tandem isomerization reaction of alkynes: total … · 2018. 1. 10. · synthesis of the chiral...

TANDEM ISOMERIZATION REACTION OF ALKYNES:

TOTAL SYNTHESIS OF ALPHA-YOHIMBINE

FENGWEI

NATIONAL UNIVERSITY OF SINGAPORE

2012

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12

TANDEM ISOMERIZATION REACTIONS OF

ALKYNES: TOTAL SYNTHESIS OF

ALPHA-YOHIMBINE

FENG WEI (BSc., Nankai University)

A THESIS SUBMITTED

FOR THE DEGREE OF DOCTOR OF PHILOSOPHY

DEPARTMENT OF CHEMISTRY

NATIONAL UNIVERSITY OF SINGAPORE

To my family

For their love, support, and encouragement

Acknowledgements

First and foremost, I would like to take this opportunity to thank my supervisor,

Associate Professor Tan Choon-Hong, for his guidance and encouragement

throughout my PhD research and study.

I would like to thank all my labmates for creating such a harmonious,

encouraging, and helpful working environment. My special thanks go to Mr. Liu

Hongjun for his pioneering work on the isomerization project.

I thank Dr Wu Jien, Mdm Han Yanhui for their assistance in NMR analysis, and

Mdm Wong Lai Kwai and Mdm Lai Hui Ngee for their assistance in Mass analysis as

well. I also owe my thanks to many other people in NUS chemistry department, for

their help and assistance from time to time.

Last but not least, I thank all my friends in Singapore who helped me settle down

at the beginning. Singapore is a great place and I enjoy the life here.

Table of Contents

Summary

List of Schemes

List of Tables

List of Figures

List of Abbreviations

Chapter 1

Introduction to allenes

1.1 General introduction to allenes--------------------------------------------------------- 2

1.2 Intramolecular conjugate addition to allenes----------------------------------------- 3

1.3 Intramolecular Diels-Alder reaction of allenes-------------------------------------- 11

1.4 Summary--------------------------------------------------------------------------------- 22

Chapter 2

Brønsted-base catalyzed tandem isomerization-aza-Michael reactions

2.1 Different approaches for the preparation of piperidines and lactams ----------- 28

2.2 Tandem isomerisation-aza-Michael reaction of alkynylamines and

alkynylamides--------------------------------------------------------------------------- 35

2.3 Summary--------------------------------------------------------------------------------- 45

Chapter 3

Total synthesis of alpha-yohimbine via intramolecular-Diels-Alder reaction

3.1 Introduction to the synthesis of alpha-yohimbine---------------------------------- 48

3.2 Tandem-isomerization intramolecular-Diels-Alder reactions of alkynoates: total

synthesis of alpha-yohimbine -------------------------------------------------------- 54

3.3 Summary--------------------------------------------------------------------------------- 71

Chapter 4

Experimental

4.1 General information-------------------------------------------------------------------- 74

4.2 Preparation and characterization of compounds for the Michael reaction ----- 75

4.3 Preparation and characterization of compounds for the IMDA reaction-------- 83

4.4 Procedures to (+)-alpha-yohimbine and characterization of compounds----- 100

Appendix-------------------------------------------------------------------------------------- 116

Summary

The aim of this study is to apply the highly enantioselective alkyne isomerization

reactions that is developed in our group to construct complex and usefull molucules

towards natural product synthesis.

We have found that a Brønsted-base catalyzed tandem isomerization-aza-Michael

reaction can be used to form useful heterocycles under mild conditions. This efficient

method was applied to the synthesis of various functionalized heterocycles with

excellent yields. Tandem isomerization-aza-Michael reaction with alkynyl-amines,

alkynyl-amide led to interesting piperidines and lactams. Asymmetric version of

tandem isomerization-aza-Michael reaction using alkynyl-amide was tested to give

high ee using a chiral bicyclic guanidine as a catalyst. Effort to synthesize larger ring

sized lactams was carried out although failed.

We have also found that chiral bicyclic guanidine could catalyze a tandem

isomerisation intramolecular-Diels-Alder (IMDA) reaction. Interesting and useful

hydroisoquinolines were obtained with moderate to high ees. The chirality was

generated at the stage of alkyne isomerisation and transferred efficiently at the [4+2]

cyclization step. We have also successfully finished the first catalytic enantioselective

synthesis of alpha-yohimbine starting from the IMDA products.

List of Schemes

Scheme 1.1.1 Natural products containing allene structure

Scheme 1.1.2 Two addition models of allenes

Scheme 1.2.1 Intramolecular Michael addition of alcohol to allene sulphoxide

Scheme 1.2.2 Cyclic vinyl sulfoxide and sulfone formation via intramolecular

Michael addition of alcohol to allenic sulphoxide and allenic

sulfone

Scheme 1.2.3 Intramolecular oxa-Michael reaction of allenyl phosphonates

Scheme 1.2.4 Intramolecular Michael addition to allenotes

Scheme 1.2.5 Intramolecular Michael addition to allenic ketones, example1

Scheme 1.2.6 Intramolecular Michael addition to allenic ketones, example 2


Scheme 1.2.8 Intramolecular conjugate addition of nitrogen to allenes

Scheme 1.3.1

Intromolecular Diels-Alder reaction between allenic ketone and

furan toward the synthesis of Periplanone B

Scheme 1.3.2 Intramolecular Diels-Alder reaction between allene and bezene

Scheme 1.3.3 Intramolecular Diels-Alder reaction of allenic amide, example 1


Scheme 1.3.5 Intramolecular Diels-Alder reaction of sulfonyl allene

Scheme 1.3.6 Total synthesis of hippadine via intramolecular Diels-Alder reaction

of allenic carbonate

Scheme 1.3.7 Intramolecular Diels-Alder reaction of allenyl ether

Scheme 1.3.8 Euryfuran synthesis via IMDAreaction of alkoxyallene

Scheme 1.3.9 Total synthesis of Forskoin via intramolecular Diels-Alder reaction

of allenyl ether

Scheme 1.3.10 Total synthesis of tirkentrins via Hetero-Diels-Alder reaction of

allene

Scheme 1.3.11 Proposal of the Intramolecular Diels-Alder reaction of vinylallene

toward the total synthesis of esperamicin A

Scheme 1.3.12 IMDA reaction of vinylallene toward the total synthesis of

cis-Dehydrofukinone

Scheme 1.3.13 IMDA reaction of vinylallene toward the total synthesis of

(+)-Compactin

Scheme 2.1.1 Piperidine formation via amine-ketone condensation

Scheme 2.1.2 Piperidine formation via ring closing metathesis

Scheme 2.1.3 Piperidine formation via intramolecular electrophilic addition of

amine to allene

Scheme 2.1.4 Piperidine formation via ruthenium catalysis

Scheme 2.1.5 Piperidine formation via radical cyclization

Scheme 2.1.6 Pyrrolidine formation via oxidative cyclization

Scheme 2.1.7 Pyrrolidine formation via cobalt mediated cyclization

Scheme 2.1.8 β–lactam synthesis via [2+2]-cycloaddition

Scheme 2.1.9 5-membered lactam formation via gold catalysis

Scheme 2.1.10 6-membered lactam formation via aza-oxy-carbanion relay

Scheme 2.2.1 Alkynyl amine synthesis

Scheme 2.2.2

Brønsted-base catalyzed tandem isomerization-aza-Michael

reaction of alkynyl-amines 141

Scheme 2.2.3 Proposed mechanism for tandem isomerization-aza-Michael

reaction of 141

Scheme 2.2.4 Synthesis of the chiral bicyclic guanidine 149

Scheme 2.2.5 Synthesis of alkynyl amide 150

Scheme 2.2.6 Synthetic schemes to different alkynyl amides and carbonates

Scheme 2.2.7 Enantioselective isomerization of alkynes to allenes

Scheme 3.1.1 Total synthesis of alpha-yohimbine, route1

Scheme 3.1.2 Total synthesis of alpha-yohimbine, route 2



Scheme 3.2.1 Initial plan for the construction of hydroisoquinoline derivative,

core sutructure of yohimbines

Scheme 3.2.2 Synthesis of IMDA substrates containing opening diene

Scheme 3.2.3 Synthesis of IMDA substrates containing cyclic diene

Scheme 3.2.4

X-ray structures of the compounds 208ba, 208ca and the X-ray

structure of the hydrogenation product of compound 208bb.

Scheme 3.2.5 Intramolecular-Diels-Alder reaction of substrate 208g and

manipulation on the IMDA product 208ga

Scheme 3.2.6 Attempt on the total synthesis starting with compound 208ca

Scheme 3.2.7 Ring opening of compound 217 with triflic acid

Scheme 3.2.8 Protection of alcohol group in compound 221

Scheme 3.2.9 Total synthesis of alpha-yohimbine 170 starting from 208ca

Scheme 3.2.10 Total synthesis of alpha-yohimbine starting from 208ha and 208hb

List of Tables

Table 1.3.1 Intramolecular [4+2] cycloaddition of allenic acid and ester

Table 2.1 Solvent effect on asymmetric tandem isomerization-aza-Michael

reaction of alkynyl amine 141c

Table 2.2 Bicyclic guanidine catalyzed enantioselective tandem

isomerization-aza-Michael reaction

Table 3.1 Solvent effect on IMDA reaction

Table 3.2

Solvent and concentration effect on the IMDA reaction of 208b

Table 3.3 Intramolecular-Diels-Alder (IMDA) reaction of 208

Table 3.4 Oxabicyclic ring opening of IMDA product 208ca

Table 3.5 Optimization of reductive oxabicyclic ring opening of IMDA product

208ca

Table 3.6 Optimization of hydrogenation of compound 222

List of Figures

Figure 1.1 Allene models

Figure 2.1 Piperidine or pyridine containing natural products

Figure 2.2 Enantioselectivity step (Gibbs free energy difference given in

kcal/mol)

Figure 2.3 Different alkyne substrates for the isomerization reaction.

Figure 2.4 Asymmetric synthesis of allenic ketones 94 and 95a-b.

List of Abbreviations

AcOH acetic acid

Ac acetyl

[] optical rotation

aq. aqueous

Ar aryl

Bn benzyl

Boc tert-Butyloxycarbonyl

iBu iso-butyl

tBu tert-butyl

c concentration

cat. catalyst

mCPBA meta-Chloroperoxybenzoic acid

Cbz Carbobenzyloxy

oC degrees (Celcius)

chemical shift in parts per million

DCM dichloromethane

DFT density functional theory

DMAP 4-dimethylaminopyridine

DMSO dimethyl sulfoxide

dd doublet of doublet

dr diastereomeric ratio

ee enantiomeric excess

EI electron impact ionization

ESI electro spray ionization

Et ethyl

Et3N triethylamine

Eoc ethoxycarbonyl

FAB fast atom bombardment ionization

FTIR fourier transformed infrared spectroscopy

g grams

ΔG Gibbs free energy

h hour(s)

HPLC high pressure liquid chromatography

HRMS high resolution mass spectroscopy

Hz hertz

i.d. internal diameter

IR infrared

J coupling constant

LRMS low resolution mass spectroscopy

Me methyl

MeCN acetonitrile

MeOH methanol

mg milligram

MHz megahertz

min. minute(s)

ml milliliter

l microliter

mmol millimole

MS mass spectroscopy

MeNO2 nitromethane

NMR nuclear magnetic resonance

NOE nuclear overhauser effect

NIS N-iodosuccinimide

ppm parts per million

iPr isopropyl

Ph phenyl

rt room temperature

rac racimic

T kelvin

TBD 1,5,7-Triazabicyclo[4.4.0]dec-5-ene

THF tetrahydrofuran

TLC thin layer chromatography

TS transition state

TsCl para-toluenesulfonyl chloride

Ts para-toluenesulfonyl

TsOH para-toluenesulfonic acid

Ns 2-nitrobenzensulfonyl

http://en.wikipedia.org/wiki/Kelvin

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6THR-4PKFH22-2&_user=10&_coverDate=11%2F19%2F2007&_rdoc=1&_fmt=full&_orig=search&_cdi=5289&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=8008a3b4302ae3e1b70082f29eaffec0#sec3.9

M mol∙l-1

mM mmol∙l-1

Chapter 1

1

Chapter 1

Introduction to Allenes

Introduction

2

1.1 General introduction to allene

Allenes are three-carbon functional groups possessing a 1, 2-diene moiety and

they are potential precursors in the synthesis of highly complex and strained target

molecules of biological and industrial importance. Allenes were first synthesized

in 1887,1 However, the structures were confirmed only in 1954.2 Surprisingly,

van’t Hoff, in 1875, was able to predict that unsymmetrically substituted allenes

should be chiral and exist in two enantiomeric forms.3 The initial development of

allene chemistry was severely impeded by limited synthetic methods and also the

false notion that such a 1, 2-diene functional group would be highly unstable.

Since the development of modern analytical technologies, especially IR and

Raman spectroscopy, allene chemistry is drawing more and more attention from

organic chemists. A lot of natural products with interesting biological activities

have been found containing the allene moiety (Scheme 1.1.1).4

Scheme 1.1.1 Natural products containing allene structure

Chapter 1

3

As a class of unique compounds, allenes have two π-orbitals perpendicular to

each other. They have been shown to demonstrate nice reactivities as well as

selectivities, which can usually be tuned by electronic or steric effects or the

nature of the catalysts involved. They are ready to undergo either electrophilic

addition or nucleophilic addition (Scheme 1.1.2). Electrophilic addition may

afford terminal attack and central attack products. The regio- and stereoselectivity

depends on the steric and electronic effects of the substituents on the allene, the

nature of the electrophile and solvent effects. However, nucleophilic addition

usually occurs at the central carbon atom with few exceptions.

Electrophilic addition

Nucleophilic addition

Scheme 1.1.2 Two addition models of allenes

Allenes have also been shown to be great precursors for cycloaddition reactions.5

They are able to afford many complex and interesting molecules via various

cycloaddition reactions, such as [2+2], [3+2] and [4+2].5 Furthermore,

intramolecular type cycloaddition usually affords more complex and interesting

structures which may be synthetically useful in natural product synthesis.

This chapter will review the progress on intramolecular conjugate addition and

intramolecular Diels-Alder cycloaddition of allenes.

1.2 Intramolecular conjugate addition to allenes

Introduction

4

In 1987, the first example of intramolecular addition of alcohols to 1, 2-allenyl

sulfoxides was reported by Parsons et al.6 This offered an efficient route for the

preparation of hydropyrans and spiroketals, which are widely distributed in nature

and are found in molecules possessing a diverse range of biological activity.7

Scheme 1.2.1 Intramolecular Michael addition of alcohol to allene sulphoxide

When alcohol 5 was treated with sodium hydride in dry THF, 5-methyl

-6-(phenylsulfinylmethyl)-3, 4-dihydro-2H-pyran (6) was obtained in 97% yield

(Scheme 1.2.1). Similarly, when alcohol 7 was treated with sodium hydride in dry

THF, nucleophilic Michael addition occurred. After removal of the silyl protecting

group with HF in MeOH, an electrophilic addition was promoted when treating 8

with catalytic amount of CSA in DCM, which afforded the (4, 5)-spiroketal 9

(Scheme 1.2.1). An interesting compound 12 of a bicyclic pyran structure was

also obtained (Scheme 1.2.1). When diol 10, the deprotection product of 7, was

treated with PTSA in benzene, an electrophilic addition took place to produce 11

Chapter 1

5

in 88% yield. After treatment of 11 with sodium hydride in THF, the bicyclic

pyran 12 was obtained in 50% yield. However, the diastereoisomers are

inseparable.

Another investigation on 1, 2-allenyl sulfoxide cyclization was reported in 2001

by Mukai et al (Scheme 1.2.2).8 When alcohol 13 was subjected to the basic

condition tBuOK/tBuOH, nucleophilic addition to allene followed by double bond

migration occurred. Cyclic vinyl sulfoxides of different sizes, five to seven, were

formed in good yields. However, eight member ring product cannot be obtained

from the corresponding allenic sulfoxide.

Scheme 1.2.2 Cyclic vinyl sulfoxide and sulfone formation via intramolecular Michael

addition of alcohol to allenic sulphoxide and allenic sulfone

Allenic sulfonyl derivatives 15 were also successfully transformed into oxacycle

16 of different sizes (Scheme 1.2.2). Five membered to eight membered cyclic

vinyl sulfones were all achieved in good yields. When a substituent group was

attached to the other side of allene, substrates 17 and 18 were also smoothly

cyclized to form the eight membered oxacycles 19 and 20 without double bond

migration.

Introduction

6

Several examples of cyclizations of allenic alcohols to prepare 2,

5-dihydrofurans9 and furans10 have also been reported. Application of this

approach to phosphorus-containing allenes can pave the way to phosphorylated

furans and dihydrofurans. However, relatively little work have been performed on

the synthesis and study of intramolecular cyclization of phosphorylated allenic

carbinols.

In 2001, Brel reported an intramolecular oxa-Michael reaction of allenyl

phosphonates (Scheme 1.2.3).11 The glycols 21a–i were easily prepared from

Scheme 1.2.3 Intramolecular oxa-Michael reaction of allenyl phosphonates

propargylic alcohols and obtained as a mixture of two diastereomers (31P NMR

spectral data, in 1:1–1.4 ratio) resulting from the chirality of the allenic group.

They are stable compounds and can be handled at ambient temperature. However,

under basic conditions, they were cyclized to 2, 3-dihydrofurans via nucleophilic

addition of the terminal alcohol to the central carbon atom of the allene system.

Dihydrofurans 22a-f were obtained in good yields and high diastereoselectivities.

Treated under acidic condition, compounds 22a-f were easily transformed into

alpha-substituted furans 23a-f, which is a system that occurs in a number of

Chapter 1

7

natural products.12

Besides allenyl sulfoxides, allenyl sulfones and allenyl phosphonates, allenoates

and 1, 2-allenic ketones are also good Michael acceptors. In 1994, Nagao found

that treatment of diethyl (acetylamino)ethynylmalonate 24 with 1M KOH

afforded trisubstituted oxazole 26 (Scheme 1.2.4) via a new mode of 5-endo

cyclization of the resultant acetylaminoallenic ester intermediate 25.13 The

intermediate was generated from hydrolysis of the ethyl ester followed by

decarboxylation. Then the amide was enolized under basic condition and attack of

the oxygen to the central carbon of the allenoate afforded the final oxazole 26.

Scheme 1.2.4 Intramolecular Michael addition to allenotes

In the same paper, an electrophilic Michael addition of carbon atom to allenyl

ketone was also reported (Scheme 1.2.5).13 Allenyl aryl ketones 28a-g were easily

prepared via the nucleophilic attack of propargylmagnesium bromide to amides

27a-g. Under the treatment of a Lewis acid BF3-OEt2, 1, 2-allenyl ketones 28

undergoes 5-endo mode cyclization to benzocycloketones 29 and 30. In this

reaction, the presence of electron donating group on the aromatic moiety seems to

be essential. The regioselectivity was controlled by the steric interaction between

the aromatic substituents and the allenic moiety.

Introduction

8


It was also found that allenyl aryl ketones are good substrates for the

construction of medium sized rings. Compounds 32, 33, 34, containing six, seven,

eight membered rings respectively, were all successfully achieved by tuning the

length of the tether connecting the aryl group and the carbonyl group.14 The

location of the C=C double bond in the products depended on the length of the

tether. This reaction proceeded through a cationic intermediate 35 which was

produced from the interaction of the Lewis acid with the carbonyl group. The

cationic intermediate 35 would attack the aromatic ring as an electrophile to

afford the 5-endo mode cyclization products.

Chapter 1

9

In these reactions, the authors also found that the cyclization mode was

determined by the substitution pattern of the aryl ring.15 For example, if one or

both ortho-positions are occupied by a methoxy group like compound 36, the

spiro-endo mode cyclization product 37 was obtained (Scheme 1.2.6).


One limitation of the above reaction is that at least two methoxy groups are

required on the phenyl ring. In 1998, Hashimi et al found that when

4-methoxybenzyl-1,2-propadienyl ketone 38 was treated with 1 mol% of

Hg(ClO4)2 in MeCN and water, the spiro-endo cyclization product 39 was formed

in good yields (Scheme 1.2.7).16 They also found that the presence of water was

important. The reason for the high efficiency of Hg(II) was believed to be the high

coordination capability of Hg(II) ion to both the carbonyl oxygen and the terminal

double bond.


Introduction

10

For the intramolecular Michael reactions of allenes, both oxygen and carbon

atoms have been involved as nucleophiles. However, no examples of aza-Michael

reaction of allenes have been reported. This is probably due to the difficulty in

obtaining such a substrate. Instead, intramolecular conjugate additions of nitrogen

atom to allenes have been well developed. These reactions are usually

electrophilic additions and catalyzed by metals, especially silver ion. Products of

these reactions are usually pyrrolines,17 pyrroles,18 piperidines19 or pyridines,20

which are all biologically important heterocycles (Scheme 1.2.8).

When the amino allenes 42a and 42b were treated with a catalytic amount of

AgNO3 in acetone (25 °C, in the dark), 3-pyrrolines were obtained in good to

excellent yields.21 The reaction readily formed both simple and annulated

3-pyrrolines (43a and 43b). The procedure was very reliable and tolerant to a

wide range of substitution patterns. As expected, the reaction showed little

diastereoselectivity in the reaction of 42b.

Chapter 1

11

Scheme 1.2.8 Intramolecular conjugate addition of nitrogen to allenes

The piperidine structure has also been achieved via intramolecular conjugate

addition of amine to allene.22 When the chiral allene 44 was treated with AgNO3,

the piperidine 45 was obtained in good yield and the natural product

(R)-(-)-Coniine was achieved in two more steps. The axial chirality of allene was

fully transferred to the central chirality of the product.

1.3 Intramolecular Diels-Alder reactions of allenes

Hydrogenation of one carbon-carbon double bond of allene will release an

enthalpy of 41 kcal/mol. This is 12 kcal/mol greater than the enthalpy of

hydrogenation of an ordinary alkene which is 29 kcal/mol. Accumulation of two

carbon-carbon double bonds imparts extra reactivity to the allene, which makes it

a remarkably active component participating in cycloaddition reactions.

Cycloaddition reactions are categorized according to assembly modes, such as

[m+n]-cycloaddition, where the variables m and n simply denote the number of

atoms that each component contributes to the ring construction. Among these

cycloaddition reactions, the [4+2] Diels-Alder reaction is the most important and

useful in natural product synthesis.23 Because it leads to increasing molecular

complexity, especially for intramolecular cyclization. As a result, the

intramolecular Diels-Alder reaction of allene (either as dienophile or part of diene)

has been drawing greater attention from organic chemists.

1.3.1 Intramolecualr Diels-Alder reaction with allenes as dienophiles

Introduction

12

Allenes participate in the Diels-Alder type [4+2]-cycloaddition mostly as an

electron-deficient dienophile. The LUMO energy level of an allene is lowered by

the introduction of an electron-withdrawing unsaturated substituent. The largest

LUMO coefficient is located on the central carbon (C2) and the next largest is on

the substituted carbon (C1). Thus, Diels-Alder reaction of activated allenes takes

place at the internal carbon-carbon double bond of the allene (Figure 1.1).

Figure1.1 Allene models

When the allenic acid 46a and the allenic ester 46b were heated in refluxing

toluene, intramolecular [4+2] cycloaddition between the diene and the internal

double bond of allene ouccurred to give two bicyclic compounds with exo-isomer

predominating (table 1.3.1).24 When a Lewis acid was used as a promoter, the

[4+2] cycloaddition can occur at 0 oC in DCM with an inverse in stereoselectivity

favouring the endo isomer.

R R’ conditions Yield(%) endo:exo

H Me Toluene, 110 oC 87 35:65

Me Et Toluene, 110 oC 83 34:66

Chapter 1

13

H Me Et2AlCl, DCM, 0 oC 65 87:13

Me Et Et2AlCl, DCM, 0 oC 49 87:13

Table 1.3.1 Intramolecular [4+2] cycloaddition of allenic acid and ester

In the approach to synthesize Periplanone B developed by Cauwberghs and De

Clercq in 1988, an allene-furan substrate 49 was synthesized as intramolecular

Diels-Alder reaction substrate (Scheme 1.3.1).25 Upon treated in refluxing

benzene, compound 49 underwent an IMDA reaction to afford the expected exo

products 50 and 51 and an endo product (not identified). The transition states

leading to the IMDA products were proposed and it was found that compound 50

should be more thermally stable than compound 51 because of the equatorial

isopropyl group. Under thermal dynamic control in refluxing mesitylene, the less

stable compound 51 was found to cyclorevert to 50 and the ratio of 50:51 changed

from 5:4 to 2:1. The IMDA product 50 was converted to 52 via a series of

synthetic manipulations, which constituted a formal total synthesis of periplanone

53.

A benzene ring can act as the diene in intramolecular [4+2] cycloaddition with

an activated allene. Aryl allene carboxylates 54 gave tricyclic lactons 55 in

moderate yields in xylene at reflux (Scheme 1.3.2).26 Allenyl amides were also

explored in the intramolecular Diels-Alder reaction. Aromatic rings and furans

were used as the dienes and the allene acted as the dienophile.

Introduction

14

Scheme 1.3.1 Intromolecular Diels-Alder reaction between allenic ketone and furan toward

the synthesis of Periplanone B

Scheme 1.3.2 Intramolecular Diels-Alder reaction between allene and bezene

In Harwood’s investigation towards the synthesis of a morphinan skeleton

(Scheme 1.3.3),27 the allenic amide 56 was designed as an intramolecular

Diels-Alder substrate and it was found that on standing at room temperature, 56

slowly underwent cycloaddition. However, the IMDA reaction was most

conveniently carried out in refluxing toluene, in which the reaction will be

finished in less than 2 h. Analysis of the crude material by NMR showed the

presence of single cycloadduct, the stereochemistry of which was initially

Chapter 1

15

assigned to be the desired diastereoisomer 57 on the basis of coupling constants

and NOE difference studies.


When compound 57 was treated with n-BuLi, the amino alcohol 58 was obtained

and its structure was confirmed by X-ray crystallographic analysis, which further

confirmed the structure and stereochemistry of compound 57.


In 1982, Himbert developed allenyl carboxanilides 59, of which the aromatic

rings acted as the diene to furnish the tricyclic lactams 60 in moderate to good

yields (Scheme 1.3.4).28 The tendency to form tricyclic lactams 60 was attributed

to the following factors: relatively easy formation of five-membered lactams,

partial activation of the benzene ring by the amino group, increased

energy-content of allene-systems relative to olefins, and comparatively high

rigidity in the allene and carboxamide moieties.

A furyl-substituted sulfonylallene readily undergoes a [4+2] cycloaddition to

give the IMDA adduct (Scheme 1.3.5). When the sulfonylallene 61 was heated in

Introduction

16

refluxing benzene, the intramolecular Diels-Alder reaction proceeded smoothly to

afford compound 62 in high yield.29 The rigid furyl diene was essential for the

Diels-Alder reaction to occur. When the furan ring was changed to an open diene,

under the same condition, compound 63 was transformed into 64 via a [2+2]

cycloaddition.

Scheme 1.3.5 Intramolecular Diels-Alder reaction of sulfonyl allene

Nitrogen containing heterocycles are common and important constituents of a lot

of natural products. Considering the efficiency of IMDA reactions of allene in

constructing complex molecules, allenic amides and allenic carbonates have great

potential in natural product synthesis. In 1986, Kanematsu and co-workers

prepared alkynyl diene carbonate 65 and subjected it to Crabbe’ homologative

allenylation. The allenic diene carbonate 66 was thus formed, and it underwent

intramolecular Diels-Alder reaction spontaneously to afford the tetrahydroindole

67. Upon dehydrogenation with DDQ, 67 was oxidized to indole 68. Differently

substituted indoles can be synthesized via this sequence.30 The natural product

hippadine 69 was successfully synthesized (Scheme 1.3.6).31

Chapter 1

17

Scheme 1.3.6 Total synthesis of hippadine via intramolecular Diels-Alder reaction of allenic

carbonate

Alkoxyallene is another type of allene that has been extensively studied. They

are usually generated from base-catalyzed isomerisation of propargyl ether to

allenyl ether. This kind of substrates usually generates furan rings after

cycloaddition. Treatment of the propargyl ether 70 with tBuOK in refluxing

tBuOH caused an intramolecular Diels-Alder reaction of the resulted intermediate

allenyl ether 71 to afford the tricyclic compounds 72, which isomerized to 73

spontaneously (Eq 1, Scheme 1.3.7).32 An asymmetric synthesis of benzofuran

lactone 74 was achieved by an analogous procedure (Eq 2，Scheme 1.3.7).33

Eq 1

Eq 2

Introduction

18

Scheme 1.3.7 Intramolecular Diels-Alder reaction of allenyl ether

An example of natural product synthesis involving allenyl ethers was reported by

Kanematsu and Soejims in 1991(Scheme 1.3.8).34 They managed to synthesize

euryfuran 80, which is a natural product possessing a synthetically challenging

structure of 3,4-disubstituted furan ring, via a furan ring transfer reaction with the

intramolecular Diels-Alder reaction of allenyl ether as the key step. Compound 75,

when heated with potassium tert-butoxide, afforded the isomerisation product 76.

This allene underwent a spontaneous intramolecular Diels-Alder reaction in

tert-butanol at reflux to give compound 77. Deprotonation of α position of the

furan oxygen initiated a ring opening of the oxybridge in 77 to give the furan

transfer product 78. Repeating this process via the intermediate 79 led to the final

target euryfuran 80.

Scheme 1.3.8 Euryfuran synthesis via IMDA reaction of alkoxyallene

An asymmetric synthesis of the intermediate 84 of forskolin by Nagashima in

1990 also employed intramolecular Diels-Alder reaction of allenyl ether (Scheme

1.3.9).35 Treatment of propargyl ether 81 with potassium tert-butoxide in refluxing

Chapter 1

19

tert-butanol affords 83 as a single stereoisomer via the allenyl ether intermediate

82. Further transformation of compound 83 led to the intermediate 84, which was

readily transformed to forskolin.

Scheme 1.3.9 Total synthesis of Forskoin via intramolecular Diels-Alder reaction of allenyl

ether

As a dienophile, an allene is able to cyclise not only with carbon dienes but also

heterodienes. Both intermolecular36 and intramolecular hetero-Diels-Alder

reactions of allenes have been developed.

An example of intramolecular hetero-Diels-Alder reaction of allene was reported

by Boger in 1991during their work toward the total synthesis of trikentrin 87

(Scheme 1.3.10).37 Treatment of 85 with acetic anhydride at 160 oC provided

indole derivatives via a cascade reaction, N-acylation followed by [4+2]

cycloaddition cascade followed by release of N2. Finally, deacetylation of 86 led

to the natural products, cis and trans (±) trikentrins 87.

