/rearrangement sequence

found widespread use over the years.

[20] Yu, P.; Cook, J. M. Tetrahedron Lett. 1997, 38, 8799-8802. [21] Pictet, A.; Spengler, T. Ber. 1911, 44, 2030. [22] Yu, P.; Wang, T.; Yu, F. X.; Cook, J. M. Tetrahedron Lett. 1997, 38, 6819-6822.


39

NH

RNH2

CO2Me

O

R' NH

NH

R'

CO2Me

R

40

+

41

NH

RN

CO2Me

R'

[H+]

+ H+, -H2O

HNH

RNH

CO2Me

R'H

-H+

Scheme 6: Pictet–Spengler reaction.

Reaction of tryptophane derivative 39 with an aldehyde 40 usually leads to tetrahydro-β-

carboline 41 as the cis-product is favored at the kinetic level.23,24 Alternatively, the

tetrahydro-β-carboline can also be prepared from tryptophane by a Bischler–Napieralski

reaction, although this sequence has been shown to lead to racemization.25

N-bromo succinimide as oxidant is frequently used instead of tBuOCl and was employed

in the synthesis of (+)-elacomine (42)26 and (–)-horsfiline (16)27 by Borschberg, in

Danishefsky’s synthesis of spirotryprostatin A (43),28,25 in Ganesan’s route to

spirotryprostatin B (17)29 and also in the synthesis of paraherquamide B (19)30 by

Williams (Scheme 7).

[23] Harrison, D. M.; Sharma, R. B. Tetrahedron Lett. 1986, 27, 521-524. [24] Kodato, S.; Nakagawa, M.; Hongu, M.; Kawate, T.; Hino, T. Tetrahedron 1988, 44, 359-377. [25] Edmondson, S.; Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N. J. Am. Chem. Soc. 1999, 121, 2147-2155. [26] Pellegrini, C.; Weber, M.; Borschberg, H. J. Helv. Chim. Acta 1996, 79, 151-168. [27] Pellegrini, C.; Strässler, C.; Weber, M.; Borschberg, H. J. Tetrahedron: Asymmetry 1994, 5, 1979-1992. [28] Edmondson, S. D.; Danishefsky, S. J. Angew. Chem. Int. Ed. 1998, 37, 1138-1140. [29] Wang, H. S.; Ganesan, A. J. Org. Chem. 2000, 65, 4685-4693. [30] Cushing, T. D.; SanzCervera, J. F.; Williams, R. M. J. Am. Chem. Soc. 1996, 118, 557-579.


15

NR''

R'

NH

Me

Me

(+)-elacomine (42) spirotryprostatin A (43)

NH

NR''

CO2Me

R'

R NH

NR''

CO2Me

R'

R

X

OH

NR''

CO2Me

R'

CO2Me

+HN

O

HNO

R

R

HN

O

MeO

a) 'X ', THF

b) AcOH, H2O

N

N

O

OH

Me

Me

HN

OH

MeO

Scheme 7: Oxidative rearrangement induced by a halogenating agent employed for the total synthesis of natural products.

Not only halogenating agents, but also other oxidants are useful reagents to convert

tetrahydro-β-carbolines into spiro-oxindoles. For this type of conversion, Pb(OAc)4 has

first been investigated by Taylor in 1963,31 and employed by Bodo to confirm the

structure of (±)-horsfiline ((±)-16) by oxidation of the Nb-methyl-tetrahydro-β-carboline.4

Pb(OAc)4 was also used by Borschberg in a model study for the synthesis of

(+)-elacomine (42).26 The tetrahydro-β-carboline 44 reacts with Pb(OAc)3+ to afford

iminium species 45, which undergoes rearrangement to 46, leading to oxindole 47

(Scheme 8).

44 45

NH

NR''R N

H

NR''R

R' R'46 47

Pb(OAc)2

NH

R OAc

NR''

R'

AcO

NH

R O

NR''

R'Pb(OAc)3 OAc

Scheme 8: Spiro-rearrangement employing Pb(OAc)4.

[31] Finch, N.; Hsu, I. H. C.; Gemenden, C. W.; Taylor, W. I. J. Am. Chem. Soc. 1963, 85, 1520-1523.


gardnerine (48)

NH

NMeO

HO

Me 49

NH

NMeO

O

Me

CO2Me

50

NN

MeO

O

Me

CO2Me

ClHH Ha b

52

NMeO

N

Me

CO2Me

O

OMe

51

NH

MeO

N

Me

CO2Me

O

O

NH

NMeO

O

Me

CO2Me

Cl H

NN

MeO

O

Me

CO2Me

Cl H

OMe

H

O

c d

53 54

RS

NH

MeO OHN

Me

O

NH

MeO O

NH

O H

OH

OHH Me

55

56

Scheme 9: a) ClCO2Me, MgO, THF/H2O, RT; b) tBuOCl, NEt3, CH2Cl2, RT; c) NaOMe, MeOH, RT; d) AcOH, H2O, MeOH, RT.

Another way to access spiro-oxindoles from tetrahydro-β-carbolines employs OsO4. In

1989, Sakai introduced OsO4 as reagent for the spiro-rearrangement following

mechanistic considerations for the selective formation of Na-demethoxyhumantenirine

(55) from gardnerine (48). He observed that spiro-rearrangement of 50 afforded either

(S)-isomer 53 or (R)-isomer 54, when 50 was treated with sodium methylate or acetic

acid, respectively. He concluded that the methoxide approaches 50 from the less hindered

face, anti to the bridged ether linkage, giving rise to transition state 51 that will ultimately

rearrange to (S)-isomer 53. On the other hand, 50 can react with water in aqueous acidic

media to form 52. After chloride elimination, rearrangement to (R)-isomer 54 is

predominantly observed (Scheme 9).32 Following this observation, the authors speculated

that a product similar to 51 could be obtained from the attack of 49 by OsO4 that would

then lead to the desired (S)-isomer selectively by pinacol-type rearrangement. Following

[32] Takayama, H.; Masubuchi, K.; Kitajima, M.; Aimi, N.; Sakai, S. Tetrahedron 1989, 45, 1327-1336.


17

this OsO4-rearrangement procedure, Sakai also converted gardnerine (48) to

Na-demethoxy-11-methoxy-(19R)-hydroxygelselegine (56).33

BnN

MeNO N

O

Ph

O

O NMeOsO

O

NMe

O

NBn

O

NO

Ph

HO

O NMeH

57 58 60

59 61

BnN

MeNO

OO

OsO

O BnN

MeNO

OHO

H

OsO4, NaHSO3 aq

L NMe

BnN O

O

THF, ∆

OsO4, ligand

THF, RT

NaHSO3 aq

Scheme 10: Pinaccol rearrangement using OsO4.

Sakai’s work was followed up by Cook, who used OsO4 to access the alstonisine

oxindole series (Scheme 10). He showed that OsO4 reacts with tetrahydro-β-carboline 57

selectively to furnish 60. The osmium is probably first complexed to the piperidine

nitrogen and then osmylation occurs intramolecularly from the convex face of the

substrate to furnish 58. The concave face is osmylated by the use of bulky ligands such as

cinchona alkaloid derivatives DHQ-CLB and (DHQ)2PHAL yielding 59 that ultimately

leads to 61 after hydrolysis.34,35

A study of the rearrangement of indole derivatives with DMDO was carried out by

Foote.36 He observed that indole derivatives 62 can be oxidized to the corresponding

epoxides 63 at low temperature. Rearrangement occurs at ambient temperature to furnish

[33] Takayama, H.; Kitajima, M.; Ogata, K.; Sakai, S. J. Org. Chem. 1992, 57, 4583-4584. [34] Peterson, A. C.; Cook, J. M. Tetrahedron Lett. 1994, 35, 2651-2654. [35] Peterson, A. C.; Cook, J. M. J. Org. Chem. 1995, 60, 120-129. [36] Zhang, X. J.; Foote, C. S. J. Am. Chem. Soc. 1993, 115, 8867-8868. For a related process, see: Adam, W.; Lévrai, A.; Mérour J.-Y.; Nemes, C.; Patonay, T. Synthesis 1997, 268-270.


oxindoles 64 (Scheme 11). This method has not yet found application in the synthesis of

oxindole natural products.

N

R

MeCOMe

N

R

MeCOMe

N

R

COMe

62 63 64

OO

Mea) b)

Scheme 11: a) DMDO, acetone, CH2Cl2, –78 °C; b) 5 h, RT.

1.2. Intramolecular Mannich Reactions

The spiro-pyrrolidine-oxindole core can also be introduced by intramolecular Mannich

reaction from precursors such as 65, available from tryptamine-derrived oxindole. By this

method, the total synthesis of a mixture of (±)-rhynchophyllol and (±)-isorhynchophyllol

(66) was achieved by van Tamelen in 1969 (Scheme 12).37

NH

N Et

O

66

OHNH

65

a) HClNH

Et

HO

HO

O

NH

N Et

O

O

H

NaIO4

b) NaBH4

Scheme 12: Intramolecular Mannich reaction.

Ban and Oishi employed the Mannich reaction to elucidate the stereochemistry of

(±)-rhynchophylline and (±)-isorhynchophylline. Comparison of the IR spectra of

oxindoles 67 and 68 with rhynchophyllane obtained by degradation of rhynchophylline

revealed that the relative stereochemistry of the ethyl substituents on the piperidine ring

in both natural products corresponds to structure 67 (Scheme 13).38

[37] van Tamelen, E. E.; Yardley, J. P.; Miyano, M.; Hinshaw Jr., W. B. J. Am. Chem. Soc. 1969, 91, 7333-7338. [38] Ban, Y.; Oishi, T. Chem. Pharm. Bull. 1963, 11, 451-460.


19

NMe

N Et

O

NMe

NH3

O Cl

Et

NMe

N Et

OEt

CHOClH

EtEt

H

CHOClH

EtEt

H

H

H

H

H

67

68

Scheme 13: Synthesis of rhynchophyllane by Mannich reaction.

The Mannich approach found application in the synthesis of a number of spiro-oxindole

alkaloids for example (±)-formosanine ((±)-15),39 salacin,40 and spirotryprostatin B

(17),41 as well as a range of unnatural spiro-oxindoles.42,43

1.3. Dipolar Cycloaddition Reactions

Palmisano was the first to successfully introduce 1,3-dipolar cycloadditions as a method

for a completely different, clearly non-biomimetical approach to the spiro-pyrrolidine-

oxindole skeleton in his synthesis of (–)-horsfiline (16) (Scheme 14).44 The N-methyl-

azomethine ylide is generated in situ from sarcosine and formaldehyde. The synthesis of

(±)-16 was achieved using the ethyl ester (R = Et), whereas asymmetric synthesis of (–)-

horsfiline was possible through the use of a chiral auxiliary (R = (–)-menthyl).

[39] Winterfeldt.E; Gaskell, A. J.; Korth, T.; Radunz, H. E.; Walkowiak, M. Chem. Ber. Recl. 1969, 102, 3558-3572. [40] Ponglux, D.; Wongseripipatana, S.; Aimi, N.; Nishimura, M.; Ishikawa, M.; Sada, H.; Haginiwa, J.; Sakai, S. Chem. Pharm. Bull. 1990, 38, 573-575. [41] von Nussbaum, F.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2000, 39, 2175-2178. [42] Jansen, A. B. A.; Richards, C. G. Tetrahedron 1965, 21, 1327-1331. [43] Rosenmund, P.; Hosseini-Merescht, M.; Bub, C. Liebigs Ann. Chem. 1994, 151-158. [44] Palmisano, G.; Annunziata, R.; Papeo, G.; Sisti, M. Tetrahedron: Asymmetry 1996, 7, 1-4.


NH

O

MeO

RO2C NMe

69

NH

O

MeO NMeRO2C

3 Å MS,toluene, ∆

(+)-16R = Et

16 R = (-)-menthyl

Scheme 14: Synthesis of horsfiline by 1,3-dipolar cycloaddition.

In his subsequent work, the [2+3]-cycloaddition with chiral auxiliaries was employed in a

more straightforward process on aromatic acrylates, the ester functionality being

ultimately incorporated into the indole core (Scheme 15).45

NO2

MeONMe

CO2R*

NO2

MeOCO2R*

NMe

16a b

PhR =

Scheme 15: a) sarcosine, (CH2O)n, 3 Å MS, toluene, ∆; b) H2, 10% Pd/C, MeOH.

Tõke successfully employed structurally more complex azomethine ylides in a study

aiming at the synthesis of different oxindole structures.46 In order to access spiro-

pyrrolidine-oxindoles without necessity for reductive cleavage of the electron-

withdrawing group (for example the ester functionality present in 69); Brown showed

that 3-methylideneindolin-2-one obtained from flash vacuum pyrolysis of the acetate of

3-hydroxy-3-methylindolin-2-one can also serve as dienophile in the 1,3-dipolar

cycloadditions. The azomethine ylides were obtained from silylated amino nitriles by

treatment with silver fluoride.47 One of the most outstanding applications of this

methodology is found in the synthesis of spirotryprostatin B (17) by Williams (Scheme

16). He employed chiral azomethine ylide 71, which is prepared by addition of

[45] Cravotto, G.; Giovenzani, G. B.; Pilati, T.; Sisti, M.; Palmisano, G. J. Org. Chem. 2001, 66, 8447-8453. [46] Nyerges, M.; Gajdics, L.; Szöllõsy, A.; Tõke, L. Synlett 1999, 111-113. [47] Bell, S. E. V.; Brown, R. F. C.; Eastwood, F. W.; Horvath, J. M. Aust. J. Chem. 2000, 53, 183-190.


21

3-methoxy-3-methyl-1-butanal to 5,6-diphenylmorpholine-2-one. Reaction with oxindole

70 led to cycloadduct 72 in 82% yield.48,49

NH

O

EtO2C

a

70

NO

O

PhPh

Me

MeMeO 71

+

NO

HN

H

CO2Et

PhPh

O

MeMeMeO

O

72

Scheme 16: a) 3 Å MS, toluene, RT.

One example of a pathway, in which the azomethine ylide is prepared by decarboxylative

condensation of an isatin derivative 73 with an α-amino acid 74 is displayed in Scheme

17. trans-Chalcones (75) were used as dipolarophiles. Following this scheme, Fokas

synthesized a library of 26,500 spiro[pyrrolidine-2,3’-oxindoles] of general structure

76.50

N O

O

a

73

+R1

R2

R3

NH

CO2H

R4

74

N OR1

R2

R3

NR4

N OR1

R2

N

R4

R3

Ph

Ph

OPh Ph

O

75 76

Scheme 17: a) dioxane/H2O, 80 90 °C.

1.4. Intramolecular Heck Reactions

The use of the Heck reaction for the synthesis of the spiro-oxindole core was pioneered

by Overman. He showed that amides like 77, in the presence of Pd(OAc)2 and PPh3,

undergo intramolecular cyclization in high yields (Scheme 18).51

[48] Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000, 122, 5666-5667. [49] Sebahar, P. R.; Osada, H.; Usui, T.; Williams, R. M. Tetrahedron 2002, 58, 6311-6322. [50] Fokas, D.; Ryan, W. J.; Casebier, D. S.; Coffen, D. L. Tetrahedron Lett. 1998, 39, 2235-2238. [51] Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52, 4130-4133.


NMe Br

ONMe

O

77

a

Scheme 18: a) Pd(OAc)2 (1 mol%), PPh3 (4 mol%), AgNO3, NEt3 (2.0 equiv), CH3CN, ∆.

Further investigations in this intramolecular Heck reaction revealed an interesting aspect.

The reaction can lead to an excess of the (R)- or the (S)-isomer when it is catalyzed by an

(R)-(+)-BINAP palladium complex, depending on the reaction conditions.52 It was found

that addition of a silver phosphate leads to the (S)-spiro-oxindole, whereas the opposite

enantiomer is obtained in the presence of PMP as base.53 Overman suggests a ‘cationic’

pathway for the silver salt mediated reaction and a ‘neutral’ pathway in the presence of a

base.54 However, this mechanistic suggestions could not account for the striking

differences in the stereochemical outcome under different conditions. The intramolecular

Heck reaction was used by Overman in the total syntheses of (±)-gelsemine ((±)-9)

(Scheme 19).55 A similar sequence was also employed by Hiemstra in the synthesis of

gelsedine (12).56,57

MOMNO

OMe

NMOM

IO

RNBr

OMeRNBr

a

(11:1)

(+)-9

Scheme 19: a) [Pd2(dba)3]·CHCl3, AgNO3, NEt3, THF, ∆.

Overman was able to expand this method to the synthesis of spiro-pyrrolidine-oxindoles.

The η3-allylpalladium species resulting from the Heck insertion can be trapped by a

[52] Ashimori, A.; Overman, L. E. J. Org. Chem. 1992, 57, 4571-4572. [53] Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6477-6487. [54] Ashimori, A.; Bachand, B.; Calter, M. A.; Govek, S. P.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6488-6499. [55] a) Earley, W. G.; Oh, T.; Overman, L. E. Tetrahedron Lett. 1988, 29, 3785-3788. b) Madin, A.; O'Donnell, C. J.; Oh, T. B.; Old, D. W.; Overman, L. E.; Sharp, M. J. Angew. Chem. Int. Ed. 1999, 38, 2934-2936. [56] van Henegouwen, W. G. B.; Fieseler, R. M.; Rutjes, F.; Hiemstra, H. Angew. Chem. Int. Ed. 1999, 38, 2214-2217. [57] van Henegouwen, W. G. B.; Fieseler, R. M.; Rutjes, F.; Hiemstra, H. J. Org. Chem. 2000, 65, 8317-8325.


23

tethered nitrogen nucleophile. This sequence of two palladium-catalyzed reactions was

applied to the synthesis of spirotryprostatin B (17) (Scheme 20).58

PdL2INSEM

NHMe

Me

N

I

O

O

H

O

N

N

O

OH

Me

Me

HN

NO

OH

Me

Me

Pd2(dba)3 CHCl3,

P(oTol)3, KOAc,THF, 70 °C

SEMN

O

SEMN

O

Scheme 20: Intramoleular Heck reaction and trapping of the η3-allylpalladium species.

1.5. Radical Cyclization Reactions

Radical cyclization has also proved successful for the construction of the spiro-

pyrrolidine-oxindole nucleus. Jones showed that precursors like 78, in the presence of

nBu3SnH and catalytic amounts of AIBN, afford the 5-exo-cyclization product 79 as

major product (Scheme 21).59,60 This general method found application in the synthesis of

(±)-horsfiline ((±)-16).61

NR

O

a

78

R'N

BrMeO

NR

O

R'NMeO

NR

O

R'N

MeO

79

Scheme 21: a) Bu3SnH, AIBN, toluene, ∆.

A very similar approach by Cossy also led to the spiro-oxindole skeleton (Scheme 22).62

[58] Overman, L. E.; Rosen, M. D. Angew. Chem. Int. Ed. 2000, 39, 4596-4599. [59] Jones, K.; Ho, T. C. T.; Wilkinson, J. Tetrahedron Lett. 1995, 36, 6743-6744. [60] Escolano, C.; Jones, K. Tetrahedron Lett. 2000, 41, 8951-8955. [61] Jones, K.; Wilkinson, J. J. Chem. Soc.-Chem. Commun. 1992, 1767-1769. [62] Cossy, J.; Cases, M.; Pardo, D. G. Tetrahedron Lett. 1998, 39, 2331-2332.


NI

O

a

OMeO

BocN

N O

OMeO

NBoc

Scheme 22: a) Bu3SnH, AIBN, benzene, ∆.

Another interesting approach by Jones ultimately led to oxindoles with a higher degree of

substitution at the pyrrolidine part. In this tandem radical sequence, the aryl radical 80

undergoes [1,5]-hydrogen atom abstraction to 81, which cyclizes intramolecularly to the

3-position of the 2-cyanoindol with formation of 82. Radical 82 is reduced in situ with

nBu3SnH to 83. Oxidation yields the spiro-pyrrolidine-oxindole 84 (Scheme 23).63

a

NMe

CN

NBr

R

ONMe

CN

N

R

ONMe

CN

N

R

O

NMe

CN

NBn

O

RNMe

CN

NBn

O

R

80 81

8283

NMe

O

NBn

O

Rb

84

Scheme 23: a) Bu3SnH, AIBN, toluene, ∆; b) KOtBu, O2, THF, RT.

An approach, relying on the effective preparartion of hindered spiro-oxindoles by

photolysis of 1-(1-alkenyl)benzotriazoles via radical intermediates has been developed by

Pleynet for the synthesis of gelsemine (9).64

[63] Hilton, S. T.; Ho, T. C. T.; Pljevaljcic, G.; Jones, K. Org. Lett. 2000, 2, 2639-2641. [64] Pleynet, D. P. M.; Dutton, J. K.; Johnson, A. P. Abstr. Pap. Am. Chem. Soc. 1999, 217, ORGN 538.


25

1.6. Asymmetric Nitroolefination

Asymmetric nitoolefination proved a powerful tool for the efficient introduction of the

spiro-center in spiro-pyrrolidine-oxindoles. Fuji showed that the enolate of 85, upon

treatment with chiral nitroenamine 86, gives the corresponding quaternary compounds 87

in high yields and enantioselectivities.65

85

NBn

O

Me

Me

NOMe

PhPh

NO2

86

+

87

NBn

O

MeMe

NO2aMeO MeO

16

Scheme 24: a) nBuLi, 86, THF, –78 °C.

This method was among others applied to the synthesis of (–)-horsfiline (16)66 and

spirotryprostatin B (17).67

1.7. Rearrangement of [(N-Aziridinomethylthiomethylene]-2-oxindoles

N-Vinylaziridines were shown to undergo facile iodide ion induced rearrangement to

2-methylthio-3,3-substituted pyrrolidines. This general method can be applied to the

synthesis of spiro-oxindoles 91 from 90, easily accessible from 89 by reaction with

aziridine (Scheme 25).68

89

NR

O

SMe

MeS

aR'

NR

O

N

MeS

R'

NR

O

R'NMeS

b

90 91

Scheme 25: a) aziridine, THF, RT; b) KI, acetone, RT.

[65] Fuji, K.; Kawabata, T.; Ohmori, T.; Node, M. Synlett 1995, 367-368. [66] Lakshmaiah, G.; Kawabata, T.; Shang, M. H.; Fuji, K. J. Org. Chem. 1999, 64, 1699-1704. [67] Bagul, T. D.; Lakshmaiah, G.; Kawabata, T.; Fuji, K. Org. Lett. 2002, 4, 249-251. [68] Kumar, U. K. S.; Ila, H.; Junjappa, H. Org. Lett. 2001, 3, 4193-4196.


2. Novel Approach to the Synthesis of Spiro-Pyrrolidine-

Oxindoles

2.1. Retrosynthetic Analysis

The Carreira-group envisioned a very direct, alternate bond-construction strategy to

spiro-pyrrolidine-oxindole ring systems. In our retrosynthetic analysis, 91 is disconnected

to cyclopropane 95 and aldimine 93 (Scheme 26). As depicted for synthon 92, the charge-

affinity pattern of the cyclopropane complements that of an aldimine. This strategy would

not only present an alternative to existing methods, but also allow for efficient late-stage

coupling of two functionalized fragments in a convergent fashion.

91

NR

O

NR1

R2

N

R2

R1

92

NR

O

93

+NR

O NR

OM

X

94

NR1

R2

93

95

Scheme 26: Our retrosynthetic analysis for the efficient assembly of the spiro-pyrrolidine-oxindole core.

The charge-affinity pattern of cyclopropanes, when substituted with electron-withdrawing

groups, is manifest in their well-known reactivity as homo-Michael acceptors. The

introduction of this 1,5-version of the classical Michael reaction is due to Bone and

Perkin69 and represents an Umpolung.70 Generally, doubly activated cyclopropanes are

[69] Bone, W. A.; Perkin, W. H. J. Chem. Soc. 1895, 67, 108-119. [70] Seebach, D. Angew. Chem. Int. Ed. Engl. 1979, 18, 239-258.


27

required for attack by a nucleophile, bearing two geminal electron-withdrawing groups

such as esters or cyano groups. In most cases, the more substituted (hindered) carbon is

attacked by the nucleophile.71 Pioneering work by Danishefsky had established the

participation of doubly activated cyclopropanes in tandem reactions resulting in ring

formation (Scheme 27).72

NH2

CO2Me

CO2Me N

O

CO2Mea

N

CO2Me

CO2MeO

O

Scheme 27: a) hydrazine/MeOH, ∆.

Intramolecular attack renders these activated cyclopropanes more prone to the cleavage

of a C–C single bond. Stork was the first to employ intramolecular nucleophilic ring

opening of Lewis acid activated cyclopropyl ketones73 and this concept of an

electrophile-assisted nucleophilic attack was later on confirmed by the work of Corey and

Balason74 (Scheme 28).

Me

O

EH

MeMe

Me

OE

Me

Me

O

a

Scheme 28: SnCl4, benzene, ∆.

Some monoactivated cyclopropanes are also opened upon intermolecular nucleophilic

attack; however, these cyclopropanes are generally found in ring systems which render

[71] a) Danishefsky, S. Accounts Chem. Res. 1979, 12, 66-72. b) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165-198. [72] a) Danishefsky, S.; Dynak, J. J. Org. Chem. 1974, 39, 1979-1980. b) Danishefsky, S.; Dynak, J.; Hatch, E.; Yamamoto, M. J. Am. Chem. Soc. 1974, 96, 1256-1259. c) Danishefsky, S.; Etheredge, S. J.; Dynak, J.; McCurry, P. J. Org. Chem. 1974, 39, 2658-2659. d) Danishefsky, S.; Dynak, J. Tetrahedron Lett. 1975, 79-80. [73] a) Stork, G.; Marx, M. J. Am. Chem. Soc. 1969, 91, 2371-2373. b) Stork, G.; Gregson, M. J. Am. Chem. Soc. 1969, 91, 2373-2374. c) Stork, G.; Grieco, P. A. J. Am. Chem. Soc. 1969, 91, 2407-2408. d) Stork, G.; Grieco, P. A. Tetrahedron Lett. 1971, 1807-1810. [74] Corey, E. J.; Balanson, R. D. Tetrahedron Lett. 1973, 34, 3153-3156.


them particularly strained or occur with strong nucleophiles such as metal selenides.75

Nickel-catalyzed additions of organolaluminums are also known with monoactivated

cyclopropanes.76 Singly activated cyclopropyl ketones undergo ring opening in reactions

with trimethylsilyl halides, reagents combining a potent, oxophilic electrophile with the

attacking nucleophile (Scheme 29).77

Me

O

IMe

OI

Me

OTMS

a b

Me

O E

Nu

via:

Scheme 29: a) TMSI (1.2 equiv), CCl4; b) H2O.

Our strategy as depicted in Scheme 26, page 26 necessitates nucleophilic ring opening of

a singly activated ring system by a weakly nucleophilic aldimine. We speculated that the

use of a catalyst exhibiting dual electrophilic and nucleophilic activation would enable

the desired reaction, provided competitive intramolecular cyclization (via O–alkylation)

is precluded. In this regard, the selection of a Lewis acidic metal possessing nucleophilic

counterions could efficiently lead to ring-opened products 94, which possess the same

reactivity pattern as synthon 92.78

[75] Smith III, A. B.; Scarborough Jr., R. M. Tetrahedron Lett. 1978, 19, 1649-1652. [76] Bagnell, L.; Meisters, A.; Mole, T. Aust. J. Chem. 1975, 28, 821-824. [77] a) Miller, R. D.; McKean, D. R. J. Org. Chem. 1981, 46, 2412-2414. b) Dieter, R. K.; Pounds, S. J. Org. Chem. 1982, 47, 3174-3177. [78] For a discussion on charge affinity patterns and retrosynthesis see: Evans, D. A.; Andrews, G. C. Accounts Chem. Res. 1974, 7, 147-155.


29

2.2. MgI2-Catalyzed Ring-Expansion Reaction of Spiro-Cyclopropyl-

Oxindoles with Aldimines

2.2.1. Initial Results79

In order to test our hypothesis, initial studies with spiro-cyclopropyl-oxindole 99 and

cyclic imine trimer 101 were carried out. Both starting materials of the reaction are easily

obtained from commercially available products and were chosen as a simple model for

the construction of tetracyclic oxindole alkaloids.

96

NBn

ONH

O

O

NBn

O

9998

a c

90% 85%

97

NBn

O

Ob

65%

Scheme 30: a) NaH, BnBr, DMF, RT; b) N2H4·H2O, ∆; c) NaH, BrCH2-CH2Br, DMF, RT.

Spiro-cyclopropyl-N-benzyl-oxindole (99) was synthesized from isatin (96) in three

steps. Protection of the amide nitrogen to 97, followed by Wolff–Kishner reduction

afforded N-benzyl oxindole (98), which was alkylated to spiro-cyclopropyl-oxindole 99

by deprotonation and reaction with 1,2-dibromo ethane (Scheme 30).80,81 The cyclic

imine precursor 101 was prepared from piperidine (100) in two steps (Scheme 31).82

HN N

N

Na, b

40%

N

3100

101

Scheme 31: a) NCS, Et2O; b) KOH, EtOH.

[79] Initial results leading to the development of the MgI2 catalyzed Ring-Expansion Reaction of spiro-cyclopropyl-oxindoles with imines were obtained by Dionicio R. Siegel. [80] Kishner, N. Russ. Phys. Chem. Soc. 1911, 43, 582-586. [81] Crestini, C.; Saladino, R. Syn. Commun. 1994, 24, 2835-2841. [82] Claxton, G. P.; Allen, L.; Grisar, J. M. Org. Synth., Coll. Vol. VI 1988, 968-969.


Initially, the reaction of spiro-cyclopropyl derivative 99 with imine trimer 101 in the

presence of a number of metal salts, for example Mg(OTf)2, ZnI2, Zn(OTf)2, LiI, was

investigated. The first notable result was obtained with MgBr2·Et2O. The desired products

102 and 103 were obtained in 13% yield upon treatment with 1.5 equivalents MgBr2·Et2O

in refluxing THF (Scheme 32).

N

3

101

NBn

O

99

+NBn

O

NMgBr2 Et2O (1.5 equiv)

THF, ∆, 2 d13%

102 103

NBn

O

N

+

major diastereomer

Scheme 32: First successful ring expansion of spiro-cyclopropyl-oxindole 99 with imine trimer 101.

At higher temperatures (in refluxing m-xylene), the reaction was catalytic in Lewis acid,

showing complete conversion using 30 mol% MgBr2·Et2O. These conditions required the

addition of DMA (one equivalent with respect to the catalyst) to the reaction mixture in

order to solubilize the catalyst. The two diastereomeric products 102 and 103 were

separated by flash column chromatography and analyzed separately. Both diaseteromers

slowly isomerize by retro-Mannich/Mannich reaction upon standing at ambient

temperature (see Scheme 1, page 9).

Interestingly, the ring-expansion reaction could also be conducted with imines possessing

an N-aryl-sulfonyl protecting group. Spiro-cyclopropyl-oxindole 99 leads to spiro-

pyrrolidine-oxindole 105 upon MgBr2·Et2O-catalyzed reaction with N-benzylidene-

benzenesulfonamide (104) (Scheme 33). The observation that the reaction with this much

weaker nucleophile was found to be even faster hints at an interesting mechanistic

duality.

104

NBn

O

99

+NBn

O

N SO2PhMgBr2 Et2O (30 mol%)

105

PhNPhO2S

PhDMA (30 mol%), m-xylene, ∆

Scheme 33: Ring expansion of spiro-cyclopropyl-oxindole 99 with benzylidene-N-sulfonamide 104.


31

2.2.2. Optimization and Scope of the Ring-Expansion Reaction

Further improvement was achieved by addition of nBu4NI to the reaction mixture. The

reaction of spiro-oxindole 99 with benzylidene-N-sulfonamide 104 was used to optimize

the reaction conditions and resulted in the adoption of 10 mol% MgI2, in THF at 60 °C as

standard conditions (Table 2).83

Lewis-Acid Additive Solvent Solubilizer Temperature Time Conversion

MgBr2·Et2O (30 mol%) none m-xylene DMA

(30 mol%) 135 °C 20 h 70%

MgBr2·Et2O (30 mol%) Bu4NI m-xylene DMA

(30 mol%) 135 °C 2 h 100%

none Bu4NI m-xylene DMA (30 mol%) 135 °C 20 h 0%

MgI2 (10 mol%) none THF none 60 °C 2 h 100%

Table 2: Optimization of the ring-expansion reaction.

The addition of nBu4NI led to considerable rate acceleration, which prompted us to

switch to MgI2 as a catalyst. The reaction rate was high even at lower temperatures,

allowing for the use of THF as solvent. This change to a more polar solvent obviated the

use of DMA.

In order to explore the scope of the reaction, a variety of N-aliphatic imines 106 were

screened. To obtain reasonable reaction times, the standard conditions were modified and

the reactions were run in a sealed tube at 80 °C (Scheme 34, Table 3)

NBn

O+

NBn

O

N R'MgI2 (10 mol%)

RTHF, 80°C, sealed tube

N

R

R'

99 106 107R' = aliphatic

Scheme 34: Ring expansion with N-aliphatic imines 106.

[83] Optimization of the reaction conditions and the reactions of 99 with N-aliphatic aldimines 106 were conducted by Phil B. Alper.


Entry Aliphatic imines Time Products:

major diastereomer/minor diastereomer Diastereomer

ratio Yield

1 101

N

3

19 h

NBn

O

N

102 103

NBn

O

N

86 : 14 68%

2 N

Et108

21 h NBn

O

N

Et

109

NBn

O

N

Et

110

91 : 9 55%

3 N

iPr111

20 h NBn

O

N

iPr

112

NBn

O

N

iPr

113

80 : 20 83%

4 N

Ph114

2 h NBn

O

N

Ph

115

NBn

O

N

Ph

116

79 : 21 99%

5 N

Ph

nBu

117 2 h

NBn

O

N nBu

Ph

118 NBn

O

N nBu

Ph

119

81 : 19 98%

Table 3: Ring expansion with N-aliphatic imines 106.

The configuration of the products of type 107 was assigned by 1H NMR correlation to the

major product of entry 5, for which a crystal structure had been obtained.

Imine trimers can be successfully employed in the reaction and act as an imine precursor

or surrogate (entry 1). The reaction with enolizable imines results in prolonged reaction

times (entry 1–3) and in a decrease in yield (entry 2), but steric bulk at the α-position

seems to be favorable (entry 3).

Next, we turned our investigations to the ring-expansion reaction of 99 with substituted

methylidene-N-arylsulfonamides 123. The substituted methylidene-N-arylsulfonamides

are conveniently prepared by reaction of the dialkyl acetals 120 with aryl-sulfonamides


33

121 in the absence of solvent (Scheme 35).84 The condensation yields a solid that can be

conveniently purified by recrystallization. Yields are generally moderate (between 44 and

75%) with exception of 149 (12%).

N

R122

OR'

RR'O

120

ArS

H2N

O O

121

160 °C, -2R'OHAr

SO O

R' = MeR' = Et

Scheme 35: Preparation of substituted methylidene-N-arylsulfonamides 122.

With the N-tosyl-protected imines 123 in hand, we focused on the exploration of the

reaction scope (Scheme 36, Table 4)

NBn

O+

NBn

O

NTsMgI2 (10 mol%)

RTHF, 60 °CNTs

R

99 123

Scheme 36: Ring expansion with N-tosyl-protected imines 123.

Entry N-tosyl-

protected imines

Time Products: major diastereomer/minor diastereomer

Diastereomer ratio Yield

1 NTs

124

Ph

8 h

NBn

O

NTs

Ph

125 NBn

O

NTs

Ph

126

91 : 9 97%

2

NTs

127

Me

8 h NBn

O

NTs

128

Me

NBn

O

NTs

129

Me

98 : 2 89%

3

NTs

130Me

34 h NBn

O

NTs

131 Me NBn

O

NTs

132 Me

64 : 36 96%

[84] Albrecht, R.; Kresze, G.; Mlakar, B. Chem. Ber. Recl. 1964, 97, 483-489.


4

NTs

133

Br

19 h NBn

O

NTs

134

Br

NBn

O

NTs

135

Br

98 : 2 82%

5

NTs

136Br

22 h

NBn

O

NTs

137 Br NBn

O

NTs

138 Br

82 : 18 92%

6

NTs

139CF3

18 h NBn

O

NTs

140 CF3 NBn

O

NTs

141 CF3

84 : 16 97%

7

NTs

142OMe

50 h

NBn

O

NTs

143 OMe

NBn

O

NTs

144 OMe

67 : 33 75%

8

NTs

145

O

4 h

NBn

O

NTs

146O

NBn

O

NTs

147

O

85 : 15 97%

9

NTs

148Ph

20 h NBn

O

NTs

149Ph

NBn

O

NTs

150Ph

74 : 26 62%

10

NTs

151Ph

Me

96 h NBn

O

NTs

152Ph

Me

NBn

O

NTs

153Ph

Me

52 : 48 55%

11 NTs

154TIPS

4 h

NBn

O

NTs

155TIPS

NBn

O

NTs

156TIPS

98 : 2 77%

Table 4: Ring expansion with N-tosyl-protected imines 123.

In the series with N-tosyl-imines derived from aromatic aldehydes (entries 1–8), the

unsubstituted systems react fast and give rise to good diastereoselectivities (entries 1 and

8). With exception of entry 2, the rate of the reaction is decreased by both electron-

withdrawing and electron-donating substituents. However, it can be observed that


35

electron-withdrawing substituents are more favorable than electron-donating ones in the

para-position (for example entry 6 vs. entry 7 or entry 5 vs. entry 3). Better

diastereoselectivities are generally observed with ortho-substituents on the aromatic ring

(entries 2 and 4). Cinnamaldehyde-derived imines are also suitable reaction partners even

though the products are obtained in lower yields and with lower diastereoselectivities

(entries 9 and 10). The reaction with the imine derived from TIPS-protected propynal is

very fast (entry 11).

In order to obtain higher levels of diastereoselectivity, we decided to change the

bulkyness of the N-protecting group of the imines. Therefore the imines 157–159 were

prepared according to the general protocol (Figure 5). These imines are derived

p-methylbenzaldehyde, as N-tosyl-imine 130 (see Scheme 35, page 33) derived from this

aldehyde led to low diastereoselectivity (64:36) in the ring expansion (entry 3,Table 4,

page 34).

NS

157

OO

Me

NS

158

OO

Me

i-Pr

i-Pri-Pr

NS

159

OO

Me

Me

MeMe

Me

Me

Figure 5: Sterically demanding N-(4-methyl-benzylidene)-sulfonamides.

Only 157 could be employed in the ring-expansion reaction, imines 158 and 159 being

probably too sterically demanding. As a result, the products of the ring expansion with 99

were obtained in 83% combined yield with significant increase in diastereoselectivity

(89:11) as compared to entry 3 (64:36) (Scheme 37).


NS

157

OO

Me

NBn

O

99

+NBn

O

NMgI2 (10 mol%)

THF, 60 °C

160

SO O

Me

NBn

O

N

161

SO O

Me

+

83%

89:11

Scheme 37: Ring expansion of 99 with N-(4-methyl-benzylidene)-(naphthalene)-sulfonamide 157.

In order to further expand the scope of our ring-expansion reaction, we next turned to the

use of other reaction partners for 99. The reaction can also be performed using aldehydes

instead of aldimines, leading to the formation of spiro-fused tetrahydrofuran derivatives.

The reaction of 99 with p-trifluoromethyl-benzaldehyde (162) affords oxolane 163

(Scheme 38).

O

162CF3

NBn

O

99

+MgI2 (10 mol%)

THF,100 °C, sealed tubeNBn

O

O

163 CF319%

Scheme 38: Ring expansion of 99 with aldehyde 162.

The use of tosylamid 165 derived from ethyl glyoxylate (164) in the reaction with 99 led

to a surprise. Instead of the expected ring-expansion product 166, we obtained the

product of the aromatic-substitution reaction 167, unambiguously characterized by X-ray

crystallographic analysis (Scheme 39, Figure 6).85 Reactions of that type are known and

generally use the N,O-(glyoxylate-hemiacetal) in the presence of a strong acid.86 Only

one reference for such a reaction of electron-rich aromatic compounds with glyoxylate-

derived imines has been reported.87

[85] CCDC 199468 contains the supplementary crystallographic data for 167. This data can be obtained free of charge via www.ccdc.cam.ac.uk/retrieving.html (or from the Cambridge Crystallographic Data Center, 12, Union Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or [email protected]). [86] Ben-Ishai, D.; Sataty, I.; Bernstein, Z. Tetrahedron 1976, 32, 1571-1573. [87] Saaby, S.; Fang, X. M.; Gathergood, N.; Jorgensen, K. A. Angew. Chem. Int. Ed. 2000, 39, 4114-4116.


37

NBn

O+

NBn

O

NTs

MgI2 (7.6 mol%)

R

THF, 60 °C

NTs

99 165

166

O

OEt

O

O

OEtNTsCO

+

toluene∆, 3 d N

BnO

TsHN

OEtO

167

164

Scheme 39: Reaction of 99 with glyoxylate-derived N-tosyl-protected imine 165.

Figure 6: ORTEP drawing of 167.


Isocyanates are also able to react with cyclopropyl-oxindole 99, giving rise to

pyrrolidinones 168 (Scheme 40). In the context of these investigations, it was shown that

deprotection of the tosyl group can be accomplished with Na/naphthalene in good yield.88

NBn

O NBn

O

N R

MgI2 (1 equiv)O

THF, 100 °C

99 168

NR

CO

+Na / naphthalene

THF,-100 °C NH

O

NH

O

R = Ts

90%

Scheme 40: Ring expansion of 130 with isocyanates.

The reaction can also be performed with other monoactivated cyclopropanes. A lead

result was obtained when cyclopropanecarboxylic acid diphenylamid 169 was employed

in the ring expansion with benzylidene-N-benzenesulfonamid (104), giving two

diastereomers of the desired pyrrolidine 170 (Scheme 41).

+MgI2 (1 equiv)

DMA, xylene, ∆N

Ph

PhO2S

169 104 170

O

NPh2 NSO2Ph

Ph

OPh2N

Scheme 41: Synthesis of substituted pyrrolidenes from cyclopropancarboxylic acid diphenylamid (169).

2.2.3. Mechanistic Aspects

Even though we have not yet undertaken detailed kinetic studies for this ring-expansion

reaction, we are able to draw some conclusions from the observations made with different

imine substrates. The hypothesized mechanistic pathway is depicted in Scheme 42.

[88] This study was undertaken by Andreas Lerchner during his diploma work. Lerchner A. Diploma Thesis, ETH Zürich, 1999.


39

NBn

OMg

I

I

NBn

O

NBn

OMgI NBn

O

I

R'

N R

NBn

N

R'

R

ONBn

OMgI

NR

R'

NR

R'+

Activation byLewis Acid

NucleophilicActivation

MgI2 acts as a bifunctional catalyst:

99

171

172 174

173

MgI2

MgI2

NBn

O

175

I

I

Scheme 42: Possible mechanistic pathways for the ring-expansion reaction.

The cyclopropane could be opened by one of the two potential nucleophiles present in the

reaction mixture: (i) I- giving rise to enolate 171 or (ii) the imine nitrogen leading directly

to enolate 172. We have evidence that the first intermediate of the ring-expansion

reaction is enolate 171. If 172 was the first intermediate, it would be doubtful that the

reaction could proceed with N-aryl-sulfonyl-protected imines, as those are poor

nucleophiles. The pathway via intermediate 171 could also be responsible for the fact that

the more nucleophilic iodide accelerates the reaction significantly as compared to

bromide and that with Mg(OTf)2, no reaction is observed (Table 5). Finally, we were able

to isolate 3-(2-iodo-ethyl)-N-benzyl-oxindole (175) as a by-product (characterized by 1H NMR and high resolution MALDI-MS) in a reaction wherein the imine decomposed.

This compound is the keto form of enolate 171 after aqueous workup. From intermediate

171, two possible pathways are depicted in Scheme 42. A nucleophilic imine could attack

intermediate 171 giving rise to 172. In this reaction the rate acceleration of iodide vs.

bromide could again be manifest, iodide being the better leaving group (Table 5). From

172, the final product 174 is obtained by cyclization of the iminium species, similar as for

the retro-Mannich reaction depicted in Scheme 1. This might be the pathway for N-alkyl-

imines. On the other hand, with more electrophilic imines like N-aryl-sulfonyl-protected

imines, the reaction is likely to proceed through adduct 173, that could close to 174 by

N-alkylation.


The leaving-group reactivity is defined as the

ratio kX/kBr and values for the reaction of

EtX with EtO- as nucleophile are given.

The nucleophilic constant is defined as:

MeOH) MeI(Nuc) MeI( log

++

=k

kn

Table 5: Leaving-group reactivities and nucleophilic constants for halogen anions.

