enantioselective brønsted and lewis acid-catalyzed

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Enantioselective Brønsted and Lewis Acid-Catalyzed Reaction Methodology: Aziridines asBuilding Blocks for Catalytic AsymmetricInductionShawn E. LarsonUniversity of South Florida, [email protected]

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Enantioselective Brønsted and Lewis Acid-Catalyzed Reaction Methodology: Aziridines as Building Blocks for Catalytic Asymmetric Induction.

by

Shawn Edward Larson

A dissertation submitted in partial fulfillment of the requirement for the degree of

Doctor in Philosophy Department of Chemistry

College of Arts and Sciences University of South Florida

Major Professor: Jon C. Antilla, Ph.D. Bill Baker, Ph.D.

Kirpal Bisht, Ph.D. Roman Manetsch, Ph.D.

Date of Approval: November 7

th 2012

Keywords: Organocatalysis, aziridine, imine, desymmetrization, phosphoric acid, phosphate salt, BrØnsted acid, enantioselective, asymmetric

Copyright © 2012, Shawn E. Larson

DEDICATION

I would like to dedicate this dissertation to my wonderful wife, Dianne Larson who has

been supportive and patient. I would also like to thank my parents for teaching me that I can

accomplish anything I set my mind to.

ACKNOWLEDGMENTS

I would like to thank my research advisor Dr. Jon C. Antilla for giving me the opportunity

to work in his lab, support and freedom to try anything. I also would like to thank Doctors Emiliy,

and Gerald Rowland, as well as Guilong Li for training, mentoring and guidance; without them I

would not be the organic chemist I am today.

I would like to thank my committee members: Dr. Roman Manetsch, Dr. Kirpal Bisht, and

Dr. Bill Baker for their time and assistance over the last five years.

I would like to thank Gajendra Ingle, Kurt Van Horn, and Ryan Cormier for the

unrestricted assistance over these years. I will give special thanks my all of the other post

doctorates, graduate students and undergraduates that have worked in the Antilla lab over the

years.

I want to recognize those that encouraged me to strive for excellence, Darlene Cowles,

Kelly Personte Williams, Dr. Joseph LeFevre, Dr. Jeffery Schneider, Dr. Casey C. Raymond,

Lawrence Fuller and Kelly Munsell Ohanesian.

i

TABLE OF CONTENTS

LIST OF TABLES ............................................................................................................................. iii LIST OF FIGURES ........................................................................................................................... iv LIST OF SPECTRA ......................................................................................................................... vii ABSTRACT ...................................................................................................................................... ix CHAPTER 1: ASYMMETRIC CATALYSIS, LIGANDS, AND CHIRAL PHOSHATE SALTS ........... 1

1.1 Catalytic Asymmetric Induction ........................................................................................... 1 1.2 BINOL as a Chiral Backbone............................................................................................... 3 1.3 Electronics and Heteroatom Variants .................................................................................. 5 1.4 Axial Chirality as a Chiral Scaffold ...................................................................................... 7 1.5 Alkaline Metals: Calcium and Magnesium ........................................................................... 9 1.5.1 Calcium Phosphate Salts ............................................................................................... 10 1.5.2 Magnesium Phosphate Salts .......................................................................................... 12

CHAPTER 2: CATALYTIC ASYMMETRIC AZIRIDINE DESYMMETRIZATION ........................... 15 2.1 Introduction to Aziridine Desymmetrization ....................................................................... 15 2.2 Mercaptans in Desymmetrization ...................................................................................... 18 2.3 Organocatalytic aziridine Desymmetrization ..................................................................... 23 2.4 Aziridine Desymmetrization by Phosphate Salt................................................................. 30 2.5 Mechanistic Insights .......................................................................................................... 31 2.6 Aniline Addition .................................................................................................................. 33 2.7 Catalytic Asymmetric Aniline Addition ............................................................................... 35 2.8 Recent Findings ................................................................................................................. 36 2.9 In Conclusions ................................................................................................................... 37

CHAPTER 3: CATALYTIC ASYMMETRIC AZA-DARZENS REACTION……. ............................. 39

3.1 Background Information .................................................................................................... 39 3.2 The Aza-Darzens Reaction, a Variant to the Darzens Epoxidation .................................. 40 3.3 Aza-Darzens with α-Halo-1,3-Dicarbonyl Compounds ...................................................... 41 3.4 Theoretical Study of the Aza-Darzens Reaction ............................................................... 45 3.5 Transition State ................................................................................................................. 48

CHAPTER 4: CONCLUSION ......................................................................................................... 53