Introduction

20

Scheme 1.3.10 Total synthesis of tirkentrins via Hetero-Diels-Alder reaction of allene

1.3.2 Intramolecular Diels-Alder reaction with allenes as dienes

Vinylallenes are commonly used as the diene component in Diels-Alder

reactions, and thus they are ubiquitously used in natural product synthesis,

especially their intramolecular Diels-Alder reaction. The natural compound 90

Esperamicin A has been found to show great DNA binding and damaging

properties which are traced to the bicyclic core structure equipped with an

enediyne bridge. Vinylallene 88 was proposed by Schreiber and Kiessling to be a

biogenetic intermediate for the synthesis of the skeleton of esperamicin A

(Scheme 1.3.11).38 Although the proposed transformation (88–>89) was not really

tested, the synthetic approach to esperamicin A was modeled in which an

intramolecular Diels-Alder reaction was employed to synthesize the highly

unsaturated bicyclic core of 90.

Scheme 1.3.11 Proposal of the intramolecular-Diels-Alder reaction of vinylallene toward the

total synthesis of esperamicin A

Siloxyvinylallenes, which have been prepared by Reich et al in two ways, have

proved to be good candidates for Diels-Alder reaction in which the

siloxyvinylallenes act as the diene components.39 They are readily prepared by

addition of vinyllithium to α-chloroacylsilane followed by a Brook rearrangement.

Chapter 1

21

The vinylallene 91 was reported to be unstable and was subjected to a Lewis acid

directly after preparation. It underwent intramolecular Diels-Alder reaction to

afford the adduct 92 in 51% yield (Scheme 1.3.12). Both Lewis acid catalysis and

thermal conditions proved to be successful for the Diels-Alder reaction. The

cycloadduct 92 was subsequently converted to the natural product 93.

Scheme 1.3.12 Intramolecular Diels-Alder reaction of vinylallene toward the total synthesis

of cis-Dehydrofukinone

(+)-Compactin 97 was synthesized by Keck and Kachensky via an

intramolecular Diels-Alder reaction which used a vinylallene as the diene

(Scheme 1.3.13).40 This work was done at a time when there was little literature

precedent on the use of vinylallenes as dienes. Model study figured that the

transition state for the Diels-Alder reaction of 94 would adopt a conformation to

give only the exo cycloaddition product. Thus, the intramolecular Diels-Alder

reaction perfectly constructed the bottom bicyclic structure. When compound 94

was heated at 140 oC for one hour in toluene in the presence of BHT, it afforded

the intermediate 95, which was immediately subjected to L-selectride to reduce

the ketone to alcohol to avoid the formation of a conjugated enone. The resulting

alcohol 96 was obtained as a 1:1 mixture of diastereomers in 84% yield. Although

the two diastereomers could be separated, their stereochemistry was unknown at

this point and both diastereomers were not separated until the end of the total

Introduction

22

synthesis of (+)-compactin. One of these compounds matched the spectral data of

97 exactly.

Scheme 1.3.13 IMDA reaction of vinylallene toward the total synthesis of (+)-Compactin

1.4 Summary

As an efficient and powerful tool for the construction of complex structures,

especially regarding natural product synthesis, intramolecular cyclization

reactions have been attracting more and more attention. As a class of reactive and

interesting compounds, allenes have been well employed in different kinds of

cyclizations. Excellent reactivity and selectivity have been achieved in these

reactions. Most of the enantioselective examples are based on chiral auxiliaries or

chiral starting materials. Some are developed under transition metal catalysis

using a chiral ligand. However, there are few examples of organocatalyst

catalyzed enantioselective intramolecular cyclization of allenes until now. The use

of chiral allenes in intramolecular cyclizations is rarely reported as well. Thus

Chapter 1

23

catalytic enantioselective formation of allene towards natural product synthesis is

quite attractive. The following chapters will describe our recent work on chiral

allene formation followed by intramolecular Michael reaction and intramolecular

Diels-Alder reaction. The first catalytic enantioselective total synthesis of

α–yohimbine based on the intramolecualr Diels-Alder reaction will also be

decribed.

Introduction

24

References:

(1) Burton, B. S.; Pechman, H. V. Chem. Ber. 1887, 20, 145.

(2) Tius, M. A.; Cullingham, J. M.; Ali, S. J. Chem.Soc., Chem. Commun. 1989, 13, 867.

(3) van’t Hoff, J. H. La Chimie dans I’Espace; Bazendijk: Rotterdam, 1875, 29.

(4) Hoffman-Röder, A.; Krause, N. Angew. Chem. Int. Ed. 2004, 43, 1196.

(5) Ma, S. M. Chem. Rev. 2005,105, 2829.

(6) Pairaudeau G.; Parsons P. J.; Underwood J. M. J. Chem. Soc., Chem. Commun. 1987, 22,

1718.

(7) a) Mishima H.; Kurabayashi M.; Tamura C. Tetrahedron Lett.,1975, 16, 711. b) Kupchan S.

M.; Voie E. J. L.; Branfman A. R.; Fei B. Y.; Brigh,W. M.; Bryan R. F. J. Am. Chem. SOC.,

1977, 99, 3199. c) Kato Y.; Fusetani N.; Matsunaga S.; Hashimoto K.; Fugita S.; Furiya T. J.

Am. Chem. SOC., 1986, 108, 2780. d) Baker R.; Herbert R.; House P. E.; Jones O. T.; Francke

W.; Reith W. J. Chem. Soc., Chem. Commun., 1980, 2, 52. e) Tachibana K.; Scheuer P. J.;

Tsukitani Y.; Kibuchi H.; Van Engen D.; Clardy J.; Gopichand Y.; Schmitz F. J. J. Am. Chem.

Soc., 1981, 103, 2469

(8) Mukai C.; Yamashita H; Hanaoka M. Org. Lett. 2001, 3, 3385.

(9) (a) Claesson, A.; Olsson, L.-I. In The Chemistry of Allenes, Vol. 2; Landor, S. R. Ed.;

Academic Press: London, 1982, 369. (b) Nikam, S. S.; Chu, K.-H.; Wang, K. K. J. Org.Chem.

1986, 51, 745. (c) Ma, S.; Shi, Z. J. Org. Chem. 1998, 63, 6387. (d) Marshall, J. A.; Yu , B.-C.

J. Org. Chem. 1994, 59, 324. (e) Hormuth, S.; Reissig, H.-U. J. Org. Chem. 1994, 59, 67.

(10) (a) Marshall, J. A.; Sehon, C. A. J. Org. Chem. 1995, 60, 5967. (b) Marshall, J. A.; Bartley, G.

S.; Wallace, E. M. J.Org. Chem. 1996, 61, 5729.

(11) Brel V. K. Synthesis, 2001, 10, 1539.

(12) Marshall, J. A.; Bart ley, G. S.; Wallace, E. M. J.Org. Chem. 1996, 61, 5729.

(13) Nagao, Y.; Lee, W.-S.; Kim, L. Chem. Lett. 1994, 23, 389.

(14) Nagao, Y.; Lee, W.-S.; Komaki, Y.; Sano, S.; Shiro, M. Chem. Lett. 1994, 23, 597.

(15) Nagao, Y.; Lee, W.-S.; Jeong, I.-Y.; Shiro, M. Tetrahedron Lett.1995, 36, 2799.

(16) Hashimi, A. S. K.; Schwarz, L.; Bolte, M. Tetrahedron Lett.1998, 39, 8969.

Chapter 1

25

(17) Lainton, J. A. H.; Huffman, J. W.; Martin, B. R.; Compton, D. R. Tetrahedron Lett. 1995, 36,

1401.

(18) Huwe, C. M.; Blechert, S. Tetrahedron Lett. 1995, 36, 1621.

(19) Hall, H.K. J. Am. Chem. Soc. 1957, 79, 5441.

(20) Pearson, R. G.; Williams, F. V. J. Am. Chem. Soc, 1953, 75, 3073.

(21) Dieter R. K.; Yu H. Y. Org. Lett. 2001, 3, 3385.

(22) Lathbury D.; Gallagher T. J. Chem.Soc., Chem. Commun. 1986, 2, 114.

(23) Corey E. J. Angew. Chem. Int. Ed. 2002, 41, 1650.

(24) Saxton H. M.; Sutherland J. K.; and Whaley C. J. Chem.Soc., Chem. Commun. 1987, 19,

1449.

(25) Cauwberghs S. G.; Clercq P. J. D. Tetrahedron Lett. 1988, 29, 6501.

(26) Himbert, G.; Fink, D. Tetrahedron Lett. 1985, 26, 4363.

(27) Finch H.; Harwood L. M.; Robertson G. M.; Sewellb R. C. Tetrahedron Lett. 1989, 30, 2585.

(28) Himbert, G.; Henn, L. Angew. Chem. Int. Ed. 1982, 21, 620.

(29) Padwa, A.; Filipkowski, M. A.; Meske, M.; Watterson, S. H.; Ni, Z. J. Am. Chem. Soc. 1993,

115, 3776.

(30) Hayakawa, K.; Yasukouchi, T.; Kanematsu, K. Tetrahedron Lett, 1986, 27, 1837.

(31) Hayakawa, K.; Yasukouchi, T.; Kanematsu, K. Tetrahedron Lett, 1987, 28, 5895.

(32) Hayakawa, K.; Yodo, M.; Ohsuki, S.; Kanematsu, K. J. Am. Chem.Soc. 1984, 106, 6735.

(33) Hayakawa, K.; Nagatsugi, F.; Kanematsu, K. J. Org. Chem. 1988, 53, 860.

(34) Kanematsu, K.; Soejima, S. Heterocycles, 1991, 32, 1483.

(35) a)Nagashima, S.; Kanematsu, K. Tetrahedron Asymm. 1990, 1, 743. b) Zieg ler, F. E.; Jaynes,

N. H.; Saindane, M. T. J. Am. Chem. Soc. 1987, 109, 8115.

(36) a) Tamura, Y.; Tsugoshi, T.; Nakajima, Y.; Kita, Y. Synthesis 1984, 11, 930. b) Bos, H. J.

T.; Slagt, C.; Boleij, J. S. M. Recl. Trav. Chim. Pays-Bas. 1970, 89, 1170.

(37) Boger, D. L.; Zhang, M. J. Am. Chem. Soc. 1991, 113, 4230.

(38) Schreiber, S. L.; Kiessling, L. L. J. Am. Chem. Soc. 1988, 110, 1623.

(39) Reich, H. J.; Eisenhart, E. K.; Olson, R. E.; Kelly, M. J. Am. Chem. Soc. 1986, 108, 7791.

Introduction

26

(40) Keck, G. E.; Kachensky, D. F.; J. Org. Chem. 1986, 51, 2487.

Chapter 2

27

Chapter 2

Brønsted-Base Catalyzed Tandem

Isomerization-aza-Michael Reactions

Brønsted-Base Catalyzed Tandem Isomerization-aza-Michael reactions

28

2.1 Different approaches for the preparation of piperidines and

lactams

2.1.1 Piperidines and Lactams in natural products

Azacycles are important heterocyclic systems which are commonly found in

natural products and valuable fine chemicals.1 In particular, functionalized

piperidines and pyridines are present in a variety of pharmacologically active

natural products including most of the alkaloids (Figure 2.1).2 The naturally

occurring cinchonine alkaloids, which are known for their highly enantioselective

catalytic activity in organic synthesis, have attracted increasing interest. These

piperidine containing natural products are synthetically challenging, because they

usually have several asymmetric centers present. Meanwhile, the most important

step in the synthesis of these natural products is usually the ring-closing step to

obtain the piperidine rings. A lot of attentions have been paid to the development

of piperidine formation methods resulting in great advancements being made in

this field.

Figure 2.1 Piperidine or pyridine containing natural products

2.1.2 Synthetic methods for piperidines and lactams

In 1971, Edwarlde Ete reported an efficient synthesis of 2-alkylidenepiperidines

Chapter 2

29

(Scheme 2.1.1).2 Compound 102, the open chain form of compound 103, was

prepared from 101 via enzymatic transamination. Asymmetric hydrogenation of

compound 103 led to the natural alkaloid (+)-coniine 98. Hydroxylation of

compound 103 led to hydroxyl imine 104, which was hydrogenated to afford the

natural alkaloid 105 conhydrine.

Scheme 2.1.1 Piperidine formation via amine-ketone condensation

Another method to prepare piperidine was developed in 2000 by Kunio

Ogasawara (Scheme 2.1.2).3 This method employed ring closing metathesis (RCM)

to form the heterocycle. When the N-protected secondary amine 106 was

subjected to ring closing metathesis condition and then hydrogenation, the

N-protected piperidine 107 was achieved in 89% yield over two steps, which is

part of the natural product 100 (+)-febrifugine.

Scheme 2.1.2 Piperidine formation via ring closing metathesis

Intramolecular electrophilic addition of an amine to allene is another way to

construct piperidine rings. Cha and co-workers reported one example in 1999


30

(Scheme 2.1.3).4 When the diastereomerically pure aminoallene 108 was

subjected to a silver salt, silver nitrate, heterocyclization occurred via two

transition states 109 and 110. The desired products quinolizidine 111 and 112,

both possessing the desired E double bond geometry, were achieved in a ratio of

7:1. From the proposed transition states, we can see that 109 is more favored than

110 due to the steric repulsion between the silyl ether group and the allene tail.

Compound 111 was successfully converted to the target natural products

clavepictine A (113) and B (114).

Scheme 2.1.3 Piperidine formation via intramolecular electrophilic addition of amine to

allene

Trost B. M. and co-workers developed another route to synthesize piperidine in

2000 (Scheme 2.1.4).5 A ruthenium catalyst (10%) and a co-catalyst CH3AlCl2

were used. When allenyl amine 115 was subjected to a methyl vinyl ketone in the

presence of ruthenium and aluminum catalyst, compound 117 was achieved in

Chapter 2

31

67% yield. It was found that both the Ru catalyst and the CH3AlCl2 co-catalyst are

essential for the formation of the product. To achieve better yield, quenching with

pyrrolidine was required, which is believed to dissociate the coordination between

the product and the Ru catalyst. Both piperidines and pyrrolidines have been

achieved using this method.

Scheme 2.1.4 Piperidine formation via ruthenium catalysis

In the same year, Lee E. and co-workers developed a radical process to

synthesize such cyclic amines (Scheme 2.1.5).6 A protected secondary amine 118

was chosen as the substrate for the radical cyclization. The radical precursor can

be alkyl bromide or alkyl selenium. When compound 118 was subjected to the

radical initiator AIBN and the hydride reductant, a mixture of diastereoisomers

119 and 120 was achieved. The reaction tolerates both alkyl and aryl R

substituents. Pyrrolidines can be formed as well. Compound 121 (-)-indolizidine

223AB was synthesized employing two consecutive radical cyclization reactions

of aminoacrylate substrates.

Conversely, the cyclization of allenyl amides can occur under oxidative

condition as developed in 2000 by Jonasson and co-workers (Scheme 2.1.6).7

When the allenyl amide 122 was subjected to palladium catalyst and LiBr, an

intermediate of π-allyl palladium complex 124 was formed. After an


32

intramolecular nucleophilic addition of the nitrogen to the π-allyl palladium

system, the pyrrolidine product 123 was formed and Pd(II) was reduced to Pd(0),

which was reoxidized by copper acetate.

Scheme 2.1.5 Piperidine formation via radical cyclization

Scheme 2.1.6 Pyrrolidine formation via oxidative cyclization

In fact, this transformation can be achieved via cobalt mediated

acylation-cyclization of allenes as well (Scheme 2.1.7).8 When compound 125 was

subjected to the acetyltetracarbonylcobalt and the base diisopropylethylamine, the

five membered ring product 126 can be achieved via the intermediate 127.

Chapter 2

33

Scheme 2.1.7 Pyrrolidine formation via cobalt mediated cyclization

Although first synthesized in 1907 by Staudinger, β- lactams were recognized in

organic chemistry only until Fleming’s discovery of penicillin in 1929.9 The

resulting recognition of the β- lactam moiety as the key pharmacophoric

component of the penam antibiotics initiated a flurry of synthetic activity.10 Today,

β-lactam rings are found in thousands of chiral compounds. Due to their high

efficacy and safe toxicological profiles, penicillin and its derivatives are still the

most commonly used antibiotics. The asymmetric synthesis of β- lactams usually

employs a [2+2] cycloaddition10 and one example is shown below (Scheme 2.1.8).

Scheme 2.1.8 β–lactam synthesis via [2+2]-cycloaddition

When an acid chloride 128 and an imine 129 were treated with the combination

of a cinchona alkaloid derivative such as benzoylquinine (BQ) and a

non-nucleophilic amine base, β- lactam products 130 were achieved in very high

ee and dr. Varieties of acid chlorides were tolerated in this process.

[2+2]-cyclization can lead to β–lactam only, 5-membered and 6-membered

lactams are formed via different methods.

In 2007, Che reported an intramolecular addition of β-ketoamide to unactivated

alkenes under gold catalysis, which led to the formation of 5-membered lactams

(Scheme 2.1.9).11 The reaction proceeded in toluene under mild condition. When


34

the β-ketoamide 131 was treated with the combination of a gold salt and a silver

salt, the alkene was activated by the gold and attacked by the enolate leading to

the formation of a 5-membered lactam 132.

Scheme 2.1.9 5-membered lactam formation via gold catalys is

Wei Ying and co-workers developed a convenient method for the synthesis of

6-membered lactams in 2010 (Scheme 2.1.10).12 Deprotonation of the starting

material 134 with a strong base NaH results in an aza-Michael reaction followed

by an electrophilic ring opening of the cyclopropane. After a double bond shift,

carbon anion 138 forms and condenses with an aldehyde to give the final product

135.

Scheme 2.1.10 6-membered lactam formation via aza-oxy-carbanion relay

2.1.3 Summary

Chapter 2

35

In summary, a lot of natural products and synthetic compounds with medical

potential are found containing heterocycles like piperidines and lactams. A great

number of methods have been developed towards the formation of such systems.

For the piperidine formation, either metal or harsh conditions were required. A

mild organo-catalytic method will thus be much more attractive. Furthermore, the

organo-catalytic enantioselective synthesis of six membered lactams is not

available. We are pleased to report our work on piperidine and axial chiral lactam

formation via organo-catalysis.

2.2 Tandem isomerisation-aza-Michael reaction of alkynylamines

and alkynylamides

2.2.1 Synthesis of alkynyl amines and chiral bicyclic guanidine catalyst.

Alkynyl amines 141a-141c were synthesized as outlined in scheme 2.2.1.

Standard amide formation protocol between different anilines and pent-4-ynoic

acid afforded different alkynyl amides 139 in around 70% yield, which were then

Scheme 2.2.1 Alkynyl amine synthesis

reduced to alkynyl amines 140 with LiAlH4. After a well-established coupling


36

between the alkyne moiety and diazo compounds,13 the desired compounds

141a-141c were obtained.

Treatment of alkynyl amines 141a-c with a brønsted base TBD formed the

products 142a-c in good yields (Scheme 2.2.2). Slightly long reaction time (24

hours) was required to ensure that the reaction proceeded to completion as the

products 142a-c were non-separable from their corresponding alkynyl-amines

141a-c.

Scheme 2.2.2 Brønsted-base catalyzed tandem isomerization-aza-Michael reaction of

alkynyl-amines 141. a Isolated yield

Since the reaction is base catalyzed and the starting material itself is a base, we

doubt whether self-catalyzed reaction is possible. For better understanding of

Scheme 2.2.3 Proposed mechanism for tandem isomerization-aza-Michael reaction of 141

the reaction, we subjected alkynyl-amine 141 to the same reaction conditions for

Chapter 2

37

one day without the presence of the base, TBD. The starting material was fully

recovered and no other product was obtained. Hence, the self-catalyzed reaction

mechanism was excluded. Therefore, we believe that the tandem isomerization-

aza-Michael reaction goes through the proposed pathway in Scheme 2.2.3.

Since we have been interested in the brønsted base, bicyclic chiral guanidine 149,

catalyzed asymmetric transformations, we expected that alkynyl amine 141c may

afford 142c with axial chirality when the reaction was catalyzed by our chiral

guanidine. The chirality was generated from the restricted rotation of the C-N

bond connecting the piperidine ring and the phenyl ring.

The chiral bicyclic guanidine was prepared by the well-established procedure

published by our lab.14 N-Tosyl aziridine 146 was readily prepared from its

Scheme 2.2.4 Synthesis of the chiral bicyclic guanidine 149

corresponding commercially available α-amino alcohol 145 via a two-step process.

Triamine unit 147 was easily obtained by treating N-tosyl aziridine 146 in MeOH

saturated with NH3 gas in a sealed vessel. After removing the solvent, the residue

was dissolved in MeCN and refluxed for 3 days. The subsequent removal of tosyl

groups was conducted in liquid ammonia in the presence of sodium. After the


38

final cyclization step, the triamine intermediate was cyclized to give the chiral

bicyclic guanidine149 and basified with 5 M KOH aqueous solution or solid

K2CO3 (Scheme 2.2.4).

The alkynyl amine 141c was treated with bicyclic guanidine 149 in different

solvents and the results are summarized in Table 2.1. The reaction proceeded

fastest in DCM and reached completion in 24 hous, however, no enantioselectivity

was observed (Entry 1). Toluene gave 0% ee as well and a non-complete reaction

(Entry 2). Pleasingly, hexane gave 7 % ee and the best ee achieved was 27% in

THF. However, the starting material cannot be completely consumed in hexane

and THF even after 3 days. Since the starting material and the product cannot be

separated and the reaction cannot proceed to completion, no further study was

conducted.

Table 2.1 Solvent effect on asymmetric tandem isomerization-aza-Michael reaction of

alkynyl amine 141c

entry solvent time conversion (%)a ee(%)

b

1 DCM 24 h 100 0

2 Toluene 24 h 70 0

3 Hexane 32 h 50 7

4 THF 3 d 60 27

adetermined by

1H NMR

b determined by HPLC

2.2.2 Bicyclic guanidine catalyzed enantioselective tandem isomerisation-

aza-Michael reaction of alkynyl amides to the synthesis of lactams.

Chapter 2

39

Based on our discovery of the tandem isomerization-aza-Michael reaction,

especially the asymmetric reaction performed on alkynyl amine141C, We were

keen to achieve a high enantioselectivity by tuning the substrates. We have

demonstrated that 3-Alkynoates bearing a tButyl ester will afford highly

enantioselective allenes when treated with bicyclic guanidine. It is believed that

the axial chirality of the piperidine 142c was transferred from the chiral allene

which was generated in situ. The poor ee of 142c is probably due to the low

energy level that is required for the rotation of the C-N bond. We expected that the

energy level could be increased by adding hindering substituents. Thus we

synthesized the alkynyl amide 150 from 139b by alkyne and diazo compound

coupling (Scheme 2.2.5). We expected that the extra carbonyl group would help to

restrict the rotation.

Scheme 2.2.5 Synthesis of alkynyl amide 150

The alkynyl amide 150 was then treated with bicyclic guanidine 149 in different

solvents. Two cyclized products were detected, which were assigned as 151 and

152 by 1H NMR. The ratio between 151 and 152 on TLC was about 4:1.

Subsequently, by passing the reaction mixture through a silica gel column slowly,

cyclic compound 151 can be fully converted to lactam 152.


40

Optimization results are summarized in Table 2.2. Similarly, the fastest reaction

was observed in DCM, full conversion was observed after stirring at rt for 4 days

as indicated by TLC analysis. However, only moderate yield was obtained after

separated by column chromatography with 60% ee (Entry 1). The best

enantioselectivity was obtained in ether type solvents (Entry 3 and 5). Different

ethers were tested as well but THF still gave the best result (Entry 5, 8 and 9).

With THF as solvent, different concentrations were tested and it was found that

dilution led to very slow reaction time (Entry 6) while concentrated reaction

afforded much lower ee (Entry 7).

Table 2.2 Bicyclic guanidine catalyzed enantioselective tandem isomerization-aza-Michael

Reaction

entry solevnt concentration(M) time(d) yield(%)a ee(%)

b

1 DCM 0.1 4 68 60

2 Toluene 0.1 3 60 81

3 Ether 0.1 2 75 85

4 Hexane 0.1 2 74 65

5 THF 0.1 3 67 89

6 THF 0.01 6 <10 nd

7 THF 0.5 2 60 73

Chapter 2

41

8 TBDME 0.1 4 70 72

9 Phenylmethyl ether 0.1 4 60 67

a isolated yield

b determined by HPLC

Having achieved the axial chiral lactam 152 with high enantiomeric purity, we

encountered some difficulty with the establishment of its absolute configuration.

Difficulty in obtaining single crystals for 152, together with the lack of heavy

atoms in 152 impeded absolute configuration determination via single crystal

X-ray diffraction.15 As a result, we had to derive the absolute configuration via

theoretical approaches. Reliable specific optical rotation can be calculated from

density functional theory (DFT) by considering thermally accessible

conformations and with judicious choice of basis set and functional coupled with

solvation model to account for solvent effects.16 The specific optical rotation for

152-Sa configuration calculated is -57.8, which agrees well with the -64.1

obtained experimentally.

In addition, we have investigated the mechanism via DFT calculation. The

enantioselective step is postulated to be the intramolecular Michael reaction. The

activation barriers for the relevant pathways are given in figure 2.2. Based on this

mechanism, the formation of Sa product is predicted to be more favourable than

the Ra product. The Gibbs free energy of activation difference (∆G‡) of the

pathways leading to the Sa lactam is 3.4 kcal/mol lower in Gibb free energy than

the pathway leading to the Ra lactam, which is consistent with the high ee


42

observed experimentally.

Figure 2.2: Enantioselectivity step (Gibbs free energy difference given in

kcal/mol)

As an interesting axial chiral lactam, compound 152 is also a potentially useful

intermediate in organic synthesis. It will be extremely interesting if different ring

sized lactams, especially larger rings, can be achieved with similar axial chirality.

Different alkynyl amides and carbonates that might lead to larger rings were

synthesized as outlined in Scheme 2.2.6.

Chapter 2

43

eq 1

eq 2

eq 3

eq 4


44

eq 5

Scheme 2.2.6 Synthetic schemes to different alkynyl amides and carbonates

However, efforts to prepare atropisomeric lactams with different ring sizes were

not too successful. Upon exposure to bicyclic guanidine 149, alkynes 153-157

were unable to complete the intramolecular Michael reactions and provided the

corresponding enantio-enriched allenes, whose absolute configurations were

determined by the Lowe-Brewster rule (Scheme 2.2.7) .17

Scheme 2.2.7 Enantioselective isomerization of alkynes to allenes

Chapter 2

45

The observation of allenes when 153, 154, 155, 156 and 157 were used as

reactants suggests that the formation of 152 from 150 proceeds via an allene

intermediate.

2.3 Summary

In conclusion, we have found that a Brønsted-base catalyzed tandem

isomerization-aza-Michael reaction can be used to form useful heterocycles under

mild conditions. This efficient method was applied to the synthesis of

functionalized piperidine with good yields. Enantioselective tandem

isomerization-aza-Michael reaction of alkynyl-amide led to an axially chiral

lactam of high enantioselectivity when a chiral guanidine was used as the catalyst.


46

References:

1. (a) Progress in Heterocyclic Chemistry; Suschitzky, H.; Scriven, E. F. V. Eds.; Pergamon:

Amsterdam, 1998; Vol. 5–7. For reviews on azacycles, see: (e) Boger, D. L.; Boyce, C. W.;

Garbaccio, R. M.; Goldberg, J. A. Chem. Rev. 1997, 97, 787. (f) Katritzky, A. R.; Rachwal, S.;

Rachwal, B. Tetrahedron 1996, 48, 15031. (g) Sunderhaus, J. D.; Martin, S. F. Chem. Eur. J.

2009, 15, 1300.

2. Leete, E. Acc. Chem. Res., 1971, 4, 100.

3. Taniguchi T.; Ogasawara, K. Org. Lett. 2000, 2, 3193.

4. Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1999, 121, 10012.

5. Trost B. M.; Pinkerton A. B.; Kremzow D. J. Am. Chem. Soc. 2000, 122, 12007.

6. Lee E.; Jeong E. J.; Min S.; Hong S. k.; Lim J.; Kim S. K.; Kim H. J.; Choi B. G.; Koo K. C.

Org. Lett. 2000, 2, 2169.

7. Jonasson, C.; Karstens, W. F. J.; Hiemstra, H.; Bäckvall, J.-E. Tetrahedron Lett. 2000, 41,

1619.

8. Bates, R. W.; Rama-Devi, T.; Ko, H.-H. Tetrahedron 1995, 51, 12939.

9. Morin, R. B.; Gorman, M., Eds. Chemistry and Biology of â-Lactam Antibiotics, Academic

Press: New York, 1982, Vols. 1-3.

10. For a review on lactam synthesis see: France S.; Weatherwax A.; Taggi A. E.; Lectka T. Acc.

Chem. Res. 2004, 37, 592.

11. Zhou C.-Y.; Che C.-M. J. Am. Chem. Soc. 2007, 129, 5828.

12. Liang F.; Lin S.; Wei Y. J. Am. Chem. Soc. 2011, 133, 1781.

13. Suárez, A.; Fu, G. C. Angew. Chem., Int. Ed. 2004, 43, 3580.

14. Ye, W.; Leow, D.; Goh, S. L. M.; Tan, C.-T.; Chian, C.-H.; Tan, C.-H. Tetrahedron Lett.

2006, 47, 1007.

15. Flack, H. D.; Bernardinelli, G. Chirality, 2008, 20, 681.

16. Kwit, M.; Rozwadowska, M. D.; Gawroński, J.; Grajewska, A. J. Org. Chem. 2009, 74, 8051.

17. a) Lowe, G. Chem. Commun. 1965, 17, 411; b) Brewster, J. H. Top. Stereochem. 1967, 2, 1.

Chapter 3

47

Chapter 3

Total Synthesis of alpha-Yohimbine via

Intramolecular-Diels-Alder Reaction

Total Synthesis of alpha-Yohimbine via Intramolecular-Diels-Alder Reaction

48

3.1 Introduction to the Synthesis of alpha-Yohimbine

Alpha-Yohimbine, also known as isoyohimbine, rauwolscine, and orynanthidine,

is an alkaloid found in various species within the genera Rauwolfia and

Pausinystalia (formerly known as Corynanthe).1 It is a stereoisomer of yohimbine.

Alpha-Yohimbine is a central nervous system stimulant, a local anesthetic and a

vague aphrodisiac.1 It acts predominantly as a α2-adrenergic receptor antagonist.2 It

has also been shown to function as a 5-HT1A receptor partial agonist and 5-HT2A,

5-HT2B receptor antagonist.3 Due to its important pharmacological effect and

synthetically challenging structure, chemists have paid considerable attention to the

synthesis of alpha-yohimbine. However, only limited numbers of successful

synthetic routes have been developed until now. There is no enantioselective total

synthesis available before this report.