Considering these results, it can be concluded that MgI2 acts as a bifunctional catalyst

where both the Lewis acidic metal center (Mg(II)) and the nucleophilic counter ion (I–)

have to operate in synergy to enable successful ring expansion.89

The ring closure of iminium 172 to 174 is a disfavored 5-endo-trig cyclization process

and deserves comment.90 Baldwin has studied the cyclization behavior of hydroxyl

enones to furanones and discovered that nucleophilic ring closure by conjugate addition

to a neutral enone is an unfavored process forming five-membered cycles; the products

could not be formed. However, under acidic conditions, cyclization is possible and this

result is explained by the reduction of rotational barriers around the C−C bond of the

enone resulting from enone protonation to 176.91 Intermediate 172 could also undergo

ring closure by contribution of its resonance structure. Alternatively, as in the mechanism

for the formation of cyclic acetals, the ring closure of 172 could be catalyzed by a

nucleophile (e.g. I-) and proceed via 177 as a 5-exo-tet process (Figure 7).92 A couple of

examples for disfavored 5-endo-trig cyclization reactions are known in literature for the

formation of pyrrolidines and tetrahydrofuranes.93,94

[89] MgI2 is a very efficient catalyst in Diels-Alder reactions and aldol additions. This is due to the efficient dissociation of I- from L2MgI2 (L is a solvent molecule). Corey, E. J.; Li, W. D.; Reichard, G. A. J. Am. Chem. Soc. 1998, 120, 2330-2336. [90] Baldwin, J. E. J. Chem. Soc. Chem. Commun. 1976, 734-736. [91] Baldwin, J. E.; Thomas, R. C.; Kruse, L. I.; Silberman, L. J. Org. Chem. 1977, 42, 3846-3852. [92] Johnson, D. D. Acc. Chem. Res 1996, 26, 476-482. [93] a) Grigg, R.; Kemp, J.; Malone, J.; Tangthongkum, A. J. Chem. Soc. Chem. Commun. 1980, 648-650. b) Auvray, P.; Knochel, P.; Normant, J. F. Tetrahedron Lett. 1985, 26, 4455-4458. Padwa, A.; Norman, B. H. J. Org. Chem. 1990, 55, 4801-4807. c) Jones, A. D.; Knight, D. W. Chem. Commun. 1996, 915-916. d) Berry, M. B.; Craig, D.; Jones, P. S.; Rowlands, G. J. Chem. Commun. 1997, 2141-2142. e) Craig, D.; Jones, P. S.; Rowlands, G. J. Synlett 1997, 1423-1425.

Leaving-Group

Reactivity

NucleophilicConstant

(nMeI values)Cl- 0.0024 4.37

Br- 1.0 5.79

I- 1.9 7.42


41

NBn

OMgI

NR

R'

172

NBn

OMgI

NR

R'

OMe

OHMe

HOH

Me

OHMe

176

NBn

O

NR

R'

172

NBn

O

NR

I

177

R'IO

O R

R O

O R

OHR

OH

H HMgI MgI

5-endo-trig 5-endo-trig 5-exo-tet5-exo-tet

Figure 7: Explanations for possible 5-endo-trig cyclization.

2.2.4. Conclusion

The MgI2-catalyzed ring-expansion reaction gives access to the spiro-pyrrolidine-

oxindole ring systems. This motif is a key structural feature in a number of natural

products and can be rapidly assembled from easily available starting materials. The

reaction proceeds with useful levels of diastereoselectivity and high yields. The dual

Lewis acidic and nucleophilic activity of MgI2 enables successful ring expansion of a

monoactivated cyclopropane. This reaction provides a useful tool for the synthesis of

complex natural products.

f) Dell'Erba, C.; Mugnoli, A.; Novi, M.; Pani, M.; Petrillo, G.; Tavani, C. Eur. J. Org. Chem. 2000, 903-912. g) Chang, K. T.; Jang, K. C.; Park, H. Y.; Kim, Y. K.; Park, K. H.; Lee, W. S. Heterocycles 2001, 55, 1173-1179. [94] a) Craig, D.; Smith, A. M. Tetrahedron Lett. 1992, 33, 695-698. b) Craig, D.; Ikin, N. J.; Mathews, N.; Smith, A. M. Tetrahedron Lett. 1995, 36, 7531-7534. c) Craig, D.; Ikin, N. J.; Mathews, N.; Smith, A. M. Tetrahedron 1999, 55, 13471-13494.

42 The Synthesis of (±)-Horsfiline

IV. The Synthesis of (±)-Horsfiline

1. Introduction

(–)-Horsfiline (16) is one of the structurally simpler oxindole alkaloids found in nature. It

was isolated in 1991 by Bodo and co-workers from the Malaysian tree Horsfieldia

superba (Figure 8), an important source of medicinal extracts and snuffs in the local

medicine.95

Figure 8: The Malaysian tree Horsfieldia superba.

1.1. Isolation

(–)-Horsfiline was found together with two achiral metabolites 178 and 179, and the two-

step conversion of 178 into (±)-16 by oxidative rearrangement supported the structural

assignment for 16. The absolute configuration of (–)-horsfiline was not known at that

time (Scheme 43).

[95] See [4], page 7.

The Synthesis of (±)-Horsfiline

43

NH

NMeMeO

O

(-)-horsfiline (16)

NH

MeO

a, b

178 179

NMeNH

MeO

NMeMe

NH

NMeMeO

O

(+)-16

Scheme 43: Alkaloids from Horsfieldia superba. a) Pb(OAc)4, CH2Cl2, RT; b) MeOH/H2O/AcOH, ∆.

Horsfiline has proven an ideal target to test new methods for the general synthesis of

spiro-oxindoles. Several groups have gotten involved in the synthesis of horsfiline. The

first syntheses yielded racemic horsfiline ((±)-16).

1.2. Synthetic Approaches

1.2.1. Jones’ and Wilkinson’s Synthesis of (±)-Horsfiline

The synthetic route by Jones and Wilkinson is based on a radical reaction as key step.

The precursor for the radical cyclization 182 was prepared from 2-bromo-4-methoxy-

aniline and 181, available from Cbz-protected glycine ethyl ester (180) in a multistep

sequence. Protection of the indole nitrogen proved important, as radical cyclization of

unprotected 182 led only to reduction and transient TMS-protection led to considerable

amounts of the undesired product from 6-endo cyclization. (±)-Horsfiline is obtained

after deprotection of 183 and treatment of 184 under Eschweiler–Clarke conditions

(Scheme 44).96

[96] See [61], page 23.


NH

NMeMeO

O

(+)-horsfiline ((+)-16)

NHCbz

CO2Et

NCbz

OEtO2C

NCbz

OHEtO2C

NCbz

EtO2C

NCbz

HO2Ca

87% 85% 89%

NH

MeO

O

NCbzBr

b c,d e

f,g

79%

180 181

182

NSEM

MeO

O

NCbzBr

NSEM

MeO

O

NCbz

183

NH

MeO

O

NH

184

94%70%

68% 75%

hj

k,l m

53%

Scheme 44: a) ethyl acrylate, Na, toluene; b) NaBH3CN, MeOH; c) BzCl, DMAP, Py; d) DBU, toluene, ∆; e) KOH, dioxane/H2O, 45 °C; f) NEt3, SOCl2¸ DME, 0 °C; g) 2-bromo-4-methoxy-aniline, Hünig’s base, DME; h) KH, THF, SEMCl; j) Bu3SnH, AIBN (cat.), toluene, ∆; k) Bu4NF, DMF/ethylenediamine, 80 °C; l) H2, Pd/C, EtOH; m) HCO2H, HCHO, ∆.

1.2.2. Laronze’s Syntheses of (±)-Horsfiline

Laronze’s syntheses of horsfiline follow two different strategies, an oxidative

rearrangement of tetrahydro-β-carboline and a spiro-cyclization of tryptamine-oxindole

with formaldehyde. The oxidative rearrangement pathway yielded (±)-horsfiline in 52%

overall yield from tetrahydro-β-carboline 185 via non isolable chloroindolenine 186.

Side-products from the rearrangement reaction can be further converted into desired

(±)-horsfiline ((±)-16). The alternative route from the 5-methoxy-Nb-methyl-tryptamine

(187), via oxo-tryptamine derivative 188 led to (±)-horsfiline in 35% overall yield

(Scheme 45).97

[97] Bascop, S. I.; Sapi, J.; Laronze, J. Y.; Levy, J. Heterocycles 1994, 38, 725-732.


45

NH

NMeMeO

O


NH

NMeMeO

N

NMeMeO

Cl

N

NMeMeO

OMeN

MeO Cl

NMe

NH

MeONHMe

NH

MeONHMe

O

185

188187

186

Route B:overall yield = 35%

Route A:overall yield = 52%

a

b

c d

e

f

Scheme 45: a) tBuOCl, NEt3, CH2Cl2; b) NaOH, MeOH/H2O, 70 °C; c) NaOMe, MeOH, ∆; d) pTsOH/H2O, toluene, ∆; e) DMSO, 37% aq HCl, 80 °C; f) (CH2O)n, AcOH, ∆.

1.2.3. Borschberg’s Approach to (+)- and (–)-Horsfiline

The first investigations towards the elucidation of the absolute configuration of horsfiline

were undertaken by Borschberg. The plan was to use of a chiral tetrahydro-β-carboline

derived from 5-methoxy-L-tryptophane (189) that would give rise to two diastereomers

after oxidative rearrangement. Those could, after separation, be reduced to the two

enantiomers of the horsfiline core. Following this strategy, both (+)- and (–)-horsfiline

could theoretically be accessed from a common intermediate. In practice, different

substituents at the piperidine nitrogen led to significant preferences for formation of one

diastereomer over the other in the rearrangement. It was therefore preferable to access

spiro-oxindole 191 from Boc-derivative 190, and 193 from N-methyl derivative 192.

NOE experiments allowed for the structural assignments of the relative stereochemistry

of 191 and 193 and thus of the absolute configuration of their reduced counterparts 16


and (+)-16. In the meantime, the absolute (R)-configuration was also determined by

X-ray crystallographic analysis (Scheme 46).98

NH

NMeMeO

O

(-)-horsfiline (16)

NH

NMeMeO

O


NH

NMeMeO

O

191

NH

NMeMeO

O

193

NH

MeO

190

NBoc

NH

MeO

192

NMe

CO2Me

CO2Me

NH

HO

189

NH3

CO2H

Cl

a-c

a-f

CO2Me

CO2Me

g,d,e,h

g

j,k

l,m

77%

68%

37% 49%

50% 66%

Scheme 46: a) 1.38% aq CH2O, MeOH, ∆, then TMSCl, MeOH, ∆; b) (Boc)2O, NEt3, THF/H2O; c) TMSCHN2, Hünig’s base, MeCN/MeOH; d) TMSCl, 4-MeC6H4OMe, MeOH, ∆; e) 1.38% aq CH2O, NaBH3CN, AcOH; f) NEt3, THF, ∆; g) NBS, AcOH, THF/H2O; h) MeOH/2 N HCl aq, ∆; j) (i) NEt3, MeOH, (ii) (CF3CO)2O, dioxane, Py; k) NaBH4, EtOH, Py, 40°C; l) 1 N NaOH, MeOH; m) ClCO2CH2CHMe2, NMO, then 2-mercaptopyridine-N-oxide, Me3CSH, hν.

1.2.4. Palmisano’s Route to (–)-Horsfiline

Another synthetic approach taking advantage of a 1,3-dipolar cycloaddition reaction was

employed by Palmisano. He was able to access (–)-16 in five steps from enantiopure

dipolarophile 195, which was obtained by Wittig olefination of 5-methoxy-isatin (194).

Dipolar cycloaddition with N-methyl azomethine yilde prepared in situ from

formaldehyde and sarcosine, yielded 196, and its C3 epimer. Hydrolysis of the ester and

formal decarboxylation afforded (–)-horsfiline 16 (Scheme 47).99

[98] See [27], page 14. [99] See [44], page 19.


47

NH

NMeMeO

O

(-)-horsfiline (16)

NH

MeO

194

O

O NH

MeO

195

O

RO2C

Me

MeMe(-)-menthyl

NH

NMeMeO

O

RO2C

76 %

a b

41 %

c,d,e

sarcosine =

65%

196

MeHN CO2H

3

= R

Scheme 47: a) (5R)-menthyl(triphenylphosphoranylidene)acetate, diglyme, ∆; b) sarcosine, (CH2O)n, toluene, ∆; c) powdered KOH, 18-crown-6 (cat.), THF, then Dowex 50W × 8; d) DCC, DMAP, 2-mercaptopyridine-N-oxide, CH2Cl2; e) Bu3SnH, AIBN (cat.), toluene, ∆.

Palmisano carefully revised his approach and concluded that a chiral precursor like 199

would still bear the electron-withdrawing ester group required for the 1,3-dipolar

cycloaddition. In contrast to his first-generation synthesis, this ester group could be

incorporated in the spiro-oxindole core instead of being reduced to the hydrocarbon stage.

The chiral cycloaddition precursor 199 was obtained by esterification of 197 with

Whitesells’ (1S,2R)-2-phenyl-1-cyclohexanol (198). 1,3-dipolar cycloaddition afforded

200 in high yield and diastereoselectivity. Ester-cleavage and reduction of the nitro

group, followed by spontaneous intramolecular lactam formation led to (–)-horsfiline

(16).

(-)-horsfiline (16)

NH

NMeMeO

O

MeO

NO2

MeO

NO2

CNMeO

NO2

CO2MeMeO

NO2

CO2Me

MeO

NO2

CO2HMeO

NO2

CO2R*

197199 HO

198

NO2

CO2R*

NMeMeO

Ph

200

55%

a b c

d

85% 76%

80%

78% 78%

ef

86% de

95%

g

Scheme 48: a) (4-ClC6H4)OCH2CN, tBuOK, DMF, –10 °C; b) MeOH, TMSCl; c) (CH2O)n, K2CO3, TDA-1, toluene, 85 °C; d) 2 M NaOH, ∆, then pH 1, 0 °C; e) 198, DCC, HOBt, DMAP, CH2Cl2, ∆; f) sarcosine, (CH2O)n, 3 Å MS, toluene, ∆; g) H2, 10% Pd/C, MeOH.


1.2.5. Fuji’s Synthesis of (–)-Horsfiline

Fuji’s synthesis of (–)-horsfiline 16 is characterized by early introduction of the chiral

quaternary center by asymmetric nitroolefination of oxindole 201 with 86. Regioselective

introduction of the aromatic methoxy group is noteworthy (202 203). In spite of the

successful implementation of these key steps, the overall synthesis is rendered awkward

by multitudes of functional group interconversions (Scheme 49).100

(-)-horsfiline (16)

NBn

O

NH

NMeMeO

O

60%

a b

65%NBn

201

O

Me

Me

NBn

O

MeMe

NO2

N

PhOMe

Ph

NO2

86

NBn

O

MeMe

NO2

c

97%

NBn

O

MeMe

NBn

O

MeMe

NHCbzNBn

O

OH

NHCbz

NBn

NCbz

O NBn

NCbz

O

MeO

202 203

d

87%

e

83%

f

70%

96%

g

h j,k

71%61%

CO2H

Scheme 49: a) nBuLi, THF, BrCH2CH=C(CH2)2; b) nBuLi, Et2O, 86; c) NaBH4, dioxane/MeOH; d) NaNO2, AcOH/DMSO; e) NEt3, DPPA, toluene, BnOH; f) (i) O3, EtOH, –78 °C, Me2S, (ii) NaBH4, MeOH; g) (i) MsCl, NEt3, CH2Cl2, (ii) NaH, THF; h) (i) Pb(CF3CO2)4, CF3CO2H, (ii) NaH, THF, MeI; j) (i) Pd/C H2, MeOH, (ii) HCHO, NaBH3CN, AcOH; k) Li/NH3.

[100] See [66], page 25.


49

2. Synthesis of (±)-Horsfiline by MgI2-Catalyzed Ring-

Expansion Reaction of Spiro-Cyclopropyl-Oxindole and 1,3,5-

Trimethyl-1,3,5-Triazinane 101

In order to evaluate the applicability of the MgI2-catalyzed ring-expansion reaction for

the synthesis of natural products, (±)-horsfiline ((±)-16) represents an ideal target. In

view of this, (±)-16 should be accessible from spiro-3-cyclopropyl-(5-methoxy-oxindole)

204 and aldimine 205 derived from methylamine and formaldehyde (Scheme 50).102


NH

NMeMeO

O

NR

MeO

O

N

+

MeN NMe

MeN

204

205 206

Me

Scheme 50: Retrosynthetic analysis.

In the context of this analysis, the major issue to be addressed was whether the triazinane

206 could be used in the ring-expansion reaction. For that reason, the reaction of spiro-

cyclopropyl-oxindole 99 with 206 was our first reaction in the synthetic approach to (±)-

horsfiline. Even though higher temperatures were required for successful conversion, the

MgI2-catalyzed ring expansion proceeded smoothly. Best yields of 207 were obtained

with one equivalent of 206 (three equivalents of ‘imine’) (Scheme 51).

NBn

O+

MeN NMe

MeN

99 206

NBn

NMe

O

207

THF, MgI2 (5 mol%),125 °C,20 h, sealed tube

97%

Scheme 51: Successful ring expansion of 99 with triazinane 206.

[101] The synthesis of (±)-horsfiline was carried out by Christian Fischer during his diploma work. Fischer C. Diploma Thesis, ETH Zürich, 2000. [102] Aldimines with sterically small substituents generally form trimers.


The conversion of triazinane 206 to N-methyl methanimine has been reported to take

place at temperatures above 250 °C, under conditions of flash vacuum pyrolysis.103 These

conditions are considerably harsher than the conditions for the formation of 207. Two

mechanistic pathways are plausible for this ring-expansion reaction (Scheme 52).

NBn

O

NBn

NMe

ONBn

OMgI

NMeN

Me

99

MgI2

MeN NMe

MeN N

BnOMgI

N

NMe

NMeMe

205

206

209

208

207

NBn

OMgI

171

I

NBn

OMgI

N

NMe

NMeMe

Scheme 52: Plausible mechanistic pathways for the formation of 207.

Intermediate 171 can either react with N-methyl methanimine (205) to form 209, or

directly with 1,3,5-trimethyl-1,3,5-triazinane (206) giving rise to ammonium 208. The

latter could then undergo fragmentation to 209, from which desired product 207 is

obtained. At present there is no clear evidence for either one of the proposed pathways.

Having solved the key issue, the synthesis of (±)-horsfiline was tackled. The synthetic

route started with the N-benzylation of commercially available 5-methoxyisatin (194) to

yield 210 as a crystalline, red solid. The corresponding oxindole 211 was obtained by

Wolff–Kishner reduction.104 The sodium enolate of 211 cleanly provided spiro-

cyclopropyl-oxindole 212 by cyclization with 1,2-dibromoethane. This set the stage for

the key step of our synthesis of (±)-horsfiline ((±)-16): the cyclopropane-

fragmentation/ring-expansion reaction. Treatment of 213 with 1,3,5-trimethy-1,3,5-

[103] Bibas, H.; Koch, R.; Wentrup, C. J. Org. Chem. 1998, 63, 2619-2626. [104] See [80], page 29.


51

triazinane (206) and 5.5 mol% MgI2 in THF at 125 °C in a sealed tube furnished desired

spiro-pyrrolidine-oxindole 213 in 83% yield. Removal of the N-benzyl protecting group

was achieved by dissolving-metal reduction (Na/NH3) and afforded (±)-horsfiline

((±)-16) in 91% yield (Scheme 53).

NH

MeO O

O NBn

MeO O

O NBn

MeO

O

NBn

MeO

ONBn

MeO

O

NMe

NBn

MeO

O

NMe

(+)-16 213 212

211210194

74% 91%

81%

83%91%

a b

c

de

Scheme 53: a) NaH, BnBr, DMF; b) N2H4·H2O, ∆; c) 1,2-dibromoethane, NaH, DMF; d) MgI2 (5.5 mol%), 1,3,5-trimethy-1,3,5-triazinane (206), THF, 125 °C, sealed tube; e) Na/NH3, –78 °C.

3. Conclusion

The short synthesis of (±)-horsfiline (five steps from commercially available material,

41% overall yield) demonstrates, for the first time, the viability of the MgI2-catalyzed

ring-expansion reaction as a method for the synthesis of spiro-pyrrolidine-oxindole

alkaloids. In the context of this synthesis, the utility of 1,3,5-trimethy-1,3,5-triazinane

(206) to serve as an efficient surrogate in the MgI2-catalyzed ring expansion could be

demonstrated.

52 The Total Synthesis of (–)-Spirotryprostatin B

V. The Total Synthesis of (–)-Spirotryprostatin B

1. Introduction

1.1. Isolation and Biological Activity

In 1996, Osada and co-workers reported the isolation of spirotryprostatin A (43), together

with spirotryprostatin B (17), from the fermentation of Asperguillus fumigatus BM939

(Figure 9).105

Figure 9: The fungus Asperguillus fumigatus.

The fungus was cultured in 400 L of fermentation medium (glucose 3%, soluble starch

2%, soybean meal, 2%, K2HPO4 0.5%, MgSO4·7H2O 0.05%, adjusted at pH 6.5 before

sterilization, containing 0.05% of CA-123 and 0.05% of KM-68 antifoam) at 28 °C for

66 h at a 200 L min-1 aeration rate. Filtration of the broth yielded a filtrate and a

filtercake. The latter was extracted with aqueous acetone; the acetone was removed by

evaporation in vacuo and the remaining aqueous phase was combined with the filtrate.

This combined aqueous phase was repeatedly extracted with ethyl acetate. The solvent

was evaporated in vacuo to yield 1.2 L of an oily extract, which was further purified as

depicted in Figure 10 leading to 1.2 mg of 43 and 11 mg of 17.

[105] a) Cui, C. B.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52, 12651-12666. b) See [5], page 7.

The Total Synthesis of (–)-Spirotryprostatin B

53

oilyresidue1.2 L

n-hexane

CHCl3

n-hexane

CHCl3H2O

activeextract66 g

n-hexane/CHCl310:90

CHCl3/MeOH99:1

repeatedHPLC

repeatedHPLC

1711 mg

431.2 mg

N

NO

OH

Me

Me

N

N

O

OH

Me

Me

H

solutionresidue

solutionresidue

aqlayerorg.layer

solutionresidue

columnchromatography

HNO

HNO

MeO

Figure 10: Isolation procedure for 43 and 17.

Structural elucidation of both compounds was possible by combined analytical methods.

The molecular formulas were obtained from HR-EI-MS measurements. The IR-spectrum

suggested the presence of a diketopiperazine system (amid-carbonyl absorptions at

1680 cm-1, near 1660 cm-1 and amid II band near 1550 cm-1) and a γ-lactam fused to an

aromatic ring (carbonyl at 1715 cm-1) for both 43 and 17. These findings were supported

by 13C NMR. Deduction of partial structures was enabled by detailed analysis of the 1H and 13C NMR spectra, with the aid of a pulse field gradient (PFG), 1H-1H COSY,

PFG-HMQC and NOE difference experiments. The connectivity between these fragments

could be established by PFG-HMBC. Assignment of the relative stereochemistry at C3

and C18 (spirotryprostatin numbering) was possible by NOE. The relative

stereochemistry at C12 could only be determined for spirotryprostatin A (43), but it was

assumed to be identical for spirotryprostatin B (17), as the biogenesis of both compounds

is probably akin. The absolute stereochemistry could not be determined, but it was

assumed that the spirotryprostatins are metabolites derived from L-tryptophane and

L-proline.


Both compounds inhibit the cell cycle in the G2/M phase. This was tested with mouse

tsFT210 cells, a mutant cell line that grows normally at 32 °C, but is arrested in the G2

phase at 39 °C. Arrested cells simultaneously pass through the M phase to enter into the

G1 phase upon transfer to 32 °C. The cycle progression in the presence of 43 and 17 is

inhibited when the temperature-arrested cells are cooled to 32 °C. The IC50 values are

197.5 µM for 43 and 14.0 µM for 17. It is supposed that the significantly stronger

inhibition activity of 17 is related to the absence of the 6-methoxy group on the oxindole

ring as compared to 43. A similar observation was made for the structurally related

compounds tryprostatin A (214) and B (215), among which the demethoxy derivative 215

is also more active (Figure 11). However, an influence of the C8–C9 olefin on the activity

cannot be completely ruled out.

N

N

O

OH

Me

Me

17 43

NH

HNN

O

OH

H

Me

Me

R

214 R = OMe, tryprostatin A215 R = H, tryprostatin B

89

spirotryprostatin B spirotryprostatin A

18

19

3

12

HNO

N

N

O

OH

Me

Me

89

18

19

3

12

HNO

H

MeO

Figure 11: Natural products isolated from Asperguillus fumigatus.

Spirotryprostatin B (17) also inhibits the growth of human chronic myelogenous

leukemia K562 cells and human promyelocytic leukemia HL-60 cells with MIC’s of 35

µg mL-1 and 10 µg mL-1 respectively.5

The spirotryprostatin skeleton is characterized by: (i) a unique spiro-fusion to a

pyrrolidine at the 3-position of the oxindole core, (ii) the annulated diketopiperazine ring

and (iii) the prenyl moiety. Only a few spiro compounds that possess a diketopiperazine

system and are derived from both tryptophane and proline (e.g. 216–219) are known,106

but none of them includes a spiro-system like 43 and 17. A 5-membered ring, spiro-fused

to the 3-position of an indole skeleton is also present for example in the tryptoquivalines

[106] a) Birch, A. J.; Wright, J. J. Tetrahedron 1970, 26, 2329-2344. b) see [30], page 14.


55

(220 and 221),107 but this ring is different to those found in the spirotryprostatins (Figure

12). The spirotryprostatins constitute the first example of a novel class of natural

diketopiperazines with a unique spiro-ring skeleton.

N N

ON

N

R

O

OH

OMe

Me

OHH

220 R = H: (+)-tryptoquivaline G

221 R = : (+)-tryptoquivalineMe

Me OAcH

MeMeNH

ON

NH

O

O

Me Me

NH

O

N

HN

O

HH

O

216 (+)-brevianamide A 217 (+)-brevianamide B

O

ONH

NN

O

Me Me

MeMe

O

R

218 R = Me: (-)-marcfortine A219 R = H: (-)-marcfortine B

Figure 12: Examples of spiro-fused indole alkaloids.

1.2. Synthetic Approaches

The difficulties associated with the isolation of significant quantities of 17 and 43 as well

as the appealing architecture render the spirotryprostatins an interesting synthetic target.

Several groups have successfully completed total syntheses of 43 and 17. Most strategies

differ in the approach to the spiro-pyrrolidine-oxindole ring system.108

1.2.1. Danishefsky’s Route to Spirotryprostatin A

Danishefsky’s synthetic plan for spirotryprostatin A envisioned the construction of the

spiro-pyrrolidine-oxindole system by a Pictet–Spengler reaction followed by oxidative

rearrangement.109

The use of 6-methoxy-L-tryptophane methylester (222) as reaction partner in the Pictet–

Spengler reaction seems straightforward. However, the proper choice of the aldehyde

component for later introduction of the prenyl side chain of crucial importance. Prenyl

aldehyde (230) itself was not used because initial studies had shown incompatibility with

[107] a) Yamazaki, M.; Fujimoto, H.; Okuyama, E. Tetrahedron Lett. 1976, 2861-2864. b) Yamazaki, M.; Fujimoto, H.; Okuyama, E. Chem. Pharm. Bull. 1977, 25, 2554-2560. c) Yamazaki, M.; Fujimoto, H.; Okuyama, E. Chem. Pharm. Bull. 1978, 26, 111-117. d) Yamazaki, M.; Okuyama, E.; Maebayashi, Y. Chem. Pharm. Bull. 1979, 27, 1611-1617. see [30], page 14. [108] For a review see: Lindel, T. Nachrichten aus der Chemie 2000, 48, 1498-1501. [109] See [25] and [28], page 14.


the planned oxidative rearrangement. Investigations employing benzyloxyacetaldehyde

(231) were undertaken on a model compound (the 6-demethoxy series). Although

rearrangement proved successful, difficulties associated with the conversion of the

benzyloxy group into the prenyl side chain where thwarted by the pronounced

recalcitrance of the C18 aldehyde towards olefination. Finally aldehyde 223 was

identified as viable precursor for incorporation of the prenyl moiety.

The cis/trans-ratio of the Pictet–Spengler reaction between 222 and 223 was not very

high; therefore attempts to find a higher-yielding sequence to 224 were undertaken:

Bischler–Napieralski reaction followed by reduction was used instead in the 6-demethoxy

series and led to improved diastereoselectivity; unfortunately, the tetrahydro-β-carboline

was obtained as a racemic mixture. Coupling of Pictet–Spengler adduct 224 with an

L-proline derivative and formation of the diketopiperazine ring were planned. Oxidative

rearrangement would then lead to the desired core of spirotryprostatin A. Surprisingly,

this sequence, when tested in the 6-demethoxy series, led to the wrong configuration at

the spiro-center. This problem could be solved by inversion of steps.

Tetrahydro-β-carboline 224 was protected as its Boc derivative 225. Oxidative spiro-

rearrangement followed by deprotection of the carbamate protecting group under

standard conditions afforded 226.110 Installation of the diketopiperazine was effected by

coupling with Troc-L-proline chloride (227) followed by deprotection of the Troc group

with concomitant ring closure and yielded 228, bearing all carbon atoms of

spirotryprostatin A. Conversion of the sulfide to the prenyl moiety by sulfoxide

elimination afforded a 2.5:1 mixture of the desired target together with isomer 229. After

HPLC separation, 229 could be isomerized to spirotryprostatin A (43) in 41% yield

(Scheme 54).

[110] The yield of this transformation was found to be superior in the 6-demethoxy series, which is probably due to the increased susceptibility of methoxy-oxindoles to aromatic bromination.


57

N

NO

OH

Me

Me

300

H

spirotryprostatin A

N

NO

OH

Me

229

H

N

NO

OH

Me

Me

H

SPh

228

NH

CO2Me

Me

MeSPh

226224 R = H225 R = Boc

NH

NR

CO2Me

Me

MeSPh

MeO

222

NH

NH2

CO2Me

MeO 50% 43%

68%

80%+

41%

a c,d

e,f

g,h

j

O

Me

MeSPh

223TrocN

Cl

OH

227

85 %b

OOBn

231

O

Me

Me

230

18HN

O

MeO

HNO

MeO

HNO

MeO

HNO

MeO

Scheme 54: a) CF3CO2H, 4 Å MS, 223, CH2Cl2, 0 °C RT; b) Boc2O, CH3CN, NEt3, ∆; c) NBS, AcOH, H2O, THF, RT; d) TFA, CH2Cl2, RT; e) NEt3, CH2Cl2, 227, 0 °C RT; f) Zn, THF, MeOH, aq NH4Cl, RT; g) NaIO4, H2O, MeOH, RT; h) toluene, ∆; j) RhCl3·3H2O, EtOH, ∆.

This synthesis is characterized by the rapid, biomimetic assembly of spirotryprostatin A

and solves the difficulties associated with the prenyl side chain. The synthetic studies that

were undertaken to enable this synthesis also led to a number of products (232-234) with

significantly higher biological activity than spirotryprostatin A (43) on MCF7 and MDA

MB-468 human breast cancer cell lines.111

[111] Depew, K. M.; Danishefsky, S. J.; Rosen, N.; SeppLorenzino, L. J. Am. Chem. Soc. 1996, 118, 12463-12464.


N

N

O

OH

OBn

H

N

N

O

OH

OBn

234

H

232

NBoc

OBn

CO2Me

233

HNO

HNO

HNO

N

NO

OH

Me

Me

43

H

HNO

MeO

IC50 (M) MCF7 cells 3 × 10-4 2.5 × 10-8 2 × 10-8 2 × 10-8

IC50 (M) MDA MB-468 cells 1.1 × 10-4 1 × 10-4 4 × 10-5 8 × 10-5

Figure 13: Biologically active intermediates.

1.2.2. Williams’s Synthesis of Spirotryprostatin B

Williams followed a completely different strategy in his synthesis of spirotryprostatin B.

Instead of using the classical, biomimetic halohydrin to oxindole spiro-ring-forming

sequence, he envisioned construction of the spiro-pyrrolidine-oxindole core by an

asymmetric 1,3-dipolar cycloaddition reaction.112

It is known that azomethine ylids generated by reaction of 5,6-diphenyl-morpholin-2-one

(235) with bulky aldehydes show a strong preference for the E-ylids.113 The cycloaddition

of known oxindolylidene acetate 70 to the azomethine ylid generated by reaction of 5,6-

diphenyl-morpholin-2-one 235 with aldehyde 236 gave rise to the key intermediate 72 via

transition state 237. The relative stereochemistry 72 was proven by X-ray

crystallographic analysis. Cleavage of the bibenzyl moiety afforded 238. Peptide

coupling with D-proline benzyl ester (239) was chosen. Deprotection of the benzyl ester

and closure of the cis-diketopiperazine yielded 240. This sequence with the L-proline

derivative was low-yielding, probably reflecting the thermodynamic instability of the

trans-diketopiperazine. Installation of the prenyl moiety was the next critical step. It

turned out that the requisite C18 side chain could be obtained without production of

[112] See [48] and [49], page 21. [113] Williams, R. M.; Zhai, W. X.; Aldous, D. J.; Aldous, S. C. J. Org. Chem. 1992, 57, 6527-6532.


59

double bond isomers by subjecting 240 to dehydrating conditions. Ester cleavage of 241

proved impossible under standard conditions, but could be accomplished with lithium

iodide in refluxing pyridine. Decarboxylation to 12-epi-spirotryprostatin B (243) was

effected using the Barton ester derived from 242. The C12 stereocenter was epimerized

yielding a 2:1 mixture of spirotryprostatin B (17) and 12-epi-spirotryprostatin B (243),

separable by chromatography on silica gel (Scheme 55).

N

NO

OH

Me

Me

17spirotryprostatin B

HN

BnO

OH

239

HNO

O

PhPh

NH

O

EtO2C

70

NO

O

PhPh

Me

MeMeO

+N

O

HN

H

CO2Et

PhPh

O

MeMeMeO

O

72

O

MeMeOMe HN

O

CO2Eta

b

235236

99 %

82 %

HN

HN CO2Et

MeMeMeO

O

238

CO2HN

HN

H

CO2Et

MeMeMeO

O

240

N

O

OH

c-e

70 %

N

HN

H

CO2Et

MeMe

O

241

N

O

OH

f

89 %

N

HN

MeMe

O

243

N

O

OH

g,h j

32 %

N

S

242OH

8

18

129 HN

O

237

Scheme 55: a) 3 Å MS, 70, toluene, ∆; b) H2, PdCl2, THF, EtOH, 60 psi, RT; c) 239, BOP, NEt3, CH3CN, RT; d) H2, Pd/C, EtOH, RT; e) BOP, NEt3, CH3CN, RT; f) TsOH (1.0 equiv), toluene, ∆; g) LiI, Py, ∆; h) DCC, DMAP, 242, BrCCl3, ∆; j) NaOMe, MeOH.

Williams’s synthesis is highlighted by the preparation of intermediate 72 in a single,

high-yielding step. Four stereocenters are set in this 1,3-dipolar cycloaddition reaction,


three of which are incorporated in the synthetic target. The presence of the ester

functionality at C8 serves as a useful handle to incorporate the C8−C9 double bond, a

structural element that presents an additional challenge in spirotryprostatin B as

compared to spirotryprostatin A. A useful synthetic precursor for the prenyl side chain

was identified with aldehyde 236.

1.2.3. Ganesan’s Approach to Spirotryprostatin B

Wang and Ganesan wished to explore a biomimetic approach to spirotryprostatin B,

focusing on the oxidative rearrangement of a tetrahydro-β-carboline, similar to

Danishefsky’s route to spirotryprostatin A.114

The synthetic planning relied on a Pictet–Spengler reaction of L-tryptophane methyl ester

(244) and prenal (231). In spite of the relatively poor yield, this approach is noteworthy

given that, for the first time, prenal itself was used and not a saturated mask. Coupling of

245 with Fmoc-L-proline chloride (246) afforded 247 and set the stage for the crucial

oxidative rearrangement without using protection and deprotection steps.

Chemoselectivity issues related to the presence of the prenyl olefin were controlled by

careful monitoring of the reaction and by avoiding large excesses of NBS. Compound

248 can thus be obtained in a straightforward sequence. One-step deprotection and

cyclization afforded 249. From 249, selective introduction of the C8−C9 double bond

could not be carried out. A mixture of compounds was obtained, among which the

desired target 17 was isolated in poor 2% yield. The C9 hydroxy derivative 250 was

obtained in 7% yield and could be converted to spirotryprostatin B in three steps via 251.

Compound 252 with the C12−C13 double bond in the L-proline part and the

corresponding C12 hydroxy derivative 253 were obtained in larger amounts than the

desired 17 (Scheme 56).

[114] See [29], page 14. Remark: The synthesis, as published, does not comprise an oxidation after selenation of compound 249, neither in the manuscript, nor in the experimental part.


61

N

NO

OH

Me

Me


N

NO

OH

Me

249

H

N

N

OH

Me

Me

MeO2C

248

NH

NH

CO2Me

Me

Me

244

NH

NH2

CO2Me

32%from 244

68%

100%

a b

c

d

FmocN

Cl

OH

246

O

Me

Me

231

245

NH

N

MeO2C

Me247

Me

Me

2%

e

Fmoc

N

NO

OH

Me

250

HO

Me

e

7%

N

NO

OH

Me

251

HO

Me

70%

f

g,h74%

N

N

O

OMe

5% from 249

H

Me

N

N

O

OOH

Me

253

H

Me

252

20% from 249

N

OH

Fmoc

HNO

HNO

HN

O

HNO

BocNO

HNO

HNO

1312

8 9

12

Scheme 56: a) 231, HC(OMe)3; b) 246, Py, CH2Cl2, 0 °C; c) NBS, THF/AcOH/H2O (1:1:1), 0 °C RT; d) 20% piperidine in CH2Cl2, RT; e) (i) LDA (3.8 equiv), –78 °C, (ii) PhSeBr –78 °C; f) Boc2O, DMAP, CH2Cl2, RT; g) MsCl, NEt3, CH2Cl2, RT; h) TFA, Et3SiH, CH2Cl2, RT.

This route is characterized by the very efficient assembly of precursor 249, made possible

by the direct use of prenal (231) and the introduction of the L-proline moiety prior to

oxidative rearrangement avoiding the use of an amine protecting group. Severe problems

were encountered in the ultimate elimination step, almost leaving the synthesis of

spirotryprostatin B uncompleted.


1.2.4. Danishefsky’s Synthesis of Spirotryprostatin B

Danishefsky’s synthesis of spirotryprostatin B is based on a different strategy than his

synthesis of spirotryprostatin A. It follows an approach to assemble the spirotryprostatin

core by intramolecular Mannich reaction.115

L-Tryptophane methyl ester hydrochloride (254) was oxidized to oxindole 255 and

reaction of 255 with aldehyde 231 afforded a mixture of four isomeric spiro-pyrrolidine-

oxindoles 256. These compounds were not separable and the mixture was processed

further by peptide coupling with N-Boc-L-proline (257) and yielded the mixture of

coupling products 258.

N

N

O

OH

Me

Me

17

N

N

OH

Me

Me

MeO2C

260

254

NH

NH3

CO2Me

73%from 254

68%

a b

cBocN

H257

O

Me

Me

231

Boc

Cl

255

NH

NH3

CO2Me

ClO95% N

HO

NH

CO2Me

Me

Me

256

HO2C

NH

O

N

MeO2C

Me

Me

258

BocN

OH

NH

O

N

MeO2C

Me

Me

259

BocN

OHPhSe

spirotryprostatin B

de

38%from 258

f,g

86%

HNO 8 9

HNO

3

Scheme 57: a) DMSO, 12 N aq HCl, AcOH, RT; b) 231, NEt3, 3 Å MS, Py, 0 °C RT; c) 257, BOP-Cl, NEt3, CH2Cl2, , 0 °C RT; d) (i) LHMDS (2.2 equiv), THF, 0 °C, (ii) PhSeCl (2.2 equiv), THF, 0 °C; e) DMDO (4.0 equiv), THF, 0 °C; f) TFA, CH2Cl2, RT; g) NEt3, CH2Cl2, RT.

Deprotonation and reaction of lithiated 258 with phenylselenyl chloride gave rise to

another mixture of products 259. Oxidative elimination of 259 proceeded readily and 260

[115] See [41], page 19.


63

could be chromatographically separated from the resulting mixture in 38% yield from

258. Deprotection and closure of the diketopiperazine afforded spirotryprostatin B (17) in

86% yield (Scheme 57).

This sequence is very short and allows for large scale production of spirotryprostatin B

(500 mg of the natural product per batch). However, the main product of the oxidative

elimination of selenide 259 is the 3-epi-diastereomer of 260, obtained from the mixture of

diastereomers. Notable is the efficient insertion of the C8−C9 double bond when the

proline nitrogen is still protected as its carbamate.

1.2.5. Overman’s Approach to Spirotryprostatin B

Overman’s strategy relies on an asymmetric Heck reaction followed by trapping of an

η3-allylpalladium species by a tethered nitrogen nucleophile.116

Key intermediate 262 was accessed from known allylic alcohol 261 in eight steps.

Several conditions for the one-pot Heck reaction/η3-allylpalladium trapping were tested

and finally best results were obtained with 10% [Pd2(dba)3]·CHCl3, 40% tri-

o-tolylphosphane and excess potassium acetate in THF at 70 °C, giving a 1:1 mixture of

264 and 265 in 72% yield. Cleavage of the SEM protecting group from 264 cleanly

provided spirotryprostatin B. Isomer 266 was obtained from 265. As it was not clear from

the beginning if the η3-allylpalladium species would be attacked anti or syn to the metal,

267 incorporating the C3−C18 Z-olefin, was first prepared. From that intermediate, the

C18 isomeric products were produced, proving the trapping of the η3-allylpalladium takes

place anti to the metal (see also Scheme 20, page 23). In this first route, the

stereochemical outcome of the key step could be tuned by using Pd/BINAP and excess

PMP in DMA at 100 °C by employing either (R)- or (S)-BINAP to a 6:1 ratio in either

way. This was not possible in the reaction with 263 as temperatures over 80 °C led to

rapid isomerization of 263 to 267 in the presence of excess PMP in DMA, leading to

formation of the undesired isomers (Scheme 58).

[116] See [58], page 23.



MeO2COH Me

MeMeO2C

Me

Me

AcO

a,b

94%

c-e

78%

Me

Me

OTBDPS

NHI

O

261 347 348

NSEM

O

Me

Me

NNH

O

OH

I263

NNH

O

OH

PO(OMe)2

262

f-h61%

N

NO

OH

Me

Me

N

N

O

OH

Me

Me

N

NO

OH

Me

Me

265

264

266+

93%

93%

j

k

k

36%

36%

N

N

O

OH

Me

Me

NSEM

O

Me

NNH

O

OH

I267

Me

SEMNO

HNO

SEMNO

HNO

18

18

3

3

Scheme 58: a) Ac2O, Py, RT; b) (i) MgBr2·Et2O, THF, ∆; (ii) Hünig’s base, AcOH, RT; c) LiOH, MeOH, RT; d) TBDPSCl, DMAP, Py, RT; e) 2-iodoaniline, 1-methyl-2-chloro-pyridinium iodide, NEt3, CH2Cl2, RT; f) NaH, THF, SEMCl, 0 °C RT; g) TBAF, THF, RT; h) (i) Dess–Martin periodinane, CH2Cl2, RT, (ii) 262, tBuOK, CH2Cl2, –78 °C RT; j) [Pd2(dba)3]·CHCl3, (oTol)3P, KOAc, THF, 70 °C; k) Me2AlCl, Hünig’s base, CH2Cl2, –78 °C.

In this synthesis it could be proven that intramolecular Heck insertions into conjugated

trienes can proceed with high stereoselectivity and that the obtained η3-allylpalladium

species is trapped in an anti fashion with production of the spiro-pyrrolidine-oxindole

ring system.


65

1.2.6. Fuji’s Route to Spirotryprostatin B

Fuji’s route is dominated by the use of a chiral precursor obtained from asymmetric

nitroolefination. The construction of the spiro-pyrrolidine-oxindole core by

intramolecular ring closure of the nitrogen nucleophile on an allylic alcohol leading to the

prenylated pyrrolidine is an innovative approach.117

Fuji’s synthesis commenced with the chiral precursor 268, obtained by asymmetric

nitroolefination. Several steps had to be devoted to functional-group and oxidation-state

adjustments in order to obtain precursor 269. Coupling of 269 with N-Boc-L-proline

chloride (270) yielded 271 from which spiro-pyrrolidine-oxindoles 273 and 274 were

accessed as a 1:1-mixture of diastereomers in a two-step sequence via 272. From 274 the

synthesis of spirotryprostatin B was completed following Danishefsky’s procedure.

Following these steps, the target 17 was obtained in modest yield together with 251 and

252 obtained before by Ganesan (Scheme 59).

With the use of precursor 268, the stereocenter at the C3 position is set at an early stage

in the synthesis. The overall sequence devotes a number of steps for functional-group

interconversions and protection/deprotection chemistry. Cyclization to the spiro-

pyrrolidine-oxindole via intramolecular nucleophilic attack on a dimethylallylic

carbocation presents a novel approach to the core and puts the prenyl side chain into the

right position, albeit as a mixture of diastereomers. The weakness of this synthesis is the

lack of stereocontrol at the C9 center. Although not present in the final product, this

center controls the stereochemical outcome of the cyclization to the spiro-pyrrolidine-

oxindole leading to a 1:1 mixture.

[117] See [67], page 25.