4.1 Conclusion ......................................................................................................................... 53 REFERENCES ............................................................................................................................... 55 APPENDIX A: SUPPORTING INFORMATION ............................................................................. 62

A1 Supporting Information for Chapter 2 ................................................................................. 62 A1.1 General Considerations ............................................................................................ 62 A1.2 Preparations of Compounds in Chapter 2 ................................................................ 63 A1.3 Preparation of Racemic Products by Desymmetrization .......................................... 65 A1.4 Procedure for the Desymmetrization of meso-Aziridines ......................................... 65 A1.5 Procedure for Desymmetrization of meso-Aziridines with Aniline ............................ 66 A1.6 Characterization of Beta Amino Thioethers and 1,2 Diamines ................................ 67

A2 Supporting Information for Chapter 3 ................................................................................. 96 A2.1 General Reaction Conditions .................................................................................... 96

ii

A2.2 Preparation of N-Acyl Imines .................................................................................... 97 A2.3 Preparation and Characterization of Catalyst: .......................................................... 97 A2.4 Characterization of Magnesium(II) salt of (R)-2,2′-Diphenyl-3,3′-

biphenanthryl-4,4′-diyl phosphate .......................................................................... 98 4.2.5 General Procedure for the Enantioselective aza-Darzens Reaction ....................... 98 4.2.6 General Procedure for the Racemic aza-Darzens Reaction ................................... 98 4.2.7 Absolute Configuration of aza-Darzens Products .................................................... 98 4.2.8 Cartesian Coordinates for the Lowest Energy Catalyst ........................................... 99 4.2.9 Cartesian Coordinates for the Middle Energy Catalyst .......................................... 102 4.2.10 Cartesian Coordinates for the High Energy Catalyst ........................................... 103 4.2.11 Characterization of Aza-Darzens Products .......................................................... 108

APPENDIX B: SPECTRA............................................................................................................. 117

B.1 1H AND

13C SPECTRA FOR COMPOUNDS IN CHAPTER 2 ........................................ 117

B.2 1H AND

13C SPECTRA FOR COMPOUNDS IN CHAPTER 3 ........................................ 147

B.3 HPLC SPECTRA FOR COMPOUND 159 ...................................................................... 147 APPENDIX C: PERMISSIONS .................................................................................................... 166 ABOUT THE AUTHOR ...................................................................................................... End Page

iii

LIST OF TABLES

Table 1.1 Catalyst Effect on Mannich Reactions ................................................................... 8 Table 1.2 Effects of Brønsted/Lewis Acid Pairings .............................................................. 14

Table 2.1 Effects of N-Substitution ...................................................................................... 22

Table 2.2 Solvent Effects on Desymmetrization .................................................................. 23

Table 2.3 Brønsted Acid Optimization ................................................................................. 24

Table 2.4 Initial Scope of Thiol Desymmetrization ............................................................... 25

Table 2.5 Functionalized Thiols for Desymmetrization ........................................................ 27

Table 2.6 Exploration of Desymmetrization Scope .............................................................. 28

Table 2.7 Modulation of Aziridine Sterics and Ring Strain ................................................... 29

Table 2.8 Trace Element Analysis by ICP-OES .................................................................. 30

Table 2.9 Evaluation of Catalyst P11 ................................................................................... 30

Table 2.10 VAPOL Phosphate Metal Salts for Aniline Ring Opening .................................... 37

Table 3.1 Optimization of Catalytic system .......................................................................... 42

Table 3.2 Scope of Aza-Darzens Reaction .......................................................................... 44

iv

LIST OF FIGURES

Figure 1.1 Tartaric Acid and Carvone ..................................................................................... 1 Figure 1.2 Privileged Ligands and Catalysts ........................................................................... 2 Figure 1.3 Developments in Modes of Activation .................................................................... 3 Figure 1.4 Timeline for the Exploitation of BINOL Backbone .................................................. 4 Figure 1.5 Functionality of BINOL Phosphoric Acid and Metal Salt ........................................ 5 Figure 1.6 Stronger Brønsted Acids ........................................................................................ 6 Figure 1.7 A Sample of 3, 3’ Substituted BINOL, VAPOL, and VANOL Phosphoric