During nineteen seventies, Tökel and co-workers did a lot of study on the

synthesis of yohimbines.4 During their work toward the total synthesis of

alloyohimbines, they found that alpha-yohimbine 170 was formed via

epimerization at C3 (Scheme 3.1.1).4c The synthesis started with the cyclization of

N-formyl tryptamine 160 using POCl3 under thermal condition, which delivered

compound 161 containing the A, B, C rings of the pentacyclic structure in

yohimbine bases. A Mannich reaction followed by an aza-Michael reaction

between 161 and 162 in refluxing EtOH formed the D ring with the necessary

Chapter 3

49

substituents for further manipulation, affording the compound 163. Upon

condensation with diethyl cyanomethylphosphonate 164, a cyano group was

introduced to form the nitrile ester 165. Pd/C catalyzed hydrogenation afforded

two products 166a and 166b. The major product 166a is a trans isomer which was

transformed into yohimbine. The minor product 166b is a cis isomer which is a

potential candidate for allo-type yohimbines. Treatment of 166b with a strong

base, potassium tert-butyloxide in DMSO, afforded the pentacyclic compound

167 which contained nitrile and ketone moieties. Reduction of the ketone using

sodium boron hydride afforded two alcohols 168a and 168b in a ratio of 2:3.



50

As a final step in the synthesis, the nitrile group was converted to methyl ester by

first converting the nitrile in 168b to acid amide using hydrogen peroxide in

alkaline methanol. Subsequent refluxing with aqueous HCl afforded the free acid,

which was converted to methyl ester using diazomethane to afford the

3-epi-alpha-yohimbine 169 and certain amount of alpha-yohimbine 170. The

alpha-yohimbine was believed to have formed via the epimerization at C3 during

hydrolysis with aqueous HCl. Since the alpha-yohimbine was formed from a

minor isomer of the hydrogenation step, the yield was extremely low.

Following the work above, the same group developed a new route that gave

better yield for the synthesis of alloyohimbines (Scheme 3.1.2).4d The readily

available compound 163 was condensed with methyl cyanoacetate 171 in

triethylammonium acetate in the presence of phosphrous pentaoxide to form

compound 172. It was found that an epimerization at C20 occurred. Reduction

with sodium boron hydride in MeOH at 0 oC afforded the compound 173, which

was then converted to diacid 174 by hydrolysis and acidification. Decarboxylation

via boiling in DMF and esterification with methanolic HCl afforded the diester

175. The condensation between the two ester groups required highly dry condition

and as expected yielded 176 (36%) and 177 (30%) in similar yields. Reduction of

the ketone 177 with sodium boron hydride afforded a mixture of alloyohimbines,

but alpha-yohimbine 170 was obtained in only 6% yield.

Although route 2 is optimized and obtained much better yield as compared to

Chapter 3

51


route 1, alpha-yohimbine is still produced as a minor product and poor selectivity

is still obtained in several steps. These reasons result in the extremely low overall

yield for alpha-yohimbine.

Another contribution was made by Wenkert E. et al in 1979 (Scheme 3.1.3).5

They constructed a structure of indoloquinolizidine with necessary functional

groups in a quite efficient way. Condensation between nicotinaldehyde and

malonic acid under piperidine catalysis afforded an unsaturated acid which was

transformed into ester 180 with acidic MeOH. Alkylation of the ester with

tryptophyl bromide yielded the desired pyridinium salt 181, which was attacked

by dimethyl sodiomalonate at the γ-position to afford the tetracycle 182. Since

only two ester groups were required, iodide- induced demethylation was


52


performed on 182, and the diester 183 was obtained in good yield. Reduction of

the diene moiety was done with sodium boron hydride which afforded a mixture

of 184, 185 and 186. Hydrogenation converted 184 to 185 and 186 in almost the

same yields. Direct hydrogenation of 183 would similarly lead to formation of

185 and 186, however, the yield for 186 is considerably low. Then compound 186

was epimerized via mercury acetate oxidation and NaBH4 reduction to 175, which

had been transformed to alpha-yohimbine in Scheme 3.1.2.

Until date, Martin S. F. and coworkers developed the most efficient method

toward the synthesis of alpha-yohimbine.6 They employed an intramolecular-

Diels-Alder (IMDA) reaction as the key step to construct the D, E rings and ring

Chapter 3

53

C was formed via mercury catalyzed oxidative cyclization.


As shown in Scheme 3.1.4, the amide 192 required for intramolecular-Diels-

Alder reaction was conveniently prepared in six direct steps. Subsequent

thermolysis of 192 in xylene at reflux proceeded smoothly to afford the

cycloadduct 193. The next stage is to set the functionality on the ring E.

Regioselective epoxidation and subsequent epoxide opening installed the required


54

alcohol that was present in the final product (193-195). The MOM protected

alcohol was then deprotected and oxidized. The following esterification afforded

the methyl ester group that was present in alpha-yohimbine (196-197). Under H2

in the presence of Pd(OH)2, the benzyl protecting was removed together with the

side chain of ester which was used as a nucleophile to open the epoxide. With the

free amine, the indole moiety was installed by alkylation to afford compound 200.

Finally, an oxidative cyclization and reduction sequence led to the final product

alpha-yohimbine 170.

In conclusion, as a pharmacologically and synthetically important natural

compound, alpha-yohimbine has attracted considerable attention of chemists.

Most of the present synthetic routes are developed during the synthesis of other

yohimbines and the overall yields are quite low. The route by Martin S. F. was the

most direct completing the synthesis in 19 steps, which is considerably reasonable.

There has been no reports on enantioselective synthesis of alpha-yohimbine. We

would like to introduce our work on bicyclic guanidine catalyzed

intramolecular-Diels-Alder reaction of alkynoates: the first enantioselective

synthesis of alpha-yohimbine, which was achieved via a shorter and more

efficient route.

3.2 Tandem isomerisation intromolecular-Diels-Alder (IMDA)

reaction of alkynoates: total synthesis of (+)-alpha-yohimbine

Our initial plan was based on the work of tandem isomerisation

Chapter 3

55

intramolecular-aza-Michael reaction of alkynoates (Eq 1, Scheme 3.2.1). We were

interested to develop an intramolecular-Diels-Alder reaction using the in-situ

generated chiral allenes, which will produce hydroisoquinoline derivatives (Eq 2,

Scheme 3.2.1).

Scheme 3.2.1 Initial plan for the construction of hydroisoquinoline derivative - core

structure of yohimbines

3.2.1 Synthesis of intramolecular-Diels-Alder (IMDA) reaction substrates

First, some Diels-Alder substrates were synthesized with open dienes (Scheme

3.2.2). Alkynyl amide 201 was then synthesized via amide coupling between (2E,

4E)-hexa-2, 4-dienoic acid and propargyl amine followed by coupling between

terminal alkyne and diazo compound. Alkynyl amide 202 was synthesized in

similar way as previously mentioned. The two compounds were both obtained

together with small amount of allenes. Since the amide and allene are inseperable,

they were not characterized and were treated with TBD in DCM together.

However, no cyclization occurred and only allene was obtained. Further thermal

treatment of the allene in toluene under reflux did not result in any reaction.


56

Scheme 3.2.2 Synthesis of IMDA substrates containing opening diene

As such, we begin to focus on alkynyl amides with cyclic diene moiety.

Substrates with a furan ring and an alkyne can be easily obtained by the protocol

as outlined in Scheme 3.2.3.

Scheme 3.2.3 Synthesis of IMDA substrates containing cyclic diene

The synthesis begins with an SN2 substitution between furfuryl amine and

propargyl bromide in the presence of 1 eq lithium hydroxide. To minimize the

production of disubstituted product 205, 3 eq of furfuryl amine was used.

Chapter 3

57

However, compound 205 was still formed in 10% yield. The desired product 206

was obtained in 80% yield. Then the secondary amine 206 was protected with an

amine protecting group (Table 3.1), such as Pivaloyl. Majority of this protecting

step uses the condition as described in Scheme 3.2.3. However, there are a few

substrates, which employ conditions that are different and can be found in chapter

4. Amides 207 are obtained in considerably good yields. Finally coupling between

terminal alkyne and diazo compounds afforded the desired IMDA subsrates 208.

In our previous cases,7 the coupling step always produced some allene as

inseperable by-products. However, we did not observe any allene and isolated

only the intramolecular-Diels-Alder cycladdition products.

3.2.2 Optimization study of the intramolecular-Diels-Alder reaction

These new substrates were subjected to our catalyst, bicyclic guanidine.

Pleasingly, guanidine was found to promote the intramolecular-Diels-Alder

(IMDA) reaction and the IMDA products were obtained in good yields, moderate

dr, and moderate to good ee.

During our initial study, we screened different solvents for this IMDA reaction

using 208a as a model substrate (Table 3.1). The reaction is generally a bit slow.

Chlorinated solvent (DCM) led to very low enantioselectivity (Entry 3) although

the reaction was a bit faster. Toluene, hexane and ether type solvents (THF and

diethyl ether) resulted in ees of same level. However, all of the ees were only

moderate. From prior experience, we postulated that the size of the ester group


58

could affect the enantioselectivity thus we changed the ethyl ester to a tert-Butyl

ester as shown in Table 3.2.

Table 3.1 Solvent effect on IMDA reaction

entry solvent time

(day)

conversiona

(%)

drb

(208aa:208ab)

eec

(208aa %/208ab %)

1 THF 2 100% 3:1 55%/56%

2 Toluene 2 100% 3:1 59%/59%

3 DCM 2 100% 7:3 38%/38%

4 Et2O 4 90% 4:1 60%/63%

5 Hexane 4 90% 4:1 60%/60%

Reactions were run on a 0.01 mmol scale with 10 mol% bicyclic guanidine in 0.5 ml solvent. a Conversion is determined

by crude 1H NMR.

b determined by crude

1H NMR.

c determined by chiral HPLC analysis.

The ee was increased by about 20% in Hexane (Entry 5, Table 3.1 vs Entry 6,

Table 3.2) and diethyl ether (Entry 4, Table 3.1 vs Entry 7, Table 3.2) giving the

best ee so far. Other ether-type solvents were screened as well, and TBME gave

similar enantioselectivity (Entry 10). Preliminary screening with various

concentrations indicated that a change in concentration would lead to a drop in ee

(Entry 10-12). We also attempted to lower the temperature but the reaction

became extremely slow and the ee was not increased. Different catalyst loadings

were also screened but the enantioselectivitives were not improved as well.

Finally, we decided to choose hexane as reaction solvent because it is cheap and

not as volatile as diethyl ether. Substrates bearing different protecting groups were

Table 3.2 Solvent and concentration effect on the IMDA reaction of 208b

Chapter 3

59

entry solvent concen-

tration(M)

time

(day)

conversiona

(%)

drb

(208ba:208bb)

eec

(208ba %/208bb %)

1 THF 0.02 4 80% 3:1 68/70

2 EA 0.02 3 80% 4.5:1 73/75

3 MeCN 0.02 2 100% 1.7:1 21/21

4 Tol 0.02 2 80% 4:1 72/75

5 DCM 0.02 2 100% 4:1 46/50

6 Hexane 0.02 4 80% 4:1 79/80

7 Ether 0.02 4 90% 4.5:1 77 /78

8 0.02 3 100% 7:1 60/62

9 PhOMe 0.02 3 90% 7:1 71/73

10 TBME 0.02 4 85% 4:1 79 /80

11 TBME 0.01 4 90% 7:3 60/35

12 TBME 0.005 4 50% 4:1 72/62

13 nBu2Od 0.02 7 0 nd nd

14 1,4-dioxaned 0.02 7 0 nd nd

Reactions were run on a 0.01 mmol scale with 10 mol% bicyclic guanidine in 0.5 ml solvent. a

Conversion is determined by

crude 1H NMR.

b determined by crude

1H NMR.

c determined by HPLC analysis.

d not determined

subjected to the optimal condition which employs hexane as solvent under room

temperature condition with a concentration of 0.02M and 10 mol% catalyst

loading.

Different N protecting groups led to slightly different reaction rates and ees

(Entry 2-8). The best result was achieved with the Boc protecting group, when a

triethyl methyl type ester was employed (Entry 9). When the nitrogen atom was

protected using tosyl group, the reaction rate increases probably due to the strong

electron withdrawing ability of sulfonyl group, but the ee obtained was bad.

Majority of the two diastereoisomers can be separated via chromatography on

silica gel. The IMDA products of 208e and 208g can be obtained only as


60

diastereoisomer mixtures. We confirmed the IMDA products 208ba and 208ca by

X-ray analysis (Scheme 3.2.3) and 1H NMR and 13C NMR analysis. We failed to

obtain any X-ray structure of the cis IMDA product, instead we obtained the X-ray

structure of the hydrogenation product of compound 208bb, which can also help

to determine the structure of the cis compound.

Table 3.3 Intramolecular-Diels-Alder (IMDA) reaction of 208

entry 208x(PG, R) time(d) conv(%)a yield(%)

b dr(10Xa/10Xb)

c ee(%/%)

d

1 208a(Piv, Et) 4 87.5 88.5 3:1 60/60

2 208b(Piv, tBu) 4 80 75 4:1 83/83

3 208c(Boc, tBu) 7 84 91 3.3:1 79/77

4 208d(Cbz, tBu) 7 76 89 4:1 77/77

5 208e(Ts, tBu)e 3 100 80 2:1 76.5/80

6 208f(4-bromo

Benzoyl, tBu )

7 84 83.3 2.5:1 65/65

7

208g( ,tBu)e

7 77 72 4:1 68/69

8 208h(Boc, CEt3) 8 85.3 80 4:1 87/87.5

9 208i (Piv, CEt3) 5 86% 80 3:1 87/88

Reactions were run on a 0.2 mmol scale with 10 mol% bicyclic guanidine in 10 ml hexane at room

temperature. a based on recovered starting material.

b isolated yield (10xa+10xb) based on

conversion. c determined by

1H NMR.

d determined by HPLC analysis.

e the reaction was run in

THF due to low solubility.

Other DA products were confirmed by comparing the 1H, 13C NMR data with

that of 10ba and 10bb. Due to the lack of heavy atoms in the molecule, the

absolute configurations of products 10ca and 10cb were determined via DFT

calculation on optical rotation to be (5S, 6S, 9R) and (5R, 6S, 9R) respectively.8

Chapter 3

61

Compound 208ba

Compound 208ca

Hydrogenation product of compound 208bb

Scheme 3.2.4 X-ray structures of the compounds 208ba, 208ca and the X-ray structure of the

hydrogenation product of compound 208bb.

3.2.3 Enantioselective total synthesis of (+)-alpha-yohimbine

To achieve the synthesis of the natural product alpha-yohimbine 170, we

designed the substrate 208g. The indole moiety was installed as a protecting group

to facilitate the IMDA reaction. The IMDA products contain all the elements that

are required in alpha-yohimbine. The natural product synthesis can be completed

in a few steps with first cyclization to form the ring C, followed by amide

reduction, olefin hydrogenation and transesterification. We proceeded to attempt

the total synthesis with 208ga according to the route as discussed (Scheme 3.2.5).


62

Scheme 3.2.5 Intramolecular-Diels-Alder reaction of substrate 208g and manipulation on the

IMDA product 208ga

We first attempted to cyclise the IMDA product 208ga via oxidative cyclization

which has been used to form the ring C by the oxidation of tertiary amine to

iminium.6 However, the amide oxidation did not work. As such, we decided to

reduce the amide instead. IMDA products are generally not stable probably due to

the double bonds. Hydrogenation of 208ga gave 210 in good yield. The amide

210 was subjected to kinds of conditions for tertiary amide reduction, like borane,

sodium boron hydride in the presence of Lewis acid, Hantzsch ester in the

presence of Tf2O, Silane in the presence of zinc acetate. But all of these

conditions did not work. Compound 210 was either recovered or decomposed.

The strong reducing reagents LiAlH4 did reduce the amide to amine, however, the

ester was reduced together, which results in a very polar compound. The change

Chapter 3

63

in oxidation state of the compound made the route not appealing.

Manipulation on other IMDA products was then planed. Deprotection of the

nitrogen atom followed by alkylation or reductive amination should install the

indole moiety without an oxidation state change. Compound 208ca was selected

to be the desired starting point due to the easy removal of Boc group as well as its

high ee (Scheme 3.2.6).

Scheme 3.2.6 Attempt on the total synthesis starting with compound 208ca

IMDA product 208ca was hydrogenated to afford two compounds 211 and 212

in a ratio of 1:4 in quantitative yield. Then the main product 212 was treated with

TFA in DCM to remove the Boc protecting group. Temperature and amount of

TFA have been screened. It was found that the reaction in a mixture of TFA and

DCM (volume ratio of 1:4) at 0 oC for 10 minutes, gave the free amine 213 in the

best yield (80%). Less TFA resulted in a longer reaction time. Longer reaction


64

time and high temperature resulted in the reaction of tert-butyl ester with TFA.

The tert-butyl ester was changed to carboxylic acid resulting in a lower yield of

the amine.

Secondary amine 213 was not purified and used directly after quenching and

extraction. Alkylation of the amine with tryptophyl bromide in DMF or MeCN in

the presence of K2CO3, afforded compound 214 in quite low yield (around 20%).

The reason is probably the oxa-bridge reduced the nucleophilicity of the nitrogen

atom. Then reductive amination using 2-(1-H-indol-3-yl)-acetaldehyde was

carried out. The condition was reported by Eric. N. Jacobsen during their

synthesis of yohimbine.9 Compound 214 was obtained in 60% yield. The

transesterification proceeded smoothly in the presence of 1 eq of CSA in refluxing

MeOH and the methyl ester 215 was achieved in 80% yield. Then the oxidative

cyclization using mercury acetate followed by NaBH4 reduction was employed to

form the ring C. Two products 216 and 217 were achieved in same yield (30%).

Compound 217 was the desired product.

In order to attain the hydroxyl group at C-18, the oxa-bridge has to be opened.

Initially Lewis acid, such as ZrCl4, and BF3 were attempted, but these were not

strong enough, only the starting material 217 was recovered. Stronger Lewis acid

BCl3 led to a messy reaction at -20 oC, and no product could be isolated. The

temperature was lowered to -78 oC but there was no reaction. Brønsted acids such

as HCl and HBr were used in EA and in toluene respectively but these did not

Chapter 3

65

work as well and no reaction was observed. Finally, it was found that

trifluoromethanesulfonic acid could promote the ring opening with DCM as

solvent. On closer analysis of the structure with NMR (1H, 13C, COSY, HMQC,

NOESY), we confirmed that the compound is 218. However, the hydroxyl group

was formed at C20 instead of C17. This result can be explained by the

neighboring carbonyl stabilization of the carbon cation intermediate 219 (scheme

3.2.7).

Scheme 3.2.7 Ring opening of compound 217 with triflic acid

So far, we observed that in acid catalysis, the carbon cation prefers to form at

C-17 rather than C-20 and alpha-yohimbine was not possible to achieve via this

route. As such, we decided to take a different approach and open the oxabicyclic

ring with a nucleophile before the double bonds were reduced.

Different conditions have been screened, however, in most results either no

reaction was observed or the starting material was decomposed and no isolation of

product was possible (Entry 1-8, Table 3.4). The palladium-catalyzed

hydrostannation of olefin led to 50% yield of 220, which would afford a tertiary

alcohol instead of the desired secondary alcohol after destannation (Entry 9).

Finally, the desired product 221 was obtained via nickel catalyzed reductive

oxabicyclic ring opening with DIBAL-H as hydride source (Entry 10). Due to the


66

low yield obtained, an optimization was done.

Table 3.4 Oxabicyclic ring opening of IMDA product 208ca

entrya condition time result

110

2 eq ZrCl4, 0.1 M in DCM 2 d Decomposition

2 TiCl4, DCM, -78 oC 1 hr Decomposition

3 2 eq SmI2, THF 24 hr No reaction

4 2 eq Red-Al, toluene, rt 24 hr No reaction

511

2 eq PhSH, 2 eq BF3-Et2O, DCM, rt 24 hr Decomposition

6 2 eq PhSH, 2 eq Et3N, DCM, rt 24 hr No reaction

7 LiNH2, -78 oC 1 hr Decomposition

812

LTBAH, Et3B, THP 24 hr No reaction

913

20 wt% Pd(OH)2, 1.5 eq Bu3SnH, THF 2 hr

220, 50% y ield

1014

0.1 eq Ni(COD)2, 0.4 eq PPh3, 1.2 eq DIBAL-H in

hexane, rt

2 hr

221, 11% yield

Reaction details see corresponding literatures. a Corresponding literatures

The reaction using Ni(COD)2 and DIBAL-H system was very fast. Catalytic

amount of Ni(COD)2 led to quite low yield (Entry 1-2, Table 3.5). Increase in the

catalyst loading gave better yield (Entry 4). Excess of DIBAL-H would decrease

the yield because of the side reaction of ester reduction (Entry 3). Actually, side

product from olefin hydroalumination was also detected via LCMS. The best yield

(50%) was achieved when 1 eq of Ni(COD)2, 4 eq of PPh3 and 1.3 eq of

DIBAL-H were used at 0 oC in this reaction (Entry 7). Decrease of temperature to

Chapter 3

67

-78 oC did not improve the result (Entry 6).

Table 3.5 Optimizat ion of reductive oxab icyclic ring opening of IMDA product 208ca

entry Ni(COD)2 PPh3 DIBAL-H temperature conversiona yield

b

1 0.1 eq 0.4 eq 1.2 eq in heptane rt 70% 11%



4 1 eq 4 eq 1.1 eq in heptane rt 80% 35%

5 1 eq 4 eq 1.3 eq in heptane -78 oC-rt 80% 40%

6 1 eq 4 eq 1.3 eq in toluene -78 oC-rt 80% 45%

7 1 eq 4 eq 1.3 eq in toluene 0 oC 90% 50%



Reaction details see chapter 7. a

based on TLC analysis b isolated yield.

Compound 221 is found to be unstable as after standing at rt or even -30 oC for

overnight, new spots were observed on TLC. Direct hydrogenation of compound

221 led to messy reaction. Thus, the alcohol was protected with acetyl group

using 1.5 eq of acetic anhydride with DMAP as catalyst in the presence of 1.5 eq

of Et3N (Scheme 3.2.8). The O-protected product 222 was obtained in 80% yield

with no ee change.

Scheme 3.2.8 Protection of alcohol group in compound 221

Having achieved compound 222, we aimed to reduce the two double bonds. It

was speculated that the bulky tert-butyl ester group would help to form the

desired product 223 during heterogeneous hydrogenation. Unfortunately, only a


68

mixture of two diastereoisomers that could not be separated was obtained and the

stereochemistry of the products could not be determined at this moment. To

increase the yield and the dr, an optimization was also performed (Table 3.6).

Table 3.6 Optimizat ion of hydrogenation of compound 222

entry catalyst catalyst loading temperature time ratio of 225a dr

b

1 10%Pd/C 30 wt% rt 2 d 70% 4:1

2 10%Pd/C 100 wt% rt 2 d 60% 4:1

3 20%Pd(OH)2 50 wt% rt 2 d 60% 3:1

4 10%Pt/C 100 wt% rt 2 d 50% 8:1

5 10%Pt/C 200 wt% rt 2 d 30% 5:1

6 10%Pt/C 50 wt% rt 3 d 50% 8:1

7 10%Pt/C 50 wt% 70 0C 3 d 10% 8:1

a based on crude nmr analysis and ESI mass analysis

b based on crude nmr analysis

By ESI mass analysis, it was found that there was always a monohydrogenated

product 225, which could not be isolated and its double bond could not be located.

By crude 1H NMR analysis, its ratio could be determined. The stereochemistry of

compounds 223 and 224 cannot be determined at this stage but the

stereochemistry of the major product 223 was later determined. A brief catalyst

screening indicated that Pt/C is better than Pd/C and Pd(OH)2/C in the perspective

of reaction rate and diastereoselectivity (Entry 2-4). More catalyst loading and

higher temperature increased the reaction rate significantly (Entry1-2, 6-7). When

using more Pt/C, a decrease of dr was observed (Entry 5). Finally, the condition of

Chapter 3

69

50 wt% Pt/C at 70 oC was used for the hydrogenation, which afforded the

products with 10% of compound 225 and a dr (223:224) of 8:1.

The products of this step are not separable and they were used together in the

following synthesis. With this result and our previous experience in hand, we

carried out the rest synthesis without much problem (Scheme 3.2.9).

Scheme 3.2.9 Total synthesis of (+)-alpha-yohimbine starting from 208ca

The inseparable mixture of 223 and 224 was treated with TFA in DCM at 0 oC,

which afforded an inseparable diisomer mixture of free amine 226 (dr 8:1). The

amine was confirmed via crude 1H NMR analysis and ESI mass analysis. Without

purification, the mixture 226 was used in the reductive amination step directly.

Unfortunately, the product 227 was inseparable again from the by-product

2-(1H-indol-3-yl) ethanol that was generated from the reduction of


70

2-(1H-indol-3-yl) acetaldehyde. The mixture of 227 and 2-(1-H-indol-3-yl)

ethanol was isolated via flushing silica gel chromatography and used together in

the transesterification step. When the mixture was treated with CSA in refluxing

MeOH in a sealed tube, the acetyl group was cleaved and the tert-butyl ester was

converted to methyl ester together, which afforded 228 in 31% yield over four

steps. An increase in ee was observed during the analysis of compound 228 with

chiral HPLC, the ee increased from 79% of IMDA product 209ca to 85% of

compound 228. The compound 228 was fully characterized and the

stereochemistry was established by NOESY analysis and also confirmed by

comparing the 1H, 13C NMR with the reported data.6 The oxidative cyclization

followed by NaBH4 reduction was subsequently carried out to finish the total

synthesis of (+)-alpha-yohimbine. The final product was also fully characterized

and confirmed by comparing the NMR data with the reported one.6

Since the ee of the starting IMDA product 208ca is 79% only, the total synthesis

was carried out starting from IMDA products 208ha and 208hb (Scheme 3.2.10).

which are inseparable. When the mixture of 208ha and 208hb was treated with

Ni(COD)2 and DIBAL-H, two products 229 and 230 were obtained. By

comparing the NMR data with that of compound 221, the trans isomer can be

identified. The synthesis was completed in the same sequence as above. However,

the ee for compound 228 was not increased and almost same as in scheme 3.2.9.

The yield dropped to 20% over the four-step sequence. This is probably due to the

Chapter 3

71

low distereoselectivity (3.5:1) at the hydrogenation step.

Scheme 3.2.10 Total synthesis of (+)-alpha-yohimbine starting from 208ha and 208hb

3.3 Summary

In conclusion, we have found that a Brønsted-base catalyzed tandem

isomerisation intramolecular-Diels-Alder reaction can be used to form useful

hydroisoquinoline derivatives under mild conditions. The IMDA products have

been obtained in moderate to high enantiomeric purity. This efficient method was

successfully applied to the catalytic enantioselective total synthesis of

(+)-alpha-yohimbine.


72

References:

1. Kohli, J. D.; De, N. N. Nature,1956, 177, 1182.

2. Perry, B. D.; ÚPrichard, D. C. European Journal of Pharmacology, 1981, 76, 461.

3. Arthur, J. M.; Casańas S. J.; Raymond J. R. Biochemical Pharmacology, 1993, 45, 2337.

4. a) Szántay, Cs.; Töke, L.; Honty, K. Tetrahedron Lett., 1965, 6, 1665 . b) Töke, L.; Honty K.;

Szántay, Cs. Chem. Ber., 1969, 102, 3248. c) Töke, L; Honty, K.; Szabó, L.; Blaskó, G.;

Szántay, C. J. Org. Chem. 1973, 38, 2496. d) Töke, L; Gábor, Z.; Blaskó, G; Honty, K.; Szabó,

L.; Tamás J.; Szántay G. J. Org. Chem. 1973, 38, 2501.

5. Wenkert, E.; Halls, T. D. J.; Kunesch, G.; Orito, K.; Stephens, R. L.; Temple, W. A.; Yadv, J. S.

J. Am. Chem. Soc. 1979, 101, 5370.

6. Martin, S. F.; Rueger, H.; Williamson, S. A.; Grzejszczak, S. J. Am. Chem. Soc. 1987, 109,

6124.

7. Liu, H.; Leow, D.; Huang, K.-W., Tan, C.-H., J. Am. Chem. Soc. 2009, 131, 7212.

8. Kwit, M.; Rozwadowska, M. D.; Gawroński, J.; Grajewska, A. J. Org. Chem. 2009, 74, 8051.

9. Mergott, D. J.; Zuend, S. J.; Jacobsen, E. N. Org. Lett. 2008, 10, 745.

10. Giovanni, V.; Stephen, B.; Jamal, E. M.; Marcella, B.; Giuseppe, Z. Tetrahedron Lett. 2002,

43, 2687.

11. Rigby, J. H.; Wilson, J. A. Z. J. Org. Chem. 1987, 52, 34.

12. Moss, R. J.; Rickborn, B. J. Org. Chem. 1985, 50, 1381.

13. Lautens, M.; Aspiotis, R.; Colucci J. J. Am. Chem. Soc. 1996, 118, 10930.

14. Lautens, M.; Ma, S.; Chiu, P. J. Am. Chem. Soc. 1997, 119, 6478.

Chapter 4

73

Chapter 4

Experimental

Experimental

74

4.1 General information

4.1.1 General procedures and methods

1H and 13C NMR spectras were recorded on a Bruker ACF300 (300MHz), Bruker

DPX300 (300MHz) or AMX500 (500MHz) spectrometer. Chemical shifts are

reported in parts per million (ppm). The residual solvent peak was used as an

internal reference. Low-resolution mass spectras were obtained on a

Finnigan/MAT LCQ spectrometer in ESI mode and a Finnigan/MAT 95XL-T

mass spectrometer in FAB mode. All high-resolution mass spectras were obtained

on a Finnigan/MAT 95XL-T spectrometer. Infrared spectras were recorded on a

BIO-RAD FTS 165 FTIR spectrometer. Enantiomeric excess values were

determined by chiral HPLC analysis on two sets: Jasco HPLC units, including a

Jasco DG-980-50 Degasser, a LG-980-02 Ternary Gradient Unit, a PU-980

Intelligient HPLC Pump, UV-975 Intelligient UV/VIS Detectors, and an AS-950

Intelligient Sampler; Dionex Ultimate 3000 HPLC units, including a Ultimate

3000 Pump, Ultimate 3000 variable Detectors. Optical rotations were recorded on

Jasco DIP-1000 polarimeter. Melting points were determined on a BÜCHI B-540

melting point apparatus. Analytical thin layer chromatography (TLC) was

performed with Merck pre-coated TLC plates, silica gel 60F-254, layer thickness

0.25 mm. Flash chromatography separations were performed on Merck 60 (0.040

- 0.063mm) mesh silica gel. Toluene and THF were distilled from

sodium/benzophenone and were stored under N2 atmosphere. Dichloromethane

Chapter 4

75

was distilled from CaH2 and was stored under N2 atmosphere. Other reagents and

solvents were commercial grade and were used as supplied without further

purification, unless otherwise stated.

4.1.2 Materials

All commercial reagents were purchased from Sigma-Aldrich, Fluka, Alfa Aesar,

Merck, TCI, and Acros of the highest purity grade. They were used without

further purification unless specified. All solvents used, mainly hexane (Hex) and

ethyl acetate (EtOAc), were distilled. Anhydrous DCM was freshly distilled from

CaH2. Anhydrous THF was freshly distilled from Na/benzophenone. MeCN and

CHCl3 were distilled from CaH2. MeOH was distilled from Mg.