268

NH

O

MeMe

NO2

NH

O

MeMe

CHO

55%

(1:1)

NH

O

MeMe

N

CNBn

Cbz

269

NH

O

MeMe

N

CO2MeBn

Cbz


N

NO

OH

Me

Me

271

HN

BocN

OH

Me

Me

MeO2C

272

HN

BocN

OH

Me

Me

MeO2C

OH

N

N

O

OH

Me

Me

N

N

O

OH

Me

Me

274

N

BocN

OH

Me

Me

MeO2C

273

N

BocN

OH

Me

Me

MeO2C

H H

a

44%

b,c

69%

e

d

87%

85%

f

21%

j

g

23% 24%

h89%

h91%

BocN

Cl

OH

270

HNO

HNO

HNO

HNO

HNO

HNO

HNO

99

3

Scheme 59: a) 20% aq TiCl3 (5.0 equiv), NH4OAc, MeOH/H2O, RT; b) (i) BnNH2, CH2Cl2, RT, then TMSCN; c) CbzCl, NEt3, CH2Cl2, RT; d) (i) K2CO3, MeOH, RT, then 1 M aq HCl; e) (i) Pd/C (80 wt%), HCO2H, MeOH, RT; (ii) 270, WSC, CH2Cl2, RT; f) (i) mCPBA, CH2Cl2, 0 °C, (ii) PhSeSePh (0.6 equiv), NaBH4, MeOH, ∆, (iii) 30% aq H2O2 (20.0 equiv), THF, 0 °C; g) pTsOH (10 mol%), CH3CN, ∆; h) (i) 4 M HCl in dioxane, 0 °C, (ii) NEt3, CH2Cl2, RT; j) (i) LHMDS (2.2 equiv), THF, 0 °C, (ii) PhSeCl (2.2 equiv), THF, 0 °C, (iii) DMDO (4.0 equiv), THF, 0 °C, (iv) 4 M HCl in dioxane, 0 °C, (v) NEt3, CH2Cl2, RT.


67

2. Synthesis of (–)-Spirotryprostatin B Employing the MgI2-

Catalyzed Ring-Expansion Reaction

Spirotryprostatin B, a natural product of manageable size and appealing structure,

presents a demanding synthetic target. With its structural features and given natural

scarcity, spirotryprostatin B is one of those molecules, for which organic synthesis is able

to provide significant quantities of synthetic material for further biological testing.

Additionally, synthesis also opens the gate for the facile access to analogues with

potentially higher biological activity and for elucidation of structure–activity

relationships. These facts, and the development of the MgI2-catalyzed ring-expansion

reaction for the straightforward access of spiro-pyrrolidine-oxindole ring systems, led us

to tackle the total synthesis of spirotryprostatin B.

2.1. Retrosynthetic Analysis

Our approach to spirotryprostatin B was driven by our interest in the feasibility of using

the MgI2-catalyzed ring-expansion reaction for the construction of spiro-pyrrolidine-

oxindoles with a higher degree of substitution on the pyrrolidine ring. If a C9-substituted

spiro-pyrrolidine-oxindole like 276 could be generated with our method, access to the

spirotryprostatin B core could be envisioned. In this respect, it is important to note that in

previous reactions of unsubstituted spiro-cyclopropyl-oxindole 99 with aldimines

(Table 3, page 32 and Table 4, page 34), the major diastereomer always possessed the

relative stereochemistry that is observed in spirotryprostatin B (17) at C3 and C18

(Scheme 60).



N

N

O

OH

Me

Me

PGN

HHO2C

NPG

R NH

O

R'

278

275

277

3

8 9

18

19

17

11

16

16

11

18

10

103

8

9

NH

O

276

3

NPG

R

R'

8 9

18

10

+

HNO

R''R''

Scheme 60: Retrosynthetic analysis of spirotryprostatin B.

The key intermediate 276 was planned to arise from ring expansion of spiro-cyclopropyl-

oxindole 278 and imine 277. The substituents R, R’ and R’’ as well as the protecting

group PG on the imine nitrogen have to fulfill a multitude of requirements:

• All together, they must be chosen in a way as to allow for successful ring

expansion, so that intermediate 276 can be accessed. In this respect, first studies

would have to focus on the regiochemistry of the cyclopropane-

fragmentation/ring-expansion reaction with a substituted cyclopropyl moiety.

• Additionally, the substituent R on imine 277 should be either the prenyl moiety

itself or a functionality that can be converted easily into the prenyl side chain.

Considering that the prenyl moiety of spirotryprostatin B is the only side chain on

the pentacyclic core, a synthesis that would allow for facile access to

spirotryprostatin B analogues at a late stage would be desirable.

• The substituent R’ of 278 has to be a functionality at the carboxylic acid oxidation

state or a synthetic equivalent and R’’ must allow for the implementation of the

C8−C9 olefin.

The remaining portion of the molecule would arise from a suitably protected

L-proline derivative 275.


69

2.2. Initial Studies

2.2.1. Regioselectivity

A study on substituent effects of the nucleophilic ring opening of activated cyclopropanes

by Danishefsky showed that nucleophilic attack preferentially takes place at the most

substituted carbon.118 This finding may be explained with the substantial dipolar

character in the transition state of the ring opening (Figure 14).119

Me

Me

CO2Et

CO2Et

Me CO2Et

CO2EtMeNu

Me CO2Et

CO2EtMe

Me CO2Et

CO2EtMeNu

Figure 14: Charge separation in the transition state of cyclopropane ring opening upon nucleophilic attack.

In order to test the regiochemical outcome of the ring-expansion reaction, we chose

methyl-substituted spiro-cyclopropyl-oxindole 282 as our first starting material. Reaction

of 98 with known cyclic sulfate 281,120 prepared in a two-step sequence from

1,2-propanediol (279) via sulfite 280,121 afforded 282. Cyclic sulfates are useful reagents

for the preparation of substituted spiro-cyclopropyl-oxindoles. Upon nucleophilic attack,

cyclic sulfate 281 acts as a synthetic equivalent of an epoxide and is opened to the

corresponding β-sulfate. Unlike in the epoxides case, this β-sulfate remains a powerful

leaving group and can react further with the sodium enolate of 98 and undergo

cyclization to cyclopropane 282 in the presence of excess of base.122

[118] Danishefsky, S.; Rovnyak, G. J. Org. Chem. 1975, 40, 114-115. [119] Chmurny, A. B.; Cram, D. J. J. Am. Chem. Soc. 1973, 95, 4237-4244. [120] a) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538-7539. b) Burgess, K.; Ho, K. K.; Ke, C. Y. J. Org. Chem. 1993, 58, 3767-3768. [121] a) Berridge, M. S.; Franceschini, M. P.; Rosenfeld, E.; Tewson, T. J. J. Org. Chem. 1990, 55, 1211-1217. b) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 655-658. [122] For a review on cyclic sulfites and cyclic sulfates see: Lohray, B. B. Synthesis 1992, 1035-1052.


NBn

O

Me

282

MeHO

OH OSO

Me

O

OSO

Me

OO

NBn

O

98

279 280

a b c

92%from 279

54%

281

H

NOE

Scheme 61: a) SOCl2, CH2Cl2, 0 °C ∆; b) NaIO4 (2.0 equiv), RuCl3·3H2O (0.5 equiv), CH3CN/CCl4/H2O, RT; c) 98, NaH, DME, RT ∆.

Methyl-substituted spiro-cyclopropyl-oxindole 282 is the major isomer of this reaction

(16:1). The relative configuration was assigned by NOE enhancements.

Spiro-cyclopropyl-oxindole 282 and imine 124 were subjected to ring-expansion

conditions. Best results (80% combined yield of ring-expansion products) were obtained

when the reaction was performed neat, at 120 °C, with 10 mol% of MgI2; however

separation of the isomers 283 proved difficult and therefore information on the

regiochemistry of the cyclopropane-fragmentation/ring-expansion reaction was still not

available (Scheme 62).

NBn

O

Me

282

NTs

Ph

124

+NBn

O

283

NTs

Ph

MgI2 (10 mol%)

neat, 120 °C, 5 h80%

Me

Scheme 62: Ring expansion of substituted spiro-cyclopropyl-oxindole 282 with imine 124.

To solve this problem, the ring expansion with p-tosyl-isocyanate 284 was carried out.

The analysis and separation of the reaction products was expected to be more facile

because the product of the ring expansion with isocyanate 284 is lacking a stereocenter

compared to 283. The overall yield of the reaction is not very high, about 50% of the

starting material 282 was generally recovered. The products 285 and 286 correspond to

the two possible diastereomers of a regioselective reaction, which were obtained in a 2:3


71

ratio. The sense of regioinduction could be unambiguously determined by X-ray

crystallographic analysis of both diastereomers. (Scheme 63, Figure 15).123

NBn

O

Me

282

NTsC

284

+NBn

O

285

NTsMgI2 (25 mol%)THF, 100 °C, 75 h

sealed tube49%O N

BnO

286

NTs

O O

Me Me

+

(2:3)

NBn

O

NTs

O

Me

not observed

Scheme 63: Ring expansion of substituted spiro-cyclopropyl-oxindole 282 with isocyanate 284.

Figure 15: ORTEP drawings of 285 (left) and 286 (right).

This result shows unambiguously that spiro-cyclopropyl-oxindoles are opened

regioselectively under our ring-expansion conditions. This finding is in full accordance

with Danishefsky’s earlier observations.

2.2.2. Substituent at the Spiro-Cyclopropyl-Oxindole Suitable for Ring Expansion

With this result in hand, we had to decide for a substituted spiro-cyclopropyl-oxindole

that would allow for efficient functionality development towards the spirotryprostatin B

core. In this respect, cyclopropyl derivative 290 displays attractive structural features,

[123] CCDC 199469 and CCDC 199470 contain the supplementary crystallographic data for 285 and 286 respectively. This data can be obtained free of charge via www.ccdc.cam.ac.uk/retrieving.html (or from the Cambridge Crystallographic Data Center, 12, Union Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or [email protected]).


bearing the requited carboxylate for the diketopiperazine ring and the methoxy-group

allowing for the incorporation of the C8−C9 olefin. Synthesis of 290 was accomplished

by rhodium-catalyzed cyclopropanation of acrylate 288 with diazo-oxindole 289.124 The

required acrylate 288 was prepared from 2,3-dibromo-propionic acid ethyl ester (287), 125

and diazo-oxindole 289 was available in a two-step sequence ― formation of the tosyl

hydrazone followed by base induced elimination ― from N-benzyl isatin (97) (Scheme

64).126

NBn

O

290

CO2MeMeO

NBn

O

287

N2MeO

OMe

O

+

BrOEt

O

BrNBn

O

97

O

289288

a

36%

b,c

61%

d

89%

Scheme 64: a) NaOMe (3.0 equiv), MeOH, RT; b) N2H3Ts, MeOH, 60 °C; c) NaOH, THF/H2O, RT; d) [Rh(OAc)2]2 (2 mol%), slow addition of 289, benzene, ∆.

Cyclopropane 290 was obtained as a separable mixture of two diastereomers in a ratio of

7:2. For convenience, only the major isomer was used for subsequent reactions. In order

to test the feasibility of the ring-expansion reaction with 290, imine 124 was chosen as

coupling partner. However, no trace of the desired product could be obtained under

various reaction conditions including increased temperatures and catalyst loadings as well

[124] a) Anciaux, A. J.; Hubert, A. J.; Noels, A. F.; Petiniot, N.; Teyssie, P. J. Org. Chem. 1980, 45, 695-702. b) Doyle, M. P.; Vanleusen, D.; Tamblyn, W. H. Synthesis 1981, 787-789. c) Padwa, A.; Austin, D. J.; Price, A. T.; Weingarten, D. M. Tetrahedron 1996, 52, 3247-3260. For recent reviews see: d) Doyle, M. P. Chemical Reviews 1986, 86, 919-939. e) Ye, T.; McKervey, M. A. Chemical Reviews 1994, 94, 1091-1160. f) Doyle, M. P.; Forbes, D. C. Chemical Reviews 1998, 98, 911-935. [125] Ogata, N.; Nozakura, S.; Murahash.S Bull. Chem. Soc. Jpn. 1970, 43, 2987-2988. [126] a) Cava, M. P.; Litle, R. L.; Napier, D. R. J. Am. Chem. Soc. 1958, 80, 2257-2263. b) Creger, P. L. J. Org. Chem. 1965, 30, 3610-3613.


73

as the use of Mg(OTf)2 as Lewis acid with non nucleophilic counterions, in order to

obtain intermediate 291 instead of 292 (Scheme 65).

NBn

O

290

CO2MeMeO

NTs

+

NBn

OMg(OTf)

MeO CO2Me

NBn

OMgI

MeO CO2MeI

291 292

124

NBn

O

NTs

Ph

CO2MeMeO

possible intermediatewith Mg(OTf)2

possible intermediatewith MgI2

OTf

Scheme 65: Unsuccesful ring expansion with spiro-cyclopropyl-oxindole 290.

This unsuccessful outcome can be rationalized in two ways: (i) the steric hindrance at the

quaternary carbon disfavors SN2 displacement and (ii) incompatibility of the dipolar

character in the transition state of the ring opening with the chosen substituents (Figure

14, page 69). In order to identify a more suitable cyclopropane, several differently

substituted cyclopropanes were prepared taking our hypothesis into consideration.

To reduce steric hinderance, we synthesized 294 by cyclopropanation of diethyl fumarate

(293) with 289,127 and 296 by palladium-catalyzed cyclopropanation of acrylonitrile

(295) with 289.128,129 These cyclopropanes failed to undergo reaction to give the ring

expanded products under a variety of conditions (Scheme 66), probably due to the

conflict of partial charges in the molecules with the dipolar character in the transition

state during ring opening (Figure 14, page 69).

[127] Waitkus, P. A.; Sanders, E. B.; Peterson, L. I.; Griffin, G. W. J. Am. Chem. Soc. 1967, 89, 6318-6327. [128] Chang, S. J.; Shankar, B. K. R.; Shechter, H. J. Org. Chem. 1982, 47, 4226-4234. [129] A simplification of the starting materials in this way (R’’ = H) requires the implementation of the C8=C9 olefin without the installation of a masked leaving group, a problem already solved in Danishefsky’s synthesis of spirotryprostatin B.


NTs

Ph

124

NBn

O

294

NBn

O

N2CO2Et+

289293

a

83%EtO2C

CO2Et

EtO2C

NBn

O

296

NBn

O

N2CN+

289295

b

88%

NC

NTs

Ph

124

NBn

O

NTs

Ph

NBn

O

NTs

Ph

CO2EtEtO2C

CN

Scheme 66: a) toluene, ∆; b) Pd(OAc)2 (1 mol%.), neat, ∆.

Spiro-cyclopropyl-oxindole 301 was the next candidate chosen with respect to our

assumptions. From a steric- and electronic point of view, 301 was believed akin to

methyl-substituted spiro-cyclopropyl-oxindole 282. The preparation of protected alcohol

300 was achieved from allyl alcohol (297) in 6 steps via cyclic sulfate 299,130 using

conditions similar to those described previously.131,132 Deprotection of the silyl group

completed the synthesis of 301 (Scheme 67).133

NBn

O

300

HOOH OS

O

OO

NBn

O

98

298

c,d e

57% 42%

299

OTBS

NBn

O

301

OH

OTBS OTBS297

OHf

96%

a,b

60%

Scheme 67: a) TBSCl, imidazole, DMF, 0 °C; b) NMO·H2O, K2OsO4 (0.3 mol%); H2O/acetone/tBuOH, RT; c) NEt3, SOCl2, CH2Cl2, 0 °C; d) NaIO4 (2.0 equiv), RuCl3·3H2O (0.5 equiv), CH3CN/CCl4/H2O, RT; e) 98, NaH, DME, RT ∆; f) nBu4NF, THF.

[130] See [121b], page 69. [131] Ogilvie, K. K.; Hakimelahi, G. H. Carbohydr. Res. 1983, 115, 234-239. [132] Bernardi, A.; Cardani, S.; Scolastico, C.; Villa, R. Tetrahedron 1988, 44, 491-502. [133] Corey, E. J.; Venkates.A J. Am. Chem. Soc. 1972, 94, 6190-6191.


75

Unfortunately, the ring-expansion reaction with 301 did not occur, and the use of the

protected species 300 did not lead to any improvement (Scheme 68).

NTs

Ph

124

NBn

O

301

NBn

O

300

NTs

Ph

124

OH

OTBS

NBn

O

NTs

Ph

OH

NBn

O

NTs

Ph

OTBS

Scheme 68: Unsuccesful ring expansion with spiro-cyclopropyl-oxindoles 301 and 300.

The ring expansion seems intolerant of a wide range of sterically and electronically

different cyclopropanes. Reevaluation of the failure to undergo ring-expansion with

highly substituted 290 and the observation that the ring expansion with methyl-

substituted spiro-cyclopropyl-oxindole 282 requires drastic reaction conditions, led to the

following speculation: A substitution that enables or even facilitates charge separation in

the transition state of cyclopropane ring opening is of utmost importance (Figure 14, page

69). In this respect, a vinyl cyclopropane should be ideally suited for ring expansion,

given the stabilization of the incipient positive charge by allylic delocalization

(Table 6).134,135

60 °C, acetone KI SN2, krel

EtOH/H2O 4:1SN1, krel

relative stability

CH3CH2Cl 1 1 CH3CH2+ 0 kcal mol−1

CH2=CHCH2Cl 33 74 CH2=CHCH2+ –24 kcal mol−1

Table 6: Significance of resonance stabilization in allylic systems.

[134] See [118], page 69. [135] Morrison, R. T.; Boyd, R. N. Lehrbuch der Organischen Chemie; Verlag Chemie: Weinheim, 1980.


Furthermore, subsequent functionalization of the double bond should allow for a

subsequent conversion to the C9 carboxylate (Figure 16).

R

EWG

R'

R' EWG

R

R' EWG

R

Figure 16: Charge separation and allylic stabilization in the transition state of cyclopropane ring opening.

In order to test our hypothesis, spiro-cyclopropyl-oxindole 303 was prepared from 289

and commercially available piperylene (302) (Scheme 69).136 In accordance with

published work, the cyclopropanation proved chemoselective and occurred at the least

substituted double bond. In a study on the regioselectivity of catalytic cyclopropanation

of monosubstituted dienes, Doyle showed that cyclopropanation of 1-substituted dienes

like piperylene takes place at the more accessible, terminal double bond with good to

excellent regioselectivity in the presence of different transition-metal catalysts including

[Rh(OAc)2]2.137

NBn

O

303

NBn

O

N2

+

289302

a

90%Me

Me

NTs

Ph

124

b

47% NBn

O

304

NTs

Me

Ph

Scheme 69: Synthesis of spiro-cyclopropyl-oxindole 303 and successful ring expansion. a) [Rh(OAc)2]2 (2 mol%), slow addition of 289, benzene, ∆; b) MgI2 (20 mol%), THF, 80 °C, sealed tube.

[136] See [124], page 72. [137] Doyle, M. P.; Dorow, R. L.; Tamblyn, W. H.; Buhro, W. E. Tetrahedron Lett. 1982, 23, 2261-2264. (These findings were confirmed by Davies: Davies, H. M. L.; Clark, T. J.; Smith, H. D. J. Org. Chem. 1991, 56, 3817-3824.) In the case of 2-substituted dienes, electronic factors associated with changes in the electrophilicities of the reactant metal carbenes proved relevant.


77

Reaction of spiro-pyrrolidine-oxindole 303 with imine 124 provided 2,5-disubstituted-3-

spiro-pyrrolidine 304 in 47% yield, and thus allowed for the first time for ring expansion

with a suitably substituted spiro-cyclopropyl-oxindole (Scheme 69).

2.2.3. Identification of a Suitable Imine for the Ring Expansion

Having found a suitable substituent for ring expansion of spiro-cyclopropyl-oxindoles,

we could address the next critical task. An imine had to be found which would allow for

facile deprotection of the pyrrolidine nitrogen after ring-expansion. Additionally, the

imine had to bear a functionality to enable access to the prenyl side chain.

For a straightforward approach to spirotryprostatin B, the direct introduction of the prenyl

moiety by ring expansion of 303 with prenal-derived allyl imine (305) would be

desirable;138 alternatively, the cyclopropane-fragmentation/ring-expansion reaction with

imine 306139 would ultimately lead to a progenitor for the prenyl moiety, related to one of

William’s intermediates.140 However, the use of either imine in the crucial key step did

not provide any trace of the desired spiro-pyrrolidines (Scheme 70).

NBn

O

303

Me

NBn

O

N

Me

NBn

O

303

Me

N

MeMe305

N

MeMe

306

OMe

+

+NBn

O

N

Me

Me

MeOMe

Me

Me

Scheme 70: Failure of the ring expansion reaction with imines 305 and 306.

[138] VanMaanen, H. L.; Kleijn, H.; Jastrzebski, J. T. B. H.; VanKoten, G. Bull. Soc. Chim. Fr. 1995, 132, 86-94. [139] Imine 306 was obtained by condensation of allylamine with known aldehyde 236: Alcaide, B.; Rodríguez-Campos, I. M.; Rodríguez-López, J.; Rodríguez-Vicente, A. J. Org. Chem. 1999, 64, 5377-5387. [140] See [48], page 21.


Both imines were found to polymerize under ring expansion conditions (MgI2 (10–20

mol%), THF, 80 °C, sealed tube), probably due to self condensation. The use of a non-

enolizable imine should prevent this undesired side reaction. Imine 309 was chosen, as

the protected alkyne was expected to serve as a viable precursor for the prenyl side chain.

The imine was accessed from triisopropyl-silyl acetylene (307) in 2 steps according to

Scheme 71.141 TIPS-acetylene (307) was converted to aldehyde 308 using ethyl formate

as formylating agent. Condensation with allylamine afforded imine 309 in 80% yield over

two steps.

N

309307 TIPS

O

TIPSTIPS

308

a b

80%over 2 steps

Scheme 71: a) (i) nBuLi, THF, –78 °C, (ii) ethyl formate (2.0 equiv), THF, −78 °C; b) allyl amine, MgSO4, CH2Cl2, RT.

Imine 309 was used in the ring-expansion reaction with 303 (MgI2 (20 mol%), THF,

80 °C, sealed tube) and the desired product 310 was obtained in 56% yield as a mixture

of diastereomers (Scheme 72).

NBn

O

303

Me

NBn

O

N

Me

+N

309TIPS

310 TIPS

MgI2 (20 mol%)THF, 80 °C, 14 h

sealed tube56%

Scheme 72: Successful ring expansion of 303 with imine 309.

2.2.4. Optimization of the Key Step

With spiro-pyrrolidine-oxindole 310 we had obtained a lead compound that could

potentially be a intermediate in the synthesis of spirotryprostatin B. Another important

point left unaddressed previously, was the question whether the benzyl protecting group

[141] a) Journet, M.; Cai, D. W.; DiMichele, L. M.; Larsen, R. D. Tetrahedron Lett. 1998, 39, 6427-6428. b) see [139], page 77.


79

was necessary for ring-expansion. Spiro-cyclopropyl-oxindole 313 was prepared from 96

in three steps, similar to the synthetic sequence described for the preparation of 303

(Scheme 73).

NH

O

96

Me

NH

O

O

311

NH

N

O

NHTs

312

NH

N2

O

313

a

90%

b

88%

c

71%

Scheme 73: a) N2H3Ts, MeOH, ∆; b) NaOH, H2O, RT; c) [Rh(OAc)2]2 (1 mol%), piperylene (4.0 equiv), slow addition of 312 in CH2Cl2, benzene, ∆.

The reaction of 313 with imine 309 gave spiro-pyrrolidine-oxindole 314, demonstrating

that protection of the indole nitrogen was not required in the ring-expansion step.

In studies employing variable amounts of MgI2, it turned out that the amount of spiro-

pyrrolidine-oxindole obtained from the reaction did never surpass the amount of MgI2

used, showing that the reaction was not catalytic in MgI2 anymore. This might be due to

complexation of MgI2 by the free indole nitrogen. After careful adjustment of the reaction

temperature, under optimal conditions at 75 °C with use of an excess of imine and one

equivalent of MgI2 314 could be obtained in 67% yield (Scheme 74).

NH

O

N

Me

+N

309TIPS

314 TIPS

MgI2 (1.0 equiv)THF, 75 °C, 15 h

sealed tube67%N

HO

Me

313

Scheme 74: Ring expansion of 405 with imine 401 under optimized conditions.


The regioselectivity of the ring-expansion reaction deserves consideration (Scheme 75).

Both 1,5- and 1,7- addition to the allyl cyclopropane could be considered to be taking

place, leading to intermediates 316 and 317 respectively. Although, in general, only

1,5-addition is observed, probably related to the general prevalence of SN2 relative to

SN2’ displacement, there are exceptions to this rule, for example 1,7-addition is observed

predominantly if the nucleophile is an enamine.142 In case compound 317 was obtained

by 1,7-addition, it could be converted to the desired product 319 by allylic displacement

to 318. It is also to be considered that the steps for the ring-expansion reaction would be

reversible under thermodynamic control. As supported by semi empirical calculations,

the five-membered ring product 319 is expected to be formed in this case (Figure 17).143

In a kinetically controlled reaction, again formation of the five-membered ring product

319 should be favored. Indeed, no trace of the seven-membered ring product (320) could

be detected experimentally.

NR''

OMgI

N

R'+

316

MgI2

MgI2

Nu

NR''

O

315

Me

R

Me

NR''

OMgI

317

Nu

Me

1,7-addition

1,5-addition

Nuallylic displacement

Nu = I , RN=CHR'

NR''

OMgI

318

NMe

RR'

NR''

O

319

N R

R'

Me

NR''

O

320

N R

Me

R'

Scheme 75: Regioselectivity of the ring-expansion reaction with allylic spiro-cyclopropyl-oxindoles 315.

[142] a) Danishefsky, S.; Rovnyak, G. J. Chem. Soc., Chem. Commun. 1972, 820-821. b) Danishefsky, S.; Rovnyak, G. J. Chem. Soc., Chem. Commun. 1972, 821-822. [143] Calculations were performed using PC SPARTAN Pro. (PM3 semi-empirical molecular orbital calculations of the equilibrium geometry).


81

Figure 17: Calculated difference in ∆Hf° between five and seven membered spiro-ring: ∆∆E = 4.7 kacl/mol in favor of five membered spiro-ring (PM3).

The value of the ring expansion as a method for the construction of the spirotryprostatin

ring system depends on its diastereoselectivity (at C3 and C18 in the product). The

diastereomers 314 turned out to be only partially separable by column chromatography,

only 321 and 322 were obtained in pure form. Pyrrolidine 321 is the major product of the

key step. All other isomers can be equilibrated with 321 when treated with acetic acid

under reflux for 16 h, resulting in a 5:1 to 7:1 ratios in favor of 321 (Scheme 76).

The co-eluting fraction was submitted to Pd-catalyzed cleavage of the allyl protecting

group with N-DNBA as allyl scavenger.144,145 The products of this high-yielding

deprotection step turned out to be separable by column chromatography (Scheme 76).

Assignment of the relative stereochemistry at C3, C18 and C9 for compounds 321-325

was possible by NOE enhancements between the protons at C18, C9 and C4.

The olefin geometry of 321, 323 and 324 was assigned by analysis of the 1H NMR

chemical shift for the allylic proton at C9, which is found at higher field for cis-olefins as

compared to trans-olefins.146 Pyrrolidines 323 and 324 can be directly compared, as

according to NOE enhancements, the relative stereochemical arrangement of the

substituents on the pyrrolidine ring is identical. For compound 321, no direct comparison

[144] Pd(PPh3)4 was prepared in situ from [Pd2dba3]·CHCl3 (6 mol% Pd) and PPh3 (18 mol%) in CH2Cl2. Ukai, T.; Kawazura, H.; Ishii, Y.; Bonnet, J. J.; Ibers, J. A. J. Organomet. Chem. 1974, 65, 253-266. [145] Garro-Helion, F.; Merzouk, A.; Guibé, F. J. Org. Chem. 1993, 58, 6109-6113. [146] Martin, G. J.; Martin, M. L.; Lefevre, F.; Naulet, N. Org. Mag. Res. 1972, 4, 121-129.


was possible, but the assignment was made as the C9 proton signal was found at very

high field (Table 7).

NH

O

N

Me

314 TIPS

NHN

O

TIPS

Me

HNO

N

TIPS

Me

mixedfraction

32132% 32%

+ +

3224%

NHHN

O

TIPS

Me

32360%

NHHN

O

TIPS32413%

Me

HNO

NH

TIPS

Me

32518%

318

18

18 18

3

3 3

columnchromato-

graphy

a

91%

9 9

9 9

4

4

4 4

4

4 9

9

3

18

18

3

NHHN

O

TIPS

Me

32686%

18

3

9

4

b

Scheme 76: a) [Pd2dba3]·CHCl3 (3 mol%), PPh3 (18 mol%), N-DNBA (3.0 equiv), CH2Cl2, 30 °C; b) AcOH, ∆.

Compound Solvent δ (cis-olefin) δ (trans-olefin) ∆δ(H)

Me-CH=CHCl-Me CCl4 4.84 4.47 0.37

Me-CH=CH(OH)-Me CCl4 4.55 4.12 0.43

Me-CH=CH(OMe)-Me CCl4 4.05 3.57 0.48

Me-CH=CH(NEt2)-Me CCl4 3.57 3.20 0.37

321 CHCl3 3.41

323 CHCl3 4.22

324 CHCl3 4.62 0.40

Table 7: Chemical shifts for the allylic proton at C9 for 321, 323 and 324 in comparison to literature values.


83

The stereochemical outcome of the ring-expansion reaction of 313 with 309 was found to

be in favor of the desired 3,18-syn-products in a ratio of 6:1. The stereocenter at C9 is not

of crucial importance, as it will be removed later on. The synthesis of spirotryprostatin B

could now be envisaged. Towards that goal, we envisioned to carry out the synthesis of

spirotryprostatin B from all suitable intermediates 323, 324 and 326. We commenced

with the synthesis from intermediate 323.

2.3. Synthesis of Spirotryprostatin B from Intermediate 323

NH

O

Me

312

NH

N2

O

313

a

71% NH

O

N

Me

N

309TIPS

314 TIPS

b

68%

NHHN

O

TIPS

Me

323

c

50%

NHHN

O

TIPS

Me

326

+ NHHN

O

TIPS324

Me

+

(4:1:5)

Scheme 77: a) [Rh(OAc)2]2 (1 mol%), piperylene (4.0 equiv), slow addition of 312 in CH2Cl2, benzene, ∆; b) MgI2 (1.0 equiv), THF, 75 °C; c) Pd(PPh3)4 (3 mol%), N-DNBA (3.0 equiv), CH2Cl2, 30 °C.

Intermediate 323 could be obtained in multigram quantities from 312 (Scheme 77,

synthesis described in the previous paragraph). In the ensuing synthetic sequence, amide

coupling of 323 and N-Boc-L-proline with concomitant resolution of the racemic material

was anticipated. Best results were obtained when 323 was treated with N-Boc-L-proline


chloride (270).147 Acid chloride 270 was prepared in situ from N-Boc-L-proline (257)

with Vilsmeier–Haack reagent from DMF and oxalyl chloride in the presence of

pyridine.148 The products 327 and 328 were obtained as a 1:1 mixture and could be

readily separated by column chromatography on silica gel leading to enantiomerically

pure 327 in 45% yield (Scheme 78).

NHHNO

TIPS

Me

323

NHNO

TIPS

Me

N

O

Boc

N

TIPS

Me

N

O

Boc

H HHNO

327 328

BocN

Cl

OH

270

b

(1:1)

+

BocN

HO

OH

a

90%

257

Scheme 78: a) DMF, oxalyl chloride, Py, 257, CH2Cl2, 0 °C; b) 270, (4.0 equiv), NEt3, CH2Cl2, 0 °C RT.

Correlation of the C12 stereocenter to the stereocenters of the spiro-pyrrolidine-oxindole

core for 327 and 328 is not possible by spectroscopic means. Fortunately, suitable

crystals for X-ray crystallographic analysis were obtained from 327 allowing for

assignment of structure 327 and, therefore, of 328 as well (Figure 18).149

[147] Buschmann, H.; Scharf, H. D. Synthesis 1988, 827-830. [148] Stadler, P. A. Helv. Chim. Acta 1978, 61, 1675-1681. [149] CCDC 196803 contains the supplementary crystallographic data for 327. This data can be obtained free of charge via www.ccdc.cam.ac.uk/retrieving.html (or from the Cambridge Crystallographic Data Center, 12, Union Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or [email protected]).


85


From 327, cleavage of the olefin followed by oxidation-state adjustments was planned

and would lead to the C9 carboxylate, required for later installation of the

diketopiperazine ring. When 327 was submitted to standard dihydroxylation conditions

(OsO4 (4 mol%), NMO·H2O), diol 329 was obtained.150 Cleavage of diol 329 by

Pb(OAc)4 was carried out without prior purification and cleanly afforded aldehyde 330 in

97% yield over two steps.151 Subsequent oxidation of aldehyde 330 to the corresponding

acid 331 following Lindgrens’ procedure152,153 and conversion to methyl ester 332 with

diazomethane afforded 332.154 Removal of the TIPS-protecting group was accomplished

in quantitative yield with TBAF in THF.155 For the large scale conversion of 327 into

333, it is noteworthy that all five steps (a–e) can be carried out without purification of any

intermediate (329–332) in 80% overall yield (Scheme 79).

[150] VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 1973-1976. [151] Rubottom, G. M. Oxidation in Organic Chemistry; Academic Press: New York, 1982. [152] Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888-890. [153] An interesting alternative to obtain 418 directly from 413 through OsO4-promoted catalytic oxidative cleavage was tested, but only traces of the desired material was obtained, making this direct method incompatible with the traditional three-step sequence. Travis, B. R.; Narayan, R. S.; Borhan, B. J. Am. Chem. Soc. 2002, 124, 3824-3825. [154] CH2N2 was prepared from N-methyl-N’-nitro-N-nitrosoguanidine and was used as an etheral solution. Fales, H. M.; Jaouni, T. M.; Babashak, J. F. Anal. Chem. 1973, 45, 2302-2303. [155] Pattenden, G.; Robertson, G. M. Tetrahedron Lett. 1986, 27, 399-402.


NHNO

TIPS

Me

N

O

Boc

H

327

NHNO

O

TIPS

N

O

Boc

H

330

NHN

OHO2C

TIPS

N

O

Boc

H

331

NHN

OMeO2C

TIPS

N

O

Boc

H

332

a b

c

d

97%over 2 steps

89%over 2 steps

NHNO

TIPS

N

O

Boc

H

329

OH

MeHO

NHN

OMeO2C

N

O

Boc

H

333

e

99%

80% overall yieldwithout purification of any intermediate

a-e

Scheme 79: a) OsO4 (4 mol%), NMO·H2O (1.2 equiv), THF/tBuOH/H2O, RT; b) Pb(OAc)4, EtOAc, RT; c) NaClO2 (10.0 equiv), 2-methy-2-butene, pH 3.6 buffer, tBuOH, RT; d) CH2N2, Et2O, RT; e) TBAF (1.2 equiv), THF, RT.

At this stage of the synthesis, conversion of alkyne side chain into the prenyl moiety was

planned. If this conversion was successful, the opportunity would be available for

introduction of the endocyclic olefin and closure of the diketopiperazine to yield

spirotryprostatin B.

Theoretically, conversion of the C19−C20 alkyne into the corresponding aldehyde by

hydrogenation followed by oxidative olefin cleavage would set the stage for aldehyde

olefination. However, as shown in Danishefsky’s elegant study en route to

spirotryprostatin A, the closely related aldehyde 334 proved amazingly recalcitrant to a

variety of olefination procedures.156 This led us to test alternative methods for the

conversion of alkynyl side chain in 333 into the prenyl moiety (Scheme 80).

[156] See [25], page 14.


87

NTsHN

OCO2Me

334

O

NTsHN

OCO2Me

Me

Meolefinationprocedures

Scheme 80: Recalcitrance of 334 to olefination procedures.

Aldehyde 335 should result from hydroboration of 333 followed by oxidative workup.

Conversion to the prenyl side chain to give 336 was planned by a sequence involving

methyl-Grignard-addition/oxidation/methyl-Grignard-addition/dehydration.

Hydroboration of alkyne 333 with dicyclohexyl borane followed by treatment with

NaOH/H2O2 was carried out.157 However, starting material was reisolated when 1–2

equivalents of borane were used and decomposition of the starting material was observed

with larger excess of reagent (Scheme 81).

NHN

OMeO2C

N

O

Boc

H

333

NHN

OMeO2C

N

O

Boc

H

335

O

NHN

OMeO2C

N

O

Boc

H

R'

Rhydroborationoxidativeworkup

c) MeMgXd) -H2O

a) MeMgXb) [O]

Scheme 81: Failure of the hydroboration reaction of 333.

Another reaction sequence that would allow installation of the prenyl moiety in the most

direct fashion is semihydrogenation of alkyne 333 to olefin 337, followed by cross

metathesis. Towards this end, hydrogenation of 333 catalyzed by Pd/BaSO4 (Rosenmund

catalyst) poisoned with quinoline yielded olefin 337 in 90% yield.158 The cross-

metathesis reaction using the second generation Grubbs’ catalyst in either refluxing

[157] a) Pelter, A. ; Smith, K.; Brown, H. C. Borane Reagents; Academic Press: New York, 1988. b) Marshall, J. A.; Johns, B. A. J. Org. Chem. 2000, 65, 1501-1510. [158] a) Rosenmund, K.W. Chem. Ber. 1918, 51, 585-593. b) Rao, A. V. R.; Reddy, S. P.; Reddy, E. R. J. Org. Chem. 1986, 51, 4158-4159. In this reference, Pd/BaSO4 is misleadingly called Lindlar’s catalyst ― which is Pd/CaCO3/PbO ― in the experimental part. c) Initial trials were undertaken using Lindlar’s catalyst, however, only recovered starting material 333 was isolated under standard conditions. Lindlar, H. Helv. Chim. Acta 1952, 35, 446-456.


CH2Cl2 or in toluene at 75 °C with 2-methyl-2-butene as cross coupling partner did not

lead to conversion of the starting material to 336.159

NHNOMeO2C

N

O

Boc

H

336

Me

Mecross

metathesis

aNHN

OMeO2C

N

O

Boc

H

333

90%NHN

OMeO2C

N

O

Boc

H

337

RuPhCl

Cl

NN MesMes

PCy3

second generationGrubbs' catalyst

Scheme 82: a) H2 (1 atm), quinoline (0.5 equiv), Pd/BaSO4 (33 wt%), EtOH, RT.

In order not to lose more precious material to find a valuable entry to 336, we decided to

use a model compound for further studies. Compound 155 was one of the products

obtained from coupling of spiro-cyclopropyl-oxindole 99 with N-tosyl-protected imines

123 (Table 4, page 34) in our general studies of the ring-expansion reaction. This

compound is available on large scale and could be easily converted to 338 by quantitative

deprotection of the silyl group.160 Alkyne 338 is a valuable model, containing the

terminal acetylene functionality in a structural array similar to 333. In his route to

spirotryprostatin A, Danishefsky had also used an N-tosyl derivative as model compound

(Scheme 80, page 87).

155

NBn

O

NTs

TIPS 338

NBn

O

NTsa

100%

339

NBn

O

NTs

OMe

O

NBn

O

NTs

R'

Rb) 2 equiv MeMgX

c) -H2O

Scheme 83: a) TBAF (1.2 equiv), THF, RT.

Conversion to ester 339 was examined from this compound; the prenyl moiety could

possibly be introduced by double methyl-Grignard addition followed by dehydration.

Three procedures are known in literature that would allow for such a conversion in a

direct way: (i) oxidation of the alkyne with H2O2 catalyzed by MeReO3,161 (ii) oxidative

[159] Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751-1753. [160] See [155], page 85. [161] Zhu, Z. L.; Espenson, J. H. J. Org. Chem. 1995, 60, 7728-7732.


89

rearrangement of the alkyne to the corresponding carboxylic acid by hydroxyl-(tosyloxy)-

iodo-benzene followed by in situ esterification,162 (iii) reaction of lithiated alkynes with

tert-butyl hydroperoxide, subsequent protonation to the ketene and solvolysis to the

carboxylic acid ester.163 None of these prescriptions led to the desired ester 339; starting

material was reisolated following procedures (i) and (ii), whereas decomposition was

observed using conditions (iii) (Scheme 83).

338

NBn

O

NTs

340

NBn

O

NTs

Me

a

69%

341

NBn

O

NTs

Me

MeNBn

O

NTs

M

Me

Scheme 84: a) nBuLi, MeI, THF, –78 °C RT.

Our next attempt relied on the use of Schwartz’s reagent (Cp2ZrHCl), which is the

reagent of choice to convert an alkyne to the corresponding alkenylzirconium species by

hydrozirconation.164 Hydrometallation takes place regioselectively at the less hindered

terminus. In order to use the hydrozirconation products for C–C bond forming reactions,

transmetallation (often to aluminum using AlCl3) is required as the alkenyl carbon

attached to zirconium in not nucleophilic enough.165 In order to convert the terminal

alkyne 338 into prenylated 341, conversion to methyl-substituted alkyne 340 was

achieved by lithiation followed by addition of MeI. Treatment of 340 with Schwartz’s

reagent,166 followed by treatment with AlCl3 and MeI however, did not lead to desired

341 (Scheme 84).

[162] Moriarty, R. M.; Vaid, R. K.; Duncan, M. P.; Vaid, B. K. Tetrahedron Lett. 1987, 28, 2845-2848. [163] Julia, M.; Pfeuty-Saint Jalmes, S.; Plé, K.; Verpeaux, J. N.; Hollingworth, G. Bull. Soc. Chim. Fr. 1996, 133, 15-24. [164] Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc. 1975, 97, 679-680. [165] Carr, D. B.; Schwartz, J. J. Am. Chem. Soc. 1977, 99, 638-640. [166] Lipshutz, B. H.; Keil, R.; Ellsworth, E. L. Tetrahedron Lett. 1990, 31, 7257-7260.


340

NBn

O

NTs

Me 342

NBn

O

NTsa

0-24%O

Me343

NBn

O

NTs

Me

MeOH

344

NBn

O

NTs

Mec

26%56%

based onrecovered 343

b

26%

Scheme 85: a) Hennion’s catalyst, CH2Cl2, RT; b) MeMgI, THF, –40 °C RT; c) SOCl2, Py, –50 °C RT.

Treatment of alkyne 340 with a catalytic amount of Hennion’s catalyst, a mixture of

HgOred (1.0 equiv) and BF3·Et2O (1.0 equiv) in trifluoroacetic acid (10.0 equiv), provided

ketone 342.167 This reaction did not prove very reproducible and 0–24% of 342 were

isolated, generally together with unreacted starting material. Treatment of 342 with

methyl-Grignard reagent led to tertiary alcohol 343.168 Under dehydrating conditions,

gem-disubstituted olefin 344 was obtained.169 In his synthesis of spirotryprostatin A

Danishefsky had shown that the natural product can be obtained from its structural isomer

229 (Scheme 54, page 57), bearing the same side chain, by treatment with RhCl3·3H2O in

refluxing EtOH. Alternatively, tertiary alcohol 343 could be methylated and eliminated

according to Williams’ procedure (Scheme 55, page 59).170

Although, according to these findings, there is a possibility to convert the alkynyl side

chain of 333 into the prenyl moiety, the reaction sequences proved very unreliable and

low yielding and a different synthetic pathway had to be found.

[167] a) Barre, V.; Massias, F.; Uguen, D. Tetrahedron Lett. 1989, 30, 7389-7392. b) Killian, D. B.; Hennion, G. F.; Nieuwland, J. J. Am. Chem. Soc. 1936, 58, 80-81. [168] Liotta, D.; Saindane, M.; Barnum, C. J. Org. Chem. 1981, 46, 3369-3370. [169] Plate, R.; Hermkens, P. H. H.; Behm, H.; Ottenheijm, H. C. J. J. Org. Chem. 1987, 52, 560-564. [170] See [48] and [49], page 21.


91

NHN

OMeO2C

N

O

Boc

HNHN

OMeO2C

N

O

Boc

H

345

O

R'

R

Scheme 86: Planned olefination to access spirotryprostatin B or side-chain analogues

We decided to return to the idea of using an olefination procedure for the introduction of

the prenyl side chain (Scheme 86), even though such a procedure had not been successful

in an earlier synthesis (Scheme 80, page 87). Two reasons prompted us to take this

decision: (i) no other reliable, short and high-yielding method is known at present, (ii) an

olefination procedure would allow for facile access to spirotryprostatin B or side-chain

analogues of this natural product from aldehyde 345. Investigations towards insertion of

the prenyl moiety by means of olefination reactions were undertaken.

a

88%NHN

OMeO2C

N

O

Boc

H

337

NHN

OMeO2C

N

O

Boc

H

346OH

HO

NHN

OMeO2C

N

O

Boc

H

345

O

b

87%

Scheme 87: a) OsO4 (1.0 equiv), NMO·H2O (1.2 equiv), THF/tBuOH/H2O, RT; b) Pb(OAc)4, RT.

The transformation of 337 to diol 346 was achived with OsO4/NMO·H2O in

THF/tBuOH/H2O with a reaction time of three days.150 This long reaction time suggests

that the accessibility of the C19−C20 olefin of 337 is very limited. The associated

difficulties with olefination processes observed by Danishefsky with aldehyde 334

(Scheme 80, page 87) might also have resulted from steric hindrance. 1H NMR

spectroscopy revealed that diol 346 was formed as a single diastereomer and in contrast

to all earlier intermediates, no rotamers due to the Boc group were observed (Scheme 87).


From 346, aldehyde 345 was obtained by glycol cleavage with Pb(OAc)4.171 With

aldehyde 345 in hand ― this compound is stable at 4 °C over an extended period of time

― we next turned our attention to the critical olefination step (Scheme 87).

Among the available procedures for the olefination of sterically hindered systems, the

Wittig reaction is a commonly used transformation.172 A variety of conditions were used,

none of which led to the desired product 336 in pure form.173 Traces of olefination

product could be observed by MS, but under all conditions we employed extensive

epimerization at C18 took place and considerable amounts of 345 were decomposed

(Scheme 88, Table 8).

NHN

OMeO2C

N

O

Boc

H

336

NHN

OMeO2C

N

O

Boc

H

345

O

Me

Me

Ph3PMe

MeI

Ph3PMe

Me

base

, T

18

Table 8, Scheme 88: Failure of Wittig reaction of 345.

Addition of iPrMgCl to aldehyde 345, followed by dehydration of the resulting alcohol

was investigated. Under careful control of the amount of Grignard reagent used,

conversion into alcohol 347 was achieved without epimerization at C18 in 97% yield.174

Various conditions for the direct dehydration of 347 were examined, but none provided

the desired product 336 (Scheme 89, Table 9).175,176

[171] See [151], page 85. [172] Wittig, G.; Schöllkopf, U. Ber. 1954, 87, 1318-1330. [173] a) Asaoka, M.; Shima, K.; Fujii, N.; Takei, H. Tetrahedron 1988, 44, 4757-4766. b) Oppolzer, W.; Wylie, R. D. Helv. Chim. Acta 1980, 63, 1198-1203. [174] Williams, L.; Zhang, Z. D.; Shao, F.; Carroll, P. J.; Joullié, M. M. Tetrahedron 1996, 52, 11673-11694. corrigendum: Williams, L.; Zhang, Z. D.; Shao, F.; Carroll, P. J.; Joullié, M. M. Tetrahedron 1997, 53, 1923-1923. [175] a) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 2339-2342. b) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327-4329. c) Dolle, R. E.; Schmidt, S. J.; Erhard, K. F.; Kruse, L. I. J. Am. Chem. Soc. 1989, 111, 278-284.

Base Solvent Temperature Outcome nBuLi THF 0 °C RT

DMSO/ NaH DMSO RT

Decomposition of 345, traces of product

with correct mass observed by MS.

DMSO/ KH PhH 60 °C

Epimerization of reisolated 345 (86%)

at C18.


93

NHN

OMeO2C

N

O

Boc

H

336

NHN

OMeO2C

N

O

Boc

H

345

O

Me

Me

18

a

97%NHN

OMeO2C

N

O

Boc

H

Me

MeRO

347 R = H348 R = X

dehydrating-agent

Table 8

XY, baseTable 9

OS

OCF3

Ph

F3C

PhF3C CF3

Ph Ph

Martin sulfurane

Scheme 89: a) iPrMgCl (2.2 equiv), Et2O, –78 °C RT.

Dehydrating agent Solvent Temperature Outcome

Martin sulfurane (2.0-5.0 equiv) CH2Cl2 –20 °C RT

POCl3 (2.0 equiv) Py/CH2Cl2 0 °C RT 347

Table 9: Reaction conditions employed for direct dehydration of 347.

The use of a two-step procedure also failed due to recalcitrance of 347 to convert to 348

(X = Tf or Ts) (Scheme 89, Table 10).177

XY Base Solvent Temperature Outcome

Tf2O Py CH2Cl2 0 °C RT

Tf2O 2,6-di-tert-butyl-4- methyl-pyridine CH2Cl2 0 °C RT

TsCl DMAP CH2Cl2 RT

TsCl Py Py RT

347

Table 10: Reaction conditions employed for conversion of 347 to 348.

We next turned our attention to the Julia–Lythgoe olefination, as this three-step sequence

has proven to be a valuable method for the generation of highly substituted olefins.178

[176] a) Mehta, G.; Murthy, A. N.; Reddy, D. S.; Reddy, A. V. J. Am. Chem. Soc. 1986, 108, 3443-3452. b) Shizuri, Y.; Yamaguchi, S.; Terada, Y.; Yamamura, S. Tetrahedron Lett. 1986, 27, 57-60. [177] a) Lefèbvre, O.; Brigaud, T.; Portella, C. J. Org. Chem. 2001, 66, 1941-1946. b) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; Wiley: New York, 1967. [178] Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 4833-4836.


NHN

OMeO2C

N

O

Boc

H

353

NHN

OMeO2C

N

O

Boc

H

345O

Me

Me

18

b

61%NHN

OMeO2C

N

O

Boc

H

Me

MeHO

PhS

OOMe

Me

PhSO

O Naa

36%

SO2Ph

NHN

OMeO2C

N

O

Boc

H

Me

MeAcOSO2Ph

c

78%

d

23%

352351

349

350

overall yield from 345:11%

Scheme 90: a) iPrI, 349 (1.5 equiv), Bu4NI, PhH/acetone/H2O, RT; b) nBuLi (2.5 equiv), 350 (2.5 equiv), THF, –78 °C; Ac2O (1.2 equiv), DMAP (1.2 equiv), CH2Cl2, RT; d) Na/Hg (2.5%, 130 wt%), Na2HPO4 (520 wt%), MeOH, RT.

Sulfone 350 was prepared by a liquid–liquid phase-transfer process from sodium benzene

sulfinate (349).179 The Julia–Lythgoe sequence commenced with the addition of lithiated

sulfone 350 to aldehyde 345 at –78 °C. Acylation of the hydroxyl group afforded 352,

which was exposed to 2.5% Na/Hg in MeOH in the presence of Na2HPO4. From this set

of reactions, the product 353 was obtained in 11% overall yield from aldehyde 345. Thus,

olefination of aldehyde 345 proved possible; however, product 353 was found to have

undergone extensive epimerization at C18 (Scheme 90).180

Given this promising result, further investigations were undertaken following the same

general direction. The use of a more hindered base instead of nBuLi and replacement of

the three-step procedure by a one-pot sequence would hopefully avoid epimerization at

C18 (epimerization could have occurred by excess base) and improve the yield of the

conversion of aldehyde 345 to 336 significantly.

The Julia–Kocieńsky reaction, a modification of the one-pot olefination reaction

developed by Julia, was tested next.181,182 The required sulfone 365 was available from

354 by alkylation under Mitsunobu conditions, followed by oxidation with Oxone.182,183

[179] Crandall, J. K.; Pradat, C. J. Org. Chem. 1985, 50, 1327-1329. [180] a) McCombie, S. W.; Cox, B.; Ganguly, A. K. Tetrahedron Lett. 1991, 32, 2087-2090. b) Gurjar, M. K.; Srinivas, N. R. Tetrahedron Lett. 1991, 32, 3409-3412. [181] Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991, 32, 1175-1178. [182] Kocieńsky, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000, 365-366. [183] Ward, R. S.; Roberts, D. W.; Diaper, R. L. Sulfur Lett. 2000, 23, 139-144.


95

Treatment of aldehyde 345 with the lithium salt of sulfone 356 (obtained by treatment of

356 with LHMDS), afforded the desired product 336 without epimerization at C18 in

78% yield. The structure of compound 336 was confirmed by X-ray crystallographic

analysis (Scheme 91, Figure 19).184 The Julia–Kocieńsky reaction is normally employed

for efficient introduction of disubstituted olefins with selective formation of the trans-

isomers. To our knowledge, the use of this reaction for the formation of trisubstituted

double bonds has not yet been the object of investigations and the known sulfone 356 has

not yet been reported as reactant in a Julia–Kocieńsky reaction.185 Furthermore, even

though Julia–Kocieńsky reactions with β-branched aryl sulfones (e.g. with 2-methyl-

heptyl-aryl-sulfone) are known,186 the use of α-branched aryl sulfones for the synthesis of

trisubstituted double bonds has not been reported.

NHN

OMeO2C

N

O

Boc

H

336

NHN

OMeO2C

N

O

Boc

H

O

Me

Me

18

c

78%

NN N

NPh

S Me

Me

OO

NN N

NPh

S Me

Me

NN N

NPh

SH

b

a

81%

85%

345356

355354

Scheme 91: a) iPrOH, PPh3, DEAD, THF, RT; b) Oxone, MeOH, H2O, RT; c) 356, LHMDS, THF, -78 °C.

[184] CCDC 196804 contains the supplementary crystallographic data for 336 This data can be obtained free of charge via www.ccdc.cam.ac.uk/retrieving.html (or from the Cambridge Crystallographic Data Center, 12, Union Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or [email protected]). [185] Nirenburg, V.L.; Postovskii, I. Y. Izv. Vyssh. Uchebn. Zaved. Khim. Tekhnol. 1965, 8, 258. [186] Blakemore, P. R.; Cole, W. J.; Kocieńsky, P. J.; Morley, A. Synlett 1998, 26-28.



From 336, the synthesis of spirotryprostatin B was completed in four steps following the

Danishefsky route.187 Thus, selenylation of 336 followed by oxidation/elimination with

DMDO afforded 357 (74%).188,189 Deprotection of the proline moiety and subsequent

lactamization to the diketopiperazine ring led to spirotryprostatin B (2) in 74% yield

(Scheme 92).

NHN

OMeO2C

N

O

Boc

H

336

Me

Me

8a,b

74%NHN

OMeO2C

N

O

Boc

H

357

Me

Me

c

74%

9


N

NO

OH

Me

Me

HNO

Scheme 92: a) PhSeCl, LHMDS, THF, 0 °C; b) DMDO, THF, 0 °C; c) (i) TFA, CH2Cl2, RT; (ii) NEt3, CH2Cl2, RT.

The analytical characteristics observed (1H and 13C NMR spectra, MS, IR, optical

rotation) were found to be identical to those reported in the literature for natural material.

[187] See [25], page 14. [188] Reich, H. J.; Reich, I. J.;Renga, J.M. J. Am. Chem. Soc. 1973, 95, 5813-5815. [189] Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Berichte 1991, 124, 2377-2377.


97


Intermediate 324 differs from 323 only by the geometry of the olefinic double bond.

Applying identical synthetic steps as for the synthesis of spirotryprostatin B from 323, the

route should lead to the common aldehyde intermediate 330 (Scheme 93).

NHN

O

O

TIPS

N

O

Boc

H

330

NHHN

O

TIPS

Me

323

NHHN

O

TIPS324

Me

steps

steps

Scheme 93: Common intermediate 330 should be accessible from 323 and 324.

Treatment of 324 with N-Boc-L-proline chloride (270) afforded a 1:1 mixture of

chromatographically separable 358 and 359 (Scheme 94). No crystals could be grown

from either of the two coupling products; structural assignment was therefore possible

only after conversion of 358 to the known intermediate 330.

NHHNO

TIPS324

NHNO

TIPS

N

O

Boc

N

TIPS

N

O

Boc

H HHNO

358 359

BocN

Cl

OH

270

a

1:1

+79%

Me Me Me

Scheme 94: a) 270, (2.5 equiv), NEt3, CH2Cl2, 0 °C RT.


The more polar coupling product was converted into the corresponding aldehyde via diol

360 in 75% overall yield. The analytical characteristics observed for aldehyde 330 were

found to be identical to those found previously (see paragraph 2.3.). Therefore, structure

358 was assigned to this diastereomer.

NHN

O

TIPS

N

O

Boc

H

358

NHN

O

O

TIPS

N

O

Boc

H

330

a b

75%over 2 steps

NHN

O

TIPS

N

O

Boc

H

360

OH

OHMeMe

Scheme 95: a) OsO4 (4 mol%), NMO·H2O (1.2 equiv), THF/tBuOH/H2O, RT; b) Pb(OAc)4, RT.


The difference between 323 and 326 concerns the relative configuration at the C9

stereocenter. This stereocenter is not present anymore in the natural product, and

employment of the synthetic sequence used for the synthesis of spirotryprostatin B from

323 to 326 should result in formation of common intermediate 357 (Scheme 96).

NHHN

O

TIPS

Me

323

steps

stepsNHHN

O

TIPS

Me

326

NHN

OMeO2C

N

O

Boc

H

357

Me

Me

Scheme 96: Common intermediate 357 should be accessible from 323 and 326.


99

Coupling of 326 with N-Boc-L-proline chloride (270) afforded a mixture of products 361

and 362 not separable by column chromatography. The mixture of products was

submitted to the conditions for conversion of the substituted vinyl group into the

C9 methyl ester followed by removal of the TIPS protecting group (see section V 2.2.4.).

All of these steps were carried out without purification of the intermediates. Compounds

363 and 364 in a 1:2 ratio resulted from this sequence as isomers separable by

chromatography on silica gel. The fact that the obtained ratio is not 1:1, as previously

observed, could be the result of a (partial) kinetic resolution of 326 with N-Boc-L-proline

chloride (270).

NHHN

O

TIPS

Me

326

NHN

O

TIPS

Me

N

O

Boc

N

TIPS

Me

N

O

Boc

H HHNO

361 362

BocN

Cl

OH

270

a+

90%

NHN

OMeO2C

N

O

Boc

HN

MeO2CN

O

Boc

HHNO

363 364

+

(1:2)

b-f

N

NO

OH

g

H

HNO

75%

365

43%

inseperableby column

chromatography

seperableby column

chromatography

9

9 12

Scheme 97: a) 270, (2.5 equiv), NEt3, CH2Cl2, 0 °C RT; b) OsO4 (4 mol%), NMO·H2O (1.2 equiv), THF/tBuOH/H2O, RT; c) Pb(OAc)4, RT; d) NaClO2 (10.0 equiv), 2-methyl-2-butene, pH 3.6 buffer, tBuOH, RT; e) CH2N2, Et2O, RT; f) TBAF (1.2 equiv), THF, RT; g) (i) TFA, CH2Cl2, RT; (ii) NEt3, CH2Cl2, RT.

Assignment of the stereochemistry for 363 and 364 was not possible by X-ray

crystallographic analysis, as from both compounds, no suitable crystals could be

obtained. The major product 364 was treated with TFA followed by triethyl amine to

yield 365. No NOE enhancements could be observed between the C9 and C12 protons,


indicating that the trans-diketopiperazine has been produced from 364. Although the

absence of an NOE is not an absolute prove, spirotryprostatin A, a cis-diketopiperazine

showed a pronounced NOE for these protons (Scheme 97).190 Assuming that our

assignment of 363 is correct, we continued our synthetic route with compound 363.

Following the same synthetic steps as in our earlier sequence, 363 was converted to

aldehyde 367 via olefin 366. In this sequence, as compared to the C9 epimeric

compounds, we observed the occurrence of 4 rotamers, probably due to restricted rotation

around the N10-C11 amide bond.

NHNOMeO2C

N

O

Boc

H

363

a

98%NHN

OMeO2C

N

O

Boc

H

366

NHNOMeO2C

N

O

Boc

H

367

O

b,c

63%

NHNOMeO2C

N

O

Boc

H

368

Me

Me

NHNOMeO2C

N

O

Boc

H

357

Me

Me

de,f

40% 68%

NN N

NPh

S Me

Me

OO

356

11

10

Scheme 98: a) H2 (1 atm), quinoline (0.5 equiv), Pd/BaSO4 (33 wt%), EtOH, RT; b) OsO4 (1.0 equiv), NMO·H2O (1.2 equiv), THF/tBuOH/H2O, RT; c) Pb(OAc)4, RT; d) 356, LHMDS, THF, –78 °C; e) PhSeCl, LHMDS, THF, 0 °C; f) DMDO, THF, 0 °C.

The Julia–Kocieńsky reaction of aldehyde 367 to product 368 proceeded in 68% yield.

From 368, the implementation of the C8−C9 double bond proved that the assumption

about the isomer assignment of 363 and 364 had indeed been correct, as the isolated

compound was identical to 357 (Scheme 98). This finding concludes the synthesis of

spirotryprostatin B from 326.

[190] See [5], page 7.


101

3. Conclusion

We have described the total synthesis of spirotryprostatin B (16 steps from 3-diazo-1,3-

dihydro-indol-2-one (312) (Scheme 100). Our approach is highlighted by the rapid

assembly of the spirotryprostatin core using our ring-expansion method for the synthesis

of highly substituted spiro-pyrrolidine–oxindole alkaloids. The limited reactivity of

aldehydes 345 and 367 towards olefination was overcome by the Kocieńsky-Julia

reaction, which allows for the facile synthesis of analogues, important for elucidating

structure–activity relationships. Over a sequence of several steps, no purification of

intermediates is required, making our approach suitable for large scale synthesis.

NH

O

N

Me

TIPS

NHN

O

TIPS

Me

AcOH, ∆

369

NH

N2

O NH

O

Me

N

309TIPS

NHN

OMeO2C

N

O

Boc

HNHN

OMeO2C

N

O

Boc

H

Me

Me

43spirotryprostatin A

N

N

OH

Me

Me

HN

O

OH

MeO MeO MeO

MeOMeOMeOMeO

Scheme 99: Suggestion for the rapid assembly of spirotryprostatin A.

The products of the key ring-expansion reaction can be equilibrated to 321 by refluxing

in acetic acid (Scheme 76, page 82). The relative stereochemistry of 321 is the same as

observed in spirotryprostatin A. Starting from diazo-oxindole 369,191 our method would

also be ideal to quickly assemble spirotryprostatin A (43) (Scheme 99).

[191] Compound 369 could be prepared from known 6-methoxy isatin. Creger, P. L. J. Org. Chem. 1965, 30, 3610-3613.


NHN

O

TIPS

Me

N

O

Boc

H

327

NH

O

N

Me

314 TIPS

NHHN

O

TIPS

Me

323

NHHN

O

TIPS

Me

326

+NHHN

O

TIPS324

Me

+

NHN

O

TIPS

N

O

Boc

H

358

NHN

O

O

TIPS

N

O

Boc

H

330

NHN

O

O

TIPS

N

O

Boc

H

330

Me

NHN

OMeO2C

N

O

Boc

H

363

NHN

OMeO2C

N

O

Boc

H

357Me

Me

NHN

OMeO2C

N

O

Boc

H

357Me

Me


N

N

O

OH

Me

Me

HNO

3.4%overall yield

from known 312

312

NH

N2

O

NH

O

Me

313

N

309TIPS

Scheme 100: The total synthesis of spirotryprostatin B.

Conclusion and Outlook

103

VI. Conclusion and Outlook

We have developed a novel method to access spiro-pyrrolidine-oxindoles by MgI2-

catalyzed ring-expansion reaction in a highly convergent manner. The products of the

ring expansion are generally obtained in good yields and high diastereoselectivities. The

starting materials can be easily prepared in short synthetic sequences (1 to 3 steps) with

high overall yields. This method is different from existing approaches to the spiro-

pyrrolidine-oxindole core and represents a valuable alternative.

This method was successfully employed in the short and high-yielding synthesis of

(±)-horsfiline ((±)-16). The use of 1,3,5-trimethyl-1,3,5-triazinane (206) to serve as an

efficient N-methyl-methylene imine equivalent in the MgI2-catalyzed ring expansion was

demonstrated.

In order to examine the viability of the method for the construction of spiro-pyrrolidine-

oxindoles with a higher degree of substitution in the pyrrolidine ring, we employed our

annulation method for the synthesis of an important key fragment in the total synthesis of

spirotryprostatin B (17). The construction of highly substituted pyrrolidines (substituents

at the 2,3 and 5 positions) can be well performed with proper selection of starting

materials. In the synthesis of spirotryprostatin B (17), the problem of late-stage

introduction of the prenyl side chain that proved difficult in earlier routes could be solved

by application of the Julia–Kocieńsky olefination proceedure. The natural product was

obtained in 16 steps from commercially available materials.

In the course of our investigations, initial results showed that the method can also be used

for the formation of spiro-tetrahydrofuryl-oxindoles and for the general formation of

substituted pyrrolidines from cyclopropyl amides. Although some of these discoveries

have already been pursued by other research groups,192 the use of nucleophiles other than

[192] a) Lautens, M.; Han, W. S. J. Am. Chem. Soc. 2002, 124, 6312-6316. b) Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4, 3147-3150. c) Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4, 4333-4336.

104 Conclusion and Outlook

imines (for example aldehydes N,N-dialkylhydrazones or carbodiimides) has not yet been

examined and would allow for a more complete view of the reaction scope and present a

useful method for the preparation of five-membered-ring heterocycles.

One of the next major goals along the line would be to achieve asymmetric induction in

the ring expansion. Several possibilities can be aimed at: (i) the use of chiral imines ―

sulfinyl imines would eventually be suitable for that purpose,193 (ii) the use of chiral

ligands for Mg ― the use of BOX-type ligands could be envisioned ― hopefully

resulting in a catalytic, asymmetric transformation.194

[193] Liu, G. C.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 1278-1284. [194] a) Corey, E. J.; Ishihara, K. Tetrahedron Lett. 1992, 33, 6807-6810. b) Corey, E. J.; Wang, Z. Tetrahedron Lett. 1993, 34, 4001-4004.

Experimental Part

105

VII. Experimental Part

1. General methods

All non-aqueous reactions were carried out using oven-dried or flame-dried glassware

under a positive pressure of dry nitrogen unless otherwise noted. Tetrahydrofuran,

acetonitrile, toluene, diethyl ether and methylene chloride were purified by distillation

and dried by passage over activated alumina under an argon atmosphere (H2O content <

30 ppm, Karl-Fischer titration).195 Benzene was distilled from sodium/benzophenone

ketyl under an atmosphere of dry nitrogen. Triethylamine and pyridine were distilled

from KOH. Ethyl glyoxylate was freshly distilled from P2O5, 1,1,1,3,3,3-

hexamethyldisilazane (HMDS), p-tosylisocyanate and quinoline were distilled prior to

use. Methyliodide was filtered through silica gel prior to use. Potassium hydride

(commercially available as a dispersion in mineral oil) was purified according to the

procedure reported by Brown.196 n-Butyl lithium was titrated with

sBuOH/phenanthroline.197 All other commercially available reagents were used without

further purification.

Except as indicated otherwise, reactions were magnetically stirred and monitored by thin

layer chromatography (TLC) using Merck Silica Gel 60 F254 plates and visualized by

fluorescence quenching under UV light. In addition, TLC plates were stained using ceric

ammonium molybdate or potassium permanganate stain.

Chromatographic purification of products (flash chromatography) was performed on E.

Merck Silica Gel 60 (230-400 mesh) using a forced flow of eluant at 0.3-0.5 bar.198

Concentration under reduced pressure was performed by rotary evaporation at 40 °C at

[195] Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518-1520. [196] Brown, C. A. J. Org. Chem. 1974, 39, 3913-3918. [197] Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9, 165-168. [198] Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.

106 Experimental Part

the appropriate pressure. Purified compounds were further dried for 12-72 h under high

vacuum (0.01−0.05 Torr). Yields refer to chromatographically purified and

spectroscopically pure compounds, unless otherwise stated.

Preparative thin layer chromatography was performed on pre coated plates silicat gel 60

F254 from E. Merck.

Kugelrohr distillations were performed with a Büchi Glass Oven B-580.

Radial chromatography was performed with a CycloGraph chromatodron using a 1mm

CaSO4-bound silica gel plate at a flow rate of 5-7 mL min–1.

Melting points were measured on a Büchi 510 apparatus. All melting points were

measured in open capillaries and are uncorrected.

Optical rotations were measured on a Jasco DIP-1000 polarimeter operating at the

sodium D line with a 100 mm path length cell, and are reported as follows: [α]DT,

concentration (g/100 ml), and solvent.

NMR spectra were recorded on a Varian Gemini 200 spectrometer operating at 200 MHz

for 1H acquisitions, a Varian Mercury 300 spectrometer operating at 300 MHz and

75 MHz for 1H and 13C acquisitions, respectively, or on a Bruker DRX500 spectrometer

operating at 500 MHz and 125 MHz for 1H and 13C acquisitions, respectively. Chemical

shifts (δ) are reported in ppm with the solvent resonance as the internal standard relative

to chloroform (δ 7.26) and benzene (δ 7.15) for 1H, and chloroform (δ 77.0) and benzene

(δ 128.0) for 13C. Data are reported as follows: s = singlet, d = doublet, t = triplet, q =

quartet, quint = quintet, m = multiplet; coupling constants in Hz. IR spectra were

recorded on a Perkin Elmer Spectrum RXI FT-IR spectrophotometer. Optical rotations

were measured on a Jasco DIP-1000 polarimeter operating at the sodium D line with a

100 mm path length cell, and are reported as follows: [α]DT, concentration (g/100 mL),

and solvent.

IR spectra were recorded on a PerkinElmer Spectrum RXI FT-IR spectrophotometer.

Absorptions are given in wavenumbers (cm–1).

Experimental Part

107

Mass spectra were recorded by the MS service at ETH Zürich. EI-MS: VG-TRIBRID

spectrometer; spectra were measured at 70 eV. FAB-MS: VG-ZAB2-SEQ spectrometer;

spectra were determined in m-nitrobenzyl alcohol (3-NOBA) as matrix. MALDI-MS:

IonSpec Ultima Fourier Transform Mass Spectrometer. Peaks are given in percent (m/z).

Elemental analyses were performed at the Mikrolabor der ETH Zürich.

High-performance liquid chromatography was performed on a Merck Hitachi (Interface

D-7000, UV-Detector L-7400, Pump L-7100, column: Säulentechnik 4 mm ID column

packed with 5 µm spherisorb SW silica gel). The detector wavelength was fixed at

λ = 254 nm. A flow rate of 0.9 mL min–1 was used. All chromatograms were taken at

ambient temperature.

Crystallographic structure determinations for 167 and 285 were performed on a Syntex

P21 diffractometer, MoKα radiation (λ = 0.71073 Å). The crystallographic structure

determination for 286 was performed on a Picker-STOE diffractometer, CuKα radiation

(λ = 1.5418 Å). Crystallographic structure determinations for 327 and 336 were

performed on a Nonius CAD4 diffractometer, CuKα radiation (λ = 1.5418 Å). The

structures were solved by direct methods199 and refined by full-matrix least-squares

analysis200 including an isotropic extinction correction. All heavy atoms were refined

anisotropically, H-atoms of the ordered part isotropically, whereby H-positions are based

on stereochemical considerations.

[199] A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M. Burla, G. Polidori, M. Camalli, J. Appl. Crystallogr., 1994, 27, 435. [200] G.M. Sheldrick, 1997, SHELXL-97 Program for the Refinement of Crystal Structures. University of Goettingen, Germany.


2. Preparation of Useful Reagents and Buffers

LHMDS, 0.330 M in THF

To a solution of HMDS (1.00 mL, 4.73 mmol, 1.00 equiv), in THF (10 mL) at −78°C was

added nBuLi (1.42 M in hexanes, 3.33 mL, 4.73 mmol, 1.00 equiv). The solution was

allowed to stir at 0°C for 30 min.

CH2N2, ≈ 0.4 M in Et2O

A solution of KOH (500 mg, 8.77 mmol, 3.90 equiv) in H2O (500 µL), was cooled to

0 °C and Et2O (5.6 mL) was added. To the biphasic mixture at 0 °C was added N-methyl-

N’-nitro-N-nitrosoguanidine (≈ 50% in H2O, 329 mg, 2.24 mmol, 1.00 equiv) in small

portions. The yellow organic solution was decanted and used immediately.

BocProCl, 0.140 M in CH2Cl2

To a solution of DMF (103 µL, 1.38 mmol, 1.00 equiv) in CH2Cl2 (10 mL) at 0 °C was

added oxalyl chloride (121 µL, 1.38 mmol, 1.00 equiv). A white precipitate was formed.

Pyridine (111 µL, 1.38 mmol, 1.00 equiv) was added dropwise to the reaction mixture;

the precipitate dissolved and the solution turned yellow. N-Boc-L-proline (297 mg,

1.38 mmol, 1.00 equiv) was then added to the solution. The reaction mixture was stirred

at 0 °C for 30 min; this solution of N-Boc-L-proline chloride solution was used for the

subsequent peptide coupling.

Rf = 0.73 (EtOAc)

Dimethyl-dioxirane, ≈ 0.09 M in acetone

In a 2 L 2-neck flask (1 exit connected to 100 mL 2-neck receiving flask with dry ice

condenser), a solution of NaHCO3 (29 g) in acetone (96 mL) and H2O (127 mL) was

cooled to 5–10 °C (ice-bath). Oxone (60 g) was added in 5 portions; in-between, the

reaction mixture was stirred for 3 min. 3 min after the last addition, the condenser was

filled with dry ice/acetone and the receiving flask was cooled with a −78 °C cooling bath.

The ice-bath was removed and the solution of DMDO in acetone distilled at reduced

Experimental Part

109

pressure (80–100 Torr). About 60 mL of solution were obtained. The solution is dried

(K2CO3) and stored over activated molecular sieves (3 Å) at −4 °C.

pH 3.6 buffer

Solution of citric acid monohydrate (1.43 g) and Na2HPO4·12H2O (2.31 g) in H2O

(98.5 mL).


3. MgI2-Catalyzed Ring-Expansion Reaction of Spiro-

Cyclopropyl-Oxindoles with Aldimines

NBn

O

O

1-benzyl isatin (97)

To a solution of isatin (20.0 g, 136 mmol, 1.00 equiv) in DMF (250 mL) was cooled to

0 °C (ice bath). NaH (60% dispersion in mineral oil, 5.71 g, 143 mmol, 1.05 equiv) was

added portionwise to the orange solution. The solution changed color to deep purple.

When the gas evolution stopped, benzyl bromide (26.7 g, 156 mmol, 1.16 equiv) was

added slowly, whereupon the mixture turned red-brown. After 15 min, H2O (1.2 L) was

introduced to precipitate the product. After filtration, the product was recrystallized from

refluxing EtOH to afford 97 (28.9 g, 90%) after drying.

mp = 130-132 °C; 1H NMR (CDCl3, 200 MHz) δ 7.65 (dd, 1H, J = 7.5, 1.3 Hz), 7.50

(dt, 1H, J = 7.9, 1.7 Hz), 7.38-7.3 (m, 5H), 7.15-7.08 (m, 1H), 6.80 (d, 1H, J = 7.9 Hz),

4.96 (s, 2H).

NBn

O

1-benzyl-1,2-dihydro-indol-2-one (98)

A solution of 1-benzyl isatin (97) (26.1 g, 117 mmol) in hydrazine hydrate (125 mL) was

heated to reflux till the gas evolution stopped (4 h). The color of the solution changed

from orange via green to yellow during this time. The reaction mixture was allowed to

cool to room temperature and the product was extracted with EtOAc (2 × 150 mL). The

combined organic layers were dried (Na2SO4), filtered, and the solvent was evaporated in

Experimental Part

111

vacuo. The yellow product was recrystallized from refluxing Et2O to afford 98 (17.0 g,

65%) after drying.

mp = 68 °C; 1H NMR (CDCl3, 200 MHz) δ 7.34-7.14 (m, 7H), 7.05-6.97 (m, 1H), 6.73

(d, 1H, J = 7.9 Hz), 4.93 (s, 2H), 3.64 (s, 2H).

NBn

O

1-benzyl-3-cyclopropyl-1,2-dihydro-indol-2-one (99)

A solution of 1-benzyl-indoline-2-one (98) (4.62 g, 20.1 mmol, 1.00 equiv) in DMF

(20 mL) was treated with dibromoethane (4.28 g, 22.8 mmol, 1.13 equiv) and cooled in

an ice/water bath. Then, NaH (1.49 g, 62.1 mmol, 3.09 equiv) was added in portions.

After ~2/3 of the NaH had been added, the cooling bath was removed, and the addition

was continued. After stirring at room temperature for 1 h, the reaction was quenched by

addition of MeOH (5 mL). The reaction mixture was diluted with EtOAc (150 mL) and

washed with water (4 × 50 mL) and brine (30 mL). The combined organic layers were

dried (Na2SO4), the solvent was removed in vacuo and the residue was purified by

column chromatography (3:17 1:5 EtOAc/hexanes) to afford a yellow solid, which was

recrystallized from toluene/cyclohexane to afford 99 (3.76 g, 73%) as a colorless solid

after drying.

mp = 103 °C; 1H NMR (CDCl3, 200 MHz) δ 7.33-7.26 (m, 5H), 7.15 (dt, 1H, J = 7.5,

1.3 Hz), 6.99 (dt, 1H, J = 7.5, 0.9 Hz), 6.86-6.84 (m, 1H), 6.80 (d, 1H, J = 7.8 Hz), 5.00

(s, 2H), 1.81 (dd, 2H, J = 7.8, 4.1 Hz), 1.56 (dd, 2H, J = 7.8, 4.1 Hz); 13C NMR (CDCl3,

75 MHz) δ 177.5, 136.5, 131.1, 129.0, 127.8, 127.6, 126.9, 122.3, 118.6, 11.2, 109.2,

44.2, 27.1, 19.5; IR (KBr) ν 1703, 1616, 1496, 1490, 1466, 1384, 1367, 1339, 1181,

1008, 948, 754, 738, 700, 457; DEI-MS: 249.1 (100 [M]+), 91.0 (100 [C7H7]+); Anal.

calcd for C17H15NO: C 81.90, H 6.06, N 5.62, found: C 81.92, H 6.22, N 5.73.


General procedure for the formation of substituted methylidene arylsulfonamides:

The aldehyde dimethyl- or diethylacetal (1.00 equiv) and the arylsulfonamide

(1.00 equiv) were mixed in a round bottom flask equipped with a Dean-Stark condenser.

The neat mixture was heated to 120−200 °C for 20 min. During this time MeOH or EtOH

distilled off the reaction mixture. The resulting melt was allowed to cool to room

temperature and the solid was recrystallized from refluxing toluene to yield the solid

product.

Remark:

If the dialkylacetals were not commercially available, the dimethyl acetals were prepared

by refluxing the aldehyde overnight in MeOH with HC(OMe)3 (3.00 equiv) and a

catalytic amount of CSA (5 mol%). The reaction mixture was quenched by addition of

NEt3 and the volatiles were evaporated. The unpurified acetals were used for imine

formation.201

NTs

Ph

N-benzylidene-p-toluenesulfonamide (124)

Reaction temperature: 160 °C, recrystallization: toluene, yield: 71%, colorless crystals.

mp = 106 °C; 1H NMR (CDCl3, 400 MHz) δ 8.98 (s, 1H), 7.81-7.50 (m, 5H), 7.88 (d, 2H,

J = 8.4 Hz), 7.29 (d, 2H, J = 8.4 Hz), 2.38 (s, 3H).

[201] Becicka, B. T.; Koerwitz, F. L.; Drtina, G. J.; Baenziger, N. C.; Wiemer, D. F. J. Org. Chem. 1990, 55, 5613-5619.

Experimental Part

113

NTs Me

N-(2-methyl-benzylidene)-p-toluenesulfonamide (127)

Reaction temperature: 160-180 °C, recrystallization: Et2O, yield: 38%, colorless solid.

mp = 90 °C; 1H NMR (CDCl3, 200 MHz) δ 9.37 (s, 1H), 8.06-8.01 (m, 1H), 7.94-7.89

(m, 2H), 7.54-7.46 (m, 1H), 7.39-7.27 (m, 4H), 2.64 (s, 3H), 2.46 (s, 3H).

NTs

Me

N-(4-methyl-benzylidene)-p-toluenesulfonamide (130)

Reaction temperature: 160 °C, recrystallization: toluene, yield: 44%, colorless solid.

mp = 113-115 °C; 1H NMR (CDCl3, 200 MHz) δ 9.00 (s, 1H), 7.91-7.80 (m, 4H),

7.37-7.27 (m, 4H), 2.44 (s, 3H).

NTs Br

N-(2-bromo-benzylidene)-p-toluenesulfonamide (133)

Reaction temperature: 138 °C, recrystallization: toluene, yield: 75%, white solid.


7.95-7.91 (m, 2H), 7.71-7.67 (m, 1H), 7.50-7.37 (m, 4H), 2.47 (s, 3H); 13C NMR (CDCl3,

100 MHz) δ 169.1, 144.8, 135.6, 134.5, 133.7, 131.1, 130.5, 129.8, 128.8, 127.9, 21.6; IR

(KBr) ν 1597, 1582, 1557, 1430, 1320, 1290, 1273, 1215, 1157, 1086, 1048, 1075, 861,

807, 787, 760, 705, 689, 657, 614, 546, 498; DEI-MS: 339.0 (0.14 [M]+), 91.0


(100 [C7H7]+); Anal. calcd for C14H12BrNO2S: C 68.20, H 5.72, N 4.68, found: C 68.14,

H 5.88, N 4.72.

NTs

Br

N-(4-bromo-benzylidene)-p-toluenesulfonamide (136)



(m, 2H), 7.69-7.64 (m, 2H), 7.40-7.36 (m, 2H), 2.47 (s, 3H).

NTs

CF3

N-(4-trifluoromethyl-benzylidene)-p-toluenesulfonamide (139)


mp = 152-153 °C; 1H NMR (CDCl3, 400 MHz) δ 9.08 (s, 1H), 8.05 (d, 2H, J = 8.0 Hz),

7.90 (ddd, 2H, J = 8.3, 8.3, 2.0 Hz), 7.75 (d, 2H, J = 8.3 Hz), 7.36 (ddd, 2H, J = 8.0, 8.0,

2.0 Hz), 2.45 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 168.4, 145.1, 136.0, 133.6, 135.6,

135.4, 134.5, 131.4, 130.0, 128.3, 21.7; IR (KBr) ν 1616, 1590, 1576, 1413, 1327, 1309,

1291, 1172, 1160, 1130, 1103, 1089, 1063, 1013, 873, 841, 789, 677, 644, 561, 551, 501;

DEI-MS: 327.1 (13.4 [M]+), 154.9 (87 [SO2-C7H7]+) 91.0 (100 [C7H7]+); Anal. calcd for

C15H12F3NO2S: C 55.04, H 3.70, N 4.28, found: C 55.09, H 3.93, N 4.33.

Experimental Part

115

NTs

OMe

N-(4-methoxy-benzylidene)-p-toluenesulfonamide (142)

Reaction temperature: 160-180 °C, recrystallization: toluene, yield: 75%, colorless solid.

mp = 127 °C; 1H NMR (CDCl3, 200 MHz) δ 8.95 (s, 1H), 7.92-7.87 (m, 4H), 7.34 (d, 2H,

J = 8.3 Hz), 7.00-6.95 (m, 2H), 3.89 (s, 3H), 2.44 (s, 3H).

NTs

O

N-(furan-2-ylmethylidene)-p-toluenesulfonamide (145)

Reaction temperature: 120 °C, recrystallization: Et2O, yield: 12%, colorless solid.


7.76-7.75 (m, 1H), 7.37-7.32 (m, 3H), 6.66 (dd, 1H, J = 3.7, 2.1 Hz), 2.44 (s, 3H).

NTs

Ph

N-(3-phenyl-allylidene)-p-toluenesulfonamide (148)


mp = 117 °C; 1H NMR (CDCl3, 200 MHz) δ 8.81 (d, 1H, J = 9.1 Hz), 7.91-7.86 (m, 2H),

7.60-7.55 (m, 2H), 7.49-7.42 (m, 5H), 7.39-7.35 (m, 1H), 7.01 (dd, 1H, J = 15.8, 9.1 Hz),

2.46 (s, 3H).


NTs

Ph

Me

N-(2-methyl-3-phenyl-allylidene)-p-toluenesulfonamide (151)

Reaction temperature: 140-200 °C, recrystallization: toluene, yield: 57%, orange solid.

mp = 104-106 °C; 1H NMR (CDCl3, 400 MHz) δ 8.72 (d, 1H, J = 0.5 Hz), 7.89-7.86

(m, 2H), 7.51-7.36 (m, 7H), 2.44 (s, 3H), 2.17 (d, 3H, J = 1.3 Hz); 13C NMR (CDCl3, 100

MHz) δ 174.6, 151.3, 144.3, 135.6, 135.1, 134.9, 130.3, 129.9, 129.7, 128.7, 128.0, 21.6,

12.8; IR (KBr) ν 1615, 1595, 1557, 1439, 1409, 1323, 1315, 1305, 1281, 1209, 1154,

1087, 1021, 841, 813, 801, 793, 750, 701, 696, 680, 656, 589, 556, 532, 515, 513; DEI-

MS: 298.0 (0.46 [M]+), 144.0 (100 [M-SO2-C7H7]+) 91.0 (37 [C7H7]+); Anal. calcd for

C17H17NO2S: C 68.20, H 5.72, N 4.68, found: C 68.14, H 5.88, N 4.72.

NTs

TIPS

N-(3-triisopropylsilanyl-prop-2-ynylidene)-p-toluenesulfonimide (154)

Reaction temperature: 175 ˚C, Kugel-Rohr distillation (160 ˚C at 0.04 Torr), yield: 57%,

colorless oil which solidifies upon standing.

mp = 39-44 ˚C; 1H NMR (CDCl3, 300 MHz,) δ 8.26 (s, 1H), 7.87-7.81 (m, 2H),

7.39-7.33 (m, 2H), 2.45 (s, 3H), 1.18-1.02 (m, 21H); 13C NMR (CDCl3, 75 MHz)

δ 154.6, 145.4, 133.9, 130.0, 128.6, 113.8, 100.7, 21.6, 18.3, 10.8; IR (KBr) ν 2943,

2890, 2866, 2179, 1668, 1595, 1572, 1462, 1329, 1306, 1295, 1189, 1160, 1080, 1019,

997, 882, 818, 706, 685, 629, 552; DEI-MS: 363.1 (0.55 [M]+), 320.0 (100 [M-iPr]+),

91.0 (75 [C7H7]+) Anal. calcd for C19H21NO2SSi C 62.76, H 8.04, N 3.85, found, C 62.75,

H 7.88, N 3.83.

Experimental Part

117

NS

OO

Me

naphthalene-2-sulfonic acid 4-methyl-benzylideneamide (157)

Reaction temperature: 170-180 °C, recrystallization: toluene, yield: 66%, colorless

crystals.


(m, 4H), 7.83 (d, 2H, J = 7.8 Hz), 7.77-7.59 (m, 2H), 7.29 (d, 2H, J = 7.8 Hz), 2.43

(s, 3H); 13C NMR (CDCl3, 75 MHz) δ 170.7, 135.5, 131.8, 130.2, 130.1, 129.8, 129.7,

129.4, 128.2, 127.8, 123.2, 22.1; IR (KBr) ν 1596, 1561, 1319, 1157, 1130, 1072, 860,

822, 798, 761, 655; MS (EI): 309.1 (10 [M]+), 191.0 (17 [SO2-C10H7]+), 127.0

(100 [C10H7]+); HiResEI-MS calcd for C18H15NSO2 [M]+ 309.0823, found, 309.0829.

NS

OO

Me

i-Pr

i-Pri-Pr

2,4,6 triisopropyl-N-(4-methyl-benzylidene)-benzenesulfonamide (158)


crystals.

mp = 167 °C; 1H NMR (CDCl3, 300 MHz) δ 8.97 (s, 1H), 7.81 (d, 2H, J = 8.1 Hz), 7.29

(d, 2H, J = 8.1 Hz), 7.19 (s, 2H), 4.35 (quint, 2H, J = 6.9 Hz), 2.90 (quint, 1H, J =

6.9 Hz), 2.43 (s, 3H), 1.29-1.24 (m, 18H); 13C NMR (CDCl3, 75 MHz) δ 168.9, 153.8,

151.4, 146.3, 131.4, 131.3, 130.5, 130.2, 124.1, 34.3, 29.8, 24.8, 23.6, 22.0; IR (KBr) ν

2957, 2867, 1594, 1561, 1459, 1423, 1360, 1309, 1255, 1228, 1153, 1038, 875, 819, 795,

765, 752, 666; MS (EI): 384.1 (0.08 [M-H]+).


NS

OO

Me

Me

MeMe

Me

Me

2,3,4,5,6 pentamethyl-N-(4-methyl-benzylidene)-benzenesulfonamide (159)

Reaction temperature: 170 °C, recrystallization: toluene, yield: 81%, colorless crystals.

mp = 170 °C; 1H NMR (CDCl3, 300 MHz) δ 9.00 (s, 1H), 7.82 (d, 2H, J = 8.1 Hz), 7.29

(d, 2H, J = 8.1 Hz), 2.63 (s, 6H), 2.43 (s, 3H), 2.29 (s, 3H), 2.25 (s, 6H); 13C NMR

(CDCl3, 75 MHz) δ 168.7, 135.8, 135.2, 131.5, 134.0, 130.1, 22.0, 19.4, 17.8, 1.0; IR

(KBr) ν 1596, 1560, 1307, 1224, 1152, 1009, 870, 804, 768, 619; MS (EI): 329.1 (0.34

[M]+), 147.1 (37 [C11H15]+).

NPhO2S

Ph

N-benzylidene-benzenesulfonamid (104)


crystals.


(m, 6H).

Experimental Part

119

NBn

O

NTs

PhNBn

O

NTs

Ph

125 126

(±)-(2'R,3R)-1'-[(4-methylphenyl)sulfonyl]-2'-phenyl-1-(phenylmethyl)spiro[indole-

3,3'-pyrrolidin]-2(1H)-one (125)

(±)-(2'R,3S)-1'-[(4-methylphenyl)sulfonyl]-2'-phenyl-1-(phenylmethyl)spiro[indole-


(General procedure for the formation of 1’-(p-toluene-sulfonyl)-spiro-3,3’-pyrrolidine

oxindoles)

A solution of 1-benzyl-spiro-3-cyclopropyl-indole-2-one (99) (100 mg, 401 µmol,

1.00 equiv), MgI2 (11.0 mg, 40.0 µmol, 10.0 mol%) and N-benzylidene-p-

toluenesulfonamide (124) (135 mg, 521 µmol, 1.30 equiv) in THF (1 mL) was heated to

60 °C for 8 h. The reaction mixture was allowed to cool to room temperature. EtOAc

(1 mL) was added, followed by H2O (1 mL) and solid Na2S2O3 (a few crystals). The

phases were separated; the aqueous layer was extracted with EtOAc (3 × 20 mL). The

combined organic layers were washed with H2O and brine (20 mL each), dried (Na2SO4)

and filtered. After removal of the solvent in vacuo, the product was purified by column

chromatography (15:85 3:7 EtOAc/hexanes) to afford a solid residue after evaporation

of the solvent. The solid was dissolved in CH2Cl2 (10 mL), washed with 1 M aq NaOH

and H2O (10 mL each) in order to remove toluene-4-sulfonamide and afford the product

as a colorless solid after drying of the organic layer (Na2SO4), filtration and evaporation

of the solvent in vacuo. Yield (both diastereomers): 198 mg (97%).