4.2 Preparation and characterization of compounds for the

Michael reaction

4.2.1 Preparation of alkynyl amines

Alkynyl amines 141a-c were synthesized according to the equation above. To a

flame-dried 50 ml rbf, pent-4-ynoic acid (2.9 mmol) and 5 ml THF were added

under N2. This is followed by DCC (3.2 mmol) and HOBT (3.2 mmol). Finally,

Experimental

76

aniline (3.4 mmol) in THF (5 ml) was added and the reaction mixture was stirred

at rt for 18 hrs. The reaction mixture was filtered and the solvent was removed

under reduced pressure. The residue was purified via flash chromatography.

Amide 139a was obtained in 70% yield.

Then in a 50 ml dry rbf equipped with a condenser, amide 139a (2 mmol) was

dissolved in 10 ml dry THF under N2, cooled to 0 oC, LiAlH4 (5 mmol) was

added. The mixture was refluxed at 70 oC overnight, and was then cooled to 0 oC,

quenched with 1ml water, stirred untill a white solid was formed. Then the solid

was filtered off and the filtrate was concentrated to afford the crude 140a.

Compound 140a was mixed together with 2 mmol of ethyl diazoacetate in 4 ml

MeCN under N2. Then 0.2 mmol of copper iodide was added. The mixture was

stirred overnight and the reaction was monitored with TLC until starting material

was consumed. After concentrated under reduced pressure, the mixture was

purified via chromatography on silco gel. Compound 141a was obtained in 60%

yield over two steps.

4.2.2 Representative procedure for Brønsted-base catalyzed tandem

isomerization-aza-Michael reaction of alkynyl-amines

Substrate 141a (0.5 mmol) was dissolved in 5 ml DCM, then TBD (0.05 mmol)

Chapter 4

77

was added and the mixture was stirred at rt for 24 hours. After concentrated, the

mixture was purified by chromatography on silco gel. Compound 142a was

obtained as pale yellow oil in 83% yield.

(E)-ethyl 2-(1-phenylpiperidin-2-ylidene)acetate (142a): Yellow oil; 83% yield;

1H NMR (300 MHz, CDCl3): δ 7.41 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.6 Hz, 1H),

7.16 (d, J = 7.3 Hz, 2H), 4.34 (s, 1H), 3.99 (q, J = 7.1 Hz, 2H), 3.47 (t, J = 6.0 Hz,

2H), 3.24 (t, J = 6.4 Hz, 2H), 1.93-1.78 (m, 4H), 1.15 (t, J = 7.1 Hz, 3H) ppm; 13C

NMR (75 MHz, CDCl3): δ 167.7, 162.2, 145.1, 128.9, 128.2, 125.8, 85.7, 57.2,

51.0, 25.3, 22.7, 19.0, 13.6 ppm; IR (film): 3020, 2977, 2896, 1556, 1422, 1216,

1137, 1046, 929 cm-1; LRMS (ESI) m/z: 268.1; HRMS (ESI) m/z:

C15H19O2N23Na1+ ([M+Na]+), Calc. 268.1308, Found 268.1302.

(E)-tert-butyl 2-(1-phenylpiperidin-2-ylidene)acetate (142b): Slight yellow

solid; 70% yield; 1H NMR (300 MHz, CDCl3): δ 7.40 (t, J = 7.6 Hz, 2H),

7.27-7.22 (m, 1H), 7.17 (d, J = 7.6 Hz, 2H), 4.32 (s, 1H), 3.44 (t, J = 6.0 Hz, 2H),

3.20 (t, J = 6.4 Hz, 2H), 1.91-1.76 (m, 4H), 1.38 (s, 9H) ppm; 13C NMR (75 MHz,

CDCl3): δ 168.8, 162.2, 146.4, 130.0, 126.8, 126.5, 89.1, 51.9, 28.6, 27.9, 26.3,

23.8, 20.3 ppm; IR (film): 3020, 2978, 2897, 1524, 1378, 1216, 1129, 1046, 929

cm-1; mp: 102.5 –103.9 °C; LRMS (ESI) m/z: 296.1; HRMS (ESI) m/z:

C17H23O2N23Na1+ ([M+Na]+), Calc. 296.1621, Found 296.1622.

Experimental

78

(E)-tert-butyl 2-(1-(2-tert-butylphenyl)piperidin-2-ylidene)acetate (142c):

White solid; 70% yield; 1H NMR (300 MHz, CDCl3): δ 7.51-7.48 (m, 1H),

7.28-7.25 (m, 2H), 7.05 (dd, J = 3.6, 5.6 Hz, 1H), 4.01 (s, 1H), 3.83-3.77 (m, 1H),

3.40-3.30 (m, 2H), 2.57-2.49 (m, 1H), 1.95-1.59 (m, 4H), 1.36-1.35 (m, 18H) ppm;

13C NMR (75 MHz, CDCl3): δ 168.6, 162.8, 146.5, 144.8, 130.1, 128.8, 127.8,

127.6, 91.9, 53.8, 35.5, 31.2, 28.6, 26.1, 23.6, 20.6 ppm; IR (film): 3020, 2977,

2896, 1524, 1424, 1218, 1129, 1046, 929 cm-1; mp: 113.5 –114.7 °C; LRMS (ESI)

m/z: 352.1; HRMS (ESI) m/z: C21H31O2N23Na1+ ([M+Na]+), Calc. 352.2247,

Found 352.2261.

4.2.3 Synthesis of alkynyl amides and procedure for Brønsted-base catalyzed

tandem isomerization-aza-Michael reaction

Compound 150 was obtained via the coupling of compound 139b with tButyl

diazoacetate, 1 To a clear and dry vial, tert-butyl 7-(2-tert-butylphenylamino)

-7-oxohept-3-ynoate (150) (36 mg, 0.1 mmol), a stirring bar and anhydrous THF

(0.9 mL) were added in this sequence. After stirring at room temperature for a

while, bicyclic guanidine 149 (2 mg, 0.01 mmol) in anhydrous THF (0.1 mL)

were added to the mixture in one portion. After the reaction was completed in 3

Chapter 4

79

days, the reaction mixture was concentrated and loaded onto a short silica gel

column, followed by flash chromatography. Product 152 (24 mg) was obtained as

white solid in 67% yield with 89% ee.

Synthesis of compounds 155,157, 159, 163, 166 follows the synthetic schemes in

Scheme 2.2.6, chapter 5. Bicyclic guanidine catalyzed isomerization of these

compounds follows the procedure above for compound 150

N-(2-tert-butylphenyl)pent-4-ynamide (139b) White solid; 62% yield; 1H

NMR (300 MHz, CDCl3): δ= 7.52 (d, J = 7.41 Hz, 1H), 7.39 (d, J = 6.9 Hz, 1H),

7.34 (s, 1H), 7.23-7.15 (m, 2H), 2.62 (d, J = 2.64 Hz, 4H), 2.03 (s, 1H), 1.41 (s,

9H); 13C NMR (75 MHz, CDCl3): δ= 169.4, 143.1, 134.8, 128.5, 126.8, 126.6,

126.4, 82.9, 69.7, 36.4, 34.6, 30.8, 14.8; LRMS (ESI) m/z: 230.2.

tert-Butyl 7-(2-tert-butylphenylamino)-7-oxohept-3-ynoate (150) colorless oil;

86% yield; 1H NMR (300 MHz, CDCl3): δ= 7.52 (d, J = 4.56 Hz, 1H), 7.47 (s,

1H), 7.42 (d, J = 4.53 Hz, 1H), 7.25-7.19 (m, 2H), 3.17 (s, 2H), 2.69-2.64 (m, 4H),

1.44 (s, 18H); 13C NMR (75 MHz, CDCl3): δ= 169.9, 167.8, 143.4, 135.1, 128.7,

126.8, 126.6, 126.5, 82.1, 81.8, 74.0, 36.8, 34.7, 30.7, 27.9, 27.1, 15.3; LRMS

(ESI) m/z: 366.1.

(E)-tert-Butyl-2-(1-(2-tert-butylphenyl)-6-oxopiperidin-2-ylidene)acetate (152)

white solid; 67% yield; 1H NMR (300 MHz, CDCl3): δ= 7.59 (d, J = 8.19 Hz, 1H),

7.40 (t, J = 7.29 Hz, 1H), 7.31 (t, J = 1.47 Hz, 1H), 6.82 (d, J = 7.89 Hz, 1H), 4.49

(s, 1H), 3.48-3.38 (m, 1H), 3.28-3.18 (m, 1H), 2.70 (t, J = 6.42 Hz, 2H), 2.02-1.94

Experimental

80

(m, 2H), 1.39 (s, 9H), 1.30 (s, 9H); 13C NMR (75 MHz, CDCl3): δ= 171.2, 166.9,

156.9, 146.7, 135.5, 131.2, 129.8, 128.8, 127.6, 102.4, 79.6, 36.0, 34.0, 31.6, 28.3,

25.7, 18.4; IR (film)/cm-1 : 2970, 1690, 1605, 1281, 1219, 1134, 771, 756; mp:

145.1-146.0oC; LRMS (ESI) m/z: 366.1; HRMS (ESI): [M+Na]+ C21H29O3N23Na1,

Calc, 366.2040. found, 366.2035; [α]29D = -64.1 (c 0.1, CHCl3); HPLC analysis:

Chiralpak IA+IA column ( Hexane/IPA=90/10, 1.0ml/min, 254nm, 25oC),

11.33min(major), 12.31(minor), 89%ee. The geometry about the C=C bond was

confirmed by NOSEY.

tert-Butyl-6-(2-(2-tert-butylphenylamino)-2-oxoethoxy)hex-3-ynoate (153)

colorless oil; 46% yield; 1H NMR (300 MHz, CDCl3): δ=8.61 (s, 1H) 7.83 (d, J =

4.92 Hz, 1H), 7.39 (d, J = 4.92 Hz, 1H), 7.24 (t, J = 4.56 Hz, 1H), 7.14 (t, J = 4.56

Hz, 1H), 4.16 (s, 1H), 3.75 (t, J = 4.26 Hz, 2H), 3.11 (t, J = 1.56 Hz, 2H), 2.59 (t,

J = 5.28 Hz, 2H), 1.43 (s, 9H). 1.42 (s, 9H); 13C NMR (75 MHz, CDCl3): δ=

167.7, 167.2, 141.4, 134.7, 126.8, 126.5, 125.9, 125.7, 81.8, 79.5, 73.9, 70.6, 69.9,

34.4, 30.5, 27.9, 27.1, 20.3; LRMS (ESI) m/z: 396.1.

tert-Butyl-5-(2-(2-tert-butylphenylamino)-2-oxoethoxy)-5-methylhex-3-ynoate

(154) colorless oil; 40% yield; 1H NMR (300 MHz, CDCl3): δ= 8.64 (s, 1H), 7.98

(d, J = 7.89 Hz, 1H), 7.38 (d, J = 7.89 Hz, 1H), 7.26-7.08 (m, 2H), 4.27 (s, 2H),

3.19 (s, 2H), 1.56 (s, 6H), 1.46(s, 9H), 1.43 (s, 9H); 13C NMR (75 MHz, CDCl3):

δ= 167.6, 166.8, 140.3, 134.9, 126.8, 126.3, 125.2, 124.9, 83.7, 82.0, 78.4, 71.8,

64.3, 34.3, 30.3, 28.7, 27.9, 27.0; LRMS (ESI) m/z: 410.2.

Chapter 4

81

tert-Butyl 6-(2-tert-butylphenylcarbamoyloxy)hex-3-ynoate 155 colorless oil;

66% yield; 1H NMR (300 MHz, CDCl3): δ= 7.54 (s, 1H), 7.37 (d, J = 7.56 Hz,1H),

7.24-7.01 (m, 2H), 4.25 (t, J = 7.02 Hz, 2H), 3.17 (s, 2H), 2.60 (t, J = 7.02 Hz,

2H), 1.46 (s, 9H), 1.40 (s, 9H); 13C NMR (75 MHz, CDCl3): δ= 167.8, 154.1,

135.1, 126.8, 126.4, 125.7, 81.7, 79.1, 73.9, 63.2, 34.6, 30.6, 27.9, 27.1, 19.7;

LRMS (ESI) m/z: 382.1.

tert-Butyl-5-(2-(2-tert-butylphenylamino)-2-oxoacetamido)pent-3-ynoate (156)

colorless oil; 50% yield; 1H NMR (300 MHz, CDCl3): δ= 9.56 (s, 1H), 7.98 (d, J

= 7.9 Hz, 1H), 7.88 (s, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.29-7.15 (m, 2H), 4.59 (s, J

= 6.4 Hz,1H), 3.72 (s, 2H), 1.46-1.47 (m, 18H); 13C NMR (75 MHz, CDCl3): δ=

166.4, 160.1, 156.5, 140.9, 133.9, 126.8, 126.5, 126.0, 124.0, 119.6, 116.5, 82.1,

47.8,47.2, 34.2, 30.5, 27.8; LRMS (EI) m/z: 395.1.

(S)-tert-Butyl 5-(N-(2-(2-tert-butylphenylamino)-2-oxoethyl)acetamido)penta

-2,3-dienoate (157) colorless oil; 67% yield; 1H NMR (300 MHz, CDCl3): δ=

8.19 (s, 1H), 7.52 (d, J = 7.29 Hz, 1H), 7.38 (d, J = 7.32 Hz, 1H), 7.23-7.12 (m,

2H), 5.68-5.64 (m, 2H), 4.29-4.10 (m, 4H), 3.24 (s, 3H), 1.46-1.38(m, 18H); 13C

NMR (75 MHz, CDCl3): δ= 211.3, 172.0, 167.4, 164.0, 142.8, 134.6, 127.8, 126.7,

126.3, 93.1, 91.3, 81.7, 51.7, 47.8, 44.2, 34.5, 30.4, 28.0, 20.1. IR (film)/cm-1

3016, 2399, 1682, 1520, 1474, 1427, 1211, 925. LRMS (ESI) m/z: 423.2; HRMS

(ESI): [M+Na]+ C23H32O4N223Na1, Calc, 423.2254. found, 423.2259. [α]29

D =

+31.7 (c 0.5, CHCl3); HPLC analysis: PHENOMENEX Lux 5u Cellulose-2

Experimental

82

column ( Hexane/IPA=80/20, 1.0ml/min, 230nm, 25oC), 29.45 min(major), 50.49

min (minor), 65%ee.

(S)-tert-Butyl 5-(2-(2-tert-butylphenylamino)-2-oxoethoxy)-5-methylhexa-2,3

-dienoate (158) colorless oil; 68% yield; 1H NMR (300 MHz, CDCl3): δ= 8.69 (s,

1H), 8.02 (dd, J = 1.32, 7.89 Hz, 1H), 7.42 (dd, J =1.65, 8.07 Hz, 1H), 7.30-7.25

(m, 1H), 7.18-7.12 (m, 1H), 5.70 (d, J =6.06, 1H), 5.59 (d, J =6.24, 1H), 4.17 (d, J

=7.89, 2H), 1.52-1.48(m, 24H); 13C NMR (75 MHz, CDCl3): δ= 210.8, 167.34,

164.3, 140.1, 134.9, 126.8, 125.2, 124.8, 100.1, 92.5, 81.6, 76.0, 63.4, 34.3, 30.4,

28.1, 27.1, 26.6, 34.3, 30.4, 28.1, 26.6. IR (film)/cm-1 1959, 1697, 1527, 1288,

1219, 1141, 1288, 1219, 1141, 1087, 910; LRMS (ESI) m/z: 410.2; HRMS (ESI):

[M+Na]+ C23H33O4N123Na1, Calc, 410.2302. found, 410.2321. [α]29

D = +45.1 (c

1.2, CHCl3); HPLC analysis: Chiralpak IB column ( Hexane/IPA=90/10,

1.0ml/min, 230nm, 25oC), 5.13min(major), 9.68(minor), 87%ee.

(S)-tert-Butyl 5-(N-(2-(2-tert-butylphenylamino)-2-oxoethyl)acetamido)penta-

2,3-dienoate (159) colorless oil; 67% yield; 1H NMR (300 MHz, CDCl3): δ= 8.19

(s, 1H), 7.52 (d, J = 7.29 Hz, 1H), 7.38 (d, J = 7.32 Hz, 1H), 7.23-7.12 (m, 2H),

5.68-5.64 (m, 2H), 4.29-4.10 (m, 4H), 3.24 (s, 3H), 1.46-1.38(m, 18H); 13C NMR

(75 MHz, CDCl3): δ= 211.3, 172.0, 167.4, 164.0, 142.8, 134.6, 127.8, 126.7,

126.3, 93.1, 91.3, 81.7, 51.7, 47.8, 44.2, 34.5, 30.4, 28.0, 20.1. IR (film)/cm-1

3016, 2399, 1682, 1520, 1474, 1427, 1211, 925. LRMS (ESI) m/z: 423.2; HRMS

(ESI): [M+Na]+ C23H32O4N223Na1, Calc, 423.2254. found, 423.2259. [α]29

D =

Chapter 4

83

+31.7 (c 0.5, CHCl3); HPLC analysis: PHENOMENEX Lux 5u Cellulose-2

column ( Hexane/IPA=80/20, 1.0ml/min, 230nm, 25oC), 29.45 min(major), 50.49

min (minor), 65%ee.

4.3 Preparation and characterization of compounds for the IMDA

reaction

5.3.1 Synthesis and Characterizations of IMDA substrates

To a flame-dried 50 ml rbf, (2E,4E)-hexa-2,4-dienoic acid (2.9 mmol) and 5 ml

THF was added under N2. This is followed by DCC (3.2 mmol) and HOBT (3.2

mmol). Finally, propargyl amine (3.4 mmol) in THF (5 ml) was added and the

reaction mixture was stirred at rt for 18 hrs. The reaction mixture was filtered and

the solvent was removed under reduced pressure. The residue was purified via

flash chromatography. The resulting (2E,4E)-N-(prop-2-ynyl)hexa-2,4-

dienamide was obtained in 70% yield. The amide was then subjected to tButyl

Experimental

84

diazoacetate catalyzed by CuI to afford comound 201 together with certain

amount of inseparable allene in 60% yield.

Representative procedure for the synthesis of IMDA substrates:

Step 1: To a 200 ml rbf was added a stirring bar, 10 mmol LiOH.H2O and 10 ml

DMF (AR grade), followed by the addition of 30 mmol Furfurylamine 6. The

mixture was stirred vigorously. Then 10 mmol propargyl bromide 7 in 30 ml

DMF was added slowly during 1 hour. After stirred for another 3 hours, the

mixture was filtered through clite via sucktion and was washed thoroughly with

Diethyl Ether. The filtrate was washed four times with water. The combined

aqueous layer was extracted again with Diethyl Ether and the combined organic

layers were washed with brine and dried over sodium sulphate, concentrated via

rotary evaporation and purified by flushing silica gel chromatography

(Hexane:EA=6:1). The product 8 was obtained as pale yellow oil in 80% yield.

(Due to the low boiling point, 8 cannot be dried under vacumn and it was dried

only under rotary evaporation)

Chapter 4

85

Step 2: To a solution of 8 (8 mmol) in dry DCM (50 mL) under nitrogen

atmosphere was added Et3N (8.8 mmol, 1.1 eq). After the mixture was cooled to 0

oC, pivaloyl chloride was added dropwisely. Then the reaction mixture was

warmed to rt and stirred till full conversion indicated by TLC (usually around 1

hour). The product was obtained as colorless oil in 95% yield by flushing silica

gel chromatography purification. (Other substrates were prepared in the same way

but with different acid chlorides or anhydrides)

Step 3: (take 10a for example) Compound 9 (6 mmol) was dissolved in MeCN

(AR grade) under N2, and 0.6 mmol CuI was added to the solution. The mixture

was stirred for 10 minutes. Then ethyl diazoacetate(9 mmol) was added and the

mixture was stirred under N2 for 10 hours. Check TLC to ensure full conversion

of starting material 9 (if not, add a bit more diazo compound and stirred till

completion). Rotary evaporate to remove solvent and load the mixture to silica gel

column. After chromatography purification, the product 10a was obtained as

colorless oil in 75% yield. The IMDA products (10aa and 10ab) were obtained

together in around 10% yields. (Other IMDA substrates were prepared in the same

way but with appropriate alkynes and dizao-compounds.)

N-(furan-2-ylmethyl)prop-2-yn-1-amine (206): Pale yellow oil, 80% yield. 1H

NMR (500 MHz, CDCl3) δ 7.36 (s, 1H), 6.31 (t, J = 1.4 Hz, 1H), 6.21 (d, J = 3.15

Hz, 1H), 3.88 (s, 2H), 3.43 (d, J = 2.5 Hz, 2H), 2.22 (q, 1H). 13C NMR (125 MHz,

Experimental

86

CDCl3) δ 152.96, 142.06, 110.14, 107.48, 81.64, 71.67, 44.62, 37.16; LRMS

(ESI) m/z 174.0 (M + K+), HRMS (ESI) m/z 136.0757 ([M + H+]), calc. for

[C8H9NO+ H+] 136.0684.

N-(furan-2-ylmethyl)-N-(prop-2-ynyl)pivalamide (207a): colorless oil, 95%

yield. 1H NMR (500 MHz, CDCl3) δ 7.35 (d, J = 1.25 Hz, 1H), 6.31 (q, 1H), 6.26

(d, J = 3.15 Hz, 1H), 4.72(s, 2H), 4.14 (d, J = 2.5 Hz, 2H), 2.22 (t, J = 2.5 Hz,

1H). 13C NMR (125 MHz, CDCl3) δ 177.10, 150.40, 142.39, 110.33, 108.75,

79.02, 72.00, 43.25, 38.98, 36.37, 28.55; LRMS (ESI) m/z 220.1 (M + H+),

HRMS (ESI) m/z 220.1339 ([M + H+]), calc. for [C13H17NO2+ H+] 220.1259.

tert-Butyl furan-2-ylmethyl(prop-2-ynyl)carbamate (207c): was prepared as

below: To a solution of 206 (8 mmol) in dry DCM (50 mL) under nitrogen

atmosphere was added Et3N (8.8 mmol, 1.1 eq). After the mixture was cooled to 0

oC, Boc anhydride (8 mmol) was added dropwisely. Then the reaction mixture

was warmed to rt and stirred till full conversion indicated by TLC (usually around

1 hour). The product was obtained as colorless oil in 95% yield by flushing silica

gel chromatography purification. Colorless oil, 1H NMR (500 MHz, CDCl3) δ

7.34 (t, J = 2.0 Hz, 1H), 6.30 (q, 1H), 6.22 (br, 1H), 4.50(s, 2H), 4.05 (br, 2H),

2.20 (s, 1H), 1.47 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 154.64, 151.06, 142.15,

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110.20, 108.00, 80.62, 79.18, 71.62, 42.18, 35.34, 28.27; LRMS (ESI) m/z 257.9

(M + Na+), HRMS (ESI) m/z 258.1113 ([M + Na+]), calc. for [C13H17NO3+ Na+]

258.1208.

Benzyl furan-2-ylmethyl(prop-2-ynyl)carbamate (207d): colorless oil, 90%

yield. 1H NMR (500 MHz, CDCl3) δ 7.38-7.31 (m, 6H), 6.32-6.2 (m, 2H), 5.20 (s,

2H), 4.60(s, 2H), 4.14-4.08 (m, 2H), 2.24 (s, 1H). 13C NMR (125 MHz, CDCl3) δ

155.42, 150.42, 142.42, 136.36, 128.46, 128.05, 127.87, 110.30, 108.85, 108.47,

78.71, 72.14, 67.70, 42.49, 42.20, 35.80. LRMS (ESI) m/z 292.0 (M + Na+),

HRMS (ESI) m/z 292.0947 ([M + Na+]), calc. for [C16H15NO3+ Na+] 292.1052.

N-(furan-2-ylmethyl)-4-methyl-N-(prop-2-ynyl) benzenesulfonamide (207e):

yellow solid, 85%yield. 1H NMR (500 MHz, CDCl3) δ 7.74-7.72 (d, J =8.8, 2H),

7.33 (s, 1H), 7.28 (d, J =8.2, 2H), 6.30-6.28 (m, 2H), 4.43 (s, 2H), 4.01 (d, J =1.9,

2H), 2.42 (s, 3H), 2.07(d, J = 2.5, 1H). 13C NMR (125 MHz, CDCl3) δ 148.57,

143.58, 142.91, 135.93, 129.44, 127.68, 110.35, 109.94, 76.39, 73.90, 42.65,

36.08, 21.47. LRMS (ESI) m/z 312.0 (M + Na+), HRMS (ESI) m/z 312.0673 ([M

+ Na+]), calc. for [C15H15NSO3+ Na+] 312.0773.

4-bromo-N-(furan-2-ylmethyl)-N-(prop-2-ynyl)benzamide (207f): colorless

Experimental

88

oil, 90% yield. 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J =8.2, 2H), 7.43 (d, J =8.2,

2H), 7.37 (s, 1H), 6.31 (br, 2H), 4.76-4.54 (brm, 2H), 4.24-3.95 (brm, 2H), 2.31(s,

1H). 13C NMR (125 MHz, CDCl3) δ 170.05, 149.26, 142.64, 133.95, 131.59,

128.79, 124.36, 110.31, 109.27, 78.13, 72.65, 44.79, 40.61, 38.35, 34.43, 33.59,

33.33. LRMS(ESI) m/z 339.9 (M + Na+), HRMS (ESI) m/z 339.9951，341.9932

([M + Na+]), calc. for [C15H12NO2Br+ Na+] 340.00057.

N-(cyclopenta-1,3-dienylmethyl)-2-(1H-indol-3-yl)-N-(prop-2-ynyl)acetamide

(207g) was prepared as below: 206 (1 mmol) was dissolved in 5 ml dry THF

under N2, then DCC (1.1 mmol) and DMAP (0.1 mmol) were added. The mixture

was stirred at rt for 30 mins. And then 2-(1H-indol-3-yl)acetic acid (1.1 mmol)

was added and the mixture was left stirring overnight. The mixture was filtered

through clite and then was concentrated and purified via silica gel

chromatography. The product was obtained as a yellow solid in 70% yield.

1H NMR (500 MHz, CDCl3) δ 8.34 (s, 1H), 7.62-7.60 (m, 1H), 7.40-7.32 (m, 2H),

7.21-7.18 (m, 1H), 7.14-7.11 (m, 1H), 7.08-7.03 (m, 1H), 6.34-6.31 (m, 2H), 4.73

(s, 1H), 4.61 (s, 1H), 4.28 (s, 1H), 4.04 (s, 1H), 4.01 (s, 1H), 3.95 (s, 1H), 2.24 (d,

1H) . 13C NMR (125 MHz, CDCl3) δ 171.29, 150.44, 149.72, 142.74, 142.32,

136.18, 127.13, 127.09, 122.7, 122.64, 122.16, 119.60, 118.59, 111.25, 110.30,

108.92, 108.73, 108.54, 78.82, 78.30, 72.62, 71.94, 43.70, 41.40, 37.03, 34.12,

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89

31.33, 31.08. LRMS(ESI) m/z 293.0 (M + H+) , HRMS (ESI) m/z 315.1113 ([M +

Na+]), calc. for [C18H16N2O2+ Na+] 315.1212.

Ethyl 5-( N - ( furan -2 - ylmethyl) pivalamido) pent -3 –ynoate (208a):

colorless oil, 75% yield. 1H NMR (500 MHz, CDCl3) δ 7.34 (s, 1H), 6.31 – 6.30

(m, 1H), 6.27 (d, J = 3.15, 1H), 4.72 (s, 2H), 4.21-4.16 (m, 4H), 3.27-3.26 (m,

2H), 1.32 (s, 9H), 1.27 (t, J =6.9, 3H). 13C NMR (125 MHz, CDCl3) δ 177.09,

168.15, 150.63, 142.30, 110.31, 108.69, 78.53, 75.97, 61.62, 43.07, 39.00, 36.80,

28.58, 26.08, 14.12. LRMS (ESI) m/z 328.15 (M + Na+), HRMS (ESI) m/z

328.1528 ([M + Na+]), calc. for [C17H23O4N + Na+] 328.1628.

tert-butyl 5-(N-(furan-2-ylmethyl)pivalamido)pent-3-ynoate (208b): colorless

oil, 70% yield. 1H NMR (500 MHz, CDCl3) δ 7.32 (s, 1H), 6.29 (d, J =1.8, 1H),

6.25 (d, J = 1.5, 1H), 4.70 (s, 2H), 4.16 (s, 2H), 3.16 (t, J =1.9, 2H), 1.44 (s, 9H),

1.31 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 177.00, 167.19, 150.69, 142.23,

110.28, 108.61, 81.87, 78.20, 76.61, 42.98, 38.96, 36.83, 28.57, 27.94, 27.08.

LRMS (ESI) m/z 356.15 (M + Na+), HRMS (ESI) m/z 356.1835 ([M + Na+]),

calc. for [C19H27O4N + Na+] 356.1940.