HPLC retention time: 125 (major): 13.8 min, 126 (minor): 15.2 min (2:8

EtOAc/hexanes), diastereomeric ratio: 91:9.

mp = 160-167 ˚C; 1H NMR (CDCl3, 500 MHz) δ 7.78-7.72 (m, 2H), 7.38-7.33 (m, 2H),

7.27-7.20 (m, 3H), 7.15-6.96 (m, 8H), 6.88-6.80 (m, 2H), 6.49 (d, 1H, J = 7.8 Hz), 4.94

(d, 1H, J = 15.7 Hz), 4.88 (s, 1H), 4.59 (d, 1H, J = 15.7 Hz), 4.20-4.03 (m, 1H), 3.97

(ddd, 1H, J = 10.8, 8.6, 4.8 Hz), 2.46 (s, 3H), 2.20-2.03 (m, 2H); 13C NMR (CDCl3,


125 MHz, * denotes minor diastereomer signals) δ 176.5, 176.0*, 143.9, 143.8*, 142.8*,

142.0, 137.0, 136.5*, 135.3, 135.2*, 135.0*, 133.4, 129.7, 128.9*, 128.8*, 128.7, 128.6,

128.4, 128.3, 128.2, 127.9*, 127.8, 127.6, 127.5, 127.2*, 127.0, 126.7*, 125.3, 122.8*,

122.2, 109.2*, 108.9, 71.7*, 70.5, 60.4*, 59.8*, 59.1, 49.0*, 48.3, 43.7, 43.4*, 35.8*,

34.2, 21.6, 21.0*, 14.2*; IR (KBr) ν 3029, 2922, 2359, 2340, 1709, 1611, 1488, 1467,

1454, 1350, 1164, 1093, 1029, 971, 815, 776, 754, 727, 699, 660, 588, 575, 550; MS

(EI): 508.1 (0.76 [M]+), 353.1 (100 [SO2-C7H7]+), 91.0 (47 [C7H7]+); Anal. calcd for

C31H28N2O3S: C 73.20, H 5.55, N 5.51, found: C 73.05, H 5.75, N 5.46.

Experimental Part

121

NBn

O

NTs

NBn

O

NTs

128 129

Me Me

(±)-(2'R,3R)-2'-(2-methylphenyl)-1'-[(4-methylphenyl)sulfonyl]-1-

(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (128)

(±)-(2'R,3S)-2'-(2-methylphenyl)-1'-[(4-methylphenyl)sulfonyl]-1-


Yield: 89%; HPLC retention time: 128 (major): 15.5 min, 129 (minor): 12.8 min (2:8


mp = 204-205 °C; 1H NMR (C6D6, 500 MHz) δ 7.98-7.96 (m, 2H), 7.69 (dd, 1H, J = 7.8,

0.9 Hz), 7.16-6.94 (m, 9H), 6.73 (d, 1H, J = 7.5 Hz), 6.67 (ddd, 1H, J = 7.7, 7.7, 1.2 Hz),

6.37 (ddd, 1H, J = 7.6, 7.6, 1.0 Hz), 6.23 (d, 1H, J = 7.5 Hz), 5.80-5.78 (m, 1H), 5.44

(s, 1H), 4.58 (d, 1H, J = 15.5 Hz), 4.23 (d, 1H, J = 15.5 Hz), 4.11 (ddd, 1H, J = 10.3, 9.0,

6.7 Hz), 3.85 (ddd, 1H, J = 9.0, 6.0, 2.2 Hz), 1.99 (ddd, 1H, J = 13.0, 10.3, 8.0 Hz), 1.94

(s, 3H), 1.66 (ddd, 1H, J = 13.0, 6.7, 2.2 Hz), 1.53 (s, 3H); 13C NMR (C6D6, 125 MHz)

δ 178.1, 143.0, 138.7, 136.5, 136.2, 135.8, 130.2, 129.5, 129.5, 128.9, 128.7, 128.4,

128.1, 127.9, 127.6, 127.5, 127.5, 126.1, 125.4, 121.9, 108.3, 65.1, 57.1, 47.3, 43.2, 34.4,

21.3, 18.8; IR (KBr) ν 1706 (vs), 1608, 1487, 1465, 1341, 1305, 1164, 1094, 1031, 774,

751, 671, 658, 588, 552; DEI-MS: 522.3 (0.85 [M]+), 367.2 (100 [M-SO2-C7H7]+), 132.1

(55 [N=CMe-C7H7]+), 91.0 (42 [C7H7]+); Anal. calcd for C32H30N2O3S: C 73.54, H 5.79,

N 5.36, found: C 73.64, H 5.93, N 5.44.


NBn

O

NTs

NBn

O

NTs

131 132Me Me

(±)-(2'R,3R)-2'-(4-methylphenyl)-1'-[(4-methylphenyl)sulfonyl]-1-


(±)-(2'R,3S)-2'-(4-methylphenyl)-1'-[(4-methylphenyl)sulfonyl]-1-




mp = 178 °C; 1H NMR (CDCl3, 500 MHz, # denotes major-, * minor diastereomer

signals) δ 7.74-7.71 (m, 2H#), 7.76-7.73 (m, 2H*), 7.36-6.61 (m, 4H), 7.25-6.84

(m, 23H), 6.50 (d, 1H#, J = 7.3 Hz), 6.44 (d, 1H*, J = 7.4 Hz), 6.48-6.46 (m, 1H#), 5.00

(s, 1H*), 4.99 (d, 1H*, J = 15.7 Hz), 4.97 (d, 1H#, J = 15.8 Hz), 4.78 (s, 1H#), 4.55

(d, 1H#, J = 15.8 Hz), 4.42 (ddd, 1H*, J = 11.4, 11.4, 5.7 Hz), 4.16 (d, 1H*, J = 15.7 Hz),

4.15-4.04 (m, 1H#, 1H*), 3.93 (ddd, 1H#, J = 10.8, 8.8, 4.6 Hz), 2.48 (s, 3H*), 2.46

(s, 3H#), 2.31 (s, 3H*), 2.24 (s, 3H#), 2.19-2.11 (m, 1H#, 1H*), 2.08-2.02 (m, 1H#), 1.96

(ddd, 1H*, J = 12.6, 11.4, 8.22 Hz); 13C NMR (CDCl3, 125 MHz, * denotes minor

diastereomer signals) δ 176.4, 176.1*, 143.9, 143.7*, 142.8*, 142.0, 137.4, 137.3*, 135.3,

135.1*, 135.0*, 133.6, 129.7, 128.9*, 128.7, 128.6, 128.5*, 128.4, 128.4, 128.3, 128.2,

127.8, 127.5, 127.5, 127.2*, 126.9, 126.9, 126.7, 125.4, 122.8*, 122.3, 122.2*, 109.3*,

109.0, 71.6*, 70.5, 59.7*, 59.1, 49.0*, 48.3, 43.6, 43.4*, 35.7*, 34.0, 21.6, 21.6*, 21.3*,

21.2; IR (KBr) ν 1711, 1612, 1597, 1489, 1467, 1459, 1380, 1351, 1164, 1092, 1029,

1019, 816, 751, 733, 709, 698, 660, 591, 584, 572, 550, 542; DEI-MS: 522.0 (2.9 [M]+),

367.0 (100 [M-SO2-C7H7]+), 132.1 (84 [N=CMe-C7H7]+), 91.0 (47 [C7H7]+); Anal. calcd

for C32H30N2O3S: C 73.54, H 5.79, N 5.36, found: C 73.43, H 5.95, N 5.48.

Experimental Part

123

NBn

O

NTs

NBn

O

NTs

134 135

Br Br

(±)-(2'R,3R)-2'-(2-bromophenyl)-1'-[(4-methylphenyl)sulfonyl]-1-


(±)-(2'R,3S)-2'-(2-bromophenyl)-1'-[(4-methylphenyl)sulfonyl]-1-




mp = 204-205 °C; 1H NMR (CDCl3, 500 MHz) δ 7.84-7.81 (m, 3H), 7.43-7.19 (m, 9H),

7.12-7.07 (m, 1H), 7.03 (ddd, 1H, J = 7.7, 7.7, 1.1 Hz), 6.62-6.60 (m, 1H), 6.54 (ddd, 1H,

J = 7.7, 7.7, 1.1 Hz), 5.74 (ddd, 1H, J = 7.7, 7.7, 1.1 Hz), 5.27 (s, 1H), 4.91 (d, 1H, J =

15.4 Hz), 4.54 (d, 1H, J = 15.4 Hz), 4.04-4.01 (m, 1H), 3.94 (ddd, 1H, J = 11.4, 8.9,

6.2 Hz), 2.47 (s, 3H), 2.38 (ddd, 1H, J = 13.1, 11.4, 7.9 Hz), 2.09 (ddd, 1H, J = 13.1, 6.2,

1.3 Hz); 13C NMR (CDCl3, 125 MHz) δ 178.0, 143.7, 143.2, 139.0, 135.8, 133.4, 132.2,

129.5, 129.2, 128.6, 128.4, 128.4, 127.8, 127.7, 127.2, 126.8, 124.4, 124.3, 121.8, 108.5,

66.8, 56.7, 47.2, 43.5, 34.4, 29.7, 21.7; IR (KBr) ν 1710, 1612, 1489, 1465, 1372, 1354,

1341, 1159, 1091, 1013, 814, 776, 751, 741, 700, 652, 587, 547; DEI-MS: 588.0

(0.3 [M]+), 433.0 (100 [M-SO2-C7H7]+), 91.0 (47 [C7H7]+); Anal. calcd for

C31H27BrN2O3S: C 63.37, H 4.63, N 4.77, found: C 63.23, H 4.88, N 4.84.


NBn

O

NTs

NBn

O

NTs

137 138Br Br

(±)-(2'R,3R)-2'-(4-bromophenyl)-1'-[(4-methylphenyl)sulfonyl]-1-


(±)-(2'R,3S)-2'-(4-bromophenyl)-1'-[(4-methylphenyl)sulfonyl]-1-




mp = 153-154 °C; 1H NMR (CDCl3, 500 MHz, # denotes major-, * minor diastereomer

signals) δ 7.75-7.69 (m, 4H), 7.38-7.35 (m, 4H), 7.27-6.89 (m, 24H), 6.53-6.48 (m, 2H),

5.02 (s, 1H*), 4.96 (d, 1H*, J = 15.9 Hz), 4.96 (d, 1H#, J = 15.7 Hz), 4.75 (s, 1H#), 4.57

(d, 1H#, J = 15.7 Hz), 4.42 (ddd, 1H*, J = 11.5, 11.5, 5.6 Hz), 4.15 (d, 1H*, J = 15.9 Hz),

4.15-4.04 (m, 1H#, 1H*), 3.93 (ddd, 1H#, J = 11.0, 9.0, 3.9 Hz), 2.49 (s, 3H*), 2.47

(s, 3H#), 2.20-2.12 (m, 2H), 2.04-1.99 (m, 2H); 13C NMR (CDCl3, 125 MHz, * denotes

minor diastereomer signals) δ 178.8*, 175.9, 144.2, 144.1*, 142.8*, 142.9, 135.7*, 135.6,

135.1, 134.9*, 134.8*, 132.8, 131.1, 130.7, 129.8, 129.2, 129.1*, 128.8*, 128.7, 128.2,

127.8*, 127.7, 127.5*, 126.9, 126.7, 125.2, 123.0*, 122.5, 122.2*, 121.9*, 121.8, 109.4*,

109.2, 71.0*, 70.2, 59.7*, 59.2, 49.0*, 48.5, 43.7, 43.5*, 35.8*, 34.0, 21.7; IR (KBr)

ν 1710, 1612, 1488, 1466, 1385, 1368, 1351, 1338, 1176, 1160, 1097, 1033, 1010, 808,

753, 740, 706, 657, 589, 548; DEI-MS: 588.0 (0.7 [M]+), 433.0 (100 [M-SO2-C7H7]+),

196.0 (43 [N=CMe-C7H7]+), 91.0 (45 [C7H7]+); Anal. calcd for C31H27BrN2O3S: C 63.37,

H 4.63, N 4.77, found: C 63.42, H 4.83, N 4.66.

Experimental Part

125

NBn

O

NTs

NBn

O

NTs

140 141CF3 CF3

(±)-(2'R,3R)-1'-[(4-methylphenyl)sulfonyl]-1-(phenylmethyl)-2'-[4-

(trifluoromethyl)phenyl]spiro[indole-3,3'-pyrrolidin]-2(1H)-one (140)

(±)-(2'R,3S)-1'-[(4-methylphenyl)sulfonyl]-1-(phenylmethyl)-2'-[4-

(trifluoromethyl)phenyl]spiro[indole-3,3'-pyrrolidin]-2(1H)-one (141)




signals) δ 7.74-7.71 (m, 4H), 7.39-6.95 (m, 26H), 6.88 (ddd, 1H#, J = 7.6, 7.6, 1.0 Hz),

6.54-6.50 (m, 2H*), 6.53 (d, 1H#, J = 12.9 Hz), 5.09 (s, 1H*), 4.95 (d, 1H#, J = 15.6 Hz),

4.93 (d, 1H*, J = 15.8 Hz), 4.90 (s, 1H#), 4.59 (d, 1H#, J = 15.6 Hz), 4.43 (ddd, 1H*, J =

11.5, 11.5, 5.7 Hz), 4.18 (d, 1H*, J = 15.8 Hz), 4.15-4.06 (m, 1H#, 1H*), 3.97 (ddd, 1H#,

J = 11.0, 8.9, 3.9 Hz), 2.47 (s, 3H#), 2.47 (s, 3H*), 2.22-2.13 (m, 2H), 2.06-2.00 (m, 2H); 13C NMR (CDCl3, 125 MHz, * denotes minor diastereomer signals) δ 175.9, 175.7*,

144.3, 144.2*, 141.9, 142.7*, 140.9, 135.1, 134.8*, 132.8, 130.0*, 129.9, 129.8, 129.6*,

129.2*, 128.8, 128.7, 128.6*, 128.2, 127.9, 127.8, 127.6*, 127.5*, 127.0, 126.6, 125.3*,

125.1, 124.8*, 124.5, 124.5, 124.5*, 122.5, 122.3*, 109.5*, 109.2, 70.9*, 70.2, 59.7*,

59.3, 49.0*, 48.6, 43.8, 43.5*, 36.1*, 34.3, 21.6, 21.6*; IR (KBr) ν 1711, 1615, 1488,

1466, 1375, 1370, 1353, 1340, 1328, 1160, 1112, 1068, 1029, 1016, 836, 810, 751, 744,

700, 657, 589, 548; DEI-MS: 576.0 (0.25 [M]+), 421.0 (100 [M-SO2-C7H7]+); Anal. calcd

for C32H27F3N2O3S: C 66.65, H 4.72, N 4.86, found: C 66.47, H 4.81, N 4.66.


NBn

O

NTs

NBn

O

NTs

143 144OMe OMe

(±)-(2'R,3R)-2'-[4-(methyloxy)phenyl]-1'-[(4-methylphenyl)sulfonyl]-1-


(±)-(2'R,3S)-2'-[4-(methyloxy)phenyl]-1'-[(4-methylphenyl)sulfonyl]-1-




mp = 153-155 °C; 1H NMR (CDCl3, 500 MHz, # denotes major-, * minor diastereomer

signals) δ 7.75-7.72 (m, 2H*), 7.72-7.69 (m, 2H#), 7.36-7.34 (m, 4H), 7.22-6.87

(m, 22H), 6.66-6.64 (m, 1H*), 6.62-6.60 (m, 1H#), 6.45 (d, 1H#, J = 8.5 Hz), 6.48

(d, 1H*, J = 7.1 Hz), 5.00 (d, 1H*, J = 16.4 Hz), 4.97 (d, 1H#, J = 15.8 Hz), 4.98

(s, 1H*), 4.73 (s, 1H#), 4.53 (d, 1H#, J = 15.8 Hz), 4.44 (ddd, 1H*, J = 11.4, 11.4,

5.7 Hz), 4.16 (d, 1H*, J = 16.4 Hz), 4.12-4.04 (m, 2H), 3.92 (ddd, 1H#, J = 10.7, 9.0,

4.5 Hz), 3.75 (s, 3H*), 3.72 (s, 3H#), 2.48 (s, 3H*), 2.46 (s, 3H#), 2.21-2.13 (m, 2H),

2.09-2.02 (m, 1H#), 2.01-1.93 (m, 1H*); 13C NMR (CDCl3, 125 MHz, * denotes minor

diastereomer signals) δ 176.3, 176.2*, 159.3*, 159.2, 143.9, 143.7*, 142.8*, 142.0, 135.2,

135.2*, 135.0*, 133.2, 129.7, 129.7*, 128.9, 128.9*, 128.7, 128.6*, 128.5, 128.5*,

128.5*, 128.4, 128.2, 128.2*, 127.8, 127.8*, 127.5, 127.3*, 126.9, 126.7*, 125.3, 122.8*,

122.3, 122.3*, 113.3*, 113.0, 109.2*, 109.0, 71.4*, 70.3, 59.8*, 59.2, 55.1, 55.0*, 49.0*,

48.0, 43.6, 43.3*, 35.5*, 33.7, 21.6, 21.6*; IR (KBr) ν 1708, 1514, 1493, 1360, 1350,

1249, 1176, 1160, 1092, 1023, 824, 757, 699, 668, 659, 575, 543; DEI-MS: 538.1

(23 [M]+), 383.1 (100 [M-SO2-C7H7]+), 148.1 (89 [N=CMe-C7H7]+), 91.0 (42 [C7H7]+);

Anal. calcd for C32H30N2O4S: C 71.35, H 5.61, N 5.20, found: C 71.24, H 5.74, N 5.18.

Experimental Part

127

NBn

O

NTs

NBn

O

NTs

146 147O O

(±)-(2'S,3R)-2'-furan-2-yl-1'-[(4-methylphenyl)sulfonyl]-1-


(±)-(2'S,3S)-2'-furan-2-yl-1'-[(4-methylphenyl)sulfonyl]-1-




mp = 161-162 °C; 1H NMR (CDCl3, 500 MHz) δ 7.75-7.72 (m, 2H), 7.33-7.07 (m, 9H),

6.84 (ddd, 1H, J = 7.6 Hz, 7.6 Hz, 1.0 Hz), 6.70-6.68 (m, 1H), 6.61 (d, 1H, J = 7.5 Hz),

6.21-6.19 (m, 1H), 6.16-6.15 (m, 1H), 4.98 (s, 1H), 4.94 (d, 1H, J = 15.7 Hz), 4.69

(d, 1H, J = 15.7 Hz), 3.95-3.92 (m, 2H), 2.44 (s, 3H), 2.35-2.28 (m, 1H) 2.18-2.11

(m, 1H); 13C NMR (CDCl3, 125 MHz) δ 176.6, 151.2, 143.6, 142.3, 141.8, 135.5, 134.3,

129.6, 128.8, 128.6, 127.9, 127.6, 127.1, 124.4, 122.5, 110.4, 109.2, 108.9, 63.2, 57.5,

47.3, 43.6, 34.5, 21.6; IR (KBr) ν 1706, 1614, 1600, 1489, 1466, 1459, 1450, 1369, 1353,

1340, 1311, 1221, 1176, 1161, 1098, 1081, 1037, 1009, 831, 815, 756, 744, 699, 661,

601, 588, 547, 532, 473; DEI-MS: 498.1 (4.5 [M]+), 343.1 (44 [M-SO2-C7H7]+), 108.1

(100 [N=CMe-C7H7]+), 91.0 (44 [C7H7]+); Anal. calcd for C29H26N2O4S: C 69.86, H 5.26,

N 5.62, found: C 69.88, H 5.37, N 5.68.


NBn

O

NTs

NBn

O

NTs

149 150Ph Ph

(±)-(2'R,3R)-1'-[(4-methylphenyl)sulfonyl]-2'-[(E)-2-phenylethenyl]-1-


(±)-(2'R,3S)-1'-[(4-methylphenyl)sulfonyl]-2'-[(E)-2-phenylethenyl]-1-





signals) δ 7.77-7.74 (m, 2H#), 7.75-7.72 (m, 2H*), 7.60-7.58 (m, 1H#), 7.36-7.33

(m, 2H#), 7.26-6.94 (m, 23H), 6.86-6.82 (m, 2H*), 6.82-6.78 (m, 2H#), 6.56-6.53

(m, 1H*), 6.55 (dd, 1H#, J = 7.7, 1.0 Hz), 6.41 (d, 1H#, J = 16.0 Hz), 6.17 (d, 1H*, J =

16.0 Hz), 6.03 (dd, 1H*, J = 16.0, 8.7 Hz), 5.82 (dd, 1H#, J = 16.0, 8.9 Hz), 5.16 (d, 1H#,

J = 16.0 Hz), 5.12 (d, 1H*, J = 17.0 Hz), 4.54 (d, 1H*, J = 8.7 Hz), 4.47 (d, 1H*, J =

17.0 Hz), 4.41 (d, 1H#, J = 16.0 Hz), 4.17 (ddd, 1H*, J = 16.7, 9.9, 6.5 Hz), 4.09-3.99

(m, 2H), 4.03 (dd, 1H#, J = 8.9, 0.7 Hz), 3.67 (ddd, 1H#, J = 13.8, 10.5, 3.3 Hz), 2.46

(s, 3H#), 2.39 (s, 3H*), 2.35-2.29 (m, 2H), 2.18 (ddd, 1H*, J = 12.8, 9.9, 8.3 Hz), 2.02

(ddd, 1H#, J = 11.3, 8.0, 3.3 Hz); 13C NMR (CDCl3, 125 MHz, * denotes minor

diastereomer signals) δ 176.3*, 175.5, 144.1, 143.4*, 142.6*, 141.9, 136.0, 135.9*,

135.1*, 134.7, 133.0, 133.3*, 132.6, 129.8, 129.6, 129.5*, 129.4*,128.8*, 128.7, 128.6,

128.6*, 128.5, 128.4*, 128.1, 127.9, 127.9*, 127.7*, 127.4*, 127.3, 126.9, 126.8*,

126.8*, 126.5, 125.4, 125.1*, 124.5, 123.1, 123.0*, 109.6, 109.3*, 72.5*, 69.9, 58.8,

58.6*, 48.0, 43.9, 43.5*, 35.2*, 33.0, 21.6, 21.5*; IR (KBr) ν 1709, 1613, 1494, 1481,

1467, 1452, 1375, 1352, 1362, 1341, 1327, 1173, 1163, 1153, 1106, 1098, 1085, 979,

971, 749, 738, 697, 664, 610, 584, 547; DEI-MS: 534.1 (40 [M]+), 379.1

(49 [M-SO2-C7H7]+), 144.1 (100 [N=CMe-CH=CH-C6H5]+), 91.0 (42 [C7H7]+); Anal.

calcd for C33H30N2O3S: C 74.13, H 5.66, N 5.24, found: C 74.09, H 5.83, N 5.17.

Experimental Part

129

NBn

O

NTs

NBn

O

NTs

152 153Ph Ph

Me Me

(±)-(2'R,3R)-2'-[(E)-1-methyl-2-phenylethenyl]-1'-[(4-methylphenyl)sulfonyl]-1-


(±)-(2'R,3S)-2'-[(E)-1-methyl-2-phenylethenyl]-1'-[(4-methylphenyl)sulfonyl]-1-





signals) δ 7.86 (d, 2H#, J = 8.2 Hz), 7.83-7.80 (m, 2H*), 7.41-6.93 (m, 29H), 6.79

(d, 1H#, J = 7.5 Hz), 6.71 (d, 1H*, J = 7.7 Hz), 6.67 (d, 1H#, J = 7.7 Hz), 5.06 (d, 1H#, J =

15.6 Hz), 5.03 (d, 1H*, J = 15.2 Hz), 4.62 (d, 1H*, J = 15.2 Hz), 4.52 (d, 1H#, J =

15.6 Hz), 4.50 (s, 1H#), 4.46 (s, 1H#), 4.19-4.11 (m, 1H#), 4.01-3.87 (m, 3H), 2.47

(s, 3H#), 2.45 (s, 3H*), 2.41-2.35 (m, 1H#), 2.10-1.81 (m, 1H#, 2H*), 1.78 (s, 3H#), 1.44

(s, 3H*); 13C NMR (CDCl3, 125 MHz, * denotes minor diastereomer signals) δ 176.9*,

175.6, 144.0*, 143.7, 142.3*, 142.2, 137.1, 137.1*, 135.5*, 135.4, 135.0, 135.0*, 129.8,

129.7*, 129.4, 129.2 , 128.8, 128.7, 128.6*, 128.2, 128.2*, 128.0, 127.9*, 127.8, 127.8*,

127.7, 127.6*, 127.5, 127.3*, 127.1, 127.0*, 126.5*, 126.4, 125.4, 125.3*, 123.4*, 122.9,

122.4, 122.3*, 109.3, 109.0*, 77.2, 75.0*, 63.9*, 58.5, 48.7*, 48.6, 44.0, 43.8*, 35.5*,

35.4, 21.7, 21.6*, 16.6*, 15.8; IR (KBr) ν 1711, 1611, 1597, 1489, 1466, 1455, 1349,

1164, 1093, 1029, 1015, 750, 731, 698, 667.9, 667.5, 588, 581, 550; DEI-MS: 548.1

(2.7 [M]+), 393.1 (26 [M-SO2-C7H7]+), 158.1 (100 [N=CMe-CMe=CH-C6H5]+), 91.0

(100 [C7H7]+); Anal. calcd for C34H32N2O3S: C 74.43, H 5.88, N 5.11, found: C 74.43,

H 6.04, N 4.99.


NBn

O

NTs

NBn

O

NTs

155 156TIPS TIPS

(±)-(2'S,3R)-1'-[(4-methylphenyl)sulfonyl]-1-(phenylmethyl)-2'-{[tris(1-

methylethyl)silyl]ethynyl}spiro[indole-3,3'-pyrrolidin]-2(1H)-one (155)

(±)-(2'S,3S)-1'-[(4-methylphenyl)sulfonyl]-1-(phenylmethyl)-2'-{[tris(1-

methylethyl)silyl]ethynyl}spiro[indole-3,3'-pyrrolidin]-2(1H)-one (156)



mp = 133-137 ˚C; 1H NMR (CDCl3, 300 MHz) δ 7.90-7.84 (m, 2H), 7.49-7.44 (m, 1H),

7.39-7.21 (m, 7H), 7.17 (ddd, 1H, J = 1.2, 7.8, 7.8 Hz), 7.03 (ddd, 1H, J = 0.9, 7.5,

7.5 Hz), 6.72 (d, 1H, J = 7.5 Hz), 4.93 (d, 1H, J = 15.6 Hz), 4.78 (d, 1H, J = 15.9 Hz),

4.49 (s, 1H), 3.90-3.70 (m, 2H), 2.46 (s, 3H), 2.20 (ddd, 1H, J = 9.0, 9.0, 12.5 Hz), 2.02

(ddd, 1H, J = 4.0, 7.2 Hz, 12.6 Hz) 0.90-0.80 (m, 21H); 13C NMR (CDCl3, 75 MHz)

δ 175.7, 144.0, 142.3, 135.6, 134.1, 129.9, 128.9, 128.7, 128.0, 127.8, 127.3, 125.0,

123.1, 109.2, 100.6, 89.5, 58.3, 57.8, 47.6, 44.0, 34.3, 21.5, 18.2, 10.8; IR (KBr)

ν 2947.1, 2863.5, 2360.2, 2343.0, 1717.0, 1611.9, 1487.5, 1466.7, 1366.8, 1352.2,

1167.1, 1092.9, 816.0, 747.7, 698.1, 681.3, 661.7, 573.3, 548.3; DEI-MS: 612.3

(2.6 [M]+), 569.3 (79 [M-iPr]+), 457.3 (100 [M-SO2-C7H7]+), 91.0 (94 [C7H7]+); Anal.

calcd for C36H44N2O3SSi: C 70.55, H 7.24, N 4.57, found: C 70.53, H 7.35, N 4.76.

Experimental Part

131

NBn

O

N

160

SO O

Me

NBn

O

N

161

SO O

Me

+

(±)-(2'R,3R)-2'-(4-methylphenyl)-1'-(naphthalen-2-ylsulfonyl)-1-


(±)-(2'R,3S)-2'-(4-methylphenyl)-1'-(naphthalen-2-ylsulfonyl)-1-




mp = 181°C; 1H NMR (CDCl3, 300 MHz) δ 8.33 (d, 2H, J = 1.5 Hz), 8.16 (d, 2H, J =

8.7 Hz), 7.95-7.93 (m, 2H), 7.85 (dd, 1H, J = 8.4 Hz, 1.9 Hz), 7.69-7.58 (m, 2H), 7.22-

6.82 (m, 12H), 6.47 (d, 1H, J = 7.5 Hz), 4.95 (d, 1H, J = 16.4 Hz), 4.90 (s, 1H), 4.52

(d, 1H, J = 16.4 Hz), 4.14-4.05 (m, 2H), 2.22 (s, 3H), 2.21-2.08 (m, 2H); 13C NMR

(CDCl3, 125 MHz) δ 176.4, 142.1, 137.5, 136.8, 135.3, 135.1, 133.7, 133.5, 129.6, 129.3,

129.2, 128.8, 128.6, 128.4, 128.0, 127.7, 127.5, 127.4, 126.9, 125.4, 123.4, 122.2, 109.0,

70.5, 59.0, 48.2, 43.6, 33.9, 21.2; IR (KBr) ν 1711, 1612, 1488, 1469, 1455, 1348, 1241,

1164, 1132, 1075, 1020, 969, 864, 817, 794, 750, 698, 657, 618, 580, 568, 547, 477;

DEI-MS: 558.2 (3.5 [M]+), 367.2 (100 [M-SO2-C10H7]+); Anal. calcd for C35H30N2O3S: C

75.24, H 5.41, N 5.01, found: C 74.99, H 5.58, N 5.02.


NBn

O

O

CF3

2'-(4-trifluoromethylphenyl)-1-(phenylmethyl)spiro[indole-3,3'-oxolane]-2(1H)-one

(163)

A solution of MgI2 (12.0 mg, 43.0 µmol, 10 mol%), oxindole 99 (107 mg, 429 µmol,

1.00 equiv) and 4-trifluoromethyl-benzaldehyde (165) (75 µL, 563 µmol, 1.31 equiv) in

THF (2 mL) was placed into a sealed tube and heated to 100 °C for 20 h. The reaction

mixture was allowed to cool to room temperature before being diluted with EtOAc

(2 mL) and quenched with H2O (2 mL) and a few crystals of Na2S2O3. The phases were

separated and the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined

organic layers were washed with brine and H2O (30 mL each), dried (NaSO4), filtered,

concentrated and purified by chromatography (95:5 2:8 EtOAc/hexanes) to afford a

single diastereomer of desired 163 (34.0 mg, 19%) as a colorless solid.

mp = 156 °C; 1H NMR (CDCl3, 200 MHz) δ 7.47-7.43 (m, 3H), 7.29-7.08 (m, 7H),

6.59-6.55 (m, 3H), 5.25 (s, 1H), 5.02 (d, 1H, J = 15.4 Hz), 4.79 (ddd, 1H, J = 7.9, 7.9,

7.9), 4.43 (ddd, 1H, J = 7.9, 7.9, 5.8 Hz), 4.22 (d, 1H, J = 15.4 Hz), 2.71-2.63 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 177.0, 143.6, 140.7, 135.4, 129.0, 128.8, 127.7, 126.9,

126.9, 126.2, 125.2, 125.2, 125.1, 123.1, 122.7, 109.6, 88.2, 68.6, 59.0, 43.7, 38.0; IR

(KBr) ν 1707, 1610, 1490, 1470, 1368, 1322, 1174, 1159, 1123, 1109, 1066, 1016, 760,

668; DEI-MS: 423.1 (12, [M]+), 249.1 (100 [M–CH(CH3)-p-CF3Ph]+), 91.0 (70 [C7H7]+);

Anal. calcd for C25H20F3NO2: C 70.91, H 4.76, N 3.31, found: C 70.99, H 4.77, N 3.45.

Experimental Part

133

NBn

O

NH

p-TolO2S

OEtO

ethyl {[(4-methylphenyl)sulfonyl]amino}[2'-oxo-1'-(phenylmethyl)-1',2'-dihydro

spiro[cyclopropane-1,3'-indol]-5'-yl]acetate (167)

To a solution of ethyl glyoxylate (164) (1.55 g, 15.2 mmol, 1.00 equiv), in toluene

(15 mL) was added p-toluenesulfonyl isocyanate (2.31 mL, 15.2 mmol, 1.00 equiv). The

reaction mixture was heated to reflux for 3 d and then cooled to room temperature before

being concentrated to give sulfonimide 165 which was used without further purification.

A solution of MgI2 (6.00 mg, 21.8 µmol, 7.6 mol%), oxindole (99) (72.0 mg, 288 µmol,

1.00 equiv) and sulfonimide 165 (149 mg, 0.584 mmol, 2.00 equiv) in THF (1 mL) was

heated to reflux for 18 h. The reaction mixture was allowed to cool to room temperature

before being diluted with EtOAc (1 mL) and quenched with H2O (1 mL) as well as a few

crystals of Na2S2O3. The phases were separated and the aqueous layer was extracted with

EtOAc (3 × 20 mL). The combined organic layers were washed with brine and H2O

(20 mL each), dried (NaSO4), filtered, concentrated and purified by chromatography (2:8

3:7 EtOAc/hexanes). The residue was dissolved in CH2Cl2 (10 mL), washed with 1 M

aq NaOH and H2O (10 mL each) in order to remove toluene-4-sulfonamid and afforded

pure 167 (42.0 mg, 29%) after drying of the organic layer (Na2SO4) and evaporation of

the solvent in vacuo.


7.10-7.02 (m, 3H), 6.70 (d, 1H, J = 7.9), 6.59-6.58 (m, 1H), 5.60 (d, 1H, J = 7.5 Hz), 5.02

(d, 1H, J = 15.4 Hz), 4.98 (d, 1H, J = 7.5 Hz), 4.90 (d, 1H, J = 15.4 Hz), 4.15-3.87

(m, 2H), 2.33 (s, 3H), 1.78-1.76 (m, 2H), 1.52-1.37 (m, 2H), 1.10 (t, 3H, J = 7.1 Hz); 13C NMR (CDCl3, 75 MHz) δ 177.0, 170.0, 143.3, 142.9, 137.1, 136.0, 131.5, 129.3,

129.2, 128.8, 127.7, 127.5, 127.1, 126.3, 117.1, 108.8, 62.3, 59.3, 44.2, 27.0, 21.4, 19.6,

19.6, 13.8; IR (KBr) ν 1742, 1709,1684, 1627, 1499, 1448, 1383, 1332, 1189, 1165,

1091, 1030, 1010, 712, 668, 560, 551; DEI-MS 504.2 (20 [M]+), 431.2 (100


[M−CO2Et]+), 91.0 (40 [C7H7]+); Anal. calcd for C28H28N2O5S: C 66.65, H 5.59, N 5.55,

found: C 66.55, H 5.70, N 5.48.

Crystal data for 167 at 293(2) K, Mr = 504.58, monoclinic space group P2(1)c, ρcalc =

1.283 mg·cm–3, Z = 4, a = 11.985(11), b = 13.454(7), c = 16.70(2) Å, α = 90.00, β =

104.00(8), γ = 90.00°, V = 2613(4) Å3. Final R(F) = 0.0681, wR(F2) = 0.1540 for 335

parameters and 2600 reflections with I >2σ(I) and 1.75 < θ < 20.03°.

CCDC 199468 (167) contains the supplementary crystallographic data for this structure.

This data can be obtained free of charge via www.ccdc.cam.ac.uk/retrieving.html (or

from the Cambridge Crystallographic Data Center, 12, Union Road, Cambridge CB21EZ,

UK; fax: (+44)1223-336-033; or [email protected]).

NSO2Ph

Ph

OPh2N

N,N-1,2-tetraphenylpyrrolidine-3-carboxamide (170)

To MgI2 (88.0 mg, 320 µmol, 1.00 equiv), N,N-diphenyl-cyclopropane carboxamide

(169) (75.0 mg, 320 µmol, 1.00 equiv) and N-benzylidene-p-toluenesulfonamide (104)

(101 mg, 410 µmol, 1.30 equiv) was added a degassed solution (by passing a stream of

Ar trough the solution) of DMA (29.5 µL, 320 µmol, 1.00 equiv) in m-xylene (1 mL).

The reaction mixture was heated to 145 °C for 48 h, then allowed to cool to room

temperature before being diluted with EtOAc (1 mL) and quenched with H2O (1 mL) as

well as a few crystals of Na2S2O3. The phases were separated and the aqueous layer was

extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine

and water (20 mL each), dried (NaSO4), filtered, concentrated and purified by column

chromatography (1:3 EtOAc/hexanes) to afford 170 (both diastereomers).

Both residues from chromatography were dissolved in CH2Cl2 (10 mL), washed with 1 M

aq NaOH and H2O (10 mL each) n order to remove benzene-sulfonamide and afforded

Experimental Part

135

pure 170 (both diastereomers) (84.0 mg, 54%) after drying of the organic layer (Na2SO4)

and evaporation of the solvent in vacuo.

Diastereomer 1: colorless oil, yield: 51.0 mg (33%).

1H NMR (CDCl3, 300 MHz) δ 7.83-7.79 (m, 2H), 7.61-7.48 (m, 4H), 7.32-7.16 (m, 12H),

7.08-6.98 (m, 1H), 6.72-6.62 (m, 1H), 4.92 (d, 1H, J = 8.1 Hz), 3.78 (ddd, 1H, J = 11.0,

6.2, 5.0 Hz), 4.43 (ddd, 1H, J = 11.0, 11.0, 8.1 Hz), 3.07 (q, 1H, J = 8.1 Hz), 1.90-1.82

(m, 2H); 13C NMR (CDCl3, 75 MHz) δ 171.4, 141.3, 137.7, 133.0, 129.3, 128.8, 127.9,

126.7, 111.2, 68.4, 53.3, 49.8, 29.3; IR (KBr) ν 1738, 1669, 1594, 1490, 1447, 1377,

1347, 1263, 1163, 1098, 761, 722, 692, 599; FAB-MS calcd for C29H26N2O3S [M+H]+

483.1743, found, 483.1746.

Diastereomer 2: colorless solid, yield: 33.0 mg (21%).


6.57-6.53 (m, 2H), 4.67 (d, 1H, J = 8.3 Hz), 3.86-3.77 (m, 1H), 3.56-3.33 (m, 2H), 2.70

(ddd, 1H, J = 13.3, 9.5, 8.3 Hz), 2.06-1.96 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 169.6,

143.0, 139.0, 132.2, 130.0, 128.8, 128.8, 128.6, 128.2, 128.2, 127.1, 126.1, 110.5, 64.4,

47.8, 47.7, 27.4; IR (KBr) ν 1674, 1493, 1444, 1347, 1308, 1177, 1163, 1099, 1075,

1052, 1018, 757, 717, 710, 697, 689, 668, 602, 572; FAB-HRMS calcd for C29H26N2O3S

[M+H]+ 483.1743, found, 483.1737.

NBn

O

I

1-benzyl-3-(2-iodo-ethyl)-1,3-dihydro-indol-2-one (175)

1H NMR (CDCl3, 300 MHz) δ 7.35-7.24 (m, 6H), 7.19 (dt, 1H, J = 7.8, 1.2 Hz), 7.03

(dt, 1H, J = 7.8, 1.2 Hz), 6.74 (d, 1H, J = 7.8 Hz), 3.66 (dd, 1H, J = 6.5, 6.5 Hz), 3.49

(ddd, 1H, J = 10.0, 8.4, 6.9, Hz), 3.35 (ddd, 1H, J = 10.0, 8.4, 6.9, Hz), 2.51-2.38

(m, 2H); HiResMALDI-MS calcd for C17H16NOI [M+H]+ 378.0355, found, 378.0345.


4. Synthesis of (±)-Horsfiline by MgI2-Catalyzed Ring-

Expansion Reaction of Spiro-Cyclopropyl-Oxindole and 1,3,5-

Trimethyl-1,3,5-Triazinane

NBn

NMe

O

1'-methyl-1-(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (207)

A 10 mL sealable tube was charged with 1-benzyl-spiro-3-cyclopropyl-indole-2-one (99)

(100 mg, 400 µmol, 1.00 equiv) and anhydrous MgI2 (5.60 mg, 20.0 µmol, 5 mol%). The

tube was sealed, evacuated and back-filled with argon. 1,3,5-Trimethylhexahydro-1,3,5-

triazine (206) (56.0 µL, 400 µmol, 1.00 equiv) and THF (0.5 mL) were added and the

tube sealed, before it was submerged in a preheated oil bath at 125 ºC. The reaction

mixture turned pale-orange, and, after a few minutes, a colorless solid was observed to

precipitate. After 20 h the reaction mixture was allowed to cool to room temperature and

was then further cooled in an ice bath. H2O (1 mL), a crystal of Na2S2O3, and EtOAc

(2 mL) were added whereupon more of the precipitate formed. The reaction mixture was

extracted with EtOAc (2 × 20 mL), the layers were separated and the combined organic

layers washed with brine, dried (Na2SO4),filtered, and concentrated in vacuo. Purification

of the yellow oil by column chromatography on silica gel (4:1 EtOAc/acetone) afforded

207 (116 mg, 97%) as colorless oil of.


7.06-7.01 (m, 1H), 6.72-6.69 (m, 1H), 4.92 (s, 2H), 3.14-3.07 (m, 1H), 2.93 (d, 1H, J =

9.0 Hz), 2.88 (d, 1H, J = 9.0 Hz), 2.82-2.73 (m, 1H), 2.48 (s, 3H), 2.47-2.39 (m, 1H),

2.17-2.08 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 180.4, 42.0, 135.9, 135.1, 128.8, 127.6,

127.2, 123.2, 123.0, 108.8, 66.7, 56.5, 53.2, 43.8, 41.7, 38.1; IR (KBr) ν 2944, 2836,

2789, 1707, 1603, 1496, 1456, 1436, 1359, 1346, 1303, 1282, 1176, 1030, 807, 739, 697,

668; DEI-MS: 324.1(29.9 [M+2H]+), 323.1(100.0 [M+H]+), 322.1(26.3 [M]+); Anal.

calcd for C20H22N2O2: C 74.51, H 6.88, N 8.69, found: C 74.36, H 6.62, N 8.45.

Experimental Part

137

NBn

MeO O

O

1-benzyl-5-methoxy-isatin (210)

5-Methoxyisatin (194) (1.00 g, 5.65 mmol, 1.00 equiv) was placed in a 2-neck flask and

DMF (10 mL) was added. NaH (95%, 142 mg, 5.92 mmol, 1.05 equiv) was added

portionwise to the brown solution which changed color to dark-blue. After the H2

evolution had stopped, benzyl bromide (771 µL, 6.49 mmol, 1.15 equiv) was added

dropwise. The color changed back to brown-red. After stirring for 1 h at room

temperature, H2O (30 mL) was added and a red sticky solid was observed to precipitate.

The aqueous layer was extracted with EtOAc (8 × 40 mL), the combined organic layers

were dried (Na2SO4) and filtered. The solvent was evaporated in vacuo. The remaining

DMF was removed under high vacuum at 60 ºC. The red solid was purified by column

chromatography on silica gel (2:1 hexane/EtOAc) and 194 (140 mg) and 210 (red solid,

1.11 g, 74%) were obtained.

mp = 117-118 °C; 1H NMR (CDCl3, 300 MHz) δ 7.37-7.31 (m, 5H), 7.16 (d, 1H, J =

2.8 Hz), 7.03 (dd, 1H, J = 8.4, 2.8 Hz), 6.68 (d, 1H, J = 8.4 Hz), 4.91 (s, 2H), 3.78

(s, 3H); 13C NMR (CDCl3, 75 MHz) δ 183.8, 158.5, 156.6, 144.6, 134.6, 129.1, 128.1,

127.4, 124.7, 118.1, 112.0, 109.6, 56.0, 44.1; IR (KBr) ν 1723, 1621, 1602, 1494, 1472,

1437, 1349, 1336, 1313, 1271, 1238, 1175, 1145, 1080, 1047, 1018, 836, 773, 695, 473;

DEI-MS 269.1 (30.4, [M+2H]+), 268.1(100.0, [M+H]+), 267.0 (32.7, [M]+); Anal. calcd

for C16H13NO3: C 71.90, H 4.90, N 5.24, found: C 71.84, H 5.09, N 5.25.

NBn

MeO

O

1-benzyl-5-methoxy-1,2-dihydro-indol-2-one (211)

1-Benzyl-5-methoxy-isatin (210) (702 mg, 2.63 mmol) was dissolved in hydrazine

hydrate (5 mL) and the solution heated to reflux. After 45 min, the reaction mixture was


allowed to cool to room temperature and a green-yellow oil separated. The reaction

mixture was diluted with water (40 mL) and extracted with Et2O (30 mL). The organic

layer was dried (Na2SO4), filtered, and the solvent evaporated in vacuo. Product 211

(647 mg, 97%) was obtained as yellow oil and used without further purification. An

analytically pure sample could be obtained by chromatography on silica gel (1:3

EtOAc/hexane).