Experimental

90

tert-butyl 5-( tert - butoxycarbonyl (furan-2-ylmethyl) amino) pent- 3 –

ynoate (208c): colorless oil, 80% yield. 1H NMR (500 MHz, CDCl3) δ 7.31 (s,

1H), 6.27 (t, J =4.1, 1H), 6.21 (br, 1H), 4.49 (s, 2H), 4.05 (br, 2H), 3.16 (t, J =3.7,

2H), 1.44 (d, 18H). 13C NMR (125 MHz, CDCl3) δ 167.25, 154.64, 151.25,

142.01, 110.12, 107.83, 91.01, 81.72, 80.35, 78.35, 41.98, 35.59, 28.24, 27.97,

27.84. LRMS (ESI) m/z 372.20 (M + Na+), HRMS (ESI) m/z 372.1787 ([M +

Na+]), calc. for [C19H27O5N + Na+] 372.1889.

tert-Butyl -5-( (benzyloxycarbonyl) (furan -2-ylmethyl) amino ) pent -3-

ynoate (208d): colorless oil, 75% yield. 1H NMR (500 MHz, CDCl3) δ

7.38-7.30 (m, 6H), 6.30-6.21 (m, 2H), 5.18 (s, 2H), 4.61 (s, 2H), 4.15-4.08 (m,

2H), 3.19 (s, 2H), 1.46 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 167.25, 154.64,

151.25, 142.01, 110.12, 107.83, 91.01, 81.72, 80.35, 78.35, 41.98, 35.59, 28.24,

27.97, 27.84. LRMS (ESI) m/z 406.20 (M + Na+), HRMS (ESI) m/z 406.1622

([M + Na+]), calc. for [C22H25O5N + Na+] 406.1733.

tert-butyl 5-(N -(furan -2 -ylmethyl) -4 -methylphenylsulfonamido)pent - 3 -

ynoate (208e) : yellow solid, 65% yield. 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J

=8.2, 2H), 7.34(s, 1H), 7.28 (d, J =8.2, 2H), 6.31 (dd, J =13.2 2H), 4.43 (s, 2H),

4.02 (s, 2H), 2.94 (t, J =1.9, 2H), 2.42 (s, 3H) 1.44 (s, 9H). 13C NMR (125 MHz,

Chapter 4

91

CDCl3) δ 166.79, 148.83, 143.38, 142.90, 136.12, 129.38, 127.88, 110.38, 109.96,

81.93, 78.52, 75.78, 42.78, 36.65, 27.94, 27.02, 21.52. LRMS (ESI) m/z 426.14

(M + Na+), HRMS (ESI) m/z 426.1336 ([M + Na+]), calc. for [C21H25O5NS +

Na+] 426.1453.

tert-butyl 5-(4-bromo-N- ( furan- 2- ylmethyl) benzamido) pent- 3- ynoate

(208f) : colorless oil , 65% yield. 1H NMR (500 MHz, CDCl3) δ 7.57 (d, J =8.2,

2H), 7.48 (d, J =8.2, 2H), 7.40 (s, 1H), 6.35 (br, 2H), 4.83, 4.59 (br, 2H), 4.31,

3.99 (br, 2H), 3.24 (t, J =2.2, 2H), 1.46 (s, 9H). 13C NMR (125 MHz, CDCl3) δ

170.14, 167.01, 142.66, 134.26, 131.66, 128.95, 124.37, 110.37, 109.29, 81.98,

77.57, 28.06, 27.95, 27.20. LRMS (ESI) m/z 454.10, 456.10 (M + Na+), HRMS

(ESI) m/z 454.0634, 456.0618 ([M + Na+]), calc. for [C21H22O4NBr + Na+]

454.0732, 456.0732.

tert-butyl 5- ( N - (furan -2 -ylmethyl) -2 -(1H-indol -3-yl)acetamido)pent-3-

ynoate (208g): white solid, 60% yield. 1H NMR (500 MHz, CDCl3) δ 8.52 (s,

1H), 7.63-7.59 (m, 1H), 7.39-7.7.30 (m, 2H),7.18-7.16(m, 1H), 7.11-7.09(m, 1H),

7.06-7.00(m, 1H), 6.32-6.23 (m, 2H), 4.72 (s, 1H), 4.63 (s, 1H), 4.30 (s, 1H), 4.05

Experimental

92

(s, 1H), 3.99 (s, 1H), 3.94 (s, 1H), 3.18(t, J =1.9), 1.47(d, J =13.8, 9H). 13C NMR

(125 MHz, CDCl3) δ 171.36, 171.32, 167.35, 167.13, 150.58, 149.94, 142.60,

142.20, 136.18, 127.15, 127.10, 122.94, 122.85, 122.01, 121.94, 119.46, 119.40,

118.60, 118.53, 118.49, 111.25, 111.19, 110.32, 110.29, 108.71, 108.57, 108.40,

82.05, 81.86, 78.07, 77.67, 77.25, 77.00, 76.75, 76.39, 43.53, 41.35, 37.43, 34.44,

31.36, 31.06, 27.90, 27.18, 27.09. LRMS (ESI) m/z 429.15 (M + Na+), HRMS

(ESI) m/z 429.1792 ([M + Na+]), calc. for [C24H26O4N2 + Na+] 429.1893.

3-ethylpentan- 3 -yl 5-(tert-butoxycarbonyl(furan-2-ylmethyl)amino) pent-

3-ynoate (208h): clorless oil, 70% yield. 1H NMR (500 MHz, CDCl3) δ 7.33 (s,

1H), 6.30-6.28 (m, 1H), 6.21 (br, 1H), 4.50 (s, 2H), 4.09 (br, 2H), 3.20 (t, J

=2.2,1H), 1.82 (q, J =15.2, 7.5, 6H), 1.49 (s, 9H), 0.82 (t, J =7.5, 9H). 13C NMR

(125 MHz, CDCl3) δ 166.96, 154.68, 151.32, 142.04, 110.16, 108.31, 107.79,

89.88, 80.41, 78.33, 42.10, 41.83, 41.71, 35.84, 35.64, 35.53, 28.29, 27.05, 26.66,

7.59. LRMS (ESI) m/z 414.0 (M + Na+), HRMS (ESI) m/z 414.2265 ([M + Na+]),

calc. for [C22H33O5N + Na+] 414.2359.

3-ethylpentan-3-yl 5-(N-(furan-2-ylmethyl)pivalamido)pent-3-ynoate (208i) :

colorless oil, 70% yield. 1H NMR (500 MHz, CDCl3) δ 7.31 (d, J =1.9, 1H),

Chapter 4

93

6.28-6.27 (m, 1H), 6.23 (d, J =3.1, 1H), 4.68 (s, 2H), 4.15 (s, 2H), 3.18 (t, J =1.2,

2H), 1.8 (q, J =15.1, 7.5, 6H), 1.29 (s, 9H), 0.83 (t, J =7.5, 9H). 13C NMR (125

MHz, CDCl3) δ 176.90, 166.71, 150.60, 142.14, 110.18, 108.47, 89.88, 77.99,

42.87, 38.84, 36.72, 28.46, 27.23, 26.98, 26.62, 7.52. LRMS (ESI) m/z 398.1 (M

+ Na+), HRMS (ESI) m/z 398.2296 ([M + Na+]), calc. for [C22H33O4N + Na+]

398.2410.

4.3.2 Representative Procedure for Bicyclic guanidine catalyzed IMDA

reactions and Characterizations of IMDA products

Substrate 208 (2 mmol) was dissolved in 100ml distilled hexane. Then bicyclic

guanidine catalyst was added and the mixture was stirred at rt for appropriate days

when TLC showed the starting material was almost completely consumed. The

solvent was removed via rotary evaporation; further purification was completed

by flushing silica gel chromatography. The products were obtained in 72-88%

yields. The two diisomers can be separated by flushing silica gel chromatography

for most of the substrates. For 208e, 208h, 208i, the IMDA product diisomers

cannot be separated by silica gel chromatography, and the products were

characterized by checking the crude 1H NMR. The IMDA products of 208h were

characterized after reductive ring opening.

Experimental

94

208aa: colorless oil, 66%yield. 1H NMR (500 MHz, CDCl3) δ 6.39 (s, 2H), 5.74

(t, J =1.8, 1H), 5.20 (d, J =4.4, 1H), 5.08 (d, J =12.6, 1H), 4.58 (d, J =17.6, 1H),

4.12-4.06 (m, 2H), 3.73 (d, J =18.3, 1H), 3.69-3.67 (m, 1H), 3.03 (d, J =12.6, 1H),

1.3(s, 9H), 1.22 (t, J =6.9, 9H). 13C NMR (125 MHz, CDCl3) δ 177.28, 169.78,

135.73, 135.00, 134.90, 116.19, 84.27, 78.68, 60.83, 48.49, 45.47, 44.44, 38.95,

28.28, 14.07. LRMS (ESI) m/z 305.9 (M + H+), HRMS (ESI) m/z 328.1528 ([M +

Na+]), calc. for [C17H23NO4 + Na+] 328.1627. [α]29D = +129.1 (c 4.5, CHCl3);

HPLC analysis: Chiralpak Ce2 (Hex/IPA = 70/30, 0.5 mL/min, 210 nm, 23°C),

23.3, 47.3(major) min, 59.5% ee.

208ab: colorless oil, 22%yield. 1H NMR (500 MHz, CDCl3) δ 6.42-6.39 (m, 2H),

5.83-5.82 (m, 1H), 5.30 (d, J =1.9, 1H), 5.13 (d, J =12.6, 1H), 4.64-4.59 (m, 1H),

4.26-4.18 (m, 2H), 3.73 (d, J =18.3, 1H), 3.07 (d, J =12,1H), 2.99 (s, 1H), 1.31(s,

9H), 1.29 (t, J =7.6, 3H). 13C NMR (125 MHz, CDCl3) δ 177.27, 170.93, 136.67,

135.31, 134.68, 116.79, 83.39, 80.22, 61.19, 47.71, 45.69, 44.69, 38.97, 28.31,

14.21. LRMS (ESI) m/z 305.9 (M + H+), HRMS (ESI) m/z 328.1526 ([M + Na+]),

calc. for [C17H23O4N + Na+] 328.1627. [α]29D = -156.7 (c 1.5, CHCl3); HPLC

analysis: Chiralpak Ce2 (Hex/IPA = 70/30, 0.5 mL/min, 210 nm, 23°C), 37.4,

62.8 (major) min, 60% ee.

Chapter 4

95

208ba: colorless oil, 60%yield. 1H NMR (500 MHz, CDCl3) δ 6.39 (s, 2H), 5.70

(s, 1H), 5.15 (d, J =4.4, 1H), 5.07 (d, J =12.6, 1H), 4.59 (d, J =17.6, 1H), 3.72 (d,

J =18.3 1H), 3.61 (d, J =1.9, 1H), 3.04 (d, J =12.6,1H), 1.40 (s, 9H), 1.31(s, 9H).

13C NMR (125 MHz, CDCl3) δ 177.34, 169.00, 153.88, 135.70, 134.99, 115.99,

84.37, 81.30, 78.86, 49.55, 45.53, 44.64, 39.01, 28.35, 27.99. LRMS (ESI) m/z

334.1 (M + H+), HRMS (ESI) m/z 356.1826 ([M + Na+]), calc. for [C19H27O4N +

Na+] 356.1940. [α]29D = +146.1 (c 1.0, CHCl3); HPLC analysis: Chiralpak

IA+Ce1 (Hex/IPA = 80/20, 1.0 mL/min, 210 nm, 23°C), 10.8 (major), 12.0 min,

83.5% ee.

208bb: colorless oil, 15%yield. 1H NMR (500 MHz, CDCl3) δ 6.40-6.37 (m, 2H),

5.80-5.78 (m, 1H), 5.24 (d, J =1.6, 1H), 5.12 (d, J =12.5, 1H), 4.61 (d, J =18, 1H),

3.73 (d, J =17.8, 1H), 3.08 (d, J =12.6, 1H), 2.92-2.91 (m, 1H), 1.48 (s, 9H),

1.31(s, 9H). 13C NMR (125 MHz, CDCl3) δ 177.19, 170.00, 136.47, 135.36,

135.04, 116.21, 83.22, 81.34, 80.18, 48.37, 45.62, 44.66, 38.88, 29.59, 28.23,

28.06. LRMS (ESI) m/z 334.1 (M + H+), HRMS (ESI) m/z 356.1819 ([M + Na+]),

calc. for [C19H27O4N + Na+] 356.1940. [α]29D = -244.7 (c 0.3, CHCl3); HPLC

analysis: Chiralpak IA+Ce1 (Hex/IPA = 80/20, 1.0 mL/min, 210 nm, 23°C), 12.8,

20.3 min(major), 83% ee.

Experimental

96

208ca: colorless oil (white solid after standing at rt for a while), 70% yield. 1H

NMR (500 MHz, CDCl3) δ 6.38 (br, 2H), 5.67 (br, 1H), 5.11 (d, J =4.4, 1H),

4.77-4.63 (m, 1H), 4.48-4.31 (m, 1H), 3.57-3.52 (m, 2H), 3.02-2.93 (m, 1H),

1.45(s, 9H), 1.38 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 169.14, 154.39, 136.41,

135.75, 135.07, 134.59, 116.69, 116.36, 84.02, 81.26, 80.26, 78.75, 49.40, 43.99,

43.13, 42.66, 29.62, 28.36, 27.96. LRMS (ESI) m/z 372.1 (M + Na+), HRMS

(ESI) m/z 372.1770 ([M + Na+]), calc. for [C19H27O5N + Na+] 372.1188. [α]29D =

+99.2 (c 1.0, CHCl3); HPLC analysis: Chiralpak IA (Hex/IPA = 90/10, 0.5

mL/min, 210 nm, 23°C), 6.3 (major), 6.9 min, 79.3% ee.

208cb: colorless oil (white solid after standing at rt for a while), 21% yield. 1H

NMR (500 MHz, CDCl3) δ 6.39 (br, 2H), 5.79 (br, 1H), 5.24 (s, 1H), 4.84-4.70

(m, 1H), 4.53-4.38 (m, 1H), 3.62-3.52 (m, 1H), 3.13-3.04 (m, 1H), 2.92-2.90 (m,

1H) 1.49(s, 9H), 1.48 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 170.21, 154.55,

136.71, 135.30, 134.28, 117.15, 116.59, 82.94, 81.34, 80.32, 80.21, 78.78, 49.43,

48.31, 44.30, 43.24, 29.65, 28.39, 28.12, 27.99. LRMS (ESI) m/z 372.1 (M +

Na+), HRMS (ESI) m/z 372.1770 ([M + Na+]), calc. for [C19H27O5N + Na+]

372.1889. [α]29D = -167.5 (c 1.0, CHCl3); HPLC analysis: Chiralpak IA (Hex/IPA

= 90/10, 0.5 mL/min, 210 nm, 23°C), 10.2, 15.0(major) min, 77% ee.

Chapter 4

97

208da: colorless oil, 71% yield. 1H NMR (500 MHz, CDCl3) δ 7.37-7.31 (m, 5H),

6.44-6.33 (m, 2H), 5.70 (d, J =23.3, 1H), 5.20-5.16 (m, 3H), 4.90-4.74 (m, 1H),

4.56-4.44 (m, 1H), 3.70-3.61 (m, 2H), 3.16-3.05 (m, 1H), 1.41(s, 9H). 13C NMR

(125 MHz, CDCl3) δ 169.09, 155.72, 155.19, 136.42, 135.27, 134.95, 134.87,

134.70, 128.56, 128.17, 128.01, 116.31, 116.88, 83.92, 83.82, 81.37, 67.54, 49.52,

43.83, 43.67, 43.52, 36.66, 31.44, 29.68, 28.01, 24.70. LRMS (ESI) m/z 406.1 (M

+ Na+), HRMS (ESI) m/z 406.1162 ([M + Na+]), calc. for [C22H25O5N + Na+]

406.1733. [α] 29D = +109.7 (c 1.2, CHCl3); HPLC analysis: Chiralpak IA

(Hex/IPA = 90/10, 0.5 mL/min, 210 nm, 23°C), 11.4 (major), 13.0 min, 77% ee.

208db:colorless oil, 18% yield. 1H NMR (500 MHz, CDCl3) δ 7.37-7.32 (m, 5H),

6.42-6.29 (m, 2H), 5.80-5.75 (m, 1H), 5.24-5.16 (m, 3H), 4.92-4.78 (m, 1H),

4.57-4.44 (m, 1H), 3.71-3.61 (m, 1H), 3.22-3.12 (m, 1H), 2.91(s, 1H), 1.48(s,

9H). 13C NMR (125 MHz, CDCl3) δ 170.04, 155.12, 153.83, 136.82, 136.45,

136.36, 135.43, 134.66, 134.35, 128.17, 128.50, 128.12, 127.94, 116.63, 116.07,

82.68, 81.35, 80.25, 67.49, 48.45, 48.31, 44.03, 43.83, 43.71, 31.57, 29.62, 28.08,

27.89. LRMS (ESI) m/z 406.1 (M + Na+), HRMS (ESI) m/z 406.1614 ([M +

Na+]), calc. for [C22H25O5N + Na+] 406.1733. [α]29D = -163.7 (c 0.3, CHCl3);

Experimental

98

HPLC analysis: Chiralpak IA (Hex/IPA = 90/10, 0.5 mL/min, 210 nm, 23°C),

27.8 (major), 30.4 min, 77% ee.

208fa: colorless oil, 60% yield. 1H NMR (500 MHz, CDCl3) δ 7.59 (d, J =8.2,

2H), 7.35 (d, J = 8.2, 2H), 6.56-6.33 (m, 2H), 5.84-4.98 (m, 3H), 4.34-3.96 (m,

2H), 3.67-3.66 (m, 1H), 3.41-3.14 (m, 1H), 1.44(s, 9H). 13C NMR (125 MHz,

CDCl3) δ 170.17, 168.88, 136.18, 135.94, 135.68, 135.26, 135.04, 134.49, 131.83,

128.79, 124.36, 115.65, 83.99, 81.51, 78.86, 67.49, 49.53, 47.71, 42.32, 27.99.

LRMS (ESI) m/z 454.1, 456.1 (M + Na+), HRMS (ESI) m/z 454.0631, 456.0613

([M + Na+]), calc. for [C21H22O4NBr + Na+] 454.0732. [α]29D = +46.65 (c 2.0,

CHCl3); HPLC analysis: Chiralpak IA+IA (Hex/IPA = 80/20, 1.0 mL/min, 230

nm, 23°C), 22.9 (major), 26.6 min, 65% ee.

208fb: colorless oil, 23% yield. 1H NMR (500 MHz, CDCl3) δ 7.57 (d, J =7.5,

2H), 7.32 (d, J = 8.4, 2H), 6.54-6.30 (m, 2H), 5.87-5.69 (m, 1H), 5.34-4.98 (m,

2H), 4.36-3.71 (m, 2H), 3.44-3.18 (m, 1H), 2.93(d, J =1.9, 1H), 1.48(s, 9H). 13C

NMR (125 MHz, CDCl3) δ 169.92, 137.01, 136.03, 135.78, 131.86, 128.72,

124.81, 124.39, 115.92, 83.08, 81.58, 80.39, 48.47, 47.81, 42.60, 29.68, 28.12.

LRMS (ESI) m/z 454.1, 456.1 (M + Na+), HRMS (ESI) m/z 454.0612, 456.0595

Chapter 4

99

([M + Na+]), calc. for [C21H22O4NBr + Na+] 454.0732. [α]29D = -68.7 (c 0.7,

CHCl3); HPLC analysis: Chiralpak IA+IA (Hex/IPA = 80/20, 1.0 mL/min, 230

nm, 23°C), 23.7, 28.9(major) min, 68% ee.

208ga: pale yellow oil, 58% yield. 1H NMR (500 MHz, CDCl3) δ = 8.30 (dd,

J=41.8, 13.1, 1H), 7.65 (dd, J=37.5, 7.9, 1H), 7.35 (d, J=8.0, 1H), 7.20 (t, J=7.5,

1H), 7.13 (t, J=7.4, 1H), 7.04 (s, 1H), 6.41 (dd, J=18.5, 5.6, 1H), 6.04 (dd,

J=265.8, 5.6, 1H), 5.68 (d, J=47.2, 1H), 5.14 (dd, J=22.6, 4.2, 1H), 4.98 (dd,

J=396.4,12.6, 1H), 3.98 (s, 1H), 3.91 (d, J=5.0, 1H), 3.67 (dd, J=138.35, 17.8,

1H), 3.61 (dd, J=16.5, 1.9, 1H), 3.09 (dd, J=12.7, 1H), 1.41 (d, J=9.6, 9H). 13C

NMR (125 MHz, CDCl3) δ = 171.15, 171.12, 169.09, 169.00, 136.30, 136.20,

135.88, 135.30, 134.92, 134.07, 127.11, 127.01, 122.75, 122.53, 122.36, 122.27,

119.84, 119.68, 118.99, 118.65, 116.21, 115.52, 111.31, 108.71, 84.24, 83.93,

81.52, 81.48, 78.95, 78.82, 77.32, 77.07, 76.81, 49.50, 45.88, 45.67, 42.38, 41.54,

32.13, 31.89, 28.03, 28.00. LRMS (ESI) m/z 407.10 (M + H+), HRMS (ESI)

m/z 429.1780 ([M + Na+]), calc. for [C24H26O4N2 + Na+] 429.1893. [α]29D =

+141.2 (c 2.5, CHCl3); HPLC analysis: Chiralpak AD+AD (Hex/IPA = 80/20, 1.0

mL/min, 230 nm, 23°C), 28.4 (major), 32.1 min, 68% ee.

Experimental

100

208gb: pale yellow oil, 14.5% yield. 1H NMR (500 MHz, CDCl3) δ 8.18 (d,

J=28.6, 1H), 7.66 (dd, J =35.6, 7.8, 1H), 7.37 (d, J =8.2, 1H), 7.22-7.21 (m, 1H),

7.19-7.06 (m, 2H), 6.38 (s, 1H), 6.06 (dd, J = 293, 5.5, 1H), 5.73 (d, J = 56.6,

1H), 5.01(dd, J =388, 12.7, 1H), 5.21 (d, J =23.4, 1H), 4.19 (dd, J = 678.4,19.0,

1H), 4.07 (dd, J = 494.2, 17.1, 1H), 3.15 (dd, J = 420, 12.9, 1H), 2.88-2.84 (m,

1H), 1.46 (d, J =3.7, 9H). 13C NMR (125 MHz, CDCl3) δ 170.96, 170.87, 170.03,

169.99, 136.89, 135.68, 135.54, 133.70, 127.03, 122.58, 122.47, 122.39, 122.13,

119.93, 119.76, 119.09, 118.61, 116.55, 115.68, 111.20, 109.01, 83.13, 82.80,

81.51, 81.44, 80.35, 80.26, 77.25, 77.00, 76.75, 49.48, 48.52, 48.26, 46.06, 45.68,

42.36, 41.70, 32.15, 32.01, 28.11, 28.00. LRMS (ESI) m/z 407.0 (M + Na+),

HRMS (ESI) m/z 429.1775 ([M + Na+]), calc. for [C24H26O4N2 + Na+] 429.1893.

[α]29D = -116.2 (c 4.5, CHCl3); HPLC analysis: Chiralpak AD+AD (Hex/IPA =

80/20, 1.0 mL/min, 254 nm, 23°C), 34.7, 46.5 min(major), 70% ee.

4.4 Procedures towards (+)-alpha-yohimbine and characterization of

compounds

Compound 208ga (0.5 mmol) was dissolved in MeOH (3 ml), 10 % Pd/C (50

mg) was added and reaction vassel was evacuated and recharged with H2 using a

balloon. Stirred untill 208ga was completely consumed. Filter through clite to

Chapter 4

101

remove Pd/C, and the product 210 was obtained as pale yellow oil after

chromatography on silco gel.

210: pale yellow oil, 75% yield. 1H NMR (500 MHz, CDCl3) δ 56(brd, J =13.25,

1H), 7.62 (t, J =8.85, 1H), 7.33 (d, J =8.15, 1H), 7.18 (t, J =7.6, 1H), 7.12(t, J

=7.6, 2H), 7.02 (d, J =11.35, 1H), 4.92 (d, J =14.5, 0.5H), 4.72-4.66 (m, 1H),

4.59(d, J =12.6, 0.5H), 4.20(d, J =15.15, 0.5H), 4.01-3.81(m, 2H), 3.34(d, J

=15.15, 0.5H ), 3.03(d, J =14.5, 0.5H), 2.94 (t, J =12.6, 0.5H), 2.67 (s, 0.5H),

2.57-2.54(m, 1H), 2.27-2.22 (m, 1H), 1.94(s, 0.5H), 1.80-1.57 (m, 4.5H), 1.48 (d,

J =6.3, 9H). 13C NMR (125 MHz, CDCl3) δ 171.17, 170.72, 136.28, 136.23,

127.33, 127.08, 122.83, 122.72, 121.95, 119.39, 118.76, 118.53, 111.30, 111.26,

109.15, 108.99, 83.82, 83.76, 81.06, 78.72, 78.43, 57.26, 57.17, 49.21, 44.60,

44.57, 42.76, 42.21, 41.24, 33.18, 33.00, 31.39, 31.14, 31.06, 30.62, 28.11, 27.07,

26.97. LRMS (ESI) m/z 433.1 (M + Na+), HRMS (ESI) m/z 433.2100, ([M +

Na+]), calc. for [C24H30O4N2 + Na+] 433.2206.

Experimental

102

Compound 208ca (1 mmol) was dissolved in MeOH (4 ml), 10 % Pd/C (100 mg)

was added and reaction vassel was evacuated and recharged with H2 using a

balloon. Stirred untill 208ca was completely consumed. Filter through clite to

remove Pd/C, and the products 211 and 212 were obtained as colorless oil in 20%

and 70% yields respectively after chromatography on silco gel. The two products

become solid after standing at rt for a while.

211: Colorless oil, 20% yield. 1H NMR (500 MHz, CDCl3) δ 4.76 (d, J =5.0, 1H),

4.29-3.96 (m, 2H), 3.07 (brs, 1H), 2.7 (d, J =8.8, 1H), 2.55 (brs, 1H), 2.17-2.12

(m, 1H), 1.76-1.73 (m, 1H), 1.55(brs, 1H), 1.47-1.22(m, 22H). 13C NMR (125

MHz, CDCl3) δ 170.78, 154.98, 81.62, 80.96, 79.67, 78.49, 53.27, 45.03, 33.06,

30.68, 28.44, 28.20, 25.28. LRMS (ESI) m/z 376.0 (M + Na+), HRMS (ESI) m/z


212: Colorless oil, 70% yield. 1H NMR (500 MHz, CDCl3) δ 4.64 (t, J =5.1, 1H),

Chapter 4

103

4.26 (brs, 1H), 4.03 (brs, 1H), 3.10-3.03 (m, 1H), 2.61 (brs, 2H), 2.19-2.15 (m,

1H), 1.76-1.71 (m, 3H), 1.64-1.56(m, 2H), 1.55-1.24(m, 19H). 13C NMR (125

MHz, CDCl3) δ 171.10, 154.80, 83.31, 80.64, 79.33, 78.28, 56.90, 42.26, 32.95,

30.54, 28.24, 27.90, 26.73. LRMS (ESI) m/z 376.0 (M + Na+), HRMS (ESI) m/z


The compound 212 (0.5 mmol) was dissolved in 3 ml DCM and cooled to 0 oC,

then 0.75 ml TFA was added and the reaction mixture was stirred at 0 oC for 10

mins . The reaction was monitored with TLC. After the reaction was finished, the

reaction mixture was quenched with saturated NaHCO3 and was extracted with

DCM for four times. The combined organic layers were dried over Na2SO4, and

then was concentrated and dried under vacumn. The crude product was used

directly in the next step.

213 (crude product from above), HOBz(5.0 mmol) and NaCNBH3 (3.5 mmol)

were mixed in 5 ml toluene in a 50 ml rbf under N2, the mixture was stirred for 30

minutes at rt. Then 2-(1H-indol-3-yl)acetaldehyde (freshly prepared from methyl

2-(1H-indol-3-yl)acetate (2.5 mmol) via DIBAL-H reduction) in another 5 ml

toluene was added and the reaction mixture was stirred at rt overnight. Then the

reaction mixture was quenched with saturated NaHCO3 and was extracted with

DCM for four times. The combined organic layers were dried over Na2SO4, and

were concentrated and purified via silica gel chromatography to afford 214 as

colorless oil in 60% yield.

Experimental

104

214: colorless oil, 60% yield. 1H NMR (500 MHz, CDCl3) δ 8.17 (s, 1H), 7.60 (d,

J =7.6, 1H), 7.33 (d, J =8.2, 1H), 7.17 (t, J =7.0, 1H), 7.10 (t, J =7.0, 1H), 7.00 (s,

1H), 4.71 (t, J =5.0, 1H), 3.35 (d, J =13.2, 1H), 3.03-2.96 (m, 3H), 2.77-2.66 (m,

3H), 2.37 (d, J =13.2, 1H), 2.13-2.10 (m, 1H), 2.00 (t, J =11.4, 1H), 1.86-1.82(m,

1H), 1.78-1.72(m, 1H), 1.65-1.59(m, 1H), 1.57-1.49(m, 3H), 1.47(s, 9H). 13C

NMR (125 MHz, CDCl3) δ 171.65, 136.21, 127.47, 121.77, 121.51, 119.06,

118.80, 114.36, 111.05, 84.39, 80.71, 78.60, 59.37, 57.52, 56.76, 52.56, 42.00,

33.72, 31.69, 28.07, 26.80, 22.83. LRMS (ESI) m/z 397.2 (M + H+), HRMS (ESI)

m/z 419.2287 ([M + Na+]), calc. for [C24H32O3N2+ Na+] 419.2413.

The compound 214 (0.25 mmol) was dissolved in 4 ml MeOH in a sealed tube,

then CSA (0.5 mmol) was added and the mixture was heated to 80 oC. After 24

hours, the mixture was cooled to rt and MeOH was evaporated away. Then the

mixture was dissolved in DCM and was quenched with 1 M NaOH. Extraction

was done with DCM for four times. The combined organic layers were dried over

Na2SO4, then was concentrated and purified via flushing silica gel

chromatography. Compound 215 was obtained as a white solid in 80% yield.

215: white solid, 80% yield. 1H NMR (500 MHz, CDCl3) δ 8.14 (s, 1H), 7.60 (d, J

=8.2, 1H), 7.34 (d, J =7.55, 1H), 7.19 (dt, J =7.0, 1H), 7.10 (t, J =8.2, 1H), 7.00

(d, J =2.5, 1H), 4.76 (t, J =5.0, 1H), 3.71 (s, 3H), 3.37 (dd, J =10.0, 1.3, 1H),

3.03-2.96 (m, 3H), 2.79-2.66 (m, 3H), 2.38 (d, J =13.25, 1H), 2.20-2.15 (m, 1H),

2.05-1.98(m, 1H), 1.87-1.83(m, 1H), 1.77-1.74(m, 1H), 1.58-1.50(m, 4H). 13C

Chapter 4

105

NMR (125 MHz, CDCl3) δ 172.89, 136.20, 127.47, 121.79, 121.50, 119.07,

118.78, 114.36, 111.04, 84.37, 78.44, 59.32, 56.69, 56.50, 52.56, 52.50, 51.76,

42.34, 33.70, 31.76, 27.07, 22.85. LRMS (ESI) m/z 355.1 (M + H+), HRMS (ESI)

m/z 355.2024 ([M + H+]), calc. for [C21H26O3N2 + H+] 355.1943.

Compound 215 (0.08 mmol) was dissolved in 1.5 ml EtOH, then an aqueous

solution of Hg(OAc)2 and EDTA-2Na (1:1, 2.4 ml of a 0.1 M solution in water,

0.24 mmol) was added. The resulting solution was heated to 85 oC and refluxed

for 3 hours. Then the mixture was cooled down to 0 oC and 2.5 ml 25% HClO4

was added and stirred at 0 oC for 10 minutes. The mixture was then extracted with

DCM (4x5 ml), the combined organic layers was washed with brine, dried over

Na2SO4 and concentrated via rotary evaporation. The residue was redissolved in

MeOH:H2O (9:1, volume ratio, 2.5 ml). The PH was adjusted to 6 using 5%

NaHCO3 solution. The mixture was cooled to 0 oC, and NaBH4 (0.6mmol, 25mg)

was added. Then the reaction was brought to rt and stirred for 1 hour. The solvents

were removed under reduced pressure, and the residue was partitioned between

cold 10%NH4OH and DCM, the aqueous layer was extracted with DCM for 4

times, and the combined organic layers were dried (Na2SO4) and evaporated under

reduced pressure. The residue was purified by flushing silco gel chromatography

(Hexane:EA 1:1, then DCM: MeOH 20:1) to afford 217 as white foam in 30%

yield.