6.62-6.59 (m, 1H), 4.90 (s, 2H), 3.76 (s, 3H), 3.61 (s, 2H); 13C NMR (CDCl3, 75 MHz)

δ 175.0, 156.0, 136.1, 128.8, 127.7, 127.4, 125.9, 112.2, 112.0, 109.4, 55.7, 43.7, 36.0; IR

(KBr) ν 1708, 1602, 1494, 1454, 1436, 1359, 1345, 1289, 1220, 1180, 1142, 1037, 806,

746, 705, 676, 621; HRMS-MS calcd for C16H15NO2 [M+H]+ 253.1103, found, 253.1104.

NBn

MeO

O

1-benzyl-3-cyclopropyl-5-methoxy -1,2-dihydro-indol-2-one (212)

An ethereal solution of 211 (402 mg, 1.59 mmol, 1.00 equiv) was concentrated in a

2-neck flask and dried under high vacuum. After the addition of DMF (2 mL) and

1,2-dibromoethane (0.150 mL, 1.70 mmol, 1.07 equiv) the reaction mixture was cooled to

0 ºC. NaH (95.0%, 114 mg, 5.75 mmol, 3.61 equiv) was added portionwise and the color

of the reaction mixture turned from yellow to auburn upon addition. After 3 h, H2O

(40 L) was added and the aqueous layer extracted with EtOAc (2 × 25 mL). The

combined organic layers were washed with H2O (4 × 20 mL) and brine (20 mL), dried

(Na2SO4), filtered, and the solvent was evaporated in vacuo. An auburn oil was obtained

which was purified by chromatography on silica gel (1:9 1:8 EtOAc/hexane) yielding

358 mg (81%) of 212 as colorless crystals.

mp = 112-113 °C; 1H NMR (CDCl3, 300 MHz) δ 7.34-7.24 (m, 5H), 6.67 (m, 2H),

6.47-6.46 (m, 1H), 4.98 (s, 2H), 3.75 (s, 3H), 1.84-1.80 (m, 2H), 1.55-1.51 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 177.1, 156.0, 136.4, 132.4, 128.8, 127.6, 127.4, 111.1,

Experimental Part

139

111.0, 109.3, 106.1, 55.8, 44.1, 27.3, 19.4. IR (KBr) ν 3060, 3037, 3009, 2916, 2838,

1692, 1602, 1491, 1475, 1454, 1438, 1382, 1350, 1334, 1286, 1239, 1077, 1056, 1031,

1003, 954, 892, 882, 806, 745, 732, 698, 652, 596, 558, 458; DEI-MS 281.1

(23.6 [M+2H]+), 280.1 (71.3 [M+H]+), 279.1 (100.0 [M]+); Anal. calcd for C18H17NO2:

C 77.40, H 6.13, N 5.01, found: C 77.31, H 6.30, N 4.96.

NBn

MeO

O

NMe

1'-methyl-5-(methyloxy)-1-(phenylmethyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one

(213)

A 10 mL sealable tube was charged with 212 (50.0 mg, 180 µmol, 1.00 equiv) and

anhydrous MgI2 (2.50 mg, 9.00 µmol, 5 mol%). The tube was closed, evacuated and

back-filled with argon. 1,3,5-trimethylhexahydro-1,3,5-triazine (26.0 µL, 180 µmol, 1.00

equiv) and THF (0.3 mL) were added and the tube sealed, before it was submerged in a

preheated oil bath at 125 ºC. The reaction mixture turned pale-orange, and, after a few

minutes, a colorless solid was observed to precipitate. After 60 h the reaction mixture was

allowed to cool to room temperature and was then further cooled in an ice bath. H2O

(1 mL), a crystal of Na2S2O3, and EtOAc (2 mL) were added, whereupon more of the

precipitate formed. The reaction mixture was extracted with EtOAc (3 × 10 mL), the

layers were separated and the combined organic layers washed with brine (10 mL), dried

(Na2SO4), filtered, and concentrated in vacuo. Purification of the yellow oil by

chromatography on silica gel (4:1 EtOAc/acetone) afforded 213 (48.0 mg, 83%) as

colorless oil.

1H NMR (CDCl3, 300 MHz) δ 7.34-7.22 (m, 5H), 7.10 (d, 1H, J = 2.5 Hz), 6.67 (dd, 1H,

J = 8.4, 2.5 Hz), 7.10 (d, 1H, J = 8.4 Hz), 4.89 (s, 2H), 3.77 (s, 3H), 3.14-3.07 (m, 1H),

2.96 (d, 1H, J = 9.3 Hz), 2.88 (d, 1H, J = 9.3 Hz), 2.81-2.72 (m, 1H), 2.49 (s, 3H),

2.47-2.39 (m, 1H), 2.18-2.08 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 180.3, 156.5, 138.9,

136.2, 135.5, 128.8, 127.6, 127.3, 112.1, 110.4, 109.1, 66.4, 56.6, 55.8, 53.7, 43.8, 41.8,


38.1; IR (KBr) ν 2944, 2836, 2789, 1707, 1603, 1496, 1456, 1436, 1359, 1346, 1303,

1282, 1176, 1030, 807, 739, 697, 668; DEI-MS: 324.1 (29.9 [M+2H]+), 323.1

(100.0 [M+H]+), 322.1 (26.3 [M]+); Anal. calcd for C20H22N2O2: C 74.51, H 6.88, N 8.69,

found: C 74.36, H 6.62, N 8.45.

NH

MeO

O

NMe

(±)-Horsfiline ((±)-16)

Ammonia (5 mL) was condensed at –78 °C and Na was added with vigorous stirring at

−42 ºC until the blue color persisted. A solution of Spiro-pyrrolidine-oxindole 213

(32.0 mg, 100 µmol) in THF (0.5 mL) was added. After 13 min H2O (25 mL) and a small

amount of NH4Cl were added. The pH of the reaction mixture was adjusted to pH 11 with

6 N aq HCl. The mixture was extracted with CH2Cl2 (6 × 20 mL) and washed with brine

(20 mL). The combined organic layers were dried (Na2SO4) and the solvent evaporated in

vacuo. Recrystallization from n-hexane yielded (±)-horsfiline ((±)-16) (21.0 mg, 91%) as

a colorless solid.

mp = 151 °C; 1H NMR (CDCl3, 300 MHz) δ 8.9 (br, 1H), 7.02 (d, 1H, J = 2.5 Hz), 6.82

(d, 1H, J = 8.3 Hz), 6.72 (dd, 1H, J = 8.3, 2.5 Hz), 3.79 (s, 3H), 3.04-2.97 (m, 1H), 2.89

(d,1H, J = 9.3 Hz), 2.84 (d, 1H, J = 9.3 Hz), 2.81-2.73 (m, 1H), 2.46 (s, 3H), 2.43-2.37

(m, 1H), 2.13-2.04 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 183.3, 156.3, 137.8, 133.7,

112.4, 110.3, 110.0, 66.3, 56.7, 55.8, 54.1, 41.7, 37.9; IR (KBr) ν 3173, 2785, 1702,

1638, 1619, 1602, 1480, 1442, 1319, 1279, 1258, 1229, 1210, 1183, 1161, 1138, 1058,

1036, 907, 883, 791, 681, 668, 641; DEI-MS 234.1 (20.4 [M+2H]+), 233.1

(100.0 [M+H]+), 232.1 (24.0 [M]+); Anal. calcd for C13H16N2O2: C 67.22, H 6.94,

N 12.06, found: C 67.37, H 6.94, N 11.86.

Experimental Part

141

5. Synthesis of (–)-Spirotryprostatin B Employing the MgI2-

Catalyzed Ring-Expansion Reaction

OSO

Me

O

4-methyl-[1,3,2]dioxathiolane 2-oxide (280)

1,2-Propane diol (279) (10.0 g, 131 mmol, 1.00 equiv) was dissolved in CH2Cl2 (30 mL)

and the solution was cooled to 0 °C. A solution of SOCl2 (11.8 mL, 162 mmol,

1.24 equiv) in CH2Cl2 (20 mL) was added via addition funnel over 1 h. The reaction

mixture was then heated to reflux for 1 h and allowed to cool to room temperature. H2O

(50 mL) was added to the reaction mixture, the layers were separated and the organic

layer was washed with H2O (2 × 50 mL) and brine (30 mL), dried (Na2SO4), filtered, then

the solvent was evaporated in vacuo and a colorless liquid was obtained. The unpurified

sulfite 280 was used for the next step.

Rf = 0.48; 1H NMR (CDCl3, 200 MHz, # denotes major-, * minor diastereomer signals)

δ 5.19-5.06 (m, 1#H),4.73 (dd, 1H#, J = 8.1, 5.8 Hz), 4.74-4.49 (m, 2H*), 4.32 (dd, 1H*,

J = 9.1, 8.3 Hz), 3.90 (dd, 1H#, J = 8.1, 7.1 Hz), 1.63 (d, 3H*, J = 6.2 Hz), 1.45 (d, 3H#,

J = 6.3 Hz).

OSO

Me

OO

4-methyl-[1,3,2]dioxathiolane 2,2-dioxide (281)

Sulfite 280 (8.00 g, 65.5 mmol, 1.00 equiv) was dissolved in CH3CN/CCl4 (1:1)

(400 mL). The solution was cooled to 0 °C. Precooled H2O (280 mL) was added to the

mixture. Solid NaIO4 (27.2 g, 131 mmol, 2.00 equiv) and RuCl3·3H2O (68.0 mg,


330 µmol, 0.5 mol%) were added in one portion. The reaction mixture was vigorously

stirred for 1 h. The phases were separated and the aqueous layer was extracted with Et2O

(300 mL). The combined organic layers were dried (Na2SO4), filtered, and the solvent

was evaporated in vacuo. Column chromatography (1:1 EtOAc/hexanes) afforded 281

(8.34 g, 92%) as colorless liquid.

Rf = 0.32; 1H NMR (CDCl3, 200 MHz,) δ 5.24-5.07 (m, 1H), 4.76 (dd, 1H, J = 8.7, 5.8

Hz), 4.34 (dd, 1H, J = 8.7, 8.7 Hz), 1.63 (d, 3H, J = 6.2 Hz).

NBn

O

Me

(±)-(1S,2S)-2-methyl-1'-(phenylmethyl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one

(282)

Cyclic sulfate 281 (68.1 mg, 490 µmol, 1.10 equiv) was dissolved in DME (1.5 mL).

NaH (95%, 54.0 mg, 1.34 mmol, 3.00 equiv) was added and to the resulting suspension, a

solution of oxindole 98 (100 mg, 450 µmol, 1.00 equiv) in DME (1 mL) was slowly

added. The reaction mixture was stirred at room temperature for 16 h and was then

quenched by addition of H2O (1 mL). The layers were separated and the aqueous layer

was extracted with EtOAc (3 × 5 mL). The combined organic layers were dried

(Na2SO4), filtered, and the solvent was evaporated in vacuo. Column chromatography

(1:19 EtOAc/hexanes) afforded 282 (64.0 mg, 54%) as a colorless oil.

Rf = 0.49 (1:3 EtOAc/hexanes); 1H NMR (CDCl3, 300 MHz) δ 7.33-7.25 (m, 5H), 7.12

(ddd, 1H, J = 7.8, 6.9, 2.2 Hz), 7.03-6.96 (m, 2H), 6.83-6.80 (m, 1H), 4.99 (s, 2H),

2.08-1.98 (m, 2H), 1.37 (d, 3H, J = 6.2 Hz), 1.37-1.33 (m, 1H); 13C NMR (CDCl3, 75

MHz) δ 177.3, 143.4, 136.3, 128.7, 128.4, 127.5, 127.4, 126.4, 121.5, 120.8, 109.0, 44.1,

32.0, 27.6, 26.0, 13.3; IR (KBr) ν 3055, 3004, 2984, 2924, 1705, 1613, 1487, 1466, 1453,

1431, 1396, 1386, 1370, 1352, 1186, 1103, 1034, 986, 870, 758, 735, 697; DEI-MS 263.2

(60 [M]+), 91.0 (100 [C7H7]+); Anal. calcd for C18H17NO: C 82.10, H 6.51, N 5.32, found:

C 81.93, H 6.64, N 5.30.

Experimental Part

143

NBn

O

285

NTs

NBn

O

286

NTs

O O

Me Me

+

(±)-(3R,5'R)-5'-methyl-1'-[(4-methylphenyl)sulfonyl]-1-(phenylmethyl)-2'H-

spiro[indole-3,3'-pyrrolidine]-2,2'(1H)-dione (285)

(±)-(3S,5'R)-5'-methyl-1'-[(4-methylphenyl)sulfonyl]-1-(phenylmethyl)-2'H-

spiro[indole-3,3'-pyrrolidine]-2,2'(1H)-dione (286)

A sealable tube was charged with spiro-cyclopropyl-oxindole 282 (885 mg, 340 µmol,

1.00 equiv) and MgI2 (23.0 mg, 84.0 µmol, 25 mol%). p-Tosylisocyanate (56.3 µL, 380

µmol, 1.10 equiv) was added followed by THF (0.3 mL). The tube was sealed and heated

to 100 °C for 3 d. The reaction mixture was allowed to cool to room temperature and

EtOAc (1 mL) was added, followed by H2O (1 mL) as well as solid Na2S2O3 (a crystal).

The phases were separated and the aqueous layer was extracted with EtOAc (3 × 20 mL).

The combined organic layers were washed with H2O and brine (20 mL each), dried

(Na2SO4) and filtered. After removal of the solvent in vacuo, the product was purified by

radial chromatography (3:17 EtOAc/hexanes) to afford the two diastereomers 285 and

286, (combined yield: 74 mg (48%)) together with unreacted 282 (45.1 mg, 51%)

Minor diastereomer 285: colorless crystals; yield: 31.0 mg (20%).

Rf = 0.25 (1:3 EtOAc/hexanes); mp = 162 °C; 1H NMR (CDCl3, 300 MHz) δ 7.98-7.93

(m, 2H), 7.35-6.99 (m, 10H), 6.68-6.64 (m, 1H), 4.83 (d, 1H, J = 15.7 Hz), 4.71 (d, 1H,

J = 15.7 Hz), 2.88 (dd, 1H, J = 13.7, 7.5 Hz), 2.47-2.40 (m, 1H), 2.40 (s, 3H), 2.10

(dd, 2H, J = 13.0, 7.1 Hz), 1.80 (d, 3H, J = 6.2 Hz); 13C NMR (CDCl3, 75 MHz) δ 173.7,

169.5, 145.3, 143.1, 135.6, 134.9, 129.7, 129.5, 129.2, 128.8, 128.3, 127.7, 127.0, 123.6,

123.4, 109.8, 58.5, 54.4, 44.1, 36.9, 22.8, 21.7; IR (KBr) ν 1739, 1704, 1609, 1487, 1467,

1365, 1328, 1211, 1176, 1119, 1077, 752, 704, 668, 577, 547; DEI-MS 460.1 (8.4 [M]+),

91.0 (100 [C7H7]+); Anal. calcd for C18H17NO: C 67.81, H 5.25, N 6.08, found: C 67.96,

H 5.36, N 5.96.


Crystal data for 285 at 293(2) K, Mr = 460.53, triclinic space group P-1, ρcalc = 1.361

mg·cm–3, Z = 2, a = 9.750(10), b = 10.807(12), c = 12.172(10) Å, α = 103.37(8), β =

95.24(8), γ = 113.10(8)°, V = 1124(2) Å3. Final R(F) = 0.0355, wR(F2) = 0.1044 for 301






Major diastereomer 286: colorless crystals, yield: 43.0 mg (29%).

Rf = 0.23 (1:3 EtOAc/hexanes); mp = 171-173 °C; 1H NMR (CDCl3, 300 MHz)

δ 7.99-7.95 (m, 2H), 7.35-6.95 (m, 10H), 6.67 (d, 1H, J = 7.9 Hz), 4.97 (d, 1H, J =

15.7 Hz), 4.83-4.72 (m, 1H), 4.79 (d, 1H, J = 15.7 Hz), 2.67 (dd, 1H, J = 13.3, 7.9 Hz),

2.42 (dd, 1H, J = 12.5, 5.0 Hz), 2.44 (s, 3H), 1.79 (d, 3H, J = 6.2 Hz); 13C NMR (CDCl3,

75 MHz) δ 173.8, 169.6, 145.1, 143.6, 135.0, 129.5, 129.3, 128.9, 128.8, 127.7, 127.3,

127.0, 127.0, 123.6, 123.3, 109.6, 58.3, 54.7, 43.9, 37.8, 23.9, 21.7; IR (KBr) ν 1737,

1700, 1612, 1461, 1468, 1342, 1203, 1188, 1167, 1127, 1080, 755, 668, 576, 547;

DEI-MS 460.1 (10.4 [M]+), 91.0 (100 [C7H7]+); Anal. calcd for C18H17NO: C 67.81,

H 5.25, N 6.08, found: C 67.95, H 5.29, N 5.92.

Crystal data for 286 at 293(2) K, Mr = 460.53, triclinic space group P-1, ρcalc = 1.295

mg·cm–3, Z = 4, a = 10.155(8), b = 14.690(14), c = 17.70(2) Å, α = 113.53(7), β =

101.53(7), γ = 90.01(7)°, V = 2362(4) Å3. Final R(F) = 0.0386, wR(F2) = 0.0879 for 599






Experimental Part

145

NBn

N2

O

1-benzyl-3-diazo-1,3-dihydro-indol-2-one (289)

1-Benzyl-isatin (97) (1.00 g, 4.22 mmol, 1.00 equiv) was suspended in MeOH (20 mL).

The suspension was heated to 60 °C, whereupon a deep-red solution was obtained. To

this hot solution was added tosylhydrazine (793 mg, 4.26 mmol, 1.01 equiv) in one

portion. A yellow product starts precipitating from the hot mixture. The reaction mixture

was stirred at 60 °C for 18 h, and then allowed to reach room temperature. The

intermediate tosylhydrazone (1.37 g, 80%) was collected by filtration and was used

without further purification.

A solution of the tosylhydrazone (1.00 g, 2.47 mmol, 1.00 equiv) in THF (10 mL) was

treated with a solution of NaOH (197 mg, 4.93 mmol, 2.00 equiv) in H2O (25 mL). The

reaction mixture was stirred for 3 h at room temperature. EtOAc (20 mL) was added to

the reaction mixture and the layers were separated The aqueous layer was ajusted to pH 7

by addition of dry-ice, and extracted with EtOAc (30 mL). The combined organic layers

were dried (Na2SO4), filtered, and the solvent was evaporated in vacuo. Column

chromatography (3:17 EtOAc/hexanes) afforded 289 (451 mg, 73%) as deep-orange

crystals.

Rf = 0.55 (1:3 EtOAc/hexanes); mp = 89 °C; 1H NMR (300 MHz, CDCl3) δ 7.32-7.20 (m,

6H), 7.12-7.04 (m, 2H), 6.84-6.82 (m, 1H), 5.03 (s, 1H). 13C NMR (75 MHz, CDCl3)

δ 136.0, 133.7, 128.8, 127.7, 127.3, 125.5, 122.2, 118.3, 116.8, 109.6, 44.3; IR (thin film)

ν 2130, 1668, 1610, 1589, 1481, 14.68, 1404, 1383, 1342, 1178, 1168, 1103, 740, 697,

681, 668, 636; DEI-MS 249.0 (13.5 [M]+), 193.0 (35 [M-N2-CO]+), 91.0 (100 [C7H7]+);

Anal. calcd for C15H11N3O: C 72.28, H 4.45, N 16.86, found: C 72.31, H 4.57, N 16.78.


MeOOMe

O

2-methoxy-acrylic acid methyl ester (288)

NaOMe (14.5 g, 231 mmol, 3.00 equiv) was dissolved in MeOH (120 mL) and the

solution was cooled to 0 °C. To this solution, 2,3 dibromo-propionic acid ethyl ester was

added slowly by addition funnel. The reaction mixture was allowed to stir at room

temperature for 6 d. Then the mixture was quenched and ajusted to pH 7 by addition of

dry-ice. The resulting white precipitate was removed by filtration; the filtrate was diluted

with CH2Cl2 (100 mL) and washed with H2O (2 × 120 mL). The organic layer was dried

over Na2SO4, filtered, and the solvent was evaporated in vacuo. The remaining product

was purified by distillation under reduced pressure (30 mbar) to give 288 (4.20 g, 36%)

as a colorless liquid.

bp = 50 °C (30 mbar); 1H NMR (300 MHz, CDCl3) δ 5.38 (d, 1H, J = 2.9 Hz), 4.65

(d, 1H, J = 2.9 Hz), 3.84 (s, 3H), 3.68 (s, 3H).

NBn

O

MeOCO2Me

methyl 2-(methyloxy)-2'-oxo-1'-(phenylmethyl)-1',2'-dihydrospiro[cyclopropane-

1,3'-indole]-2-carboxylate (290)

In a 50 mL two-neck flask equipped with a reflux condenser and a CaCl2 drying tube was

placed [Rh(OAc)2]2 (4.42 mg, 10.0 µmol, 2 mol%). Benzene (2 mL) and acrylate 288

(291 mg, 2.51 mmol, 5.00 equiv) were added and the mixture was heated to reflux. A

solution of diazo-oxindole 289 (125 mg, 500 µmol, 1.00 equiv) in benzene (2 mL) was

added to the refluxing mixture by syringe pump over a period of 5 h. The reaction

mixture was allowed to reach room temperature and was then filtered over Celite eluting

with benzene. Evaporation of the solvent yielded an orange oil. The product was purified

by column chromatography (1:4 EtOAc/hexanes) to afford 290 (two diastereomers)

(150 mg, 89%).

Experimental Part

147


Rf = 0.26 (1:3 EtOAc/hexanes); 1H NMR (CDCl3, 300 MHz) δ 7.33-7.23 (m, 5H),

7.20-7.11 (m, 2H), 7.00 (dt, 1H, J = 7.5, 0.9 Hz), 6.77 (d, 1H, J = 7.8 Hz), 4.99 (d, 1H,

J = 15.9 Hz), 4.90 (d, 1H, J = 15.9 Hz), 3.84 (s, 3H), 3.47 (s, 3H), 2.59 (d, 2H, J =

6.2 Hz), 2.02 (d, 2H, J = 6.2 Hz); 13C NMR (CDCl3, 75 MHz) δ 186.9, 164.1, 140.8,

133.6, 126.4, 125.3, 125.3, 124.9, 123.0, 120.1, 119.8, 106.7, 55.6, 50.1, 41.5, 35.7, 23.2,

11.7; IR (KBr) ν 2948, 1743, 1710, 1616, 1489, 1468, 1378, 1348, 1277, 1234, 1190,

1134, 1014, 750, 697; FAB-MS 338.0 (100 [M]+).

Diastereomer 2: colorless solid, yield: 116 mg (69%).

Rf = 0.20 (1:3 EtOAc/hexanes); mp = 76 °C; 1H NMR (CDCl3, 300 MHz) δ 7.33-7.26 (m,

5H), 7.18-7.13 (m, 2H), 6.95 (dt, 1H, J = 7.6, 1.2 Hz), 6.77 (d, 1H, J = 7.9 Hz), 5.08 (d,

1H, J = 16.1 Hz), 4.90 (d, 1H, J = 16.1 Hz), 3.76 (s, 3H), 3.53 (s, 3H), 2.54 (d, 2H, J =

6.2 Hz), 2.51 (d, 2H, J = 6.2 Hz); 13C NMR (CDCl3, 75 MHz) δ 172.0, 168.4, 143.6,

136.3, 129.0, 127.9, 127.8, 127.6, 125.5, 122.6, 122.1, 109.0, 58.8, 52.8, 44.4, 39.3, 25.4;

IR (KBr) ν 1718, 1702, 1610, 1559, 1540, 1488, 1467, 1457, 1437, 1368, 1295, 1203,

1167, 1108, 1040, 751, 736; MS (MaldiTOF) 338.4 (100 [M]+).

NBn

O

CO2Et

EtO2C

meso-diethyl 2'-oxo-1'-(phenylmethyl)-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-

2,3-dicarboxylate (294)

A solution of diethyl fumarate (293) (62.0 mg, 361 µmol, 1.00 equiv) and diazo-oxindole

289 (108 mg, 433 µmol, 1.20 equiv) in toluene (0.5 mL) was heated to reflux for 3 d. The

solvent was evaporated in vacuo and the residue was purified by column chromatography

(1:4 EtOAc/hexanes) to afford 294 (118 mg, 83%) as a white solid.


Rf = 0.37; 1H NMR (300 MHz, CDCl3) δ 7.38-7.26 (m, 6H), 7.22-7.16 (m, 1H), 7.00

(dt, 1H, J = 7.5, 0.9 Hz), 6.78 (d, 1H, J = 8.1 Hz), 5.06 (d, 1H, J = 15.6 Hz), 4.86 (d, 1H,

J = 15.6 Hz), 4.27-4.09 (m, 4H), 3.33 (s, 2H), 1.28-1.21 (m, 6H); HiResMALDI-MS

calcd for C23H23NO5 [M+Na]+ 416.1474, found, 416.1466.

NBn

O

NC

2'-oxo-1'-(phenylmethyl)-1',2'-dihydrospiro[cyclopropane-1,3'-indole]-2-carbonitrile

(296)

A mixture of diazo-oxindole 289 (108 mg, 660 µmol, 1.00 equiv) and Pd(OAc)2

(1.42 mg, 6.60 µmol, 1 mol%) in acrylonitrile (295) (16.5 mL) was heated to reflux for

16 h. The solvent was evaporated in vacuo and the residue was purified by column

chromatography (1:4 EtOAc/hexanes) to afford the 296 (two diastereomers) (160 mg,

80%).

Diastereomer 1: 85.0 mg (47%).

Rf = 0.35; 1H NMR (300 MHz, CDCl3) δ 7.38-7.24 (m, 6H), 7.25-7.19 (m, 1H), 7.17

(dt, 1H, J = 7.3, 0.9 Hz), 6.88 (d, 1H, J = 7.6 Hz), 5.01 (d, 1H, J = 15.3 Hz), 4.96 (d, 1H,

J = 15.3 Hz), 2.52 (dd, 1H, J = 6.8, 5.0 Hz), 2.21 (dd, 1H, J = 6.8, 3.4 Hz), 1.94 (dd, 1H,

J = 5.0, 3.4 Hz).

Diastereomer 2: 75.0 mg (41%).

Rf = 0.18; 1H NMR (300 MHz, CDCl3) δ 7.37-7.25 (m, 5H), 7.23 (dt, 1H, J = 7.4,

0.9 Hz), 7.22 (dt, 1H, J = 7.3, 0.8 Hz), 6.86-6.80 (m, 2H), 5.07 (d, 1H, J = 15.8 Hz), 4.98

(d, 1H, J = 15.8 Hz), 2.35 (dd, 1H, J = 6.1, 5.0 Hz), 2.26 (dd, 1H, J = 5.0, 3.3 Hz), 2.02

(dd, 1H, J = 6.1, 3.3 Hz).

Experimental Part

149

HOOH

OTBS

1-(tert-butyl-dimethyl-silanyloxy)-propane-1,2-diol (298)

Allyl alcohol (297) (1.00 mL, 15.0 mmol, 1.00 equiv) was dissolved in DMF (7 mL), and

the solution was cooled to 0 °C. Imidazole (1.30 g, 19.0 mmol, 1.30 equiv) was added

followed by TBSCl (2.88 g, 19.0 mmol, 1.30 equiv). The reaction mixture was allowed to

stir for 15 min, and was quenched by addition of H2O (20 mL). The layers were

separated, and the aqueous layer was extracted with EtOAc (3 × 40 mL). The combined

organic layers were dried (Na2SO4), filtered, and the solvent was carefully removed to

afford TBS-protected allyl alcohol.

Rf = 0.73; (1:1 EtOAc/hexanes).

To a solution of K2OsO4 (17.3 mg, 47.0 µmol, 0.3 mol%) and NMO·H2O (2.15 g, 15.9

mmol, 1.06 equiv) in a mixture of H2O/acetone/tBuOH (6:15:2, 11.5 mL) was slowly

added the protected allylalcohol. The reaction mixture was stirred at room temperature

for 16 h, then quenched by addition of 10% aq Na2SO4. The mixture is filtered though

Celite (eluting with CH2Cl2) and the layers of the filtrate were separated. The aqueous

layer was extracted with EtOAc (2 × 15 mL) and the combined organic layers were dried

(Na2SO4) and filtered. Column chromatography (EtOAc) afforded 298 (1.86 g, 60%).

Rf = 0.40; 1H NMR (200 MHz, CDCl3) δ 3.75-3.65 (m, 5H), 2.56 (d, 1H, J = 4.6 Hz),

2.10 (d, 1H, J = 5.0 Hz), 0.93-0.91 (m, 9H), 0.10-0.09 (m, 6H).

OSO

OO

OTBS

tert-butyl-(2,2-dioxo-2λ6-[1,3,2] dioxathiolan-4-ylmethoxy)-dimethyl-silane (299)

A solution of protected glycerol 298 (1.86 g, 9.01 mmol, 1.00 equiv) and NEt3 (4.99 mL,

36.0 mmol, 4.00 equiv) in CH2Cl2 (27 mL) was cooled to 0 °C. A solution of SOCl2

(0.98 mL, 13.5 mmol, 1.50 equiv) in CH2Cl2 (2.25 mL) was added dropwise. The


reaction mixture was then stirred at 0 °C for 1 h and diluted with Et2O (50 mL). H2O

(50 mL) was added to the reaction mixture, and the layers were separated. The organic

layer was washed with H2O (2 × 50 mL) and brine (30 mL), dried (Na2SO4) and the

solvent was evaporated in vacuo. The compound was filtered through a plug of silica gel

eluting with 1:1 EtOAc/hexanes and a yellow oil was obtained.

A solution of the intermediate sulfite in CH3CN/CCl4 (1:1, 54 mL) was cooled to 0 °C.

Precooled H2O (40 mL) was added to the mixture. Solid NaIO4 (3.85 g, 18.0 mmol,

2.00 equiv) and RuCl3·3H2O (9.30 mg, 45.0 µmol, 0.5 mol%) were added in one portion.

The reaction mixture was vigorously stirred for 1 h. The phases were separated and the

aqueous layer was extracted with Et2O (3 × 30 mL). The combined organic phases were

dried (Na2SO4), filtered, and the solvent was evaporated in vacuo. Column

chromatography (1:3 EtOAc/hexanes) afforded 299 (1.38 g, 57%) as colorless liquid.


4.75-4.61 (m, 2H), 3.94-3.91 (m, 2H), 0.92-0.89 (m, 9H), 0.12-0.11 (m, 6H).

NBn

O

OTBS

2-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1'-

(phenylmethyl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one (300)

Cyclic sulfate 299 (1.38 g, 5.14 mmol, 1.00 equiv) was dissolved in DME (20 mL) and

NaH (95%, 375 mg, 15.6 mmol, 3.00 equiv) was added. A solution of oxindole 98

(1.16 g, 5.21 mmol, 1.01 equiv) in DME (10 mL) was slowly added to the suspension.

The reaction mixture was stirred at room temperature for 16 h and was then quenched by

addition of MeOH (3 mL), followed by H2O (30 mL) was added. The layers were

separated and the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined

organic phases were dried (Na2SO4), filtered, and the solvent was evaporated in vacuo.

Experimental Part

151

Column chromatography (1:19 EtOAc/hexanes) afforded 300 (two diastereomers) (876

mg, 43%) along with unreacted oxindole 98 (146 mg, 13%).


Rf = 0.50 (1:3 EtOAc/hexanes); 1H NMR (CDCl3, 300 MHz) δ 7.33-7.24 (m, 5H), 7.13

(dt, 1H, J = 7.9, 1.6 Hz), 6.99 (dt, 1H, J = 6.1, 0.8 Hz), 6.83 (dd, 1H, J = 7.1, 0.8 Hz),

6.76 (d, 1H, J = 7.5 Hz), 5.06 (d, 1H, J = 15.8 Hz), 4.92 (d, 1H, J = 15.8 Hz), 4.16-4.13

(m, 2H), 2.25-2.18 (m, 1H), 1.86-1.76 (m, 1H), 0.88 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H).

Diastereomer 2: colorless oil, yield: 841 mg (41%).


7.19-7.11 (m, 1H), 7.07-6.94 (m, 2H), 6.79 (d, 1H, J = 7.9 Hz), 5.07 (d, 1H, J = 15.8 Hz),

4.92 (d, 1H, J = 15.8 Hz), 4.01 (dd, 1H, J = 11.2, 5.4 Hz), 3.88 (dd, 1H, J = 11.2, 7.1 Hz),

2.32-2.21 (m, 1H), 2.05-1.95 (m, 1H), 1.64-1.55 (m, 1H), 0.81 (s, 9H), 0.03 (s, 3H), -0.02

(s, 3H).

NBn

O

OH

2-(hydroxymethyl)-1'-(phenylmethyl)spiro[cyclopropane-1,3'-indol]-2'(1'H)-one

(301)

Spiro-cyclopropyl-oxindole 300 (diastereomer 2) (654 mg, 1.66 mmol, 1.00 equiv), was

dissolved in THF (1 mL) and a solution of Bu4NF (1 M in THF, 4.89 mL, 4.99 mmol,

3.00 equiv) was added. The reaction mixture was stirred for 30 min at room temperature,

diluted with EtOAc (15 mL) and H2O (5 mL) was added. The layers were separated and

the organic layer was washed with brine (2 × 10 mL). The combined organic phases were

dried (Na2SO4), filtered, and the solvent was evaporated in vacuo. Column

chromatography (2:1 EtOAc/hexanes) afforded 301 (445 mg, 96%) as a colorless solid.


Rf = 0.80 (1:1 EtOAc/hexanes); mp = 119 °C; 1H NMR (CDCl3, 300 MHz) δ 7.33-7.27

(m, 5H), 7.25-7.14 (m, 1H), 7.09-6.96 (m, 2H), 6.85-6.82 (m, 1H), 5.04 (d, 1H, J =

15.8 Hz), 4.96 (d, 1H, J = 15.8 Hz), 4.15-4.06 (m, 1H), 3.87 (dd, 1H, J = 12.5, 8.7 Hz),

2.46-2.30 (m, 1H), 2.02 (dd, 1H, J = 9.1, 4.6 Hz), 1.58 (dd, 1H, J = 7.5, 4.2 Hz);

13C NMR (CDCl3, 75 MHz) δ 176.4, 143.3, 136.1, 128.8, 127.6, 127.3, 127.1, 122.1,

120.4, 109.4, 61.0, 44.2, 34.4, 31.0, 22.3; IR (KBr) ν 3407, 3026, 2916, 1687, 1612,

1490, 1467, 1451, 1432, 1391, 1356, 1305, 1193, 1152, 1124, 1102, 1054, 1032, 1017,

964, 757, 751, 736, 695, 668; DEI-MS 279.1 (43 [M]+), 235.1 (59 [M-CH2=CHOH]+),

91.0 (100 [C7H7]+); Anal. calcd for C18H17NO2: C 77.40, H 6.13, N 5.01, found: C 77.46,

H 6.10, N 5.00.

NBn

O

Me

1'-(phenylmethyl)-2-[1-prop-1-en-1-yl]spiro[cyclopropane-1,3'-indol]-2'(1'H)-one

(303)

In a 3-neck flask equipped with a reflux condenser and an addition funnel was placed

[Rh(OAc)2]2 (7.2 mg, 16 µmol, 5 mol%). Benzene (5 mL) and piperylene (302) (mixture

of isomers, 162 µL, 1.62 mmol, 5.00 equiv) were added and the suspension was heated to

reflux. A solution of 289 (81.0 mg, 325 µmol, 1.00 equiv) in benzene (5 mL) was added

over 4 h by syringe pump. The reaction mixture was allowed to cool to room temperature

and filtered over Celite. The filter cake was washed with benzene. The filtrate was

concentrated in vacuo and purified by column chromatography (1:7 EtOAc/hexanes) to

afford 303 (mixture of isomeric products) (85.0 mg, 90%).

Fraction 1: colorless oil, yield: 8.0 mg (8%).

Rf = 0.61 (1:3 EtOAc/hexanes); 1H NMR (CDCl3, 300 MHz, two isomers, # denotes

major-, * minor isomer signals) δ 7.31-7.21 (m, 10H), 7.19-7.09 (m, 2H), 7.06-6.94

Experimental Part

153

(m, 2H), 6.95-6.80 (m, 2H), 6.79-6.72 (m, 2H), 5.98-5.83 (m, 2H), 5.77-5.62 (m, 2H),

5.05-4.86 (m, 4H) 2.71 (dd, 1H*, J = 6.4, 6.4 Hz), 2.52 (dd, 1H#, J = 6.1, 6.1 Hz), 1.73

(d, 3H#, J = 5.2 Hz), 1.67 (d, 3H*, J = 5.3 Hz).

Fraction 2: colorless oil, yield: 77.0 mg (82%).

Rf = 0.52 (1:3 EtOAc/hexanes); 1H NMR (CDCl3, 300 MHz, one isomer) δ 7.32-7.22

(m, 5H), 7.14 (dt, 1H, J = 1.6, 7.5 Hz), 7.02-6.90 (m, 2H), 6.80 (d, 1H, J = 7.8 Hz), 5.80

(ddd, 1H, J = 15.2, 6.5, 0.9 Hz), 5.53-5.45 (m, 1H) 5.02 (d, 1H, J = 15.9 Hz), 4.95 (d, 1H,

J = 15.9 Hz), 2.70-2.62 (m, 1H), 2.09 (dd, 1H, J = 9.0, 4.7 Hz), 1.74-1.71 (m, 3H), 1.65

(dd, 1H, J = 7.6, 4.7 Hz).

NBn

O

NTs

Me

Ph

1'-[(4-methylphenyl)sulfonyl]-2'-phenyl-1-(phenylmethyl)-5'-[1-prop-1-en-1-

yl]spiro[indole-3,3'-pyrrolidin]-2(1H)-one (304)

A sealable tube with side inlet was charged with MgI2 (2.0 mg, 7.3 µmol, 20 mol%),

imine 124 (12.2 mg, 47.0 µmol, 1.30 equiv) and cyclopropane 303 (10.5 mg, 36.0 µmol,

1.00 equiv). THF (0.1 mL) was added by syringe. The tube was sealed, placed into an oil

bath at 80 °C and heated for 14 h. The reaction mixture was allowed to reach room

temperature. EtOAc (4 mL) and H2O (5 mL) were added to the reaction mixture,

followed by Na2S2O3 (small crystal). This biphasic mixture was stirred for 1 h, then the

phases were separated and the organic phase was washed with brine (10 mL), dried over

Na2SO4, filtered, and concentrated in vacuo. The products could only be partially

separated by column chromatography (3:17 EtOAc/hexanes) and one major fraction was

obtained which could be identified as the desired product of the ring expansion 314

(mixture of isomers) (9.3mg, 47%).


Rf = 0.32 (1:3 EtOAc/hexanes); 1H NMR (CDCl3, 300 MHz, mixture of isomers, only the

major one is described) δ 7.62-6.87 (m, 16H), 6.62-6.48 (m, 2H), 5.84-5.64 (m, 2H),

5.22-5.14 (m, 1H), 5.06-4.70 (m, 1H), 4.71 (d, 1H, J = 11.2 Hz), 4.24 (d, 1H, J =

11.2 Hz), 2.42 (s, 3H), 2.33-2.20 (m, 2H), 1.72-1.69 (m, 3H).

N

MeMe

allyl-(3-methyl-but-2-enylidene)-amine (305)

Allyl amine (1.56 mL, 20.9 mmol, 1.00 equiv) was cooled to 0 °C and prenal (231)

(2.00 mL, 20.9 mmol, 1.00 equiv) was slowly added. KOH (powdered, 200 mg) was

added to the mixture. Stirring was continued for 2 h. The mixture was filtered, and the

filtrate was Kugelrohr distilled (at 30 mbar) to give desired imine 305 (875mg, 34%) as

colorless liquid.

1H NMR (200 MHz, CDCl3) δ 8.20 (dt, 1H, J = 9.6, 1.3 Hz), 6.09-5.92 (m, 2H),

5.24-5.09 (m, 2H), 4.12-4.09 (m, 2H), 1.94 (s, 3H), 1.90 (s, 3H).

N

MeMeOMe

allyl-(3-methoxy-3-methyl-butylidene)-amine (306)

A solution of oxalyl chloride (3.78 mL, 43.1 mmol, 1.10 equiv) in CH2Cl2 (100 mL) was

cooled to –60 °C. A solution of DMSO (6.10 mL, 86.0 mmol, 2.20 equiv) in CH2Cl2

(20 mL) was slowly added and stirring was continued till the gas evolution had stopped.

A solution of 3-methoxy-3-methyl-butanol (5.00 mL, 39.1 mmol, 1.00 equiv) in CH2Cl2

(40 mL) was added and a white suspension formed. NEt3 (27.0 mL, 196 mmol,

5.00 equiv) was added and the mixture was stirred for 15 min at –60 °C and was then

Experimental Part

155

allowed to reach room temperature. H2O (150 mL) was introduced. The organic layer was

separated, washed with 1 M aq HCl (200 ml), sat. aq NaHCO3 (200 mL) and brine

(200 mL), dried over Na2SO4, filtered, concentrated in vacuo and distilled under reduced

pressure (bp (10 mbar) = 55 °C) to yield the corresponding aldehyde (1.88 g, 41%).

To a solution of the intermediate aldehyde (520 mg, 4.48 mmol, 1.00 equiv) and allyl

amine (335 µL, 4.48 mmol, 1.00 equiv) in CH2Cl2 (6 mL) was added MgSO4 (20 mg).

The reaction mixture was allowed to stir at room temperature for 12 h, filtration and

evaporation of the solvent afforded imine 306 (612 mg, 88%) as colorless oil which was

used without further purification.

1H NMR (300 MHz, CDCl3) δ 7.78-7.70 (m, 1H), 6.07-5.91 (m, 2H), 5.21-5.08 (m, 2H),

4.15-4.01 (m, 2H), 3.22 (s, 3H), 2.51-2.23 (m, 2H), 1.12 (s, 6H).

O

TIPS

triisopropylsilanyl-propynal (308)

A solution of triisopropylsilanyl-acetylene (307) (15.0 mL, 67.5 mmol, 1.00 equiv) in

THF (100 mL) was cooled to −78 °C. nBuLi (1.60 M in hexanes, 42.2 mL, 67.5 mmol,

1.00 equiv) was added dropwise and the mixture was stirred at −78 °C for 0.5 h. A

solution of ethyl formate (10.9 mL, 135 mmol, 2.00 equiv) in THF (100 mL) was added

dropwise. The reaction mixture was stirred for 45 min at −78 °C, then poured onto ice-

water (100 mL) containing a trace of hydroquinone and acetic acid (1 mL). The product

was extracted with Et2O (2 × 200 ml); the combined organic layers were dried (Na2SO4)

filtered, and concentrated in vacuo. The unpurified aldehyde 308 was used for subsequent

imine formation.

Rf = 0.89 (1:3 EtOAc/hexanes); 1H NMR (300 MHz, CDCl3) δ 9.21 (s, 1H), 1.12-1.10

(m, 21H).


N

TIPS

Ally-(3-triisopropylsilanyl-prop-2-ynylidene)-amine (309)

A solution of triisopropylsilanyl-propynal (308) (67.5 mmol, 1.00 equiv) in CH2Cl2

(100 mL) was treated with allyl amine (5.05 mL, 67.5 mmol, 1.00 equiv) and MgSO4

(6 g) at room temperature for 9 h. The reaction mixture turned slightly orange. The

MgSO4 was filtered off and the filter cake was washed with CH2Cl2 (3 × 20 mL). The

solvent was evaporated in vacuo and the product was purified by distillation under

reduced pressure (0.5 mbar, 90-95 °C) to afford imine 309 (Z and E isomer) (13.4 g, 80%

over two steps) as a colorless liquid.

Rf = 0.50, 0.38 (1:50 EtOAc/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.58-7.57 (m, 2H),

6.07-5.94 (m, 2H), 5.25-5.11 (m, 4H), 5.25-5.11 (m, 4H), 4.33 (dddd, 1H, J = 5.6, 1.87,

1.87, 1.87 Hz), 4.16 (dddd, 1H, J = 5.6, 1.9, 1.9, 1.3 Hz) 1.10-1.09 (m, 42H); 13C NMR

(75 MHz, CDCl3) δ 145.7, 143.7, 134.9, 134.6, 116.9, 116.0, 103.4, 101.8, 98.3, 95.1,

64.2, 58.8, 18.6, 18.6, 11.2, 11.2; IR (thin film) ν 2945, 2867, 1644, 1612, 1593, 1464,

1384, 1366, 1072, 1027, 995, 919, 883, 678; EI-MS 249.2 (1.2 [M]+), 206.1

(100 [NC-C ≡ C-TIPS]); Anal. calcd for C15H27NSi: C 72.22, H 10.91, N 5.61, found:

C 72.25, H 10.84, N 5.57.