217: white foam, 30% yield. 1H NMR (500 MHz, CDCl3) δ 7.79 (s, 1H), 7.47 (d,

Experimental

106

J =7.55, 1H), 7.30 (d, J =8.2, 1H), 7.14-7.07 (m, 2H), 4.83 (t, J =5.0, 1H), 3.67 (s,

3H), 3.28 (d, J =10.7, 1H), 3.24-3.20 (m, 2H), 3.11-3.07 (m, 1H), 2.99-2.94 (m,

1H), 2.79(dd, J =26.17, 10.1, 1H), 2.74-2.69 (m, 2H), 2.34-2.19(m, 3H),

2.01-1.96(m, 1H), 1.75-1.70(m, 1H), 1.63-1.52(m, 2H). 13C NMR (125 MHz,

CDCl3) δ 172.89, 136.20, 127.47, 121.79, 121.50, 119.07, 118.78, 114.36, 111.04,

84.37, 78.44, 59.32, 56.69, 56.50, 52.56, 52.50, 51.76, 42.34, 33.70, 31.76, 27.07,

22.85. LRMS (ESI) m/z 353.25 (M + H+), HRMS (ESI) m/z 353.1851 ([M + H+]),

calc. for [C21H24O3N2 + H+] 353.1787.

Compound 217 (0.1 mmol) was dissolved in dry DCM under N2 in a dry rbf,

then 0.5 eq of triflic acid was added. The mixture was stirred at rt for12 hrs untill

compound 217 was completely consumed. Purification by flushing silica gel

chromatography afforded 218 as colorless oil in 50% yield.

218: colorless oil, 50% yield. 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 1H), 7.48 (d,

J =7.55, 1H), 7.31 (d, J =8.2, 1H), 7.15 (t, J = 6.95, 1H), 7.10 (t, J = 6.95, 1H),

5.87 (d, J =9.45, 1H), 5.73-5.70 (m, 1H), 3.86 (s, 3H), 3.82-3.81 (m, 1H), 3.32 (d,

J = 12, 1H), 3.10-3.04 (m, 2H), 2.97-2.95 (m, 1H), 2.89 (d, J = 10.1, 1H),

2.74-2.69(m, 2H), 2.41 (d, J = 10.7, 1H), 2.40-2.21(m, 1H), 1.96 (d, J = 19.55,

1H), 1.84-1.79(m, 1H), 1.47-1.44 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 174.30,

135.99, 134.15, 127.22, 125.16, 121.51, 121.08, 119.49, 118.12, 110.82, 108.42,

Chapter 4

107

69.64, 66.70, 59.13, 52.81, 52.04, 422.61, 41.43, 33.66, 29.10, 21.88. LRMS

(ESI) m/z 353.19 (M + H+), HRMS (ESI) m/z 353.1875 ([M + H+]), calc. for

[C21H24O3N2 + H+] 353.1787.

In glovebox, to a100ml rbf was add 208ca (2 mmol), then 8 mmol of PPh3 and 2

mmol of Ni(COD)2 was added. The mixture was dissolved in 20 ml dry toluene.

After stirring in glovebox for 1 hour at rt, the rbf was sealed with a rubber septum

and taken out of the glovebox. Under protection of N2 balloon, the mixture was

cooded to 0oC. 2.5 mmol DIBAL-H (1 M in toluene) was diluted with 20 ml dry

toluene and was added to the mixture slowly during 1 hour using a syringe pump.

After addition, the reaction was monitored with TLC, if there is still a lot of

starting material (due to the inaccurate concentration) remained. A bit more

DIBAL-H should be added to ensure full conversion. After full conversion, the

reaction mixture was quenched with saturated NH4Cl solution, and was extracted

with DCM (4x50 ml), the combined organic layers were dried over Na2SO4,

concentrated and purified by flushing silica gel chromatography. 221 was

obtained as colorless oil in 50% yield.

Experimental

108

(5S,6S)-di-tert-butyl 6-hydroxy -3,5,6,7- tetrahydroisoquinoline

-2,5(1H)-dicar- boxylate (221): colorless oil, 50% yield. 1H NMR (500 MHz,

CDCl3) δ 5.54(brs, 1H), 5.48 (brs, 1H), 4.19-4.15 (m, 1H), 4.07-3.98 (t, J =16.3,

2H), 3.94(t, J =23.35, 2H), 3.19 (dd, J =8.2, 1.9, 1H), 2.56-2.50(m, 1H), 2.21(dd,

J = 17.65, 6.95, 1H), 2.06 (brs, 1H), 1.49(s, 9H), 1.45(s, 9H). 13C NMR (125

MHz, CDCl3) δ 171.26, 154.60, 129.45, 121.69, 119.90, 81.66, 79.92, 67.80,

54.38, 45.42, 43.70, 32.42, 28.40, 28.15. LRMS (ESI) m/z 374.2 (M + Na+),

HRMS (ESI) m/z 374.1940, ([M + Na+]), calc. for [C19H29O5N + Na+] 374.2046.

[α]29D = +46.2 (c 0.3, CHCl3); HPLC analysis: Chiralpak IC(Hex/IPA = 90/10,

1.0 mL/min, 230 nm, 23°C), 13.1 (major), 17.5 min, 75.6% ee.

In a dry rbf, 221 (0.6 mmol) was dissolved in 12ml dry DCM under N2, cooled

to 0oC, then Et3N (0.9 mmol) and DMAP (0.06 mmol) were added. Finally, Ac2O

(0.9 mmol) was added and the reaction mixture was brought to rt and stirred. The

reaction was monitored with TLC untill completion (usually around 10 hours).

Rotary evaporate to remove solvent and purified by flushing silica gel

chromatography. 222 was obtained as colorless oil in 80% yield.

(5S,6S)-di-tert-butyl 6- acetoxy -3,5,6,7-tetrahydroisoquinoline-2,5(1H)-

dicarboxyl- ate (222): colorless oil, 80% yield. 1H NMR (500 MHz, CDCl3) δ

5.53(br, 1H), 5.45 (br, 1H), 5.27-5.23 (m, 1H), 4.01(brs, 4H), 3.33(dd, J = 8.5,

Chapter 4

109

1.85, 1H), 2.65(dt, J =17.65, 4.4, 1H), 2.18 (dd, J =17.0, 5.1, 1H), 2.00(s, 3H),

1.44 (d, J =3.8, 18H). 13C NMR (125 MHz, CDCl3) δ 170.01, 169.89, 154.65,

129.32, 128.81, 119.13, 81.44, 79.22, 69.95, 51.17, 43.71, 29.47, 28.39, 27.95,

21.04. LRMS (ESI) m/z 416.1 (M + Na+), HRMS (ESI) m/z 416.2055, ([M +

Na+]), calc. for [C21H31O6N + Na+] 416.2151. [α]29D = +20.2 (c 5.0, CHCl3);

HPLC an alysis: Chiralpak IC(Hex/IPA = 90/10, 1.0mL/min, 254 nm, 23°C),

14.4, 21.01(major) min, 79% ee.

222(0.25 mmol, 110 mg) was dissolved in 2.5 ml EtOH in a 10 ml schlenk flask

which was equipped with an adapter attaching with a H2 balloon, and then Pt/C

(50 wt%, 55 mg) was added. The system was evacuated and charged with H2 (4

times). The reaction mixture was heated to 70 oC, and left stirred for 4 days. The

reaction was monitored by checking curde 1H NMR untill the reaction was

finished. Pt/C was filtered off and the filtrate was concentrated and used directly

in the next step without further purification. Crude 1H NMR shows that a mixture

223 of diisomers (8:1) was obtained.

The mixture 223 was dissolved in 3 ml DCM and cooled to 0 oC, then 0.75 ml

Experimental

110

TFA was added and the reaction mixture was stirred at 0 oC for 10 mins . The

reaction was monitored with TLC. After the reaction was finished, the reaction

was quenched with saturated NaHCO3 and extracted with DCM for 4 times. The

combined organic layers were dried over Na2SO4, then was concentrated and

dried under vacumn. The crude product (a mixture of diisomers 8:1 shown by

crude 1H NMR) was used directly in the next step.

226 (crude product form above), HOBz and NaCNBH3 were mixed in 5ml

toluene in a 50ml rbf under N2, the mixture was stirred for 30 minutes at rt. Then

2-(1H-indol-3-yl)acetaldehyde (freshly prepared from methyl 2-(1H-indol-3-yl)

acetate via DIBAL-H reduction) in another 5ml toluene was added and the

reaction mixture was stirred at rt overnight. Then the reaction mixture was

quenched with saturated NaHCO3 and extracted with DCM for 4 times. The


purified via silica gel chromatography. A mixture of 227 and

2-(1H-indol-3-yl)ethanol which is produced from the reduction of the aldehyde

was obtained as evidenced by crude 1H NMR. The mixture can not be separated

and was used directly in the next step.

Chapter 4

111

The mixture of 227 and 2-(1H-indol-3-yl)ethanol, obtained from above, was

dissolved in 4 ml MeOH in a sealed tube, then CSA (0.25 mmol) was added and

the mixture was heated to 80 oC. After 24 hours, the mixture was cooled to rt and

MeOH was evaporated away. Then the mixture was dissolved in DCM and was

quenched with 1 M NaOH. Extraction was done with DCM for four times. The


purified via flushing silica gel chromatography. Compound 228 was obtained as

white foam in 31% yield over four steps.

(4S,5S,6S,8S)-methyl-(2-(1H-indol-3-yl)ethyl)-6-hydroxydecahydroisoquinoli

ne-5-carboxylate 228: white foam, 31% yield over 4 steps. 1H NMR (500 MHz,

CDCl3) δ 7.95(br, 1H), 7.60 (d, J=8.2, 1H), 7.35 (d, J=8.2, 1H), 7.18 (t, J= 7.6,

1H), 7.11(t, J= 6.9, 1H), 7.04(brs, 1H), 4.05(dt, J= 11.1, 3.8, 1H), 3.74 (s, 3H), 3.0

(brd, J=10.7, 1H), 2.93-2.89(m, 4H), 2.68-2.62(m, 1H), 2.59-2.53(m, 1H), 2.48

(dd, J=10.1, 5.5, 1H), 2.20-2.16(m, 2H), 2.10-2.05(m, 2H), 1.93(brt, J= 11.7, 2.0,

1H), 1.77-1.69(m, 2H), 1.54-1.51 (m, 1H), 1.36 (dq, J= 24.9, 11.0, 3.8, 1H),

1.21-1.18 (m, 1H). 13C NMR (125 MHz, CDCl3) δ 174.85, 136.18, 127.57,

121.91, 121.48, 119.16, 118.82, 114.77, 111.04, 66.11, 59.35, 58.85, 54.69, 54.62,

51.73, 37.84, 36.62, 33.10, 24.56, 23.47, 22.84. LRMS (ESI) m/z 357.1 (M + H+),

Experimental

112

HRMS (ESI) m/z 357.2176, ([M + H+]), calc. for [C21H28O3N2 + H+] 357.2100.

[α] 29D = +6.7 (c 0.8, CHCl3); HPLC analysis: Chiralpak IC (Hex/IPA =

90/10(30mins)70/30, 1.0 mL/min, 254 nm, 23°C), 37.8, 40.2 (major) min,

85.3% ee.

Reported data2 : 1H NMR (CDCl3, 360 MHz) δ 8.11 (brs, 1H), 7.59 (d, J =7.5,

1H), 7.33 (d, J =7.5, 1H), 7.17 (t, J =7.5, 1H), 7.10 (t, J =7.5, 1H), 7.01 (brs, 1H),

4.04 (ddd, J =11.0 , 10.5 , 4.0 , 1H) , 3.73 (s , 3H) , 2.97 (brd , J =12.0, 1H),

2.80-2.95 (m, 4H), 2.52-2.70 (m, 2H), 2.48 (dd, J =10.5, 5.0, 1H), 1.98-2.22 (m,

4H), 1.92 (brt, J =12.0Hz, 1H), 1.65-1.80 (m, 2H), 1.51 (m, 1 H), 1.35 (dq, J =3.0,

12.0Hz, 1H), 1.20 (m, 1H); 13C NMR (CDCl3,) δ 174.6, 136.2, 127.5, 121.7,

121.6, 119.0, 118.7, 111.4, 111.0, 66.0, 59.3, 58.7, 54.6, 54.5, 51.6, 37.8, 36.6,

33.2, 24.5, 23.3, 22.7; mass spectrum, m/e 356.2092 (C21H28N2O3, requires

m/e356.2100).

228 (28 mg, 0.08 mmol) was dissolved in 1.5 ml EtOH, then an aqueous solution

of Hg(OAc)2 and EDTA-2Na (1:1, 2.4 ml of a 0.1 M solution in water, 0.24 mmol)

was added. The resulting solution was heated to 85 oC and refluxed for 3 hours.

Then the mixture was cooled down to 0 oC and 2.5 ml 25% HClO4 was added and

stirred at 0 oC for 10 minutes. The mixture was then extracted with DCM (4x5 ml),

Chapter 4

113

the combined organic layers were washed with brine, dried over Na2SO4 and

concentrated via rotary evaporation. The residue was redissolved in MeOH:H2O

(9:1, volume ratio, 2.5 ml). The PH was adjusted to 6 using 5% NaHCO3 solution.

The mixture was cooled to 0 oC, and NaBH4 (0.6 mmol, 25 mg) was added. Then

the reaction was brought to rt and was stirred for 1 hour. The solvent was removed

under reduced pressure, and the residue was partitioned between cold

10%NH4OH and DCM, the aqueous layer were extracted with DCM for four

times, and the combined organic layers were dried (Na2SO4) and evaporated under

reduced pressure. The residue was purified by flushing silica gel chromatography

(Hexane: EA 1:1, then DCM: MeOH 20:1) to afford 1 as white foam in 30%

yield.

(+)-Alpha-Yohimbine 170: white foam, 30% yield. 1H NMR (500 MHz,

CDCl3) δ 7.74(brs, 1H), 7.46 (d, J =7.8, 1H), 7.30 (d, J =8.0, 1H), 7.13 (t, J = 7.7,

1H), 7.08(t, J = 7.6, 1H), 4.00(dt, J = 10.9, 4.3, 1H), 3.84 (s, 3H), 3.15 (brd, J

=11.2, 1H), 2.99-2.92(m, 2H), 2.84(dd, J =11.3, 1.8, 1H), 2.70-2.67(m, 2H),

2.61-2.50(m, 3H), 2.45-2.41(m, 1H), 2.10-2.04(m, 2H), 1.82 (brd, J =12.6, 1H),

1.71 (q, J = 24.5, 11.9,1H), 1.61-1.54(m, 2H), 1.41-1.33(m, 1H). 13C NMR (125

MHz, CDCl3) δ 174.71, 135.99, 134.47, 127.32, 121.44, 119.46, 118.10, 110.77,

108.48, 66.07, 60.55, 60.24, 54.73, 53.30, 51.98, 37.95, 36.56, 33.11, 27.75, 24.60,

21.73. LRMS (ESI) m/z 355.2 (M + H+), HRMS (ESI) m/z 355.2013, ([M + H+]),

calc. for [C21H26O3N2 + H+] 355.1943. [α]29D = +16.0 (c 0.25, EtOH);

Experimental

114

Reported data2 : 1H NMR(CDCl3, 500 MHz) δ 7.77 (brs, 1H), 7.45 (d, J =7.8,

1H), 7.27( brd , J =7.8, l H ) , 7.12 (dt , J =1.1, 7.8, lH ) , 7.07 (dt , J =1.1, 7.8,

1H), 3.99 (dt , J =4.4, 11.0, 1H), 3.83 (s, 3H), 3.13 (dd, J =11.2, 2.1, 1H),

2.90-3.00(m, 2H), 2.83 (dd, J =11.4, 1.9, 1H), 2.77 (brs, 1H), 2.67 (m, 1H), 2.58

(dd, J =11.4, 3.0,1H), 2.56 (dd, J =11.0, 4.5, 1H), 2.52 (m, 1 H), 2.42 (ddt, J =12.5,

3.5, 4.5, 1H), 2.09 (dq, J =13.0, 3.5, 1H), 2.04 ( dq , J =13.0, 3.5, 1H), 1.81 (m,

1H), 1.70 (dt, J =11.2, 12.5, 1H), 1.61(dt, J =12.5, 3.5, 1H), 1.54 (dq, J =13.0, 3.5,

1H), 1.35 (ddt, J =11.0, 3.5, 13.0 Hz, 1H); 13C NMR (CDCl3,) δ 174.6, 136.1,

134.6, 127.4, 121.4, 119.5, 118.1, 110.8, 108.6, 66.1, 60.6, 60.3, 54.9, 53.3,

51.8,38.1, 36.7, 33.3, 27.8, 24.7, 21.8; mass spectrum, m/e 354.1937 (C21H26N2O3

requires m/e 354.1943).

Reported optical rotation3: [α]29D = -26.0(c1.3, EtOH); [α]29

D = -15.0 (c 1.3,

pyridine)

Chapter 4

115

References:

1. Suárez, A.; Fu, G. C. Angew. Chem. Int. Ed. 2004, 43, 3580.

2. Martin, S. F.; Rueger, H.; Williamson, S. A.; Grzejszczak, S. J. Am. Chem. Soc. 1987, 109,

6124.

3. Stoll, von A.; Hofmann, A.; Brunner, R. Helv. Chim. Acta. 1955, 32, 270.

116

Appendix

Copies of NMR Spectra

142a 2.0

000

1.2

742

2.0

695

0.9

746

2.0

694

2.0

976

2.0

414

4.1

135

3.0

502

Inte

gra

l

7.4

314

7.4

071

7.3

808

7.2

853

7.2

600

7.2

366

7.1

753

7.1

509

4.3

420

4.0

206

3.9

963

3.9

729

3.9

495

3.4

849

3.4

655

3.4

450

3.2

570

3.2

356

3.2

142

1.9

276

1.9

062

1.8

857

1.8

662

1.8

390

1.8

175

1.7

961

1.7

766

1.6

296

1.1

737

1.1

494

1.1

260

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

nv13fdw2 1 fdw5233

16

7.7

110

16

2.1

688

14

5.1

045

12

8.8

864

12

8.1

766

12

5.7

962

85

.673

7

76

.403

175

.980

175

.557

1

57

.173

6

50

.950

2

25

.346

7

22

.665

2

19

.037

3

13

.552

3

(ppm)

-20-100102030405060708090100110120130140150160170180190200

nv13fdw1 2 fdw5233

117

142b

2.0

000

1.2

736

2.1

137

0.8

623

2.1

491

2.3

165

2.2

503

2.2

312

9.8

944

Inte

gra

l

7.4

285

7.4

032

7.3

778

7.2

736

7.2

600

7.2

493

7.2

240

7.1

811

7.1

558

4.3

186

3.4

625

3.4

431

3.4

226

3.2

171

3.1

957

3.1

742

1.9

100

1.8

896

1.8

691

1.8

019

1.7

805

1.7

610

1.6

140

1.4

669

1.3

753

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

nv14fdw 3 fdw5236B

16

8.7

549

16

2.2

465

14

6.4

255

12

9.7

707

12

6.7

821

12

6.5

165

89

.148

3

77

.408

076

.987

476

.559

4

51

.890

8

28

.557

827

.945

326

.292

423

.813

020

.278

3

(ppm)

0102030405060708090100110120130140150160170180190200210220

nv14fdw 31 fdw5236B

118

142c

1.01

04

2.41

39

1.01

00

1.00

00

1.02

64

2.13

35

1.02

18

3.19

60

1.09

76

18.4

28

Inte

gral

7.50

937.

4899

7.47

727.

2824

7.26

977.

2600

7.25

037.

0681

7.05

647.

0496

7.03

70

4.01

283.

8249

3.76

933.

7576

3.42

553.

3992

3.38

563.

3671

3.35

153.

3048

3.26

482.

5821

2.56

842.

5441

2.52

562.

5129

2.49

152.

4730

1.95

191.

9363

1.91

981.

9042

1.88

671.

8769

1.84

581.

7620

1.74

161.

7231

1.71

531.

7075

1.69

191.

6763

1.58

471.

3598

1.34

81

(ppm)

0.01.02.03.04.05.06.07.08.09.0

nv15fdw 2 fdw5236A

168.

6295

162.

8368

146.

5140

144.

7652

130.

1323

128.

7966

127.

8078

127.

5717

91.9

155

77.4

006

76.9

800

76.5

520

53.7

651

35.4

721

31.1

774

28.5

652

26.1

226

23.6

432

20.6

104

(ppm)

020406080100120140160180200220

nv15fdw 3 fdw5236A

119

139b

1.0

240

0.9

712

0.9

639

1.1

206

0.9

052

4.1

947

1.0

000

10

.214

Inte

gra

l

7.5

285

7.5

134

7.4

025

7.3

873

7.3

407

7.2

600

7.2

335

7.2

184

7.2

033

7.1

831

7.1

680

7.1

541

2.6

293

2.6

205

2.0

381

1.4

090

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

1H AMX500 fdw06011 1.1 fdw7119

169.

3817

143.

0534

134.

8422

128.

4565

126.

7983

126.

5801

126.

4492

82.9

348

77.4

218

77.0

000

76.5

709

69.7

197

36.3

948

34.6

057

30.7

655

14.7

867

(ppm)

020406080100120140160180200220

13C Standard AC300 ju01fdw 11.1 fdw7119

120

150

2.8

557

1.9

453

2.0

000

3.9

655

18

.910

Inte

gra

l

7.5

282

7.5

130

7.4

714

7.4

235

7.4

084

7.2

861

7.2

546

7.2

407

7.2

256

7.2

042

7.1

890

3.1

761

2.6

933

2.6

832

2.6

567

2.6

441

1.6

494

1.4

376

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

1H AMX500 fdw06011 3.1 fdw4234

16

9.9

213

16

7.8

444

14

3.3

807

13

5.0

803

12

8.7

112

12

6.7

800

12

6.5

614

12

6.4

594

82

.144

981

.824

2

77

.255

177

.000

076

.744

973

.961

2

36

.839

334

.653

1

30

.725

2

27

.883

127

.117

9

15

.341

5

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500 fdw06011 31.1 fdw4234

82

.144

9

81

.824

2

(ppm)

8182838485

12

8.7

112

12

6.7

800

12

6.5

614

12

6.4

594

(ppm)

125.0126.0127.0128.0129.0

121

152

1.00

00

1.04

60

1.10

08

0.94

25

0.89

06

1.04

50

1.01

15

1.89

77

2.05

69

9.03

56

8.90

62

Inte

gral

7.60

197.

5746

7.39

347.

3691

7.34

677.

3136

7.30

877.

2882

7.26

00

6.83

056.

8042

4.48

81

3.48

303.

4606

3.42

463.

4031

3.38

273.

2755

3.25

513.

2337

3.19

763.

1791

2.72

332.

7019

2.68

04

2.02

111.

9997

1.97

821.

9578

1.93

541.

5536

1.39

001.

2965

(ppm)

0.01.02.03.04.05.06.07.08.09.0

jun29fdw1 1.1 fdw5159

17

1.2

343

16

6.8

880

15

6.8

670

14

6.6

616

13

5.4

895

13

1.1

801

12

9.7

854

12

8.7

523

12

7.6

455

10

2.3

865

79

.621

777

.415

476

.994

776

.574

1

36

.025

533

.981

531

.583

228

.255

225

.694

7

18

.381

9

(ppm)

0102030405060708090100110120130140150160170180190200210220

oc19fdw 2 fdw5159

122

153

0.9

410

0.9

225

1.0

260

1.0

175

0.9

501

1.9

684

2.0

124

1.9

368

1.9

830

18

.000

Inte

gra

l

8.6

065

7.8

425

7.8

399

7.8

261

7.8

235

7.3

987

7.3

962

7.3

823

7.3

798

7.2

600

7.2

524

7.2

499

7.2

373

7.2

222

7.2

184

7.1

528

7.1

503

7.1

377

7.1

226

7.1

201

4.1

636

3.7

653

3.7

514

3.7

388

3.1

185

3.1

135

3.1

084

2.6

079

2.6

041

2.5

953

2.5

903

2.5

852

2.5

777

2.5

726

1.5

968

1.4

291

1.4

228

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

1H AMX500 fdw06011 2.1 fdw4231

7.8

425

7.8

399

7.8

261

7.8

235

7.3

987

7.3

962

7.3

823

7.3

798

7.2

600

7.2

524

7.2

499

7.2

373

7.2

222

7.2

184

7.1

528

7.1

503

7.1

377

7.1

226

7.1

201

(ppm)

7.17.27.37.47.57.67.77.87.9

167.

6944

167.

2071

141.

3806

134.

7113

126.

8274

126.

4710

125.

9473

125.

6637

81.7

711

79.5

165

77.4

218

77.0

000

76.5

709

73.9

526

70.6

361

69.9

525

34.4

166

30.4

673

27.9

072

27.0

708

20.2

706

(ppm)

020406080100120140160180200220

13C Standard AC300 jun02fdw 21.1 fdw4231

123

154

1.0

098

1.0

074

1.1

039

1.2

342

1.0

168

2.0

000

1.9

428

6.3

889

19

.555

Inte

gra

l

8.6

371

7.9

904

7.9

641

7.3

923

7.3

660

7.2

609

7.2

336

7.2

083

7.1

352

7.1

099

7.0

846

4.2

747

3.1

946

1.5

603

1.4

551

1.4

337

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

jun16fdw 3.1 fdw7140

16

7.5

940

16

6.8

412

14

0.2

769

13

4.9

425

12

6.7

832

12

6.3

315

12

5.1

557

12

4.9

119

83

.699

681

.978

978

.358

177

.426

077

.003

076

.580

071

.769

0

64

.298

0

34

.335

3

30

.348

828

.728

427

.896

727

.065

0

(ppm)

0102030405060708090100110120130140150160170180190200210220


124

155

0.9

546

1.0

449

1.1

543

0.9

618

0.9

136

2.0

000

1.9

029

1.9

084

18

.122

Inte

gra

l

7.5

532

7.5

298

7.3

788

7.3

535

7.2

600

7.2

415

7.2

181

7.1

947

7.1

538

7.1

295

7.1

051

6.5

305

4.2

768

4.2

544

4.2

310

3.1

665

2.6

191

2.5

967

2.5

733

1.4

572

1.4

046

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5


16

7.7

733

15

4.0

788

13

5.1

361

12

6.8

191

12

6.4

176

12

5.6

719

81

.692

179

.118

177

.433

277

.010

276

.587

2

73

.891

3

63

.193

9

34

.550

3

30

.642

8

27

.918

227

.143

9

19

.708

8

(ppm)

0102030405060708090100110120130140150160170180190200210220


125

156

1.00

00

1.10

74

0.78

15

1.09

95

1.27

59

0.85

58

1.75

11

1.77

75

18.1

58

Inte

gral

9.56

06

7.99

277.

9883

7.96

647.

9620

7.88

377.

4388

7.43

397.

4125

7.40

767.

2985

7.29

367.

2733

7.25

967.

2481

7.20

277.

1977

7.17

757.

1517

7.14

68

4.60

704.

5856

3.72

33

1.47

821.

4639

(ppm)

0.01.02.03.04.05.06.07.08.09.010.0

1H normal range AC300 jun08fdw 2.1 fdw5188.1

166.

4433

160.

1595

156.

4720

140.

9224

133.

8966

126.

7982

126.

4855

125.

9836

124.

0345

119.

5761

116.

4705

82.0

838

47.7

988

47.2

024

34.2

565

30.4

673

27.8

053

(ppm)

020406080100120140160180200220

13C Standard AC300 jun08fdw 21.1 fdw5188.1

126

157

0.89

17

1.02

20

1.16

22

2.05

88

4.17

95

2.00

00

3.11

29

19.1

32

Inte

gral

8.07

907.

5410

7.51

757.

3915

7.36

687.

2600

7.22

827.

2069

7.18

177.

1422

4.26

544.

2381

3.18

45

2.27

51

1.44

461.

4018

1.37

88

(ppm)

0.01.02.03.04.05.06.07.08.09.0

1H normal range AC300 jun02 3.1 fdw5207

127

158

1.03

07

1.04

67

1.18

57

0.84

39

1.00

46

1.00

00

0.95

82

2.14

50

0.09

32

25.3

61

Inte

gral

8.68

958.

0365

8.03

218.

0102

8.00

527.

4377

7.43

227.

4108

7.40

597.

2996

7.27

667.

2508

7.24

597.

1802

7.17

477.

1539

7.15

007.

1292

7.12

43

5.70

975.

6895

5.60

515.

5843

4.31

444.

2377

4.18

784.

1615

4.11

16

3.23

34

1.52

361.

5050

1.49

621.

4798

(ppm)

0.01.02.03.04.05.06.07.08.09.0

1H normal range AC300 jun07fdw1 2.1 fdw7122A

210.

8160

167.

3453

164.

3197

140.

0933

134.

9222

126.

8492

126.

3692

125.

1837

124.

8346

100.

1209

92.5

133

81.5

529

77.4

218

77.0

000

76.5

709

75.9

963

63.4

286

34.3

438

30.3

946

28.0

818

27.0

708

26.6

054

(ppm)

020406080100120140160180200220

13C Standard AC300 jun07fdw1 21.1 fdw7122A

128

159

0.9

126

0.9

814

1.1

283

2.1

407

1.8

497

4.0

000

3.1

862

19

.403

Inte

gra

l

8.1

921

7.5

356

7.5

113

7.3

964

7.3

720

7.2

600

7.2

347

7.2

113

7.1

850

7.1

480

7.1

256

5.6

822

5.6

617

5.6

442

4.2

885

4.2

651

4.2

388

4.1

920

4.1

813

4.1

511

4.1

024

2.2

782

2.2

373

2.2

042

1.4

640

1.4

299

1.3

851

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5


21

1.3

414

17

2.0

363

16

7.3

759

16

4.0

204

14

2.8

479

13

4.6

025

12

7.7

984

12

6.6

584

12

6.2

712

93

.082

091

.268

0

81

.739

377

.423

077

.000

076

.577

0

51

.740

6

47

.754

2

44

.198

0

34

.511

5

30

.718

630

.424

728

.022

8

20

.974

8

(ppm)

0102030405060708090100110120130140150160170180190200210220


129

206

15

2.9

655

14

2.0

636

11

0.1

376

10

7.4

850

81

.636

777

.271

577

.023

876

.768

7

71

.667

6

44

.624

1

37

.161

9

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500 fdw6070.2

130

207a

1.00

00

1.03

79

1.02

19

2.15

98

2.16

55

0.96

62

9.83

82

Inte

gral

7.35

337.

3508

7.26

00

6.32

206.

3182

6.31

576.

3119

6.26

656.

2602

4.72

22

4.14

984.

1447

2.22

592.

2209

2.21

71

1.33

08

(ppm)

0.01.02.03.04.05.06.07.08.09.0

1H AMX500 fdw1223 2 fdw6087

177.

1013

150.

4003

142.

3915

110.

3344

108.

7530

79.0

205

77.2

934

77.0

384

76.7

833

72.0

028

43.2

468

38.9

837

36.3

748

28.5

482

(ppm)

020406080100120140160180200220

13C AMX500 fdw1223 21 fdw6087

131

207c

1.0

000

1.0

478

0.9

871

2.1

313

2.1

397

0.9

921

9.4

316

Inte

gra

l

7.3

422

7.3

406

7.3

381

7.2

600

6.3

051

6.3

004

6.2

972

6.2

925

6.2

245

4.4

990

4.0

484

2.1

990

1.4

699

(ppm)

0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6

fdw10227

15

4.6

375

15

1.0

648

14

2.1

476

11

0.1

972

10

8.0

025

80

.623

879

.180

177

.320

877

.000

076

.686

571

.619

0

42

.176

9

35

.344

9

28

.272

4

(ppm)

0102030405060708090100110120130140150160170180190200210220

fdw10227

132

207d

6.39

98

2.09

32

2.24

82

2.35

24

2.33

32

1.00

00

Inte

gral

7.37

547.