NBn

O

N

Me

TIPS

1-(phenylmethyl)-5'-[1-prop-1-en-1-yl]-1'-prop-2-en-1-yl-2'-{[tris(1-methylethyl)

silyl]ethynyl}spiro[indole-3,3'-pyrrolidin]-2(1H)-one (310)

A sealable tube with side inlet was charged with MgI2 (2.2 mg, 7.9 µmol, 20 mol%), and

cyclopropane 303 (11.5 mg, 40.0 µmol, 1.00 equiv). Imine 309 (60 µL, 238 µmol,

Experimental Part

157

6.00 equiv) was added by syringe, followed by THF (0.1 mL). The tube was sealed,

placed into an oil bath at 80 °C and heated for 14 h. The reaction mixture was allowed to

reach room temperature. EtOAc (4 mL) and H2O (5 mL) were added to the reaction

mixture, followed by Na2S2O3 (small crystal). This biphasic mixture was stirred for 1 h,

then the phases were separated and the organic phase was washed with brine (10 mL),

dried over Na2SO4, filtered, and concentrated in vacuo to give products 310. The products

could only be partially separated by column chromatography (1:19 EtOAc/hexanes) and

one major fraction was obtained, containing three isomers of 310 (12 mg, 56%).

Rf = 0.40 (1:9 EtOAc/hexanes); 1H NMR (CDCl3, 300 MHz, mixture of isomers, integral

ratios are described) δ 7.58-7.50 (m, 1H), 7.32-7.19 (m, 5H), 7.16-7.03 (m,1H), 7.02-6.96

(m, 1H), 6.64-6.59 (m, 1H), 6.08-5.82 (m, 1.17H), 5.77-5.58 (m, 1.72H), 5.43-5.38

(m, 0.28H), 5.30-5.19 (m, 1.28H), 5.13-5.08 (m, 0.55H), 4.98-4.81 (m, 2H), 4.23

(s, 0.55H),3.93 (s, 0.28H), 3.72 (s, 0.17H), 3.63-3.40 (m, 2.45H), 3.29-3.20 (m, 0.55H),

2.56-2.48 (m, 0.28H), 2.38-2.10 (m, 1.55H), 1.90-1.82 (m, 0.17H), 1.76-1.67 (m, 3H),

1.07 (s, 5.88H), 0.98 (s, 3.57H),0.88 (s, 11.55H).

NH

N

O

NHTs

3-(tosyl-hydrazono)-1,3-dihydro-indol-2-one (311)

Isatin (96) (9.44 g, 64.2 mmol, 1.00 equiv) was suspended in MeOH (300 mL). The

suspension was heated to reflux, whereupon a deep-red solution was obtained. To this hot

solution was added tosylhydrazine (12.1 g, 64.8 mmol, 1.02 equiv) in one portion. A

yellow product starts precipitating from the hot mixture. The reaction mixture was

allowed to cool to room temperature and the pure tosylhydrazone 311 (18.2 g, 90%) was

filtered off.

Rf = 0.12 (EtOAc); mp = 207 °C; 1H NMR (300 MHz, CD3OD) δ 7.97 (d, 2H, J =

8.09 Hz), 7.86 (d, 1H, J = 7.47 Hz), 7.41-7.35 (m, 3H), 7.11-7.06 (m, 1H), 6.91 (d, 1H,

J = 7.47 Hz), 2.43 (s, 3H).


NH

N2

O

3-diazo-1,3-dihydro-indol-2-one (312)

3-Tosylhydrazone-1,3-dihydro-indol-2-one (311) (12.0 g, 38.1 mmol, 1.00 equiv) was

treated with a solution of NaOH (3.04 g, 76.1 mmol, 2.00 equiv) in H2O (375 mL). The

reaction mixture was stirred for 15 h in a waterbath at 50 °C, and then allowed to cool to

room temperature. The reaction mixture was neutralized by addition of dry ice,

whereupon diazoketone 312 (5.36 g, 88%). precipitated: The product was directly used in

the subsequent reaction.

Rf = 0.54 (3:1 EtOAc/hexanes); mp = 168 °C (decomp.); 1H NMR (300 MHz, CDCl3)

δ 8.69 (br, 1H,), 7.21-7.06 (m, 3H), 7.01-6.98 (m, 1H).

NH

O

Me

2-[1-prop-1-en-1-yl]spiro[cyclopropane-1,3'-indol]-2'(1'H)-one (313)

In a 3-neck flask equipped with a reflux condenser and an addition funnel was placed

[Rh(OAc)2]2 (214 mg, 485 µmol, 1 mol%). Benzene (280 mL) and piperylene (mixture of

isomers, 19.5 mL, 194 mmol, 4.00 equiv) were added and the suspension was heated to

reflux. A solution of 312 (7.72 g, 48.5 mmol, 1.00 equiv) in CH2Cl2 (340 mL) was added

over 3 h by syringe pump. The reaction mixture was allowed to cool to room temperature

and the solvent was partially removed (reduced to 1/10 of its volume). The remaining

suspension was filtered over Celite and the filter cake was washed with acetone. The

filtrate was concentrated in vacuo and purified by column chromatography (1:3

EtOAc/hexanes) to afford 313 (mixture of isomeric products) (69.1 g, 71%). The mixture

was used without further purification in the upcoming ring-expansion step.

Experimental Part

159

Ring expansion of 313 with 309:

NH

O

N

Me

+N

309TIPS

314 TIPS

NH

O

Me

313

A sealable tube with side inlet was charged with MgI2 (5.69 g, 20.5 mmol, 1.00 equiv). A

solution of cyclopropane 313 (4.08 g, 20.5 mmol, 1.00 equiv) in THF (35 mL) was added

via cannula, followed by imine 309 (6.12 g, 24.4 mmol, 1.20 equiv). The tube was sealed,

placed into an oil bath at 75 °C and heated for 15 h. The reaction mixture was allowed to

reach room temperature. EtOAc (250 mL) and H2O (150 mL) were added to the reaction

mixture, followed by Na2S2O3 (500 mg). This biphasic mixture was stirred for 3 h, then

the phases were separated and the organic phase was washed with brine, dried over

Na2SO4, filtered, and concentrated in vacuo to give 314. The following products were

obtained by careful column chromatography purification (4:21 EtOAc/hexanes):

NHN

O

TIPS

Me

(±)-(2'R,3S,5'S)-1'-allyl-5'-[(1E)-prop-1-en-1-yl]-2'-[(triisopropylsilyl)ethynyl]spiro-

[indole-3,3'-pyrrolidin]-2(1H)-one (321)

Pale yellow solid, 2.93 g (32%).

Rf = 0.59 (1:3 EtOAc/hexanes); mp = 121 °C; 1H NMR (300 MHz, CDCl3) δ 8.84

(br, 1H), 7.50 (d, 1H, J = 7.5 Hz), 7.14 (ddd, 1H, J = 7.5, 7.5, 1.3 Hz), 7,00 (ddd, 1H, J =

7.5, 7.5, 1.3 Hz), 6.85 (d, 1H, J = 7.5 Hz), 6.04-5.91 (m, 1H), 5.74-5.60 (m, 1H),

5.46-5.37 (m, 1H), 5.24-5.20 (m, 2H), 3.83 (s, 1H), 3.59-3.37 (m, 3H), 2.50 (dd, 1H, J =

13.1, 8.1 Hz), 1.82 (dd, 1H, J = 13.7, 8.1 Hz), 1.58 (ddd, 3H, J = 8.8, 6.2, 1.3 Hz),


0.83-0.82 (m, 21H); 13C NMR (75 MHz, CDCl3) δ 181.1, 140.4, 134.7, 132.5, 132.1,

129.1, 127.9, 125.6, 122.9, 119.6, 109.3, 103.1, 87.5, 63.1, 62.6, 56.0, 50.9, 42.2, 18.4,

17.8, 10.9; IR (thin film) ν 3207, 2942, 2864, 1712, 1618, 1471, 1337, 1234, 1171, 990,

912, 881, 749, 673; HiResMALDI-MS calcd for C28H40N2SiO [M+H]+ 449.2988, found,

449.2989; Anal. calcd for C28H40N2SiO: C 74.95, H 8.98, N 6.24, found: C 74.95, H 8.89,

N 6.01.

HNO

N

TIPS

Me

(±)-(2'R,3R,5'R)-1'-allyl-5'-[(1E)-prop-1-en-1-yl]-2'-[(triisopropylsilyl)ethynyl]spiro-

[indole-3,3'-pyrrolidin]-2(1H)-one (322)

Pale yellow oil, 350 mg (3.8%).

Rf = 0.65 (1:3 EtOAc/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.65-7.57 (m, 3H),

7.22-7.16 (m, 1H), 7.04-6.98 (m, 1H), 6.81 (d, 1H, J = 7.5 Hz), 5.85-5.62 (m, 2H),

5.51-5.42 (m, 1H), 5.20 (d, 1H, J = 18.1), 5.00 (d, 1H, J = 10.0 Hz), 3.92 (s, 1H),

3.55-3.37 (m, 2H), 3.22 (dd, 1H, J = 13.7, 8.1 Hz), 2.70 (dd, 1H, J = 13.1, 8.7 Hz), 1.80

(dd, 1H, J = 13.1, 6.9 Hz), 1.70 (ddd, 3H, J = 11.8, 6.2, 1.3 Hz), 1.11 (s, 21H); 13C NMR

(75 MHz, CDCl3) δ 178.1, 140.0, 136.3, 136.1, 132.5, 129.0, 127.8, 124.1, 122.3, 116.8,

109.0, 99.5, 90.6, 64.3, 62.5, 55.2, 50.7, 41.6, 18.7, 17.8, 11.3; IR (thin film) ν 3207,

3082, 2942, 2865, 2159, 1716, 1620, 1471, 1332, 1234, 1176, 995, 964, 917, 883, 750,

677; HiResMALDI-MS calcd for C28H40N2SiO [M+H]+ 449.2988, found, 449.2983.

Experimental Part

161

mixed fraction

NH

O

N

Me

TIPS

Co-eluting fraction

2.90 g (32%) Rf = 0.45 (1:3 EtOAc/hexanes).

Allyl-deprotection of the co-eluting fraction:

mixed fraction

NH

O

N

Me

TIPS

NHHN

O

TIPS

Me

323

NHHN

O

TIPS324

Me

HNO

NH

TIPS

Me

325

+ +

To a solution of the co-eluting fraction (3.07 g, 6.85 mmol, 1.00 equiv) and NDMBA

(3.42 g, 21.9 mmol, 3.20 equiv) in CH2Cl2 (150 mL) was added a solution of freshly

prepared Pd(PPh3)4 (from [Pd2dba3]·CHCl3 (212 mg, 205 µmol, 6 mol% Pd) and PPh3

(323 mg, 1.23 mmol, 18 mol%) in 20 mL CH2Cl2). The reaction mixture was stirred at

30 °C for 12 h. CH2Cl2 (350 mL) was added and the organic solution was washed with

sat. aq Na2CO3 (2 × 175 mL), dried over Na2SO4, filtered, and concentrated in vacuo.

Purification by column chromatography (1.5:8.5 1:4 EtOAc/hexanes) afforded:


NHHN

O

TIPS

Me

(±)-(2'R,3S,5'R)-5'-[(1E)-prop-1-en-1-yl]-2'-[(triisopropylsilyl)ethynyl]spiro[indole-


Pale yellow oil, 1.68 g (60%).

Rf = 0.71 (1:3 EtOAc/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.89 (br, 1H), 7.38 (d, 1H,

J = 7.47 Hz), 7.23-7.18 (m, 1H), 7.06-7.01 (m, 1H), 6.87 (d, 1H, J = 7.5 Hz), 5.69-5.63

(m, 2H), 4.35 (s, 1H), 4.22 (ddd, 1H, J = 7.5, 7.5, 7.5 Hz), 2.25-2.21 (m, 2H), 1.71

(d, 3H, J = 5.0 Hz), 0.86-0.85 (m, 21H); 13C NMR (75 MHz, CDCl3) δ 179.9, 140.4,

133.0, 131.5, 128.1, 126.9, 124.5, 122.5, 109.7, 103.7, 86.6, 60.4, 59.7, 58.7, 43.2, 18.4,

17.7, 10.9; IR (thin film) ν 3209, 2942, 2864, 1715, 1684, 1621, 1472, 883, 750, 679;

HiResMALDI-MS calcd for C25H36N2SiO [M+H]+ 409.2675, found, 409.2674; Anal.

calcd for C25H36N2SiO: C 73.48, H 8.88, N 6.85, found: C 73.29, H 8.97, N 6.66.

NHHN

O

TIPS

Me

(±)-(2'R,3S,5'R)-5'-[(1Z)-prop-1-en-1-yl]-2'-[(triisopropylsilyl)ethynyl]spiro[indole-


Pale yellow oil, 350 mg (13%).


J = 7.5 Hz), 7.24-7.19 (m, 1H), 7.07-7.02 (m, 1H), 6.88 (d, 1H, J = 7.5 Hz), 5.68-5.55 (m,

2H), 4.62 (ddd, 1H J = 8.1, 8.1, 8.1 Hz), 4.37 (s, 1H), 2.34-2.12 (m, 2H), 1.71 (d, 3H, J =

5.0 Hz), 1.58 (br, 1H), 0.88-0.86 (m, 21H); 13C NMR (75 MHz, CDCl3) δ 140.3, 132.7,

Experimental Part

163

131.3, 128.2, 185.8, 124.7, 122.5, 109.5, 103.8, 86.7, 59.5, 58.9, 54.4, 43.4, 18.4, 13.4,

10.9; IR (thin film) ν 3199, 2943, 2865, 2170, 1714, 1621, 1471, 1337, 1236, 1110, 996,

919, 883, 750, 679; HiResMALDI-MS calcd for C25H36N2SiO [M+H]+ 409.2675, found,

409.2676.

HNO

NH

TIPS

Me

(±)-(2'R,3R,5'S)-5'-[1-prop-1-en-1-yl]-2'-[(triisopropylsilyl)ethynyl]spiro[indole-3,3'-

pyrrolidin]-2(1H)-one (325)

Pale yellow solid 510 mg (18%).

Rf = 0.73 (1:3 EtOAc/hexanes); mp = 63 °C; 1H NMR (300 MHz, CDCl3) δ 9.35 (br, 1H),

7.23-7.17 (m, 2H), 7.05-7.00 (m, 1H), 6.90 (d, 1H, J = 7.5 Hz), 5.78-5.64 (m, 2H), 4.00-

3.94 (m, 2H), 2.75 (br, 1 H) 2.44-2.31 (m, 1H), 2.21-2.08 (m, 1H), 1.73 (d, 3H, J = 5.6

Hz), 0.89 (s, 21H); 13C NMR (75 MHz, CDCl3) δ 181.7, 141.6, 131.0, 130.6, 128.2,

128.0, 122.3, 122.01, 109.7, 101.8, 85.8, 62.3, 62.1, 60.2, 43.3, 18.5, 17.9, 11.1; IR (thin

film) ν 3186, 2942, 2865, 2175, 1706, 1621, 1472, 1439, 1345, 1109, 968, 883, 745, 678;

HiResMALDI-MS calcd for C25H36N2SiO [M+H]+ 409.2675, found, 409.2677.


Allyl-deprotection of 321:

NHHN

O

TIPS

Me

(±)-(2'R,3S,5'S)-5'-[(1Z)-prop-1-en-1-yl]-2'-[(triisopropylsilyl)ethynyl]spiro[indole-


To a solution of 321 (1.63 g, 3.63 mmol, 1.00 equiv) and NDMBA (1.82 g, 11.6 mmol,

3.20 equiv) in CH2Cl2 (45 mL) was added a solution of freshly prepared Pd(PPh3)4 (from

[Pd2dba3]·CHCl3 (75.0 mg, 72.0 µmol, 4 mol% Pd) and PPh3 (114 mg, 436 µmol,

12 mol%) in 5 mL CH2Cl2). The reaction mixture was stirred at 30 °C for 12 h. CH2Cl2

(200 mL) was added to the reaction mixture and the organic solution was washed with

sat. aq Na2CO3 (2 × 100 mL), dried over Na2SO4, filtered, and concentrated in vacuo.

Purification by column chromatography (9:41 EtOAc/hexanes) afforded 326 (1.27 g,

86%) as a pale yellow solid.


J = 7.5 Hz), 7.16 (dd, 1H, J = 7.5, 7.5 Hz), 7.00 (dd, 1H, J = 7.5, 7.5 Hz), 6.85 (d, 1H, J =

7.5 Hz), 5.79-5.51 (m, 2H), 4.21 (s, 1H), 3.95 (ddd, 1H, J = 8.1, 8.1, 8.1 Hz), 2.58

(dd, 1H, J = 13.1, 8.1 Hz), 2.18 (br, 1H), 1.88 (dd, 1H, J = 13.1, 8.1 Hz), 1.73-1.70

(m, 3H), 0.83-0.82 (m, 21H); 13C NMR (75 MHz, CDCl3) δ 181.1, 140.4, 133.5, 131.7,

127.9, 127.8, 124.4, 122.5, 109.6, 103.0, 86.9, 60.5, 60.1, 58.9, 43.9, 18.4, 17.8, 10.9; IR

(thin film) ν 3212, 2943, 2865, 2176, 1713, 1621, 1472, 1340, 1235, 1112, 965, 883, 748,

679; HiResMALDI-MS calcd for C25H36N2SiO [M+H]+ 409.2675, found, 409.2684.

Experimental Part

165


Coupling of 323 with N-Boc-L-proline chloride.

NHHNO

TIPS

Me

323

NHNO

TIPS

Me

N

O

Boc

N

TIPS

Me

N

O

Boc

H HHNO

327 328

+

To a solution of 323 (141 mg, 345 µmol, 1.00 equiv) and NEt3 (48.0 µL, 345 µmol,

1.00 equiv) in CH2Cl2 (15 mL) at 0 °C was added N-Boc-L-proline chloride (270) (0.14 M

in CH2Cl2, 10.0 mL, 1.38 mmol, 4.00 equiv). The reaction mixture was allowed to warm

slowly to room temperature and was stirred for 8 h. The reaction was quenched by

addition of 10% aq NaHCO3 (10 mL). The phases were separated; the organic layer was

washed with sat. aq NaHCO3 (10 mL). The organic phase was dried over Na2SO4,

filtered, and concentrated in vacuo. Purification by column chromatography (1:3

EtOAc/hexanes) afforded:

NHNO

TIPS

Me

N

O

Boc

H

tert-butyl (2S)-2-({(2'R,3S,5'R)-2-oxo-5'-[(1E)-prop-1-en-1-yl]-2'-[(triisopropylsilyl)-

ethynyl]-1,2-dihydro-1'H-spiro[indole-3,3'-pyrrolidin]-1'-yl}carbonyl)pyrrolidine-1-

carboxylate (327)

Colorless crystals, 94 mg (45%).

Rf = 0.63 (1:1 EtOAc/hexanes), [α]D23 (c 0.250, CHCl3) = +15.6; mp = 191 °C; 1H NMR

(300 MHz, CDCl3 # denotes major-, * minor rotamer signals) δ 7.94-7.78 (m, 2H),

7.25-7.15 (m, 4H), 7.06-7.01 (m, 2H), 6.90-6.83 (m, 2H), 5.76-5.50 (m, 4H), 5.35*

(s, 1H), 5.20-5.18* (m, 1H), 2.26# (s, 1H), 4.98-4.74 (m, 3H), 3.67-3.63# (m, 1H),


3.59-3.54* (m, 1H), 3.52-3.38 (m, 2H), 2.88-2.00 (m, 10H), 1.88-1.71 (m, 5 H),

1.66-1.64* (m, 3H), 1.53* (s, 9H), 1.49-1.47# (m, 9H), 0.85-0.81 (m, 42H); 13C NMR

(75 MHz, CDCl3, * denotes minor rotamer signals) δ 179.3, 176.9*, 171.2, 170.5*, 154.5,

154.4*, 141.0, 140.6*, 133.6, 130.7*, 130.5, 128.8, 128.5*, 127.6, 127.4*, 125.6, 124.0*,

122.9*, 122.1, 110.3*, 109.9, 102.3*, 99.0, 92.0*, 87.3, 79.6, 79.2*, 60.4*, 59.6, 59.2*,

58.7*, 58.4, 58.1, 57.1, 56.6*, 46.5, 46.3*, 43.6, 39.8*, 30.1*, 29.1, 28.6*, 28.5, 23.1*,

22.8, 18.5*, 18.3, 17.8, 17.6*, 11.1, 10.9*; IR (thin film) ν 3212, 2942, 2865, 1729, 1689,

1472, 1397, 1366, 1299, 1254, 1164, 1126, 970, 919.3, 883, 750, 677; HiResMALDI-MS

calcd for C35H51N3SiO4 [M+Na]+ 628.3546, found, 628.3491; Anal. calcd. for

C35H51N3SiO4: C 69.38, H 8.48, N 6.94, found: C 69.40, H 8.36, N 6.92.

Crystal data for 327 at 223 K, Mr = 605.88, monoclinic space group P2(1), ρcalc =

1.116 g·cm–3, Z = 2, a = 12.642(2), b = 11.274(2), c = 13.052(4) Å, α = 90.00, β =

104.26(2), γ = 90.00°, V = 1802.9(7) Å3. Final R(F) = 0.0564, wR(F2) = 0.1601 for 464

parameters and 3015 reflections with I >2σ(I) and θ < 64.99°. The iPr3Si groups in 327

are diordered. The disorder could be resolved for the atoms C(20), C(21), C(22), C(23),

and C(25), i.e., two peaks were refined with population parameters of 0.6 and 0.4,

respectively. (Only one population is displayed for clarity.)

CCDC 196803 contains the supplementary crystallographic data for 327. This data can be

obtained free of charge via www.ccdc.cam.ac.uk/retrieving.html (or from the Cambridge

Crystallographic Data Center, 12, Union Road, Cambridge CB21EZ, UK; fax:

(+44)1223-336-033; or [email protected]).

Experimental Part

167

N

TIPS

Me

N

O

Boc

HHNO

tert-butyl (2S)-2-({(2'S,3R,5'S)-2-oxo-5'-[(1E)-prop-1-en-1-yl]-2'-

[(triisopropylsilyl)ethynyl]-1,2-dihydro-1'H-spiro[indole-3,3'-pyrrolidin]-1'-

yl}carbonyl)pyrrolidine-1-carboxylate (328)

White solid, 94 mg (45%).

Rf = 0.50 (1:1 EtOAc/hexanes), [α]D26 (c 0.745, CHCl3) = −31.6; mp = 99 °C; 1H NMR

(300 MHz, CDCl3 # denotes major-, * minor rotamer signals) δ 7.69* (br, 1H), 7.58#

(br, 1H), 7.47# (d, 1H, J = 7.5 Hz), 7.26-7.14 (m, 3H), 7.0-6.93 (m, 2H), 6.90-6.84

(m, 2H), 6.09* (ddd, 1H, J = 15.6, 8.7, 1.9 Hz), 5.76-5.59 (m, 2H), 5.52# (dd, 1H, J = 8.7,

3.7 Hz), 5.41* (ddd, 1H, J = 15.6, 7.5, 1.9 Hz), 5.17* (s, 1H), 4.97-4.86 (m, 2H), 4.86#

(s, 1H), 4.55-4.48* (m, 1H), 3.65-3.36 (m, 4H), 2.69*(dd, 1H, J = 13.7, 8.7 Hz),

2.28-2.09 (m, 5H), 1.92-1.72 (m, 6 H), 1.76# (dd, 3H, J = 6.2, 1.3 Hz), 1.68* (dd, 3H, J =

6.2, 1.3 Hz), 1.47# (s, 9H), 1.42* (s, 9H), 0.96-0.95* (m, 21H), 0.83-0.82# (m, 21 H); 13C NMR (75 MHz, CDCl3, * denotes minor rotamer signals) δ 179.0, 176.6*, 171.0,

154.3*, 154.2, 140.9, 140.4*, 133.5, 130.6, 130.4*, 128.7, 128.4*, 127.5, 127.3*, 125.5,

123.9*, 122.8*, 122.1, 110.2*, 109.8, 102.3, 99.0*, 92.0*, 87.3, 79.6, 79.2*, 59.7, 59.2,

58.7*, 58.5, 58.1*, 57.2*, 56.7, 46.6, 46.4*, 43.8, 39.9*, 30.3*, 29.2, 28.7*, 28.6, 23.2*,

22.9, 18.7*, 18.4, 17.9, 17.8*, 11.2, 11.0*; IR (thin film) ν 3214, 2943, 2866, 2175, 1728,

1702, 1676, 1622, 1472, 1401, 1366, 1241, 1164, 1126, 883, 750, 678; HiResMALDI-

MS calcd for C35H51N3SiO4 [M+Na]+ 628.3546, found, 628.3535.


NHNO

O

TIPS

N

O

Boc

H

tert-butyl (2S)-2-({(2'R,3S,5'R)-5'-formyl-2-oxo-2'-[(triisopropylsilyl)ethynyl]-1,2-

dihydro-1'H-spiro[indole-3,3'-pyrrolidin]-1'-yl}carbonyl)pyrrolidine-1-carboxylate

(330)

A solution of 327 (405 mg, 668 µmol, 1.00 equiv) and NMO·H2O (108 mg, 802 µmol,

1.20 equiv) in THF/tBuOH/H2O (4:4:1, 20 mL) was stirred at room temperature for

30 min before OsO4 (4 wt% in H2O, 170 µL, 270 µmol, 4 mol%) was added. The reaction

mixture was stirred at room temperature for 16 h, then quenched by addition of 2 M aq

Na2S2O3 (25 mL) and EtOAc (25 mL). The biphasic mixture was stirred for 3 h, the

phases separated; the organic layer was washed with brine (25 mL), dried over Na2SO4,

filtered, and concentrated in vacuo. The unpurified product (329) was used in the

subsequent reaction.

Rf = 0.67, 0.51 (3:1 EtOAc/hexanes).

To a solution of diols 329 in EtOAc (20 mL) was added Pb(OAc)4 (344 mg, 1.00 mmol,

1.50 equiv). A yellow suspension was obtained and after stirring for 10 min, the mixture

was filtered through a plug of silica gel, eluting with EtOAc. Purification by column

chromatography (1:1 EtOAc/hexanes) afforded 330 (385 mg, 97%) as a white solid.

Rf = 0.83 (3:1 EtOAc/hexanes), mp = 90 °C; [α]D26 (c 0.290, CHCl3) = +50.8; 1H NMR

(300 MHz, CDCl3 # denotes major-, * minor rotamer signals) δ 9.64* (d, 1H, J = 2.8 Hz),

9.52# (d, 1H, J = 3.1 Hz), 8.91 (m, 2H), 7.36-7.32 (m, 2H), 7.27-7.22 (m, 2H), 7.06-6.99

(m, 2H), 6.93-6.89 (m, 2H), 5.57# (s, 1H), 5.16* (s, 1H), 4.85-4.65 (m, 4H), 3.57-3.41

(m, 4H), 2.42-2.03 (m, 10H), 1.86-1.80 (m, 2H), 1.51* (s, 9H), 1.45# (s, 9H), 0.91-0.90

(m, 42H); 13C NMR (75 MHz, CDCl3, * denotes minor rotamer signals) δ 198.7, 197.2*,

177.4*, 177.3, 174.1, 173.6*, 154.4, 153.4*, 140.6, 140.6*, 129.4*, 129.1, 128.1, 127.7*,

125.0*, 124.9, 122.5, 110.4, 101.6, 101.1*, 91.8*, 90.7, 80.49*, 79.8, 65.1, 64.8*, 60.4,

57.4, 56.5*, 47.2, 34.8*, 34.5, 31.9, 30.2, 29.7*, 28.5, 24.7, 23.2*, 18.5, 11.0; IR (thin

Experimental Part

169

film) ν 3243, 2944, 2866, 1730, 1687, 1655, 1623, 1472, 1403, 1367, 1299, 1257, 1164,

883, 752, 669; HiResMALDI-MS calcd for C33H47N3SiO5 [M+Na]+ 616.3183, found,

616.3158; Anal. calcd for C33H47N3SiO5: C 66.75, H 7.98, N 7.08, found: C 66.91,

H 7.82, N 6.87.

NHN

OMeO2C

TIPS

N

O

Boc

H

methyl (2'R,3S,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2-

oxo-2'-[(triisopropylsilyl)ethynyl]-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-

carboxylate (332)

A solution of NaClO2 (73.0 mg, 808 µmol, 10.0 equiv) in pH 3.6 buffer (1.5 ml) was

added to a solution of aldehyde 330 (48.0 mg, 810 µmol, 1.00 equiv) and 2-methyl-2-

butene (1 mL) in tBuOH (3 mL). The reaction mixture was stirred at room temperature

for 30 min; 2 M aq HCl was added (10 mL), and the product was extracted with EtOAc

(3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and

concentrated in vacuo; Rf = 0.08 (3:1 EtOAc/hexanes). The product 331 was dissolved in

Et2O (5 mL) and a solution of CH2N2 in Et2O (≈ 0.4 M in Et2O) was added untill the

yellow color of CH2N2 persisted. The solvent was evaporated in vacuo and the product

was purified by column chromatography (4:6 EtOAc/hexanes) to afford 332 (45 mg,

89%) as a white solid.



7.28-7.23 (m, 2H), 7.21-7.10 (m, 2H), 7.06-6.98 (m, 2H), 6.94-6.87 (m, 2H), 5.46*

(s, 1H), 5.24# (s, 1H), 5.19-5.16# (m, 1H), 5.08-5.05* (m, 1H), 4.90-4.74 (m, 2H), 3.78#

(s, 3H), 3.72* (s, 3H) 3.67-3.35 (m, 4H), 2.6-2.48 (m, 2H), 2.34-2.26 (m, 2H), 2.22-2.02

(m, 4H), 1.98-1.91 (m, 2H), 1.84-1.77 (m, 2H), 1.58# (s, 9H), 1.47* (s, 9H), 0.83-0.82

(m, 42H); 13C NMR (75 MHz, CDCl3, * denotes minor rotamer signals) δ 176.1*, 175.9,


174.6*, 174.2, 171.2, 153.9, 141.1, 130.6*, 130.4, 129.3, 123.9, 123.0, 110.9, 101.0*,

100.4, 91.9, 91.2*, 80.5, 79.4*, 61.2*, 60.6*, 60.4, 59.4, 57.5, 57.3*, 52.6, 52.4*, 47.2*,

47.1, 37.1, 36.8*, 32.4, 31.5*, 28.6*, 28.4, 24.3*, 23.4, 18.4, 11.0; IR (thin film) ν 3242,

3945, 2866, 2173, 1732, 1700, 1622, 1472, 1367, 1366, 1299, 1202, 1174, 1114, 884,

752, 679; HiResMALDI-MS calcd for C34H49N3SiO6 [M+Na]+ 646.3288, found,

646.3277; Anal. calcd for C34H49N3SiO6: C 65.46, H 7.92, N 6.74, found: C 65.72,

H 7.98, N 6.57.

NHN

OMeO2C

N

O

Boc

H

methyl (2'S,3S,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'-

ethynyl-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate (333)

To a solution of 332 (134 mg, 215 µmol, 1.00 equiv) in THF (5 mL), was added TBAF

(1.0 M in THF, 260 µL, 260 µmol, 1.2 equiv). The reaction mixture was stirred at room

temperature for 8 h, diluted with CH2Cl2, washed with sat. aq NaHCO3, dried over

Na2SO4, filtered, and concentrated in vacuo. The product was purified by column

chromatography (13:7 EtOAc/hexanes) to afford 333 (99.0 mg, 99%) as a white solid.



7.73-7.52 (m, 1H), 7.32-7.23 (m, 2H), 7.16-6.88 (m, 5H), 5.57* (dd, 1H, J = 9.3, 5.0 Hz),

5.36-5.36* (m, 1H), 5.15-5.14# (m, 1H), 4.99-4.91 (m, 2H), 4.84-4.74# (m, 1H),

4.36-4.27* (m, 1H), 3.77# (s, 3H), 3.73* (s, 3H) 3.70-3.36 (m, 3H), 2.93-2.70 (m, 2H),

2.60-2.51 (m, 2H), 2.39-1.78 (m, 10H), 1.58# (s, 9H), 1.46* (s, 9H); 13C NMR (75 MHz,

CDCl3, * denotes minor rotamer signals) δ 178.1*, 175.3, 173.6, 173.4*, 171.5*, 170.4,

154.4*, 153.5, 140.6*, 140.3, 129.7, 129.1, 129.0*, 128.9*, 126.2*, 123.9, 122.8, 122.4*,

110.3, 109.5*, 80.3, 79.9*, 79.4, 79.3*, 61.0*, 60.4, 58.8, 58.4*, 57.7*, 57.5, 56.1, 54.1*,

52.7*, 52.6, 47.2, 47.0*, 38.1*, 37.3, 32.5, 29.6*, 28.5*, 28.3, 24.8, 24.0*; IR (thin film)

Experimental Part

171

ν 3243, 2978, 1729, 1686, 1621, 1473, 1400, 1366, 1301, 1174, 752; HiResMALDI-MS

calcd for C25H29N3O6 [M+Na]+ 490.1954, found, 490.1944; Anal. calcd for C25H29N3O6:

C 64.23, H 6.25, N 8.99, found: C 64.18, H 6.36, N 8.90.

NHNOMeO2C

N

O

Boc

H

methyl (2'S,3S,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2-

oxo-2'-vinyl-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate (337)

To a solution of 333 (20.0 mg, 430 µmol, 1.00 equiv) and quinoline (2.6 µL, 22 µmol,

0.50 equiv) in EtOH (2 mL), was added Pd/BaSO4 (6.6 mg, 33 wt%). The reaction

mixture was stirred at room temperature under H2 atmosphere for 10 h. The solution was

filtered over Celite and the solvent was evaporated in vacuo. The product was purified by

column chromatography (7:3 EtOAc/hexanes) to afford 337 (18.0 mg, 90%) as a white

solid.

Rf = 0.45 (3:1 EtOAc/hexanes), mp = 112 °C; [α]D24 (c 1.590, CHCl3) = −3.4; 1H NMR

(300 MHz, CDCl3 # denotes major-, * minor rotamer signals) δ 8.56-8.40 (m, 2H), 7.70#

(d, 1H, J = 7.5 Hz), 7.30-7.19 (m, 2H), 7.15-6.99 (m, 3H), 6.94-6.85 (m, 2H), 5.57-5.24

(m, 4H), 5.14-4.99 (m, 2H), 4.92-4.78 (m, 3H), 4.72-4.61 (m, 2H), 4.33-4.29# (m, 1H),

3.79# (s, 3H), 3.78* (s, 3H) 3.67-3.35 (m, 4H), 2.64-2.52 (m, 3H), 2.42-2.09 (m, 3H),

2.02-1.70 (m, 6H), 1.57* (s, 9H), 1.49# (s, 9H); 13C NMR (75 MHz, CDCl3, * denotes

minor rotamer signals) δ 178.7, 176.5*, 174.6*, 173.9, 172.5, 171.5*, 154.9*, 153.8,

141.0, 140.9*, 135.1, 134.7*, 129.2, 128.8*, 125.9, 123.7*, 122.9*, 122.7, 119.6*, 119.4,

114.6, 111.0*, 110.1, 80.4*, 79.8, 68.9*, 68.1, 61.1*, 59.8, 59.1*, 57.8, 57.1*, 56.4, 52.9,

52.6*, 47.3, 47.0*, 38.1, 37.0*, 32.2*, 29.6, 28.6, 28.5*, 24.9, 23.4*; IR (thin film)

ν 3241, 2978, 1727, 1683, 1619, 1473, 1400, 1366, 1300, 1269, 1203, 1174, 1123, 753;

HiResMALDI-MS calcd for C25H31N3O6 [M+Na]+ 492.2110, found, 492.2100; Anal.

calcd for C25H31N3O6: C 63.95, H 6.65, N 8.95, found: C 63.74, H 6.69, N 8.87.


NBn

O

NTs

(±)-(2'R,3R)-2'-ethynyl-1'-[(4-methylphenyl)sulfonyl]-1-(phenylmethyl)spiro[indole-


To a solution of 155 (14.6 mg, 24.0 µmol, 1.00 equiv) in THF (0.5 mL), was added

TBAF (1.0 M in THF, 29 µL, 29 µmol, 1.2 equiv). The reaction mixture was stirred at

room temperature for 10 h, diluted with CH2Cl2, washed with sat. aq NaHCO3, dried over


chromatography (1:3 EtOAc/hexanes) to afford 338 (11 mg, 100%) as colorless oil.


7.50-7.43 (m, 1H), 7.41-7.37 (m, 2H), 7.32-7.19 (m, 6H), 7.06 (ddd, 1H, J = 7.8, 7.8,

0.9 Hz), 6.72 (d, 1H, J = 7.5 Hz), 5.01 (d, 1H, J = 15.4 Hz), 4.76 (d, 1H, J = 15.4 Hz),

4.46 (d, 1H, J = 3.4 Hz), 3.93-3.82 (m, 1H), 3.78-3.67 (m, 1H), 2.47 (s, 3H), 2.25 (d, 1H,

J = 3.4 Hz), 2.22-2.03 (m, 2H).

NBn

O

NTs

Me

(±)-(2'R,3R)-1'-[(4-methylphenyl)sulfonyl]-1-(phenylmethyl)-2'-prop-1-yn-1-

ylspiro[indole-3,3'-pyrrolidin]-2(1H)-one (340)

A solution of 338 (42.0 mg, 92.0 µmol, 1.00 equiv) in THF (2 mL), was cooled to

−78 °C. nBuLi (1.60 M in hexane, 63.0 µL, 101 µmol, 1.10 equiv) was added dropwise

and the reaction mixture was stirred for 30 min. MeI (6.3 µL, 14 µmol, 1.50 equiv) was

added and the reaction mixture was allowed to warm to room temperature slowly. After

12 h, H2O was added to the mixture and the product was extracted with CH2Cl2

(2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over

Experimental Part

173


chromatography (7:13 EtOAc/hexanes) to afford 340 (30 mg, 69%) as colorless oil.


7.44-7.41 (m, 1H), 7.39-7.32 (m, 2H), 7.32-7.21 (m, 5H), 7.19-7.16 (m, 1H), 7.07-7.02

(m, 1H), 6.69 (d, 1H, J = 7.8 Hz), 5.25 (d, 1H, J = 15.7 Hz), 4.67 (d, 1H, J = 15.7 Hz),

4.46-4.39 (m, 1H), 3.89-3.80 (m, 1H), 3.76-3.68 (m, 1H), 2.46 (s, 3H), 2.26-2.06 (m, 2H),

1.54 (d, 3H, J = 2.2 Hz).

NBn

O

NTs

O

Me

(±)-(2'R,3R)-1'-[(4-methylphenyl)sulfonyl]-2'-(2-oxopropyl)-1-


Preparation of Hennion’s catalyst: To a stirred, suspension of HgOred (5.0 mg, 23 µmol,

1.0 equiv) and BF3·Et2O (3.0 µL, 23 µmol, 1.0 equiv) was added CF3CO2H (17.7 µL, 231

µmol, 10.0 equiv). A colorless solution was obtained.

To an aliquot of Hennion’s catalyst (2.0 µL, 2.2 µmol, 10 mol%) was added a solution of

340 (10.5 mg, 22.3 µmol, 1.00 equiv) in CH2Cl2 (2 mL). After 5 min, NaOMe (5 mg) was

added followed by H2O (0.2 mL). The layers were separated; the organic layer was dried

over Na2SO4, filtered, and concentrated in vacuo. The product was purified by column

chromatography (1:3 EtOAc/hexanes) to afford 342 (2.6 mg, 24%) as colorless oil.


7.43-7.40 (m, 2H), 7.38-7.22 (m, 6H), 7.01 (dt, 1H, J = 7.8, 0.9 Hz), 6.61 (d, 1H, J =

7.8 Hz), 6.46 (dt, 1H, J = 7.5, 0.9 Hz), 5.54 (d, 1H, J = 7.2 Hz), 4.86 (d, 1H, J = 15.6 Hz),

4.72 (d, 1H, J = 15.6 Hz), 4.24 (dd, 1H, J = 11.0, 3.1 Hz), 3.91 (ddd, 1H, J = 9.7, 7.2,

2.2 Hz), 3.60 (dd, 1H, J = 18.7, 11.0 Hz), 3.41 (ddd, 1H, J = 17.2, 10.6, 7.2 Hz), 3.23

(dd, 1H, J = 18.7, 3.1 Hz), 2.52 (s, 3H), 2.10 (s, 1H), 1.77 (ddd, 1H, J = 8.7, 6.2, 2.2 Hz).


NBn

O

NTs

Me

MeOH

(±)-(2'R,3R)-2'-(2-hydroxy-2-methylpropyl)-1'-[(4-methylphenyl)sulfonyl]-1-


A solution of 342 (56.0 mg, 114 µmol, 1.00 equiv) in THF (10 mL) was cooled to

−40 °C. MeMgI (3.0 M in Et2O, 45 µL, 140 µmol, 1.2 equiv) was added and the reaction

mixture was allowed to reach room temperature over a period of 4 h. Sat. aq NH4Cl was

added (15 mL). The layers were separated; the organic layer was dried over Na2SO4,

filtered, and concentrated in vacuo. The product was purified by column chromatography

(1:3 EtOAc/hexanes) to afford 343 (15.0 mg, 26%) as colorless oil, together with 342

(24.0 mg).


7.44-7.40 (m, 2H), 7.38-7.22 (m, 5H), 7.09 (dt, 1H, J = 7.5, 0.9 Hz), 6.74-6.67 (m, 1H),

6.14 (d, 1H, J = 7.7 Hz), 4.83 (s, 2H), 4.22-4.17 (m, 1H), 4.01-3.96 (m, 1H), 3.64-3.54

(m, 1H), 2.61-2.50 (m, 1H), 2.52 (s, 3H), 2.35-2.16 (m, 2H), 2.04-2.02 (m, 2H), 1.79-1.65

(m, 1H), 1.18 (s, 3H), 0.79 (s, 3H); HiResMALDI-MS calcd for C29H32N2SO4 [M+Na]+

527.1981, found, 527.1984.

NBn

O

NTs

Me

(±)-(2'R,3R)-1'-[(4-methylphenyl)sulfonyl]-2'-(2-methylprop-2-en-1-yl)-1-(phenyl-

methyl)spiro[indole-3,3'-pyrrolidin]-2(1H)-one (344)

A solution of 343 (15.0 mg, 29.7 µmol, 1.00 equiv) in pydidine (0.2 mL) was cooled to

−50 °C. SOCl2 (4.0 µL, 50 µmol, 1.7 equiv) was added and the mixture was allowed to

reach room temperature over a period of 2 h. CH2Cl2 (15 mL) was added. The layers

were separated; the organic layer was washed with 1 M aq HCl (10 mL), then brine

(10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The product was

Experimental Part

175

purified by column chromatography (1:4 EtOAc/hexanes) to afford 344 (3.8 mg, 26%) as

colorless oil, together with 343 (6.5 mg, 56%).


7.43-7.40 (m, 2H), 7.32-7.21 (m, 5H), 7.09 (dt, 1H, J = 7.8, 1.2 Hz), 6.84-6.79 (m, 1H),

6.61 (d, 1H, J = 7.8 Hz), ), 6.41 (d, 1H, J = 6.9 Hz), 5.02 (d, 1H, 15.6 Hz), 4.52 (d, 1H,

15.6 Hz), 4.32-4.27 (m, 2H), 4.21 (dt, 1H, J = 10.6, 4.4 Hz), 4.03, (ddd, 1H, J = 11.2, 9.9,

5.9 Hz), 3.77, (ddd, 1H, J = 11.2, 7.2, 4.0 Hz), 2.91-2.76 (m, 2H), 2.50 (s, 3H), 2.13

(ddd, 1H, J = 10.0, 5.9, 4.4 Hz), 1.73 (ddd, 1H, J = 12.8, 9.3, 7.2 Hz), 1.39 (s, 3H).

NHNOMeO2C

N

O

Boc

H

OHHO

methyl (2'R,3S,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'-

(1,2-dihydroxyethyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate

(346)

A solution of 337 (17.0 mg, 36.0 µmol, 1.00 equiv) and NMO·H2O (6.0 mg, 43 µmol, 1.2

equiv) in THF/tBuOH/H2O (4:4:1, 1 mL) was stirred at room temperature for 30 min

before OsO4 (4 wt% in H2O, 230 µL, 36.0 µmol, 1.00 equiv) was added. The reaction

mixture was stirred at room temperature for 3 d. The reaction was quenched by addition

of a 2 M aq Na2S2O3 (2 mL) and EtOAc (2 mL) was added. The biphasic mixture was

stirred for 6 h. The phases were separated; the organic layer was washed with brine

(5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by column

chromatography (3:1 EtOAc/hexanes) afforded diol 346 (16.0 mg, 88%) as colorless oil.

Rf = 0.18 (3:1 EtOAc/hexanes), [α]D26 (c 1.545, CHCl3) = −1.4; 1H NMR (300 MHz,

CDCl3) δ 8.33 (br, 1H), 7.67 (d, 1H, J = 7.5 Hz), 7.20 (ddd, 1H, J = 7.5, 7.5, 1.3 Hz),

7.03 (ddd, 1H, J = 7.5, 7.5, 1.3 Hz), 6.81 (d, 1H, J = 7.5 Hz), 5.39 (d, 1H, J = 9.3 Hz),

5.27 (d, 1H, J = 10.6 Hz), 4.52 (s, 1H), 4.34 (dd, 1H, J = 8.1, 4.4 Hz), 4.07 (ddd, 1H, J =


8.7, 8.7, 8.7 Hz), 3.78 (s, 3H), 3.65-3.45 (m, 4H), 3.25-3.15 (m, 1H), 3.11 (dd, 1H, J =

13.7, 10.0 Hz), 2.68 (d, 1H, J = 14.9 Hz), 2.44-2.10 (m, 3H), 1.91-1.81 (m, 1H), 1.48

(s, 9H); 13C NMR (75 MHz, CDCl3,) δ 181.5, 175.7, 171.3, 155.7, 141.1, 128.8, 128.0,

127.7, 122.5, 109.8, 80.7, 71.7, 69.9, 62.1, 59.7, 58.6, 54.8, 52.8, 47.8, 38.1, 30.0, 28.5,

24.9; IR (thin film) ν 3449, 2977, 1722, 1660, 1474, 1412, 1368, 1328, 1206, 1165, 1131,

1030, 755; HiResMALDI-MS calcd for C25H33N3O8 [M+Na]+ 526.2165, found,

526.2155.

NHNOMeO2C

N

O

Boc

H

O

methyl (2'R,3S,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'-(1-

hydroxy-2-methylpropyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-

carboxylate (345)

To a solution of diol 346 (88.0 mg, 0.175 mmol, 1.00 equiv) in EtOAc (5 mL) was added

Pb(OAc)4 (90.0 mg, 0.262 mmol, 1.50 equiv). A yellow suspension was obtained and

after stirring for 10 min, the mixture was filtered through a plug of silica gel, eluting with

EtOAc. Evaporation of the solvent and purification by column chromatography (3:1

EtOAc/hexanes) afforded 345 (72 mg, 87%) as a colorless oil.

Rf = 0.51 (3:1 EtOAc/hexanes), [α]D24 (c 0.760, CHCl3) = +16.0; 1H NMR (300 MHz,

CDCl3) δ 9.05 (d, 1H, J =4.7 Hz), 8.15 (br, 1H), 7.84 (d, 1H, J = 7.5 Hz), 7.23 (ddd, 1H,

J = 7.5, 7.5, 0.9 Hz), 7.02 (ddd, 1H, J = 7.5, 7.5, 0.9 Hz), 6.87 (d, 1H, J = 7.5 Hz), 5.60

(dd, 1H, J = 8.4, 8.4 Hz), 4.53 (d, 1H, J = 4.7 Hz), 4.25 (dd, 1H, J = 8.1, 4.1 Hz), 3.82

(s, 3H), 3.55-3.38 (m, 2H), 2.78-2.61 (m, 2H), 2.34-1.96 (m, 3H), 1.92-1.80 (m, 1H), 1.49

(s, 9H); 13C NMR (75 MHz, CDCl3,) δ 195.0, 176.1, 173.9, 171.4, 154.5, 139.8, 129.3,

126.4, 125.4, 122.8, 110.4, 79.9, 70.3, 59.0, 56.9, 53.8, 52.9, 47.0, 40.4, 29.3, 28.4, 24.8;

IR (thin film) ν 3250, 2979, 2251, 1732, 1681, 1652, 1651, 1474, 1404, 1367, 1272,

1210, 1165, 1131, 912, 732; HiResMALDI-MS calcd for C24H29N3O7 [M+Na]+

494.1903, found, 494.1907.

Experimental Part

177

NHNOMeO2C

N

O

Boc

H

Me

MeHO

methyl (2'S,3S,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'-(1-

hydroxy-2-methylpropyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-

carboxylate (347)

A solution of aldehyde 345 (10.4 mg, 22.1 µmol, 1.00 equiv) in Et2O (2 mL) was cooled

to −78 °C. iPrMgCl (2.0 M in Et2O, 16 µL, 33 µmol, 1.5 equiv) was added slowly and the

reaction mixture was stirred for 2 h; then the mixture was allowed to reach room

temperature slowly. After 14 h, Et2O (5 mL) and sat. aq NH4Cl (5 mL) were added, the

layers were separated and the organic layer was washed with brine (10 mL), dried

(Na2SO4), filtered, and the solvent was evaporated in vacuo. Purification by column

chromatography (1:1 EtOAc/hexanes) afforded 347 (11.1 mg, 97%) as colorless oil.

Rf = 0.38 (3:1 EtOAc/hexanes); 1H NMR (300 MHz, CDCl3) 8.25-7.85 (br, 1H), 7.61

(d, 1H, J = 7.5 Hz), 7.26-7.21 (m, 1H), 7.09-7.04 (m, 1H), 6.85 (d, 1H, J = 7.8 Hz), 5.28

(d, 1H, J = 9.3 Hz), 4.67 (s, 1H), 4.29-4.25 (m, 1H), 4.02 (d, 1H, J = 12.1 Hz), 3.76

(s, 3H), 3.54-3.43 (m, 2H), 3.31 (dd, 1H, J = 13.1, 10.3 Hz), 3.20-3.13 (m, 1H), 2.65

(d, 1H, J = 13.1 Hz), 2.47-2.38 (m, 1H), 2.27-2.09 (m, 2H), 1.92-1.49 (m, 3H), 1.28-1.23

(m, 9H), 0.87-0.83 (m, 6H); HiResMALDI-MS calcd for C27H37N3O7 [M+Na]+ 538.2529,

found, 538.2510.

PhS

OOMe

Me

(propane-2-sulfonyl)-benzene (350)

To a solution of sulfinate 349 (7.83 g, 47.7 mmol, 1.50 equiv) and Bu4NI (750 mg) in

H2O/acetone (4:3, 17.5 mL) was added iPrI (5.40 g, 31.8 mmol, 1.00 equiv) followed by

benzene (7.5 mL). The reaction mixture was heated to reflux for 24 h, then cooled to


room temperature and poured onto a mixture of H2O (30 mL) and EtOAc (30 mL). The

layers were separated and the organic layer was washed with 1 M aq Na2S2O3 (30 mL).

The solvent was evaporated to afford a colorless oil. Purification by column

chromatography (3:1 EtOAc/hexanes) afforded 350 (3.13 g, 36%) as colorless oil.

1H NMR (300 MHz, CDCl3) δ 7.92-7.87 (m, 2H), 7.70-7.62 (m, 1H), 7.59-7.56 (m, 2H),

3.19 (quint, 1H, J = 6.9 Hz), 1.30 (d, 6H, J = 6.9 Hz).

NN N

NPh

S Me

Me

5-(isopropylthio)-1-phenyl-1H-tetrazole (355)

To a mixture of iPrOH (79.0 µl, 1.03 mmol, 1.00 equiv), triphenylphosphine (296 mg,

1.13 mmol, 1.10 equiv) and 2-phenyl-2H-tetrazole-5-thiol (201 mg, 1.13 mmol,

1.10 equiv) in THF (12 ml) was added DEAD (178 µl, 1.13 mmol, 1.10 equiv) dropwise

over 10 min. The yellow solution was stirred at room temperature for 8 h and then

concentrated under reduced pressure. A mixture of pentane and EtOAc (9:1, 20 ml) was

added, the suspension was filtered over Celite and the filtrate concentrated under reduced

pressure. Purification by flash chromatography (1:9 EtOAc/hexanes) provided

5-(isopropylsulfanyl)-1-phenyl-1H-tetrazole (355) (183 mg, 81% yield) as a colorless oil.

Rf = 0.77 (1:3 EtOAc/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.58-7.52 (m, 5H), 4.16

(quint, 1H, J = 6.5 Hz), 1.52 (d, 6H, J = 6.5 Hz).

Experimental Part

179

NN N

NPh

S Me

Me

OO

5-(isopropylsulfonyl)-1-phenyl-1H-tetrazole (356)

To a solution of 5-(isopropylsulfanyl)-1-phenyl-1H-tetrazole (183 mg, 0.831 mmol,

1.00 equiv) in methanol (8 mL) was added an aqueous solution (8 mL) of Oxone (1.53 g,

2.49 mmol, 3.00 equiv) at room temperature. After stirring at room temperature for 2 d,

the mixture was diluted with Et2O (20 mL), washed with H2O (25 mL). The layers were

separated and the aqueous phase was extracted with Et2O (3 × 20 mL). The combined

organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in

vacuo. Purification by flash chromatography (1:4 EtOAc/hexanes) provided sulfone 356

(177 mg, 85% yield) as a white solid.

Rf = 0.38 (1:3 EtOAc/hexanes); mp = 67 °C; 1H NMR (300 MHz, CDCl3) δ 7.69-7.56 (m,

5H), 4.03 (quint, 1H, J = 6.9 Hz), 1.52 (d, 6H, J = 6.9 Hz).

NHNOMeO2C

N

O

Boc

H

Me

Me


methylprop-1-en-1-yl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-

carboxylate (336)

To a solution of sulfone 356 (28.3 mg, 112 µmol, 2.30 equiv) in THF (0.7 mL) at −78°C

was added dropwise LHMDS (0.330 M in THF, 340 µL, 120 µmol, 2.3 equiv). The

yellow solution was stirred at −78°C for 30 min. This solution was added in one portion

with a precooled syringe to a solution of aldehyde 345 (23.0 mg, 49.0 µmol, 1.00 equiv)

in THF (0.7 mL) at −78 °C. The reaction mixture was stirred at -78°C for 3 h; then the

mixture was slowly warmed to room temperature and stirred for 8 h. The reaction mixture

was diluted with Et2O (10 mL) and washed with H2O (10 mL). The organic layer was


dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by

column chromatography (3:2 EtOAc/hexanes) to afford 336 (19 mg, 78%) as white

crystals.

Rf = 0.28 (3:1 EtOAc/hexanes), [α]D24 (c 0.985, CHCl3) = +30.7; mp = 231 °C; 1H NMR

(300 MHz, CDCl3, # denotes major-, * minor rotamer signals) δ 7.92 (br, 2H), 7.51-7.45

(m, 1H*), 7.38-7.17 (m, 1H#), 7.12-6.96 (m, 4H), 6.89 (d, 1H#, J = 7.5 Hz), 6.81 (d, 1H*,

J = 7.5 Hz), 5.50 (t, 1H*, J = 7.8 Hz), 5.50 (d, 1H*, J = 9.7 Hz), 5.22 (d, 1H*, J =

9.7 Hz), 4.98 (t, 1H*, J = 9.0 Hz), 4.84-4.70 (m, 2H#), 4.46 (dd, 1H#, J = 8.7, 2.2 Hz),

4.29 (dd, 1H*, J = 8.1, 3.4 Hz), 3.78 (s, 3H#), 3.73 (s, 3H*), 3.70-3.50 (m, 2H), 3.45-3.34

(m, 2H), 2.70-2.53 (m, 2H), 2.35-1.72 (m, 10H), 1.72 (s, 3H#), 1.59 (s, 9H#), 1.57

(s, 9H*), 1.53 (s, 3H#), 1.53 (s, 3H*), 1.51 (s, 3H*); 13C NMR (75 MHz, CDCl3,) δ 176.0,

174.0, 171.2, 153.5, 139.9, 137.9, 129.5, 128.7, 123.7, 122.8, 121.4, 110.1, 80.2, 63.0,

60.7, 58.8, 57.2, 52.4, 46.8, 37.3, 32.2, 28.4, 25.9, 23.2, 18.3; IR (thin film) ν 3246, 2977,

2931, 1727, 1698, 1619, 1472, 1434, 1401, 1366, 1298, 1270, 1202, 1173, 1167, 752;

HiResMALDI-MS calcd for C27H35N3O6 [M+Na]+ 520.2423, found, 520.2409.

Crystal data for 336 at 193 K, Mr = 616.95, orthorhombic space group P2(1)2(1)2(1),

ρcalc = 1.311 g·cm–3, Z = 4, a = 8.9350(10), b = 13.870(2), c = 25.228(7) Å, α = 90.00, β =

90.00, γ = 90.00°, V = 3126.5(10) Å3. Final R(F) = 0.0608, wR(F2) = 0.1778 for 395

parameters and 2945 reflections with I >2σ(I) and θ < 69.98°.





Experimental Part

181

NHN

OMeO2C

N

O

Boc

H

Me

Me

methyl (2'S,3S)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'-(2-

methylprop-1-en-1-yl)-2-oxo-1,1',2,2'-tetrahydrospiro[indole-3,3'-pyrrole]-5'-

carboxylate (357)

To a solution of 336 (9.0 mg, 180 µmol, 1.0 equiv) in THF (1 mL) at 0 °C was added

LHMDS (0.330 M in THF, 121 µL, 400 µmol, 2.20 equiv). The solution was kept at 0 °C

for 30 min and a solution of phenylselenyl chloride (7.6 mg, 400 µmol, 2.2 equiv) in THF

(1 mL) was added. The reaction mixture was stirred at 0 °C for 90 min, and quenched by

addition of sat. aq NaHCO3 (10 mL). The product was extracted with EtOAc (3 × 10

mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in

vacuo. The unpurified mixture was used without for the subsequent reaction.

Rf = 0.59, 0.51 (3:1 EtOAc/hexanes).

To a solution of the intermediate selenide in THF (0.5 mL) at 0 °C was added DMDO

(≈ 0.09 M in acetone, 80.0 µL, 72.0 µmol, 4.00 equiv). Stirring was continued for 3 h, the

solvent was evaporated in vacuo. Column chromatography (11:9 EtOAc/hexanes)

afforded 357 (6.9 mg, 74% over two steps) as a colorless oil.

Rf = 0.50 (3:1 EtOAc/hexanes), [α]D25 (c 0.220, CHCl3) = +42.0; 1H NMR (300 MHz,

CDCl3, # denotes major-, * minor rotamer signals) δ 7.97-7.60 (br, 2H), 7.26-7.19

(m, 2H), 7.14-7.10 (m, 2H), 7.07-6.97 (m, 2H), 6.85 (d, 2H, J = 7.5 Hz), 5.71-5.67

(m, 2H*), 5.49-5.44 (m, 2H#), 5.31-5.23 (m, 2H), 4.52-4.48 (m, 1H*), 4.37-4.35

(m, 1H#), 3.85 (s, 3H#), 3.84 (s, 3H*), 3.68-3.55 (m, 2H), 3.47-3.29 (m, 2H), 2.18-1.65

(m, 8H), 1.58 (s, 6H), 1.50 (s, 9H#), 1.45 (s, 9H*), 1.42 (s, 3H*), 1.25 (s, 3H#); 13C NMR

(75 MHz, CDCl3,) δ 177.2, 171.7, 162.1, 153.6, 140.3, 140.0, 137.6, 129.1, 128.9, 127.5,

126.8, 122.3, 122.0, 109.8, 80.2, 65.5, 58.2, 52.6, 46.8, 31.5, 28.6, 25.4, 23.4, 18.3, 17.8;

IR (thin film) ν 3248, 2977, 2932, 1732, 1694, 1619, 1472, 1400, 1366, 1260, 1228,


1164, 1126, 753; HiResMALDI-MS calcd for C27H33N3O6 [M+Na]+ 518.2267, found,

518.2276.

N

NO

OH

Me

Me

HNO

spirotryprostatin B (17)

A solution of 357 (4.7 mg, 10 mmol, 1.0 equiv) in CH2Cl2/TFA (5:1, 0.6 mL) was stirred

at room temperature for 30 min. The solvent was evaporated in vacuo and the product

was dissolved in CH2Cl2 (0.5 mL), and NEt3 (5.2 µL, 38 µmol, 4.0 equiv) was added. The

reaction mixture was stirred at room temperature for 4 h, and quenched by addition of sat.

aq NaHCO3 (10 mL). The product was extracted with CH2Cl2 (3 × 10 mL). The

combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo.

Column chromatography (75:20:8 CH2Cl2/EtOAc/iPrOH) afforded spirotryprostatin B

(17) (2.6 mg, 74% over two steps) as a white solid.

Rf = 0.23 (75:20:8 CH2Cl2/EtOAc/i-PrOH), mp = 136 °C; [α]D26 (c 0.045, CHCl3) =

−148.8; 1H NMR (500 MHz, CDCl3) δ 7.53 (br, 1H), 7.24 (ddd, 1H, J = 7.6, 7.6, 1.1 Hz),

7.07 (d, 1H, J = 7.6 Hz), 7.00 (ddd, 1H, J = 7.6, 7.6, 1.1 Hz), 6.85 (d, 1H, J = 7.6 Hz),

5.78 (s, 1H), 5.43 (d, 1H, J = 8.9 Hz), 5.21 (ddd, 1H, J = 8.9, 8.9, 1.4 Hz), 4.34 (dd, 1H.

J = 10.7, 6.1 Hz), 3.80 (ddd, 1H, J = 12.2, 12.2, 8.2 Hz), 3.57 (m, 1H), 2.51-2.47 (m, 1H),

2.13-2.09 (m, 1H), 2.04-1.93 (m, 2H), 1.57 (s, 3H), 1.28 (d, 3H, J = 1.2 Hz); 13C NMR

(125 MHz, CDCl3,) δ 177.8, 162.6, 155.1, 140.3, 138.4, 138.3, 129.1, 127.9, 127.3,

122.3, 120.5, 116.3, 109.8, 64.2, 61.8, 61.6, 44.9, 29.3, 25.5, 22.1, 18.3; IR (thin film)

ν 3212, 2926, 1855, 1725, 1682, 1644, 1471, 1434, 1326, 1293, 1215, 1157, 1105, 753;


Experimental Part

183



NHHNO

TIPS324

NHNO

TIPS

N

O

Boc

N

TIPS

N

O

Boc

H HHNO

358 359

+

Me Me Me

To a solution of 324 (150 mg, 367 µmol, 1.00 equiv) and NEt3 (51.0 µL, 367 µmol, 1.00

equiv) in CH2Cl2 (13 mL) at 0 °C was added N-Boc-L-proline chloride (0.140 M in

CH2Cl2, 6.70 mL, 918 µmol, 2.50 equiv). The reaction mixture was allowed to warm

slowly to room temperature and stirred for 8 h. The reaction was quenched by addition of

10% aq NaHCO3 (10 mL). The phases were separated; the organic layer was washed with

sat. aq NaHCO3 (10 mL). The organic phase was dried over Na2SO4, filtered, and

concentrated in vacuo. Purification by column chromatography (1:3 EtOAc/hexanes)

afforded:

NHNO

TIPS

N

O

Boc

H

Me

tert-butyl (2S)-2-({(2'R,3S,5'R)-2-oxo-5'-[(1Z)-prop-1-en-1-yl]-2'-[(triisopropylsilyl)-


carboxylate (358)

White solid, 89 mg (40%).

Rf = 0.59 (1:1 EtOAc/hexanes), [α]D26 (c 0.425, CHCl3) = −4.03; mp = 86-87 °C;

1H NMR (300 MHz, CDCl3 # denotes major-, * minor rotamer signals) δ 8.47 (br, 1H*),

8.34 (br, 1H#), 7.37-7.13 (m, 4H), 7.10-6.99 (m, 2H), 6.94-6.84 (m, 2H), 5.66-5.41

(m, 4H), 5.41 (s, 1H*), 5.25-5.13 (m, 2H), 5.14 (s, 1H#), 4.95-4.68 (m, 2H), 3.69-3.34


(m, 4H), 2.39-1.96 (m, 8H), 1.85-1.64 (m, 10H), 1.55 (s, 9H#), 1.45 (s, 9H*), 0.82 (s,

42H); 13C NMR (75 MHz, CDCl3, * denotes minor rotamer signals) δ 176.3*, 176.2,

173.3*, 172.9, 154.1*, 153.5, 140.1, 131.6*, 130.7, 128.7, 128.4*, 127.8, 127.1*, 124.8,

124.4*, 124.2, 123.7*, 122.9, 122.8*, 110.1*, 109.9, 102.0*, 101.1, 90.8, 89.5*, 79.9,

79.2*, 58.7, 57.9*, 57.7, 56.7, 56.5*, 56.1*, 54.5*, 47.3, 40.2, 40.0*, 32.2, 30.4*, 29.8*,

29.3, 28.8, 28.5*, 24.7, 23.5*, 18.5, 13.2, 13.1*, 11.0; IR (thin film) ν 3206, 2942, 2865,

2171, 1728, 1688, 1471, 1397, 1297, 1166, 1121, 883, 768, 752, 676; HiResMALDI-MS

calcd for C35H51N3SiO4 [M+Na]+ 628.3546, found, 628.3535.

N

TIPS

N

O

Boc

HHNO

Me

tert-butyl (2S)-2-({(2'S,3R,5'S)-2-oxo-5'-[(1Z)-prop-1-en-1-yl]-2'-[(triisopropylsilyl)-


carboxylate (359)

White solid, 87mg (39%).

Rf = 0.42 (1:1 EtOAc/hexanes), [α]D26 (c 0.450, CHCl3) = −9.87; mp = 96 °C; 1H NMR

(300 MHz, CDCl3 # denotes major-, * minor rotamer signals) δ 8.71 (br, 1H*), 8.57

(br, 1H#), 7.48 (d, 1H#, J = 7.5 Hz), 7.25-7.19 (m, 3H), 7.04-6.88 (m, 4H), 6.12-6.05

(m, 1H*), 5.71-5.45 (m, 3H), 5.29-5.15 (m, 2H), 5.19 (s, 1H*), 4.68-4.87 (m, 1H), 4.90

(s, 1H#), 3.68-3.36 (m, 4H), 2.70 (dd, 1H#, J = 13.1, 8.1 Hz), 2.32-2.10 (m, 5H),

2.00-1.77 (m, 7H), 1.73-1.67 (m, 6H), 1.48 (s, 9H#), 1.43 (s, 9H*), 0.96-0.95 (m, 21H*),

0.85-0.82 (m, 21 H#); 13C NMR (75 MHz, CDCl3, * denotes minor rotamer signals)

δ 178.6, 176.3*, 170.7, 170.3*, 154.2*, 154.1, 140.7, 140.3*, 133.2, 132.2*, 131.1,

130.5*, 128.7, 128.4*, 125.5, 125.5*, 124.8, 124.0*, 122.9*, 122.1, 110.1, 109.7*, 102.0,

99.0*, 91.9*, 87.3, 79.7, 79.1*, 59.1, 58.6*, 58.1, 57.0*, 56.4, 55.7*, 53.7*, 53.5, 46.5,

46.4*, 43.1, 39.3*, 30.2*, 29.7, 28.6, 28.5*, 23.3*, 22.9, 18.6, 18.4*, 13.3*, 13.0, 11.2,

11.0*; IR (thin film) ν 3208, 2942, 2865, 2171, 1728, 1704, 1676, 1621, 1472, 1399,

1366, 1265, 1166, 1125, 883, 749, 678; HiResMALDI-MS calcd for C35H51N3SiO4

[M+Na]+ 628.3546, found, 628.3536.

Experimental Part

185

NHNO

O

TIPS

N

O

Boc

H

tert-butyl (2S)-2-({(2'R,3S,5'R)-5'-formyl-2-oxo-2'-[(triisopropylsilyl)ethynyl]-1,2-

dihydro-1'H-spiro[indole-3,3'-pyrrolidin]-1'-yl}carbonyl)pyrrolidine-1-carboxylate

(330)

A solution of 358 (21.6 mg, 35.7 µmol, 1.00 equiv) and NMO·H2O (5.0 mg, 43 µmol,

1.2 equiv) in THF/tBuOH/H2O (4:4:1, 1 mL) was stirred at room temperature for 30 min

before OsO4 (4 wt% in H2O, 9.0 µL, 1.4 µmol, 4 mol%) was added. The reaction mixture

was stirred at room temperature for 16 h. The reaction was quenched by addition of 2 M

aq Na2S2O3 (2 mL) and EtOAc (5 mL) was added. The biphasic mixture was stirred for

3h. The phases were separated; the organic layer was washed with brine (5 mL), dried

over Na2SO4, filtered, and concentrated in vacuo. The mixture of isomeric products was

used without further purification.

Rf = 0.16 (3:1 EtOAc/hexanes).

To a solution of diols in EtOAc (1.5 mL) was added Pb(OAc)4 (18.3 mg, 53.6 µmol,


was filtered through a plug of silica gel, eluting with EtOAc. Purification by column

chromatography (1:1 EtOAc/hexanes) afforded 330 (18 mg, 85%) as a white solid.




NHHNO

TIPS

Me

326

NHNO

TIPS

Me

N

O

Boc

N

TIPS

Me

N

O

Boc

H HHNO

361 362

+

inseperableby column

chromatography

To a solution of 326 (150 mg, 367 µmol, 1.00 equiv) and NEt3 (51.0 µL, 367 µmol,

1.00 equiv) in CH2Cl2 (10 mL) at 0 °C was added N-Boc-L-proline chloride (0.140 M in

CH2Cl2, 7.00 mL, 929 µmol, 2.50 equiv). The reaction mixture was allowed to warm

slowly to room temperature and stirred at room temperature for 8 h. The reaction was

quenched by addition of 10% aq NaHCO3 (10 mL). The phases were separated; the

organic layer was washed with sat. aq NaHCO3 (10 mL). The organic phase was dried

over Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography

(11:9 EtOAc/hexanes) afforded the product as a mixture of isomers 361/362 (182 mg,

82%), which were used for the following steps without further separation.


Experimental Part

187

Transformation to 363/364

NHNO

TIPS

Me

N

O

Boc

N

TIPS

Me

N

O

Boc

H HHNO

361 362

+ NHNOMeO2C

N

O

Boc

HN

MeO2CN

O

Boc

HHNO

363 364

+

(1:2)inseperableby column

chromatography

seperableby column

chromatography

Dihydroxylation and diol cleavage:

A solution of 361/362 (122 mg, 202 µmol, 1.00 equiv) and NMO·H2O (33.0 mg,

242 µmol, 1.20 equiv) in THF/tBuOH/H2O (4:4:1, 5 mL) was stirred at room temperature

for 30 min before OsO4 (4 wt% in H2O, 52.0 µL, 81.0 µmol, 4 mol%) was added. The

reaction mixture was stirred at room temperature for 16 h. The reaction was quenched by

addition of 2 M aq Na2S2O3 (5 mL) and EtOAc (5 mL). The biphasic mixture was stirred

for 3 h. The phases were separated; the organic layer was washed with brine (10 mL),

dried over Na2SO4, filtered, and concentrated in vacuo. The mixture of isomeric products

was used without further purification.


To a solution of diols in EtOAc (10 mL) was added Pb(OAc)4 (104 mg, 303 µmol,


was filtered through a plug of silica gel, eluting with EtOAc. The mixture of isomeric

products was used without further purification.


Oxidation and ester formation:

A solution of NaClO2 (182 mg, 2.01 mmol, 10.0 equiv) in pH 3.6 buffer (3.5 mL) was

added to a solution of the aldehydes and 2-methyl-2-butene (2.1 mL) in tBuOH (7 mL).

The reaction mixture was stirred at room temperature for 30 min, 2 M aq HCl was added

(5 mL), and the product was extracted with EtOAc (3 × 10 mL). The combined organic

layers were dried over Na2SO4, filtered, and concentrated in vacuo.



The products were dissolved in Et2O (4 mL) and a solution of CH2N2 in Et2O (≈ 0.4 M in

Et2O) was added untill the yellow color of CH2N2 persisted. The solvent was evaporated

in vacuo and the unpurified products were used for the next reaction.


TIPS deprotection:

To a solution of the esters in THF (6 mL), was added TBAF (1.0 M in THF, 240 µL, 240

µmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 8 h, and

diluted with CH2Cl2. The organic solution was washed with sat. aq NaHCO3, and dried

over Na2SO4, filtered, and concentrated in vacuo. The product was purified by column

chromatography (13:7 EtOAc/hexanes) to afford the two isomers 363 and 364 in

combined yield of 72 mg (75%).

NHNOMeO2C

N

O

Boc

H

methyl (2'S,3S,5'S)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'-


Colorless oil, 25 mg (26%).


CDCl3 mixture of 4 rotamers, relative integration is given) δ 8.53-8.51 (m, 0.8H), 8.42

(s, 0.07H), 8.39 (s, 0.13H), 7.64-7.54 (m, 1H), 7.34-7.20 (m, 1H), 7.13-7.01 (m, 1H),

6.93-6.88 (m, 1H), 5.50 (d, 0.08H, J = 2.3 Hz), 5.46 (d, 0.31H, J = 2.3 Hz), 5.29

(m, 0.15H), 5.15-5.03 (m, 0.8H), 4.87 (d, 0.46H, J = 2.3 Hz), 4.85-4.82 (m, 0.2H),

4.68-4.65 (m, 0.4H), 4.58-4.54 (m, 0.46H), 4.26-4.22 (m, 0.14H), 3.86 (s, 0.16H),

3.77-3.77 (m, 0.84H), 3.67-3.39 (m, 2H), 2.73 (d, 0.08H, J = 2.3 Hz), 2.70 (d, 0.46H, J =

2.3 Hz), 2.66 (d, 0.31H, J = 2.3 Hz), 2.58-2.41 (m, 1.15H), 2.39-2.06 (m, 3H), 1.98-1.74

(m, 2H), 1.52-1.28 (m, 9H); 13C NMR (75 MHz, CDCl3, mixture of rotamers) δ 178.7,

Experimental Part

189

178.6, 172.3, 171.6, 171.5, 154.3, 153.7, 141.4, 141.3, 129.5, 126.2, 126.0, 125.7, 125.6,

125.4, 124.9, 122.2, 122.0, 110.2, 80.2, 80.0, 79.6, 79.5, 58.6, 58.2, 57.6 56.0, 55.5, 54.5,

53.1, 53.0, 52.5, 52.4, 47.1, 36.5, 31.5, 30.2, 28.6, 28.5, 24.3, 22.0; IR (thin film) ν 3246,

2977, 2116, 1721, 1687, 1673, 1620, 1473, 1402, 1366, 1261, 1241, 1166;


N

MeO2CN

O

Boc

HHNO

methyl (2'R,3R,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'-


Colorless solid, 46 mg (49%).

Rf = 0.22 (3:1 EtOAc/hexanes); mp = 142-144 °C [α]D26 (c 1.00, CHCl3) = +31.5;

1H NMR (300 MHz, mixture of rotamers, only the major rotamer is described) δ 8.30

(br, 1H), 7.62 (d, 1H, J = 7.1 Hz), 7.31 (dt, 1H, J = 7.8, 1.2 Hz), 7.11-7.06 (m, 1H), 6.92

(d, 1H, J = 7.5 Hz), 4.88 (dd, 1H, J = 8.1, 9.7 Hz), 4.69 (d, 1H, J = 2.2 Hz), 4.58 (dd, 1H,

J = 8.4, 2.2 Hz), 3.78 (s, 3H), 3.69-3.58 (m, 1H), 3.56-3.36 (m, 1H), 2.67 (d, 1H, J = 2.2

Hz), 2.57-2.46 (m, 3H), 2.19-1.71 (m, 3H), 1.49 (s, 9H); 13C NMR (75 MHz, CDCl3,

mixture of rotamers, the two major ones are described) δ179.4, 178.8, 171.8, 171.6,

171.4, 171.2, 154.2, 154.0, 141.7, 141.6, 132.1, 132.0, 129.5, 129.1, 128.6, 128.4, 125.9,

125.8, 125.4, 124.9, 122.1, 122.0, 110.3, 110.1, 80.3, 80.1, 79.7, 79.5, 78.7, 78.5, 58.4,

58.3, 57.6, 55.2, 55.1, 53.8, 53.0, 52.4, 46.9, 46.8, 40.7, 36.6, 30.0, 29.4, 28.5, 28.4, 23.4,

23.1, 14.3, 12.9; IR (thin film) ν 3233, 2977, 1716, 1621, 1473, 1403, 1364, 1331, 1262,

1240, 1168, 1128, 754; HiResMALDI-MS calcd for C25H29N3O6 [M+Na]+ 490.1954,

found, 490.1945.


N

NO

OH

H

HNO

(2R,3R,5aS,10aR)-3-ethynyl-5a,6,7,8-tetrahydro-1H,5H-spiro[dipyrrolo[1,2-a:1',2'-

d]pyrazine-2,3'-indole]-2',5,10(1'H,10aH)-trione (365)

A solution of 364 (15.3 mg, 41.6 µmol, 1.00 equiv) in CH2Cl2/TFA (5:1, 2 mL) was

stirred at room temperature for 30 min. The solvent was evaporated in vacuo and the

product was dissolved in CH2Cl2 (1 mL), and NEt3 (22.8 µL, 166 µmol, 4.00 equiv) was

added. The reaction mixture was stirred at room temperature for 4 h, and quenched by

addition of sat. aq NaHCO3 (10 mL). The product was extracted with CH2Cl2 (3 × 20

mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in

vacuo. Column chromatography (75:20:8 CH2Cl2/EtOAc/iPrOH) afforded 365 (6.0 mg,

43% over two steps) as a colorless oil.

Rf = 0.24 (75:20:8 CH2Cl2/EtOAc/iPrOH), [α]D23 (c 0.250, CHCl3) = −74.1; 1H NMR

(300 MHz, CDCl3) δ 8.14 (br, 1H), 7.45 (d, 1H, J = 7.6 Hz), 7.29 (ddd, 1H, J = 7.6, 7.6,

1.2 Hz), 7.08 (ddd, 1H, J = 7.6, 7.6, 1.2 Hz), 6.91 (d, 1H, J = 7.6 Hz), 5.12 (ddd, 1H, J =

11.8, 8.1, 5.6 Hz), 4.91 (d, 1H, J = 2.5 Hz), 4.22 (ddd, 1H, J = 11.8, 68.1,.2 Hz), 4.06

(ddd, 1H, J = 15.6, 9.3, 6.8 Hz), 3.30 (ddd, 1H, J = 12.5, 10.0, 5.0 Hz), 2.66 (dd, 1H, J =

13.1, 5.6 Hz), 2.58 (d, 1H, J = 2.5 Hz), 2.57-2.38 (m, 1H), 2.18-1.79 (m, 4H); 13C NMR

(125 MHz, CDCl3,) δ 179.6, 165.0, 164.4, 140.7, 129.4, 126.6, 122.7, 110.0, 109.7, 78.1,

62.7, 58.0, 54.2, 53.3, 44.5, 38.6, 28.5, 22.1, 20.6; IR (thin film) ν 3262, 2925, 2125,

1715, 1660, 1619, 1472, 1445, 1311, 1189, 755; HiResMALDI-MS calcd for C19H17N3O3

[M+Na]+ 336.1343, found, 336.1350.

Experimental Part

191

NHNOMeO2C

N

O

Boc

H

methyl (2'S,3S,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2-

oxo-2'-vinyl-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate (366)

To a solution of 363 (170 mg, 364 µmol, 1.00 equiv) and quinoline (22.0 µL, 182 µmol,

0.50 equiv) in EtOH (4 mL) was added Pd/BaSO4 (50 mg, 33 wt%). The reaction mixture

was stirred at room temperature under H2 atmosphere for 24 h. The solution was filtered

over Celite to remove the catalyst and the solvent was evaporated in vacuo. The product

was purified by column chromatography (57:43 EtOAc/hexanes) to afford 366 (167 mg,

98%) as a colorless oil.



(s, 0.38H), 8.58 (s, 0.07H), 7.57 (d, 0.26H, J = 8.1 Hz), 7.32-7.12 (m, 1.74H), 7.09-6.85

(m, 2H), 5.99-5.84 (m, 0.68H), 5.77-5.29 (m, 2H), 5.22-5.20 (m, 0.32H), 5.14-5.03

(m, 1H), 4.95-4.83 (m, 0.55H), 4.68-4.64 (m, 0.45H), 4.58-4.55 (m, 0.15H), 4.43-4.36

(m, 0.69H), 4.29-4.22 (m, 0.16H), 3.86-3.85 (m, 0.25H), 3.87-3.86 (m, 2.57H), 3.67-3.33

(m, 2H), 2.70-2.18 (m, 2.85H), 2.11-1.74 (m, 3.15H), 1.48-1.40 (m, 9H); 13C NMR

(75 MHz, CDCl3, mixture of 4 rotamers) δ 180.5, 179.7, 179.6, 178.7, 178.5, 173.5,

173.2, 172.4, 172.3, 171.8, 171.6, 171.4, 154.3, 154.2, 153.7, 153.6, 141.5, 141.4, 136.0,

135.9, 129.4, 129.3, 129.0, 128.9, 126.2, 126.2, 126.0, 122.0, 121.8, 121.7, 119.5, 119.1,

110.3, 110.2, 80.0, 79.6, 79.4, 79.3, 65.0, 64.0, 58.6, 58.5, 58.2, 57.9, 57.6, 57.4, 57.2,

56.9, 56.2, 55.9, 55.5, 54.5, 54.0, 52.9, 52.4, 52.4, 52.3, 47.2, 47.1, 36.4, 35.9, 35.8, 32.0,

31.5, 30.7, 30.2, 29.7, 29.1, 28.5, 24.3, 23.0; IR (thin film) ν 3242, 2977, 1721, 1687,

1473, 1403, 1366, 1257, 1242, 1202, 1167, 1125, 754, 668; HiResMALDI-MS calcd for

C25H31N3O6 [M+Na]+ 492.2110, found, 492.2105.


NHNOMeO2C

N

O

Boc

H

O

methyl (2'R,3S,5'R)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'-

formyl-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylate (367)

A solution of 366 (60.0 mg, 128 µmol, 1.00 equiv) and NMO·H2O (21.0 mg, 154 µmol,

1.20 equiv) in THF/tBuOH/H2O (4:4:1, 5 mL) was stirred at room temperature for 30 min

before OsO4 (4 wt% in H2O, 813 µL, 128 µmol, 1.00 equiv) was added. The reaction

mixture was stirred at room temperature for 2 d. The reaction was quenched by addition

of 2 M aq Na2S2O3 (5 mL) and EtOAc (5 mL). The biphasic mixture was stirred for 6 h.

The phases were separated; the organic layer was washed with brine (10 mL), dried over

Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography (3:2

EtOAc/hexanes) afforded the diol as colorless oil.


To a solution of the unpurified diol in EtOAc (5 mL) was added Pb(OAc)4 (43.0 mg, 125

µmol, 1.00 equiv). A yellow suspension was obtained, and, after stirring for 10 min, the

mixture was filtered through a plug of silica gel, eluting with EtOAc. Evaporation of the

solvent and purification by column chromatography (7:3 EtOAc/hexanes) afforded 367

(38 mg, 63%) as a colorless oil.



(d, 0.38H, J = 2.8 Hz), 9.04-8.95 (m, 0.52H), 8.83-8-69 (m, 0.48H), 7.29-7.20 (m, 1H),

7.12-6.87 (m, 3H), 5.24-4.87 (m, 1.48H), 4.83 (d, 0.18H, J = 2.8 Hz), 4.76-4.63

(m, 0.24H), 4.57-4.52 (m, 0.28H), 4.48-4.48 (m, 0.10H), 4.41-4.37 (m, 0.25H), 4.22-4.15

(m, 0.47H), 3.90 (s, 0.63H), 3.87 (s, 0.66H), 3.82-3.78 (m, 1.71H), 3.67-3.35 (m, 2H),

2.92-2.77 (m, 0.27H), 2.74-2.54 (m, 0.79H), 2.45-2.25 (m, 1.11H), 2.21-1.75 (m, 3.83H),

1.47-1.39 (m, 9H); 13C NMR (75 MHz, CDCl3, mixture of 4 rotamers) δ 197.3, 197.2,

178.2, 177.8, 173.0, 172.6, 172.0, 171.5, 154.1, 153.6, 141.0, (132.0), (131.9), 129.8,

129.5, (128.5), (128.3), 126.3, 125.5, 125.3, 124.8, 123.1, 122.7, 122.2, 110.7, 110.2,

Experimental Part

193

80.4, 80.3, 79.8, 79.3, 70.2, 69.8, 69.3, 67.3, 60.0, 59.4, 58.3, 57.4, 56.4, 53.3, 53.1, 52.7,

47.0, 46.8, 40.4, 37.3, 31.2, 30.0, 29.7, 29.2, 28.5, 28.5, 24.5, 24.0, 23.3, 23.2;


NHNOMeO2C

N

O

Boc

H

Me

Me


methylprop-1-en-1-yl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-

carboxylate (368)

To a solution of sulfone 356 (10.6 mg, 41.9 µmol, 2.50 equiv) in THF (0.5 mL) at −78°C

was added dropwise LHMDS (0.330 M in THF, 123 µL, 41.9 µmol, 2.50 equiv). The

yellow solution was stirred at −78°C for 30 min. This solution was added in one portion

with a precooled syringe to a solution of aldehyde 367 (7.9 mg, 17 µmol, 1.0 equiv) in

THF (0.5 mL) at −78 °C. The reaction mixture was stirred at -78°C for 3 h; then the

mixture was slowly warmed to room temperature and stirred for 8 h. The reaction mixture

was diluted with Et2O (10 mL) and washed with H2O (10 mL). The organic layer was

dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by

column chromatography (11:9 EtOAc/hexanes) to afford 368 (5.7 mg, 68%) as a

colorless oil,


CDCl3 mixture of 4 rotamers, relative integration is given) δ 7.82 (br, 1H), 7.24-7.17

(m, 1H), 7.14-7.05 (m, 1H), 7.03-6.93 (m, 1H), 6.89-6.84 (m, 1H), 5.56-5.51 (m, 0.82H),

5.44-5.34 (m, 0.32H), 5.22 (d, 0.16H, J = 9.7 Hz), 5.17 (d, 0.18H, J = 9.2 Hz), 5.11-5.06

(m, 0.82H), 4.89-4.86 (m, 0.18H), 4.81 (d, 0.52H, J = 9.3 Hz), 4.46-4.36 (m, 0.42H),

4.27-4.25 (m, 0.46H), 4.20-4.18 (m, 0.12H), 3.86 (s, 0.40H), 3.79-3.74 (m, 2.60H),

3.64-3.59 (m, 0.68H), 3.57-3.52 (m, 0.32H), 3.49-3.34 (m, 1H), 2.63-2.77 (m, 0.32H),

2.57-2.50 (m, 0.68H), 2.45-2.21 (m, 1.19H), 2.12-1.91 (m, 2.51H), 1.80-1.71 (m, 1.30H),


1.70 (s, 1.30H), 1.70 (s, 2.06H), 1.44-1.43 (m, 9H), 1.70 (s, 0.94H), 1.70 (s, 1.03 H), 1.70

(d, 1.20H, J = 1.0 Hz), 1.70 (s, 0.77H); 13C NMR (125 MHz, CDCl3, mixture of

4 rotamers) δ 179.3, 172.9, 172.3, 153.8, 140.7, 137.1, 132.2, 132.0, 128.8, 128.5, 127.0,

126.4, 123.3, 122.8, 122.0, 121.6, 120.6, 109.4, 109.3, 79.9, 79.8, 61.7, 61.6, 58.9, 58.6,

58.5, 57.8, 57.6, 52.4, 52.3, 46.9, 36.0, 35.8, 31.3, 29.9, 29.7, 28.5, 28.5, 28.3, 25.5, 25.3,

24.1, 23.0, 17.8, 17.7; IR (thin film) ν 3227, 2976, 1724, 1695, 1624, 1468, 1401, 1366,

1260, 1242, 1202, 1167, 1118, 755; HiResMALDI-MS calcd for C27H35N3O6 [M+Na]+

520.2423, found, 520.2413.

NHN

OMeO2C

N

O

Boc

H

Me

Me

methyl (2'S,3S)-1'-{[(2S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl]carbonyl}-2'-(2-

methylprop-1-en-1-yl)-2-oxo-1,1',2,2'-tetrahydrospiro[indole-3,3'-pyrrole]-5'-

carboxylate (357)

To a solution of 368 (3.3 mg, 6.6 µmol, 1.0 equiv) in THF (1 mL) at 0 °C was added

LHMDS (0.330 M in THF, 76.0 µL, 25.2 µmol, 3.80 equiv). The solution was kept at

0 °C for 30 min and a solution of phenylselenyl chloride (4.8 mg, 25 µmol, 3.8 equiv) in

THF (1 mL) was added. The reaction mixture was stirred at 0 °C for 90 min; and then

quenched by addition of sat. aq NaHCO3 (6 mL). The product was extracted with EtOAc

(3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and

concentrated in vacuo. The mixture of isomeric products was used for elimination

without further purification.

Rf = 0.59, 0.51 (3:1 EtOAc/hexanes).

To a solution of the selenide in THF (1 mL) at 0 °C was added DMDO (≈ 0.09 M in

acetone, 300 µL, 265 µmol, 4.00 equiv). After stirring for 3 h, the solvent was evaporated

in vacuo. Preparative TLC (3:1 EtOAc/hexanes) afforded 357 (1.3 mg, 40% over two

steps) as a colorless oil.

Curriculum Vitae

195

VIII. Curriculum Vitae

1972 Born on August 25, in Stuttgart, Germany.

1979-1983 Primary school in Ensheim, Germany.

1983-1992 High school in Saarbrücken, Germany.

Abitur: Scientific Maturity, July 1992.

1992-1995 Studies in Chemistry at the Universität des Saarlandes, Germany.

1995-1998 Studies in Chemistry at ECPM Strasbourg, France.

1996 Internship (6 weeks): Wacker Chemie GmbH, Burghausen, Germany.

1997 Internship (3 month): Toray Inc., Kyoto, Japan.

1998 Diploma thesis in the group of Prof. Dr. Francois Diederich, under the

supervision of Laurent Ducry at the ETH Zürich.

• Studies towards the Synthesis of a New Ligand for Asymmetric Phase-Transfer Catalysis Bearing Binaphthyl and Cinchona Alkaloid Moieties.

1998-2003 Ph.D. thesis under the direction of Prof. Dr. Erick M. Carreira at the ETH

Zürich.

• Novel Approach to Spiro-Pyrrolidine-Oxindoles and its Application to the Synthesis of (±)-Horsfiline and (−)-Spirotryprostatin B.

• Supervision of two diploma theses.

• Teaching assistant and head teaching assistant in the practica of organic chemistry and teaching assistant for chemistry exercises and lectures.

Zürich, January 2003 Christiane Marti

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