3627

7.34

897.

3363

7.33

257.

3262

7.31

997.

3123

7.26

06

6.31

636.

2016

5.20

06

4.60

30

4.14

914.

0823

2.23

91

(ppm)

0.01.02.03.04.05.06.07.08.09.0

1H AMX500 fdw0617 1.1 fdw7149

155.

4194

150.

4203

142.

4187

136.

3556

128.

4634

128.

0480

127.

8731

110.

2960

108.

8531

108.

4669

78.7

052

77.2

551

77.0

000

76.7

449

72.1

393

67.7

013

42.4

943

42.1

955

35.7

972

(ppm)

020406080100120140160180200220

13C AMX500 fdw0617 11.1 fdw7149

133

207e

2.00

00

1.00

17

2.21

05

1.96

62

2.09

55

2.11

17

0.21

86

3.29

29

0.94

81

Inte

gral

7.76

477.

7470

7.36

007.

3197

7.30

33

6.32

126.

3174

6.31

36

4.45

40

4.03

804.

0342

2.44

32

2.10

402.

0990

2.09

52

(ppm)

0.01.02.03.04.05.06.07.08.09.0

1H AMX500 fdw1223 1 fdw6086

148.

6441

143.

6595

142.

9818

136.

0078

129.

5147

127.

7585

110.

4291

110.

0137

77.3

298

77.0

748

76.8

197

73.9

777

42.7

294

36.1

562

21.5

450

(ppm)

020406080100120140160180200220

13C AMX500 fdw1223 11 fdw6086

134

207f

2.16

83

2.19

52

1.05

03

2.12

92

2.36

51

2.37

33

1.00

00

Inte

gral

7.54

377.

5273

7.43

787.

4214

7.37

357.

2600

6.31

57

4.76

38

4.53

56

4.23

68

3.95

31

2.30

91

(ppm)

0.01.02.03.04.05.06.07.08.09.0

1H AMX500 fdw08101 1.1 fdw7202

170.

0452

149.

2616

142.

6446

133.

9508

131.

5897

128.

7913

124.

3606

110.

3106

109.

2758

78.1

295

77.2

551

77.0

000

76.7

449

72.6

494

(ppm)

020406080100120140160180200220

13C AMX500 fdw08101 31.1 fdw7202

135

207g

136

208a

0.8

599

0.9

002

0.8

607

1.8

961

3.8

960

1.8

975

9.0

000

3.2

652

Inte

gra

l

7.3

413

7.2

606

6.3

138

6.3

075

6.3

037

6.2

785

6.2

722

4.7

203

4.2

071

4.1

920

4.1

781

4.1

643

3.2

742

3.2

704

3.2

666

1.7

084

1.3

238

1.2

898

1.2

759

1.2

621

(ppm)

0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6

1H AMX500 fdw1018 1.1 fdw11023A

17

7.0

940

16

8.1

451

15

0.6

262

14

2.3

041

11

0.3

125

10

8.6

874

78

.532

377

.293

477

.045

676

.790

675

.974

4

61

.618

3

43

.071

9

38

.998

336

.797

5

28

.577

3

26

.077

8

14

.119

2

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500 fdw1018 11.1 fdw11023A

137

208b

0.9

131

0.9

809

0.9

379

2.0

858

2.0

378

2.0

000

9.5

675

9.8

028

Inte

gra

l

7.3

211

6.2

885

6.2

848

6.2

570

6.2

520

4.7

051

4.1

642

3.1

733

3.1

695

3.1

645

1.4

448

1.3

061

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

1H AMX500fdw1225 2 fdw6089

17

7.0

065

16

7.1

904

15

0.6

918

14

2.2

385

11

0.2

833

10

8.6

145

81

.869

978

.204

377

.322

677

.067

576

.812

476

.615

7

42

.977

2

38

.961

836

.833

9

28

.570

027

.943

3

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500fdw1225 21 fdw6089

138

208c

1.0

000

2.0

846

2.0

788

1.9

780

1.8

456

20

.551

Inte

gra

l

7.3

106

7.2

600

6.2

792

6.2

695

6.2

627

6.2

101

4.4

940

4.0

450

3.1

723

3.1

645

3.1

577

1.4

425

1.4

387

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

de17fdw 6 fdw6081

16

7.2

548

15

4.6

364

15

1.2

493

14

2.0

106

11

0.1

178

10

7.8

302

91

.005

781

.715

380

.350

178

.350

477

.420

677

.000

076

.572

0

41

.978

4

35

.588

0

28

.238

327

.972

727

.847

227

.131

5

(ppm)

0102030405060708090100110120130140150160170180190200210220

de17fdw 61 fdw6081

139

208d

5.83

72

1.90

55

1.98

16

1.94

37

2.04

04

1.92

11

9.00

00

Inte

gral

7.38

497.

3668

7.35

927.

3477

7.33

077.

3263

7.32

197.

3181

7.29

787.

2600

6.29

806.

2098

5.18

09

4.60

84

4.15

204.

1279

4.10

444.

0808

3.19

00

1.46

48

(ppm)

0.01.02.03.04.05.06.07.08.09.0

1H normal range AC300 jun19fdw 1.1 fdw7154

167.

1780

155.

3884

150.

5737

142.

2825

136.

3914

128.

3765

127.

9256

127.

7874

110.

2013

108.

7030

108.

3321

81.8

147

77.9

237

77.4

291

77.0

000

76.5

782

67.5

087

42.2

423

41.9

659

35.9

512

27.8

781

27.1

436

(ppm)

020406080100120140160180200220

13C Standard AC300 jun19fdw 11.1 fdw7154

140

208e

1.9

045

0.9

822

2.2

502

0.9

223

0.9

473

2.0

338

2.0

309

2.0

000

3.1

223

9.4

207

Inte

gra

l

7.7

485

7.7

321

7.3

362

7.2

896

7.2

732

7.2

606

6.3

238

6.3

175

6.2

961

6.2

923

4.4

302

4.0

155

2.9

413

2.9

375

2.9

337

2.4

181

1.4

423

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

1H AMX500fdw1225 3 fdw6090

16

6.7

896

14

8.8

263

14

3.3

826

14

2.9

016

13

6.1

171

12

9.3

763

12

7.8

823

11

0.3

781

10

9.9

627

81

.928

278

.517

777

.286

177

.031

176

.776

075

.777

6

42

.780

4

36

.651

7

27

.943

327

.017

8

21

.523

2

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500fdw1225 31 fdw6090

141

208f

2.0

104

1.8

929

1.0

000

1.8

661

2.0

528

2.1

796

1.8

405

8.9

493

Inte

gra

l

7.5

811

7.5

647

7.4

878

7.4

714

7.3

996

7.2

861

6.3

506

4.8

315

4.5

856

4.3

146

3.9

880

3.2

505

3.2

467

3.2

417

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

1H AMX500 fdw0811

16

7.0

100

14

2.6

629

13

4.2

533

13

1.6

590

12

8.9

553

12

4.3

716

11

0.3

725

10

9.2

867

81

.980

977

.572

177

.258

777

.003

776

.748

6

28

.061

727

.952

427

.201

8

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500 fdw7203.1

142

208g 1.

1055

1.10

07

2.13

46

1.14

98

1.14

53

1.11

51

2.11

32

1.04

46

1.13

93

1.18

61

1.08

38

1.24

49

1.08

32

1.99

25

9.00

00

Inte

gral

8.51

827.

6269

7.60

807.

5903

7.38

867.

3331

7.32

567.

3180

7.30

037.

2600

7.18

567.

1717

7.15

667.

1163

7.10

627.

0923

7.05

706.

9952

6.32

716.

2855

6.25

526.

2502

6.23

126.

2262

4.71

964.

6276

4.60

24

4.30

494.

2796

4.05

273.

9884

3.94

18

3.18

913.

1853

3.18

15

1.89

31

1.48

961.

4619

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

1H AMX500 fdw0902 1.1 fdw7229

1.10

07

2.13

46

1.14

98

1.14

53

1.11

51

2.11

32

7.62

697.

6080

7.59

037.

3886

7.33

317.

3256

7.31

807.

3003

7.26

007.

1856

7.17

177.

1566

7.11

637.

1062

7.09

237.

0570

6.99

52

6.32

716.

2855

6.25

526.

2502

6.23

126.

2262

(ppm)

6.46.66.87.07.27.47.6

1.04

46

1.13

93

1.18

61

1.08

38

1.24

49

1.08

32

Inte

gral

4.71

96

4.62

764.

6024

4.30

494.

2796

4.05

27

3.98

84

3.94

18

(ppm)

3.94.04.14.24.34.44.54.64.7

171.

3642

171.

3277

167.

3561

167.

1302

150.

5806

149.

9393

142.

6009

142.

2001

136.

1807

127.

1517

127.

1080

122.

9396

122.

8521

122.

0141

121.

9485

119.

4635

119.

4052

118.

6109

118.

5380

118.

4943

111.

2507

111.

1996

110.

3252

110.

2887

108.

7146

108.

5689

108.

4086

82.0

502

81.8

680

78.0

785

77.6

777

77.2

551

77.0

000

76.7

522

76.3

952

43.5

364

41.3

575

37.4

369

34.4

418

31.3

592

31.0

677

27.9

050

27.1

835

27.0

961

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500 fdw0902 11.1 fdw7229

82.0

502

81.8

680

78.0

785

77.6

777

77.2

551

77.0

000

76.7

522

76.3

952

(ppm)

757677787980818283

143

208h

0.8

432

0.8

823

0.8

306

1.7

832

1.8

030

1.8

143

6.2

620

8.8

870

9.0

000

Inte

gra

l

7.3

281

7.2

600

6.2

943

6.2

905

6.2

880

6.2

842

6.2

136

4.4

977

4.0

867

3.2

068

3.2

030

3.1

979

1.8

464

1.8

313

1.8

162

1.8

010

1.4

594

0.8

303

0.8

152

0.8

000

(ppm)

0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6

1H AMX500 boc eoc DA sub

16

6.9

626

15

4.6

761

15

1.3

166

14

2.0

398

11

0.1

575

10

8.3

066

10

7.7

891

89

.884

1

80

.410

578

.326

377

.255

177

.000

076

.744

9

42

.100

841

.831

141

.714

535

.840

935

.644

235

.534

928

.291

227

.045

126

.658

8

7.5

878

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500 fdw0807-1 11.1 boc eoc DA sub

144

208i

0.8

760

0.9

261

0.8

579

1.9

472

1.8

915

1.9

339

6.6

961

9.0

000

9.8

348

Inte

gra

l

7.3

117

7.3

079

7.2

600

6.2

817

6.2

779

6.2

754

6.2

716

6.2

363

6.2

300

4.6

843

4.1

510

3.1

841

3.1

803

3.1

752

1.8

237

1.8

086

1.7

935

1.7

783

1.2

904

0.8

076

0.7

925

0.7

773

(ppm)

0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6

1H AMX500 fdw0128 3 fdw6143.2

17

6.8

953

16

6.7

148

15

0.6

025

14

2.1

418

11

0.1

794

10

8.4

742

89

.884

1

77

.991

177

.247

877

.000

076

.744

976

.570

1

42

.873

2

38

.843

336

.715

4

28

.458

827

.234

526

.979

526

.615

1

7.5

222

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500 fdw0128 31 fdw6143.2

145

208aa

2.00

00

1.00

36

0.99

32

1.01

40

1.07

74

2.09

49

1.04

99

1.01

78

1.00

84

9.55

91

3.39

75

Inte

gral

7.26

00

6.39

395.

7433

5.73

965.

7358

5.73

205.

2050

5.19

625.

0966

5.07

144.

5999

4.56

464.

1208

4.11

324.

1044

4.09

944.

0905

4.08

424.

0767

4.07

044.

0615

4.05

523.

7514

3.71

483.

6858

3.68

213.

6770

3.67

323.

0441

3.01

89

1.30

181.

2362

1.22

111.

2072

(ppm)

0.01.02.03.04.05.06.07.08.09.0

1H AMX500 fdw1026 1.1 fdw11026.1

177.

2815

169.

7828

135.

7289

135.

0002

134.

9055

116.

1915

84.2

728

78.6

834

77.2

551

77.0

000

76.7

449

60.8

366

48.4

918

45.4

748

44.4

473

38.9

453

28.2

766

14.0

663

(ppm)

020406080100120140160180200220

13C AMX500 fdw1026 11.1 fdw11026.1

146

208ab

2.0

000

0.9

161

0.9

011

0.9

728

1.0

542

1.9

478

1.1

545

1.0

215

0.9

103

12

.994

Inte

gra

l

7.2

600

6.4

229

6.4

115

6.3

977

6.3

863

5.8

316

5.8

278

5.8

240

5.8

202

5.8

165

5.3

033

5.2

996

5.1

508

5.1

256

4.6

352

4.6

314

4.5

986

4.5

961

4.5

923

4.2

557

4.2

481

4.2

406

4.2

330

4.2

267

4.2

191

4.2

128

4.2

053

4.1

989

4.1

914

4.1

838

4.1

775

3.7

514

3.7

148

3.0

807

3.0

567

2.9

975

2.9

937

1.3

144

1.3

081

1.2

930

1.2

791

(ppm)

0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6

1H AMX500 fdw1027 1.1 fdw11026.2

17

7.2

742

17

0.9

342

13

6.6

690

13

5.3

063

13

4.6

795

11

6.7

890

83

.391

080

.221

077

.255

177

.000

076

.744

9

61

.193

7

47

.712

145

.686

244

.687

8

38

.967

2

28

.305

8

14

.212

0

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500 fdw1027 11.1 fdw11026.2

147

208ba

2.0

000

1.0

029

0.9

891

1.0

341

1.0

737

1.1

568

1.0

156

1.0

308

9.6

137

9.6

677

Inte

gra

l

7.2

606

6.4

084

5.7

200

5.7

150

5.7

112

5.7

074

5.7

036

5.1

691

5.1

603

5.0

909

5.0

670

4.6

182

4.6

131

4.5

879

4.5

829

3.7

520

3.7

167

3.6

360

3.6

323

3.6

272

3.6

234

3.0

637

3.0

385

1.4

109

1.3

201

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

1H AMX500 fdw02061 4 fdw6229.1

17

7.3

252

16

9.0

031

13

5.6

925

13

4.9

783

11

5.9

874

84

.360

281

.299

578

.851

077

.247

877

.000

076

.744

9

49

.541

2

45

.504

044

.629

5

38

.996

3

28

.334

927

.977

8

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500 fdw02061 41 fdw6219.1

148

208bb

2.13

58

1.00

00

0.92

64

0.97

59

1.21

92

1.12

06

1.03

87

0.93

15

10.2

31

10.9

48

Inte

gral

7.26

057.

2591

6.40

266.

3912

6.38

386.

3824

6.38

116.

3710

6.36

925.

7994

5.79

625.

7925

5.78

845.

7847

5.24

065.

2374

5.13

895.

1138

4.62

964.

5935

3.75

213.

7164

3.09

213.

0669

2.91

852.

9144

2.91

072.

9071

1.47

811.

3118

(ppm)

0.01.02.03.04.05.06.07.08.09.0

fdw0802 5.1 fdw7189.3

177.

1917

170.

0059

136.

4701

135.

3573

135.

0373

116.

2148

83.2

244

81.3

407

80.1

843

77.3

697

76.9

478

76.5

260

48.3

722

45.6

230

44.6

630

38.8

809

29.5

933

28.2

333

28.0

587

(ppm)

020406080100120140160180200220

13C Standard AC300 aug02fdw 11.1 fdw7189.3

149

208ca

2.0

000

1.0

459

1.0

772

0.9

939

0.8

841

1.8

889

0.8

861

24

.217

Inte

gra

l

7.2

607

6.3

933

5.6

822

5.1

237

5.1

162

4.7

896

4.6

421

4.6

194

4.4

946

4.4

606

4.3

484

4.3

156

3.5

806

3.5

768

3.5

302

3.0

561

3.0

347

2.9

414

1.8

408

1.5

180

1.4

588

1.4

323

1.3

932

1.2

646

1.2

218

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

1H AMX500 fdw0330 2.1 fdw6274.1

16

9.0

725

13

6.3

522

13

5.6

818

13

5.0

114

13

4.6

033

13

4.3

555

11

6.6

108

11

6.2

099

83

.934

281

.186

880

.188

578

.709

177

.251

776

.996

676

.741

5

49

.370

2

44

.021

243

.831

843

.081

242

.614

8

28

.317

027

.916

2

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500

150

208cb

2.0

952

1.0

000

0.9

506

1.1

218

1.1

258

1.1

828

1.1

256

0.9

631

19

.353

Inte

gra

l

7.2

600

6.3

939

5.7

900

5.2

365

4.8

381

4.7

045

4.5

343

4.5

028

4.3

755

3.6

178

3.6

127

3.5

560

3.5

207

3.1

311

3.0

454

2.9

155

2.9

117

2.9

067

2.9

029

1.4

972

1.4

846

(ppm)

0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6

1H AMX500 fdw0419 5 fdw7027.2

151

208da

5.0

000

2.0

582

1.0

430

3.2

693

1.0

885

1.1

038

2.1

431

1.0

813

9.7

907

Inte

gra

l

7.3

729

7.3

615

7.3

451

7.3

338

7.3

287

7.3

237

7.3

174

7.3

098

7.2

606

6.4

437

6.4

084

6.3

983

6.3

252

5.7

263

5.6

797

5.1

994

5.1

565

4.8

955

4.8

703

4.7

694

4.7

442

4.5

627

4.5

261

4.4

782

4.4

429

3.7

054

3.6

688

3.6

512

3.6

134

3.1

582

3.1

330

3.0

801

3.0

549

1.4

172

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

1H AMX500 fdw0425 1.1 fdw7156.1

16

9.0

924

13

6.4

231

13

6.1

900

13

5.6

434

13

5.2

645

13

4.8

709

13

4.7

033

12

8.5

601

12

8.1

738

12

8.0

135

11

6.3

100

11

5.8

800

83

.910

381

.374

378

.838

377

.329

877

.074

876

.819

7

67

.564

8

49

.521

2

43

.917

243

.829

843

.669

543

.523

736

.659

031

.441

330

.209

729

.685

028

.008

9

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500 fdw0625 11.1 fdw7156.1

152

208db

4.9

799

1.9

584

0.9

843

3.0

229

1.0

087

1.0

600

1.0

649

1.0

000

0.9

279

9.4

553

Inte

gra

l

7.3

735

7.3

621

7.3

470

7.3

356

7.3

306

7.3

193

7.2

600

6.4

166

6.3

750

6.2

943

5.8

026

5.7

572

5.2

365

5.1

798

5.1

558

4.9

163

4.8

961

4.8

003

4.7

751

4.5

734

4.5

381

4.4

763

4.4

410

3.7

085

3.6

720

3.6

467

3.6

114

3.2

219

3.1

967

3.1

462

3.1

235

2.9

067

1.4

808

(ppm)

0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6

1H AMX500 fdw0726 1.1 fdw7173.3

17

0.0

379

15

5.1

206

15

3.8

235

13

6.8

147

13

6.4

504

13

6.3

556

13

5.4

301

13

4.3

443

12

8.4

999

12

8.1

136

12

7.9

314

11

6.6

287

11

6.0

676

82

.676

981

.350

680

.250

2

77

.255

177

.000

076

.744

9

67

.482

7

48

.448

148

.309

644

.024

643

.827

943

.711

3

31

.570

529

.617

528

.072

6

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500

13

6.8

147

13

6.4

504

13

6.3

556

13

5.4

301

13

4.3

443

12

8.4

999

12

8.1

136

12

7.9

314

(ppm)

126128130132134136

11

6.6

287

11

6.0

676

(ppm)

116.0117.0118.0

48

.448

148

.309

6

44

.024

643

.827

943

.711

3

(ppm)

4244464850

31

.570

5

29

.617

5

28

.072

6

(ppm)

283032

153

208fa

2.0

000

1.9

883

1.9

513

2.9

940

1.9

417

1.0

050

1.0

207

8.8

397

Inte

gra

l

7.5

789

7.5

582

7.3

419

7.3

362

7.3

315

7.3

196

7.3

149

7.2

600

6.5

230

6.4

384

6.4

255

5.9

918

5.9

592

5.9

030

5.7

782

5.7

757

5.6

114

5.5

370

5.3

388

5.2

523

5.1

739

5.1

651

4.9

522

4.9

142

4.3

155

4.3

005

4.1

236

4.1

057

4.0

499

3.9

160

3.9

035

3.8

097

3.7

783

3.7

554

3.7

388

3.7

225

3.6

520

3.6

463

3.6

410

3.6

353

3.6

300

3.6

240

3.3

669

3.1

176

2.9

266

2.9

216

1.4

166

(ppm)

0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6

fdw10256C.1

17

0.1

752

16

8.8

847

13

6.1

760

13

5.9

354

13

5.6

802

13

5.2

646

13

5.0

386

13

4.4

917

13

1.8

304

12

8.7

899

12

4.3

568

11

5.6

511

83

.992

3

81

.513

3

78

.859

377

.313

577

.000

076

.679

2

49

.533

847

.710

9

42

.322

7

27

.988

0

(ppm)

0102030405060708090100110120130140150160170180190200210220

fdw10256C.1

154

208fb

2.0

807

2.0

000

1.9

188

1.0

476

2.0

182

2.2

299

1.0

475

0.7

566

9.7

066

Inte

gra

l

7.5

811

7.5

660

7.3

305

7.3

136

7.2

600

6.5

350

6.4

292

6.4

195

6.3

046

5.8

745

5.6

890

5.3

437

5.2

562

4.9

846

4.3

599

4.0

489

3.9

325

3.7

113

3.4

374

3.1

796

2.9

300

2.9

263

1.4

799

(ppm)

0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6

fdw1016 2.1 fdw10256C.2

169.

9178

169.

9032

137.

0080

136.

0315

135.

7837

131.

8558

128.

7150

124.

8089

124.

3935

115.

9183

83.0

814

81.5

802

80.3

851

77.2

515

76.9

965

76.7

414

48.4

664

47.8

033

42.6

001

29.6

796

28.1

201

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500 fdw1221 11.1 fdw10256C.2

155

208ga

1.0

052

0.9

831

0.9

699

1.0

518

1.0

518

1.0

000

1.0

343

0.4

894

0.4

725

1.0

339

0.5

688

1.0

219

0.5

205

0.5

220

0.5

603

1.0

729

1.0

090

0.5

794

1.0

184

0.5

391

0.5

197

0.5

661

10

.479

Inte

gra

l

8.3

574

8.3

263

8.2

690

8.2

475

7.6

951

7.6

795

7.6

200

7.6

044

7.3

594

7.3

434

7.2

600

7.2

169

7.2

027

7.1

867

7.1

482

7.1

327

7.1

189

7.0

434

6.4

305

6.4

191

6.3

934

6.3

825

6.3

156

6.3

041

5.7

843

5.7

728

5.7

234

5.6

290

5.3

918

5.3

670

5.1

701

5.1

614

5.1

248

5.1

165

4.8

719

4.8

348

4.5

994

4.5

738

4.3

567

4.3

219

3.9

756

3.9

161

3.9

060

3.8

222

3.7

874

3.6

275

3.6

238

3.5

945

3.5

469

3.5

093

3.3

115

3.2

858

2.8

919

2.8

672

1.6

791

1.6

604

1.4

167

1.3

975

(ppm)

0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6

fdw1012 1.1 fdw10256A.1

171.

0800

171.

0508

169.

0176

168.

9229

136.

2245

136.

1735

136.

1297

135.

8091

135.

2334

134.

8472

133.

9945

127.

0351

126.

9404

122.

6772

122.

4586

122.

2910

122.

1963

119.

7696

119.

6093

118.

9170

118.

5745

116.

1405

115.

4482

111.

2361

108.

6418

84.1

708

83.8

574

81.4

453

81.4

089

78.8

729

78.7

490

77.2

478

77.0

000

76.7

449

49.4

246

45.8

101

45.5

987

42.3

121

41.4

668

32.0

588

31.8

256

27.9

560

27.9

341

(ppm)

020406080100120140160180200220

13C AMX500 fdw1012 21.1 fdw10256A.1

156

208gb

0.8

489

0.8

477

0.8

424

0.9

449

1.8

042

0.8

689

0.4

512

0.4

756

0.8

829

0.4

753

0.8

550

0.4

985

0.4

982

0.4

843

2.0

060

0.4

933

0.5

408

0.4

992

0.4

567

0.8

673

9.0

000

Inte

gra

l

8.1

467

8.1

041

7.7

043

7.6

887

7.6

324

7.6

168

7.3

782

7.3

621

7.2

600

7.2

330

7.2

183

7.2

110

7.2

037

7.1

954

7.1

469

7.1

322

7.0

635

6.3

820

6.2

602

6.2

492

5.7

866

5.6

734

5.6

620

5.4

138

5.3

886

5.2

374

5.1

907

4.8

903

4.8

522

4.6

379

4.6

122

4.3

315

4.2

976

3.9

976

3.9

106

3.8

377

3.8

029

3.5

332

3.4

956

3.3

751

3.3

490

2.9

542

2.9

286

2.8

883

2.8

407

2.8

374

1.5

756

1.4

657

1.4

584

(ppm)

0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6

fdw1016 1.1 fdw10256A.2

17

0.9

525

17

0.8

723

17

0.0

270

16

9.9

905

13

6.8

913

13

6.1

844

13

5.6

743

13

5.5

358

13

3.6

994

12

7.0

315

12

2.5

789

12

2.4

696

12

2.3

894

12

2.1

271

11

9.9

263

11

9.7

587

11

9.0

955

11

8.6

073

11

6.5

522

11

5.6

777

11

1.1

960

10

9.0

098

83

.132

382

.797

181

.507

381

.441

780

.355

980

.253

877

.251

477

.003

776

.748

6

49

.479

348

.517

348

.255

046

.061

545

.682

542

.359

541

.696

3

32

.157

232

.011

428

.105

4

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500 fdw1014 11.1 fdw10256A.2

157

210

1.00

00

0.97

66

0.98

91

1.01

99

0.98

44

0.97

51

0.45

17

1.00

51

0.55

43

0.54

05

0.55

56

1.98

04

0.53

58

0.44

85

0.46

13

0.53

82

1.02

14

1.01

94

0.55

19

1.63

80

1.46

58

1.58

09

9.64

42

1.00

81

Inte

gral

8.56

838.

5418

7.63

797.

6202

7.60

267.

3428

7.32

657.

2874

7.20

047.

1853

7.17

017.

1361

7.12

107.

1058

7.03

027.

0075

4.93

234.

9033

4.71

674.

7067

4.69

664.

6827

4.67

264.

6625

4.59

954.

5743

4.21

504.

1847

4.00

823.

9767

3.85

063.

8368

3.80

523.

3539

3.32

363.

0400

3.01

102.

9669

2.94

292.

9177

2.67

442.

5710

2.54

452.

2709

2.25

832.

2495

2.22

431.

9406

1.80

451.

7818

1.77

171.

7603

1.68

971.

6721

1.65

701.

6469

1.59

901.

5876

1.57

251.

4842

1.47

16

(ppm)

0.01.02.03.04.05.06.07.08.09.0

1H AMX500 fdw0302 2.1 fdw9021

171.

1766

170.

7248

136.

2774

136.

2337

127.

3285

127.

0807

122.

8322

122.

7156

121.

9504

119.

3926

118.

7586

118.

5326

111.

2963

111.

2599

109.

1538

108.

9862

83.8

229

83.7

646

81.0

610

78.7

217

78.4

302

77.3

226

77.0

675

76.8

124

57.2

604

57.1

730

49.2

079

44.6

023

44.5

731

42.7

586

42.2

120

41.2

428

33.1

757

33.0

008

31.3

903

31.1

352

31.0

550

30.6

178

28.1

109

27.0

688

26.9

741

(ppm)

020406080100120140160180200220

13C AMX500 fdw0302 21.1 fdw9021

158

211

1.0

000

1.0

873

1.0

629

1.0

960

1.1

073

1.0

521

1.0

912

1.8

138

1.2

416

3.6

451

20

.124

0.9

238

Inte

gra

l

7.2

606

4.7

909

4.7

820

4.3

093

4.1

378

3.9

739

3.0

851

2.7

233

2.7

056

2.5

720

2.1

849

2.1

723

2.1

673

2.1

597

2.1

559

2.1

484

2.1

433

2.1

307

1.7

979

1.7

878

1.7

764

1.7

651

1.7

538

1.7

285

1.5

684

1.5

016

1.4

688

1.4

436

1.4

146

1.4

058

1.3

881

1.3

806

1.3

150

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

1H AMX500 fdw0331 5 fdw 6280.2

17

0.7

812

15

4.9

822

81

.612

980

.964

379

.674

578

.486

677

.255

177

.000

076

.744

9

53

.265

0

45

.030

3

33

.064

430

.681

528

.444

228

.203

825

.281

5

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500 fdw0301 21.1 fdw7027.2

159

212

1.0

000

1.1

496

1.0

134

1.1

466

2.0

745

1.0

336

2.9

307

2.5

305

22

.369

1.6

406

Inte

gra

l

7.2

606

4.7

203

4.6

421

4.2

613

4.0

319

3.9

777

3.0

990

3.0

674

2.6

148

2.1

925

2.1

862

2.1

799

2.1

723

2.1

635

2.1

584

2.1

509

1.7

487

1.7

449

1.7

386

1.7

348

1.7

285

1.7

248

1.7

210

1.7

147

1.7

071

1.6

352

1.6

277

1.6

176

1.6

100

1.5

924

1.5

861

1.5

684

1.5

583

1.5

457

1.5

356

1.5

281

1.5

180

1.4

953

1.4

751

1.4

714

1.4

424

1.4

058

1.4

020

1.3

793

1.3

718

1.3

541

1.3

478

1.3

226

1.3

049

1.2

810

1.2

734

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

1H AMX500 fdw0331 3 fdw 76280.1

17

1.3

588

15

5.0

424

83

.531

480

.907

979

.596

278

.510

477

.278

877

.023

876

.768

7

57

.107

4

42

.452

5

33

.161

130

.749

028

.446

228

.395

128

.147

428

.103

626

.923

1

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500

160

214

0.9

733

1.0

000

0.9

846

1.0

293

1.0

655

1.0

249

1.0

520

1.0

375

3.1

916

3.2

210

1.0

576

1.6

853

1.2

717

1.0

954

1.1

656

1.1

616

3.4

746

9.7

978

Inte

gra

l

8.1

685

7.6

100

7.5

948

7.3

427

7.3

263

7.2

607

7.1

876

7.1

737

7.1

574

7.1

170

7.1

031

7.0

880

7.0

023

4.7

204

4.7

103

4.7

002

3.3

600

3.3

336

3.0

272

3.0

146

3.0

070

2.9

932

2.9

856

2.9

604

2.7

725

2.7

612

2.7

486

2.7

360

2.7

297

2.7

158

2.6

982

2.6

843

2.6

717

2.6

591

2.3

817

2.3

552

2.1

271

2.1

207

2.1

144

2.1

056

2.0

981

2.0

905

2.0

842

2.0

501

2.0

186

1.9

959

1.9

707

1.8

573

1.8

434

1.8

358

1.8

308

1.8

169

1.7

766

1.7

652

1.7

514

1.7

413

1.7

274

1.7

211

1.6

543

1.6

442

1.6

366

1.6

190

1.6

127

1.5

912

1.5

673

1.5

572

1.5

509

1.5

383

1.5

307

1.5

219

1.5

143

1.5

068

1.4

979

1.4

891

1.4

702

(ppm)

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5

1H AMX500 fdw0405 1 fdw7014.3

17

1.6

484

13

6.2

099

12

7.4

723

12

1.7

736

12

1.5

113

11

9.0

627

11

8.7

931

11

4.3

551

11

1.0

539

84

.389

480

.709

378

.603

277

.255

177

.000

076

.752

2

59

.371

957

.520

956

.763

052

.558

2

42

.006

0

33

.720

331

.687

1

28

.072

626

.804

6

22

.825

7

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500 fdw0405 11 fdw7014.3

161

215

1.0

000

0.9

895

0.9

624

1.0

165

1.0

271

0.9

834

1.0

060

3.0

808

1.0

511

3.0

818

3.1

678

1.0

532

1.0

544

1.1

501

1.0

977

1.0

699

4.1

561

Inte

gra

l

8.1

400

7.6

130

7.5

966

7.3

432

7.3

281

7.2

600

7.1

932

7.1

907

7.1

768

7.1

629

7.1

604

7.1

226

7.1

062

7.0

923

7.0

129

7.0

079

4.7

675

4.7

575

4.7

461

3.7

060

3.3

770

3.3

744

3.3

505

3.3

480

3.0

290

3.0

176

3.0

076

2.9

962

2.9

874

2.9

697

2.9

622

2.7

932

2.7

895

2.7

819

2.7

756

2.7

718

2.7

680

2.7

554

2.7

428

2.7

352

2.7

226

2.7

088

2.7

025

2.6

987

2.6

886

2.6

848

2.6

772

2.6

646

2.3

936

2.3

671

2.1

969

2.1

906

2.1

830

2.1

755

2.1

667

2.1

604

2.1

528

2.0

507

2.0

330

2.0

292

2.0

065

1.9

838

1.9

801

1.8

716

1.8

578

1.8

502

1.8

452

1.8

363

1.8

313

1.7

695

1.7

594

1.7

481

1.7

443

1.7

380

1.5

779

1.5

678

1.5

413

1.5

262

1.5

060

1.5

022

(ppm)

0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6

1H AMX500 fdw0331 1.1 fdw9157

17

2.8

945

13

6.2

026

12

7.4

723

12

1.7

882

12

1.4

967

11

9.0

700

11

8.7

785

11

4.3

551

11

1.0

393

84

.367

578

.442

977

.247

877

.000

076

.744

9

59

.320

8

56

.690

156

.500

652

.499

951

.756

5

42

.341

3

33

.698

431

.760

0

27

.074

2

22

.847

5

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500 fdw0331 11.1 fdw9157

162

217

0.9

733

0.9

583

0.9

852

1.0

051

0.9

767

1.0

000

2.9

261

1.0

518

2.0

519

1.0

625

1.0

588

1.0

600

2.0

976

1.0

611

2.0

922

1.0

608

1.1

176

1.2

016

0.8

827

Inte

gra

l

7.7

882

7.4

768

7.4

617

7.3

092

7.2

928

7.2

600

7.1

541

7.1

516

7.1

377

7.1

238

7.1

213

7.1

024

7.0

999

7.0

860

7.0

722

4.8

369

4.8

268

4.8

154

3.6

657

3.2

950

3.2

736

3.2

358

3.2

332

3.2

244

3.2

131

3.2

105

3.2

042

3.1

097

3.1

034

3.0

958

3.0

882

3.0

769

3.0

706

3.0

101

3.0

063

2.9

950

2.9

899

2.9

849

2.9

786

2.9

735

2.9

685

2.9

609

2.9

521

2.9

458

2.9

395

2.8

248

2.8

046

2.7

668

2.7

579

2.7

441

2.7

365

2.7

214

2.6

962

2.6

886

2.3

318

2.3

242

2.3

129

2.3

066

2.2

990

2.2

663

2.2

599

2.2

410

2.2

335

2.2

297

2.2

183

2.2

032

2.1

931

2.0

141

2.0

103

2.0

065

1.9

889

1.9

851

1.9

813

1.9

662

1.9

624

1.9

586

1.7

544

1.7

418

1.7

393

1.7

304

1.7

178

1.7

052

1.6

964

1.6

258

1.6

132

1.6

069

1.6

006

1.5

892

1.5

703

1.5

439

1.5

186

(ppm)

0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6

1H AMX500 fdw0505 1.1 fdw10019

17

2.1

295

13

5.9

720

13

4.5

524

12

7.3

108

12

1.4

602

11

9.4

742

11

8.1

621

11

0.7

341

10

8.3

824

84

.456

6

79

.939

677

.423

077

.000

076

.577

0

62

.029

460

.767

5

54

.121

0

51

.418

0

47

.510

446

.764

8

29

.528

528

.847

327

.936

7

22

.093

3

(ppm)

0102030405060708090100110120130140150160170180190200210220

may04fdw 11.1 fdw10019

163

218

1.0

000

1.0

270

1.1

821

1.1

613

1.0

831

1.0

090

1.0

185

2.8

381

1.3

095

1.0

461

2.1

665

1.1

597

1.0

491

2.1

240

1.0

115

1.2

212

1.1

445

1.1

532

1.2

371

Inte

gra

l

7.7

050

7.4

592

7.4

441

7.2

953

7.2

789

7.1

415

7.1

390

7.1

251

7.1

112

7.1

087

7.0

898

7.0

759

7.0

621

7.0

595

5.8

619

5.8

429

5.7

043

5.6

992

5.6

904

5.6

841

5.6

778

5.6

702

5.6

639

3.8

283

3.7

955

3.7

880

3.7

804

3.3

114

3.2

887

3.0

782

3.0

693

3.0

643

3.0

479

3.0

441

3.0

378

3.0

277

3.0

151

2.9

622

2.9

584

2.9

508

2.9

433

2.9

382

2.9

332

2.9

269

2.9

180

2.9

130

2.9

067

2.9

017

2.8

764

2.8

563

2.7

163

2.7

088

2.6

924

2.6

861

2.6

709

2.3

986

2.3

772

2.2

322

2.2

234

2.2

133

2.2

070

2.1

982

2.1

881

2.1

755

1.9

473

1.9

448

1.9

145

1.9

082

1.8

099

1.8

036

1.7

960

1.7

847

1.7

771

1.7

708

1.5

539

1.4

443

1.4

203

(ppm)

0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6

1H AMX500 fdw0505 1.1 fdw10022.1

17

4.3

612

13

5.9

859

13

4.1

495

12

7.2

192

12

5.1

569

12

1.5

059

12

1.0

759

11

9.4

946

11

8.1

173

11

0.8

226

10

8.4

251

77

.278

877

.023

876

.768

7

69

.641

7

66

.697

6

59

.126

0

52

.807

852

.035

4

42

.612

841

.425

0

33

.656

6

29

.102

0

21

.880

2

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500 fdw0505 51.1 fdw10022.1

164

221

0.9

843

1.0

040

1.0

229

2.1

092

2.1

764

0.9

651

1.0

303

1.1

829

1.8

512

9.3

819

9.8

550

Inte

gra

l

7.2

600

5.5

429

5.4

849

4.1

914

4.1

813

4.1

737

4.1

636

4.1

586

4.1

485

4.1

019

4.0

741

4.0

414

3.9

859

3.9

392

3.9

090

3.2

042

3.2

005

3.1

878

3.1

841

2.5

587

2.5

487

2.5

398

2.5

234

2.5

134

2.5

045

2.2

385

2.2

246

2.2

032

2.1

893

2.0

557

2.0

330

1.4

922

1.4

493

(ppm)

0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6

1H AMX500 fdw10213

17

1.2

622

15

4.5

959

12

9.4

545

12

1.6

862

11

9.8

935

81

.663

979

.922

277

.255

177

.000

076

.744

9

67

.803

3

54

.380

0

45

.416

543

.704

0

32

.423

1

28

.400

528

.145

5

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500 fdw10215

165

222

1.0

031

1.0

108

1.0

000

4.1

522

0.9

767

1.0

845

1.1

454

3.0

866

21

.435

Inte

gra

l

7.2

600

5.5

303

5.4

521

5.2

668

5.2

567

5.2

517

5.2

491

5.2

391

5.2

353

5.2

252

4.0

136

3.3

454

3.3

417

3.3

278

3.3

253

2.6

785

2.6

697

2.6

596

2.6

432

2.6

344

2.6

243

2.2

045

2.1

944

2.1

704

2.1

604

2.0

015

1.4

493

1.4

417

(ppm)

0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6

1H AMX500 fdw0824 2.1 fdw10217

17

0.0

087

16

9.8

921

15

4.6

542

12

9.3

160

12

8.8

132

11

9.1

283

81

.438

079

.922

277

.255

177

.000

076

.744

9

69

.953

1

51

.173

6

43

.711

3

29

.471

828

.385

927

.948

7

21

.040

3

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500 fdw0824 21.1 fdw10217

166

227

0.9

589

0.9

461

0.9

180

0.9

525

0.9

666

0.9

293

1.0

000

1.0

005

3.8

670

1.0

268

1.0

265

0.9

986

1.9

576

2.0

819

1.0

396

2.2

465

1.2

833

1.1

653

1.0

806

Inte

gra

l

7.9

496

7.6

080

7.5

916

7.3

583

7.3

419

7.2

600

7.1

970

7.1

818

7.1

667

7.1

213

7.1

075

7.0

923

7.0

381

7.0

343

4.0

792

4.0

704

4.0

565

4.0

489

4.0

351

4.0

262

3.7

363

3.0

126

2.9

912

2.9

319

2.9

130

2.9

017

2.8

954

2.8

865

2.6

760

2.6

634

2.6

520

2.6

394

2.6

331

2.6

205

2.5

940

2.5

802

2.5

751

2.5

625

2.5

512

2.5

373

2.4

957

2.4

856

2.4

755

2.4

654

2.2

032

2.1

931

2.1

843

2.1

780

2.1

679

2.1

616

2.1

011

2.0

935

2.0

847

2.0

797

2.0

696

2.0

608

2.0

557

2.0

280

2.0

217

1.9

549

1.9

498

1.9

309

1.9

271

1.9

069

1.9

044

1.7

720

1.7

645

1.7

468

1.7

393

1.7

216

1.7

141

1.6

964

1.6

876

1.6

082

1.5

375

1.5

287

1.5

086

1.5

010

1.3

989

1.3

913

1.3

711

1.3

636

1.3

484

1.3

421

1.3

207

1.3

131

1.2

564

1.2

072

1.2

009

1.1

808

1.1

757

(ppm)

0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6

1H AMX500 fdw0922 1.1 fdw10243.3

0.9

461

0.9

180

0.9

525

0.9

666

0.9

293

7.6

080

7.5

916

7.3

583

7.3

419

7.2

600

7.1

970

7.1

818

7.1

667

7.1

213

7.1

075

7.0

923

7.0

381

7.0

343

(ppm)

7.07.27.47.6

1.0

000

Inte

gra

l

4.0

792

4.0

704

4.0

565

4.0

489

4.0

351

4.0

262

(ppm)

4.004.10

1.0

005

3.8

670

1.0

268

1.0

265

0.9

986

1.9

576

2.0

819

1.0

396

2.2

465

1.2

833

1.1

653

1.0

806

Inte

gra

l2.2

032

2.1

931

2.1

843

2.1

780

2.1

679

2.1

616

2.1

011

2.0

935

2.0

847

2.0

797

2.0

696

2.0

608

2.0

557

2.0

280

2.0

217

1.9

549

1.9

498

1.9

309

1.9

271

1.9

069

1.9

044

1.7

720

1.7

645

1.7

468

1.7

393

1.7

216

1.7

141

1.6

964

1.6

876

1.6

082

1.5

375

1.5

287

1.5

086

1.5

010

1.3

989

1.3

913

1.3

711

1.3

636

1.3

484

1.3

421

1.3

207

1.3

131

1.2

564

1.2

072

1.2

009

1.1

808

1.1

757

(ppm)

1.21.41.61.82.02.22.42.62.83.0

17

4.8

475

13

6.1

807

12

7.5

671

12

1.9

121

12

1.4

821

11

9.1

574

11

8.8

222

11

4.7

704

11

1.0

393

77

.255

177

.000

076

.744

9

66

.112

7

59

.350

058

.847

2

54

.693

454

.620

551

.727

4

37

.844

936

.620

733

.100

9

24

.560

123

.474

322

.840

3

(ppm)

-100102030405060708090100110120130140150160170180190200210220

13C AMX500 fdw0922 11.1 fdw10243.3

167

170

0.9

833

0.8

913

0.9

333

1.0

546

1.0

265

1.1

440

3.0

000

1.1

265

2.3

334

1.1

591

2.0

626

3.4

618

1.1

857

2.5

277

1.2

067

1.3

157

2.5

058

1.4

593

Inte

gra

l

7.6

772

7.4

661

7.4

505

7.3

154

7.2

994

7.2

600

7.1

482

7.1

464

7.1

322

7.1

185

7.1

162

7.0

956

7.0

933

7.0

800

7.0

658

4.0

260

4.0

173

4.0

049

3.9

962

3.9

866

3.9

774

3.8

419

3.1

631

3.1

599

3.1

420

3.1

388

2.9

858

2.9

744

2.9

661

2.9

588

2.9

542

2.9

465

2.9

396

2.9

222

2.9

171

2.9

103

2.9

052

2.8

585

2.8

558

2.8

361

2.7

051

2.6

982

2.6

671

2.6

116

2.6

052

2.5

887

2.5

823

2.5

718

2.5

622

2.5

507

2.5

416

2.5

232

2.5

150

2.5

017

2.4

884

2.4

587

2.4

504

2.4

417

2.4

330

2.4

243

2.1

523

2.1

449

2.1

248

2.1

179

2.0

987

2.0

913

2.0

730

2.0

671

2.0

552

2.0

465

2.0

396

2.0

318

1.8

394

1.8

147

1.7

478

1.7

226

1.6

988

1.6

741

1.6

054

1.5

976

1.5

797

1.5

733

1.5

509

1.5

445

1.4

226

1.4

103

1.3

929

1.3

869

1.3

681

1.3

622

1.3

425

1.3

343

(ppm)

0.00.40.81.21.62.02.42.83.23.64.04.44.85.25.66.06.46.87.27.68.08.48.89.29.6

fdw1001 1.1 fdw10248.1

17

4.7

104

13

5.9

937

13

4.4

698

12

7.3

244

12

1.4

403

11

9.4

644

11

8.1

009

11

0.7

732

10

8.4

837

77

.320

877

.000

076

.686

5

66

.070

4

60

.550

960

.237

4

54

.732

453

.303

351

.976

3

37

.947

936

.555

333

.113

8

27

.747

4

24

.597

6

21

.732

1

(ppm)

0102030405060708090100110120130140150160170180190200210220

sep26fdw 1.1 fdw10248.1

168

Chiral HPLC Chromatograms

152

0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0 19.0

-100

0

100

200

300

400

500

600

700

800

900062008 #151 [modified by TCH] fdw4221 UV_VIS_3mAU

min

1 - 11.3932 - 12.320

WVL:254 nm

0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0 19.0

-50

0

50

100

150

200

250

300

350

400062008 #152 [modified by TCH] fdw4215A UV_VIS_3mAU

min

1 - 11.380

2 - 12.313

WVL:254 nm

169

158

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

-500

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000062008 #212 [modified by TCH] fdw5189 UV_VIS_1mAU

min

1 - 5.173

2 - 9.700

WVL:230 nm

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

-200

250

500

750

1,000

1,250

1,500

1,750

2,000

2,250

2,500

2,750

3,000062008 #219 [modified by TCH] fdw5206A UV_VIS_1mAU

min

1 - 5.127

2 - 9.680

WVL:230 nm

170

159

10.0 20.0 30.0 40.0 50.0 60.0

-50

0

50

100

150

200

250

300

350

400

450

500

550

600062008 #224 [modified by TCH] fdw5212 UV_VIS_1mAU

min

1 - 29.527

2 - 49.527

WVL:230 nm

10.0 20.0 30.0 40.0 50.0 60.0

-50

100

200

300

400

500

600

700

800

900

1,000062008 #227 [modified by TCH] fdw5214A UV_VIS_1mAU

min

1 - 29.447

2 - 50.493

WVL:230 nm

171

208aa+208ab 11023A.2 Ce2 3005210

0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0

-150

0

200

400

600

800

1,000Template #250 [modified by TCH]fdw11023A.2 UV_VIS_1mAU

min

1 - 23.067

2 - 36.733

3 - 47.053

4 - 62.593

WVL:210 nm

No. Ret.Time Peak Name Height Area Rel.Area

min mAU mAU*min %

1 23.07 n.a. 755.450 594.200 31.14

2 36.73 n.a. 280.832 355.800 18.65

3 47.05 n.a. 371.223 603.155 31.61

4 62.59 n.a. 165.165 355.015 18.61

Total: 1572.669 1908.171 100.00

172

208aa(11024E)

0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0

-150

0

200

400

600

800

1,000Template #255 [modified by TCH]fdw11024E UV_VIS_1mAU

min

1 - 23.313

2 - 47.300

WVL:210 nm


min mAU mAU*min %

1 23.31 n.a. 415.694 301.873 20.11

2 47.30 n.a. 695.470 1199.169 79.89

Total: 1111.164 1501.042 100.00

208ab(11024E)

0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0

-150

0

200

400

600

800

1,000Template #255 [modified by TCH]fdw11024E UV_VIS_1mAU

min

1 - 37.367

2 - 62.767

WVL:210 nm

173


min mAU mAU*min %

1 37.37 n.a. 66.753 77.490 19.83

2 62.77 n.a. 149.742 313.194 80.17

Total: 216.496 390.684 100.00

(6098.3) I A+Ce1 2010210

0.0 5.0 10.0 15.0 20.0 25.0 30.0

-40

50

100

150

200

250

300Template #53 [modified by TCH]fdw6098.3 UV_VIS_3mAU

min

1 - 10.807

2 - 12.020

3 - 13.060

4 - 21.180

WVL:210 nm


min mAU mAU*min %

1 10.81 n.a. 128.070 26.615 20.11

2 12.02 n.a. 111.397 27.096 20.47

3 13.06 n.a. 137.198 39.752 30.03

4 21.18 n.a. 79.010 38.913 29.40

174

208ba(6106A)

0.0 5.0 10.0 15.0 20.0 25.0 30.0

-100

250

500

750

1,000

1,250

1,500Template #69 [modified by TCH]fdw6106A UV_VIS_3mAU

min

1 - 10.873

2 - 11.980

WVL:210 nm


min mAU mAU*min %

1 10.87 n.a. 890.852 248.318 91.80

2 11.98 n.a. 78.836 22.166 8.20

Total: 969.687 270.485 100.00

208bb(6106A)

0.0 5.0 10.0 15.0 20.0 25.0 30.0

-100

200

400

600

800

1,000Template #69 [modified by TCH]fdw6106A UV_VIS_3mAU

min

1 - 12.793

2 - 20.340

WVL:210 nm

175


min mAU mAU*min %

1 12.79 n.a. 12.751 3.499 8.56

2 20.34 n.a. 73.254 37.350 91.44

Total: 86.005 40.849 100.00

(6083A) IA1005210

0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0

-20

50

100

150

200Template #31 [modified by TCH]fdw6083A UV_VIS_1mAU

min

1 - 5.427

2 - 6.060

3 - 9.2604 - 14.280

WVL:210 nm


min mAU mAU*min %

1 5.43 n.a. 83.255 16.165 36.42

2 6.06 n.a. 75.527 15.453 34.81

3 9.26 n.a. 21.429 6.199 13.97

4 14.28 n.a. 15.454 6.572 14.80

176

208ca(10183)

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

-400

-300

-200

-100

0

100

200Template #191 [modified by TCH]fdw10183 UV_VIS_1mAU

min

1 - 6.293

2 - 6.953

WVL:210 nm


min mAU mAU*min %

1 6.29 n.a. 356.253 100.644 89.69

2 6.95 n.a. 43.810 11.573 10.31

Total: 400.063 112.218 100.00

208cb(10183)

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0

-400

-300

-200

-100

0

100


min

1 - 10.153

2 - 14.987

WVL:210 nm

177


min mAU mAU*min %

1 10.15 n.a. 42.171 19.689 11.46

2 14.99 n.a. 234.569 152.125 88.54

Total: 276.741 171.815 100.00

(7173) IA 1005210

0.0 10.0 20.0 30.0 40.0 50.0

-100

500

1,000

1,500

2,000

2,500Template #129 [modified by TCH] UV_VIS_1mAU

min

1 - 12.2872 - 13.4803 - 28.093

4 - 35.660

WVL:210 nm


min mAU mAU*min %

1 12.29 n.a. 1663.108 1110.012 12.96

2 13.48 n.a. 1592.875 1165.708 13.61

3 28.09 n.a. 1751.224 3122.662 36.46

4 35.66 n.a. 1293.867 3165.506 36.96

Total: 6301.073 8563.888 100.00

178

208da(7176B)

0.0 10.0 20.0 30.0 40.0 50.0

-100

250

500

750

1,000

1,250

1,500Template #132 [modified by TCH]fdw7176B UV_VIS_1mAU

min

1 - 11.360

2 - 12.973

WVL:210 nm


min mAU mAU*min %

1 11.36 n.a. 829.910 483.929 88.77

2 12.97 n.a. 101.669 61.198 11.23

Total: 931.579 545.128 100.00

208db(7176B)

0.0 10.0 20.0 30.0 40.0 50.0

-100

250

500

750

1,000

1,250


min

1 - 27.833

2 - 36.447

WVL:210 nm

179


min mAU mAU*min %

1 27.83 n.a. 63.142 57.022 11.42

2 36.45 n.a. 305.894 442.345 88.58

Total: 369.036 499.367 100.00

(7204A) IA+IA 2010230

0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0

-30

50

100

150

200

250


min

1 - 22.573

2 - 23.767

3 - 26.140

4 - 29.953

WVL:230 nm


min mAU mAU*min %

1 22.57 n.a. 187.129 98.149 35.73

2 23.77 n.a. 64.880 40.789 14.85

3 26.14 n.a. 161.353 98.817 35.98

4 29.95 n.a. 48.909 36.911 13.44

Total: 462.271 274.666 100.00

180

208fa (7209)

0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0

-30

500

1,000

1,500

2,000Template #151 [modified by TCH]fdw7209 UV_VIS_3mAU

min

1 - 22.907

2 - 26.560

WVL:210 nm


min mAU mAU*min %

1 22.91 n.a. 955.640 652.162 82.54

2 26.56 n.a. 180.696 137.934 17.46

Total: 1136.336 790.096 100.00

208fb (7209)

0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0 40.0

-100

250

500

750

1,000

1,250

1,500Template #139 [modified by TCH]fdw7204C UV_VIS_2mAU

min

1 - 23.7072 - 29.807

WVL:254 nm

181


min mAU mAU*min %

1 23.71 n.a. 15.291 6.643 10.55

2 29.81 n.a. 76.987 56.344 89.45

Total: 92.278 62.988 100.00

(7217) AD+AD 2010230

0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0

-20

50

100

150

200

250


min

1 - 26.453

2 - 32.307

3 - 35.107

4 - 46.893

WVL:230 nm


min mAU mAU*min %

1 26.45 n.a. 253.946 269.899 36.68

2 32.31 n.a. 236.165 267.775 36.40

3 35.11 n.a. 80.771 101.649 13.82

4 46.89 n.a. 39.806 96.409 13.10

Total: 610.688 735.732 100.00

182

208ga(7218)

0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0

-20

125

250

375

500

625


min

1 - 26.407

2 - 32.080

WVL:230 nm


min mAU mAU*min %

1 26.41 n.a. 113.000 109.982 15.90

2 32.08 n.a. 520.009 581.562 84.10

Total: 633.009 691.544 100.00

208gb(7218)

0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0

-50

100

200

300

400

500


min

1 - 34.7532 - 46.533

WVL:230 nm

183


min mAU mAU*min %

1 34.75 n.a. 2.873 1.965 5.10

2 46.53 n.a. 18.460 36.539 94.90

Total: 21.332 38.504 100.00

(10257B racemic) IA0505210

0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0

-150

200

400

600

800

1,000

1,200Template #258 [modified by TCH]fdw10257B racemic UV_VIS_1mAU

min

1 - 11.353

2 - 12.827

3 - 19.5874 - 30.213

WVL:210 nm


min mAU mAU*min %

1 11.35 n.a. 820.119 442.261 41.73

2 12.83 n.a. 730.318 453.532 42.80

3 19.59 n.a. 95.021 82.064 7.74

4 30.21 n.a. 53.037 81.877 7.73

Total: 1698.496 1059.734 100.00

184

208ha(Fdw10257B)

0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0

-150

0

200

400

600

800


min

1 - 11.413

2 - 12.900

WVL:210 nm


min mAU mAU*min %

1 11.41 n.a. 572.142 318.666 93.36

2 12.90 n.a. 42.654 22.660 6.64

Total: 614.796 341.327 100.00

208hb(Fdw10257B)

0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0

-150

0

125

250

375

500

625

800Template #257 [modified by TCH]fdw10257B UV_VIS_1mAU

min

1 - 19.673

2 - 30.173

WVL:210 nm

185


min mAU mAU*min %

1 19.67 n.a. 6.486 5.440 5.94

2 30.17 n.a. 42.169 86.146 94.06

Total: 48.656 91.586 100.00

(6153A IC 2010210)

0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0

-20

25

50

75

100

125


min

1 - 20.627

2 - 28.367

3 - 39.233

4 - 50.380

WVL:210 nm


min mAU mAU*min %

1 20.63 n.a. 39.832 31.684 14.49

2 28.37 n.a. 72.730 78.051 35.70

3 39.23 n.a. 52.440 77.598 35.49

4 50.38 n.a. 16.231 31.316 14.32

Total: 181.232 218.649 100.00

186

208ia(6157B)

0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0

-20

100

200

300

400


min

1 - 27.027

2 - 36.867

WVL:210 nm


min mAU mAU*min %

1 27.03 n.a. 31.929 31.876 6.51

2 36.87 n.a. 314.382 457.704 93.49

Total: 346.311 489.580 100.00

208ib(6157B)

0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0

-20

100

200

300

400


min

1 - 19.920

2 - 47.100

WVL:210 nm

187


min mAU mAU*min %

1 19.92 n.a. 10.687 6.298 4.50

2 47.10 n.a. 73.856 133.622 95.50

Total: 84.543 139.920 100.00

208haa IC1010230 (fdw10208.2) racemic

0.0 5.0 10.0 15.0 20.0 25.0 30.0

-20.0

-10.0

0.0

10.0

20.0

30.0

40.0

50.0Template #198 fdw10208.2 UV_VIS_1mAU

min

1 - 14.000

2 - 18.060

WVL:230 nm


min mAU mAU*min %

1 14.00 n.a. 39.723 33.897 50.06

2 18.06 n.a. 31.631 33.813 49.94

Total: 71.354 67.710 100.00

188

(11029.2) chiral

0.0 5.0 10.0 15.0 20.0 25.0 30.0

-50

0

50

100

150

200

250


min

1 - 14.633

2 - 19.820

WVL:230 nm


min mAU mAU*min %

1 14.63 n.a. 248.287 253.329 91.68

2 19.82 n.a. 17.897 22.985 8.32

Total: 266.184 276.315 100.00

208hbb IC 1010230 (fdw10208.1) racemic

0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0

-100

0

100

200

300Template #199 fdw10208.1 UV_VIS_3mAU

min

1 - 13.167

2 - 24.540

WVL:254 nm

189


min mAU mAU*min %

1 13.17 n.a. 175.800 135.423 49.98

2 24.54 n.a. 101.102 135.516 50.02

Total: 276.902 270.939 100.00

fdw11029.1 chiral

0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0

-50

200

400

600

800

1,000

1,200

1,500Template #260 [modified by TCH]fdw11029.1 UV_VIS_1mAU

min

1 - 13.773

2 - 27.327

WVL:230 nm


min mAU mAU*min %

1 13.77 n.a. 1185.044 1142.111 89.44

2 27.33 n.a. 80.712 134.839 10.56

Total: 1265.756 1276.951 100.00

190

221 (fdw10131) IC 1010254 racemic

0.0 5.0 10.0 15.0 20.0 25.0 30.0

-20

0

20

40

60


min

1 - 13.173

2 - 17.687

WVL:254 nm


min mAU mAU*min %

1 13.17 n.a. 36.508 28.741 49.53

2 17.69 n.a. 29.468 29.285 50.47

Total: 65.976 58.026 100.00

fdw10215 chiral

0.0 5.0 10.0 15.0 20.0 25.0 30.0

-100

200

400

600

800

1,000Template #206 [modified by TCH]fdw10215 UV_VIS_1mAU

min

1 - 13.047

2 - 17.527

WVL:254 nm

191


min mAU mAU*min %

1 13.05 n.a. 673.317 635.175 87.81

2 17.53 n.a. 78.342 88.182 12.19

Total: 751.659 723.356 100.00

222 (fdw10130) IC1010254 racemic

0.0 5.0 10.0 15.0 20.0 25.0 30.0

-30

0

20

40

60

80


min

1 - 14.360

2 - 21.027

WVL:254 nm


min mAU mAU*min %

1 14.36 n.a. 47.588 33.203 48.58

2 21.03 n.a. 32.812 35.144 51.42

Total: 80.400 68.347 100.00

192

fdw10217 chiral

0.0 5.0 10.0 15.0 20.0 25.0 30.0

-30

0

20

40

60

80


min

1 - 14.393

2 - 21.013

WVL:254 nm


min mAU mAU*min %

1 14.39 n.a. 10.294 7.729 10.56

2 21.01 n.a. 58.427 65.490 89.44

Total: 68.721 73.219 100.00

227 (FDW10207) AD1010(30mins)->1030230 racemic

30.0 35.0 40.0 45.0 50.0 55.0 60.0

-20

50

100

150


min

1 - 37.9332 - 40.853

WVL:230 nm

193


min mAU mAU*min %

1 37.93 n.a. 114.622 117.133 51.08

2 40.85 n.a. 119.569 112.200 48.92

Total: 234.191 229.334 100.00

FDW10220.2 chiral

30.0 35.0 40.0 45.0 50.0 55.0 60.0

-20

100

200

300

400


min

1 - 37.773

2 - 40.233

WVL:254 nm


min mAU mAU*min %

1 37.77 n.a. 19.135 16.124 7.33

2 40.23 n.a. 344.631 203.987 92.67

tandem isomerization reaction of alkynes: total … · 2018. 1. 10. · synthesis of the chiral...

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