Acids ...................................................................................................................... 7 Figure 1.8 Development of Vaulted Binapthols and Vaulted Biphenanthrols ......................... 9 Figure 1.9 BINOL Phosphoric Acid and BINOL Calcium Phosphate Salts ........................... 10 Figure 1.10 Calcium Phosphate Catalyzed Mannich Reaction ............................................... 10 Figure 1.11 Calcium Phosphate Catalyzed Mannich Reaction of Cyclic Diketones

and Amidation ...................................................................................................... 11 Figure 1.12 Benzoyloxylation, Chlorination, and Michael Addition to Oxindole ...................... 12 Figure 1.13 Synergistic Effects of Brønsted Acid and Lewis Acid .......................................... 13 Figure 1.14 Preparation of Chiral Phosphine Oxides .............................................................. 13 Figure 1.15 Magnesium Catalyzed Aminocyclization ............................................................. 13 Figure 2.1 Nucleophilic Aziridine Desymmetrization ............................................................. 15 Figure 2.2 Chiral Chromium Azide Complex for Desymmetrization ...................................... 16 Figure 2.3 Yttrium Catalyzed Desymmetrization ................................................................... 16 Figure 2.4 Direct Synthesis of Tamiflu .................................................................................. 17 Figure 2.5 Gadolinium Catalyzed Desymmetrization with TMSCN....................................... 17 Figure 2.6 Organocatalytic Desymmetrization ...................................................................... 17 Figure 2.7 Proposed Mechanism for Organocatalytic Desymmetrization ............................. 18 Figure 2.8 Common Chiral β-amino Thioethers .................................................................... 19

v

Figure 2.9 Post Desymmetrization Structural Modification ................................................... 19 Figure 2.10 Zinc Dialkyl Tartrate Desymmetrization ............................................................... 20 Figure 2.11 Desymmetrizations with Cinchonine-derived Ammonium Salts .......................... 20 Figure 2.12 7-azabicyclo[4.1.0]heptan-7-yl(4-(trifluoromethyl)phenyl) methanone ................ 31 Figure 2.13 Proposed Mechanism .......................................................................................... 32 Figure 2.14 Tin Catalyzed Desymmetrization with Aniline ...................................................... 33 Figure 2.15 Lewis Acid Catalyzed Ring Openings .................................................................. 34 Figure 2.16 DABCO Catalyzed Ring Opening ........................................................................ 34 Figure 2.17 Niobium and Titanium BINOL Catalyzed Desymmetrization ............................... 35 Figure 2.18 Various Metal Catalyzed openings by Schneider et al ........................................ 36 Figure 2.19 VAPOL Phosphate Metal Salts for Aniline Ring Opening .................................... 36 Figure 3.1 Aziridination from Imines ...................................................................................... 39 Figure 3.2 Brønsted Acid Catalyzed Aziridination ................................................................. 40 Figure 3.3 Darzens Epoxidation ............................................................................................ 40 Figure 3.4 Catalysts for Aza-Darzens Reactions .................................................................. 41 Figure 3.5 Low Enegry Structure of diVAPOL PhosphatE Magnesium Salt ......................... 45 Figure 3.6 Middle Enegry Structure of diVAPOL Phosphate Magnesium Salt ..................... 46 Figure 3.7 High Enegry Structure of diVAPOL Phosphate Magnesium salt ......................... 47 Figure 3.8 Possible Interconversion Between Figures 3.5-3.7 ............................................. 48 Figure 3.9 Possible Transition States by Ishihara ................................................................. 48 Figure 3.10 Proposed Transition State for Aza-Darzens Reaction ......................................... 49 Figure 3.11 Possible Transition States ................................................................................... 50 Figure 3.12 Three Dimensional Model of Transition State Two .............................................. 51 Figure 3.13 Alternate View of Transition State Two ................................................................ 51 Figure A.1 Example for the Preparation of Aziridines ........................................................... 63 Figure A.2 Preparation of VAPOL by Wulff ........................................................................... 64 Figure A.3 Preparation of BINOL Phosphoric Acids .............................................................. 65 Figure A.4 General Desymmetrization of meso-Aziridines .................................................... 65

vi

Figure A.5 Desymmetrization of meso-Aziridines with Aniline .............................................. 66 Figure A.6 Preparations of N-Acyl Imines ............................................................................. 97 Figure A.7 Absolute Configuration of aza-Darzens Products ................................................ 99

vii

LIST OF SPECTRA

Spectra B1.1. 1H and

13C Spectra for Compound 94aa ..................................................... 118

Spectra B1.2.

1H and

13C Spectra for Compound 94ab ..................................................... 119

Spectra B1.3.

1H and

13C Spectra for Compound 94ac ..................................................... 120

Spectra B1.4.

1H and

13C Spectra for Compound 94ad ..................................................... 121

Spectra B1.5.

1H and

13C Spectra for Compound 94ae ..................................................... 122

Spectra B1.6.

1H and

13C Spectra for Compound 94af ...................................................... 123

Spectra B1.7

1H and

13C Spectra for Compound 94ag ..................................................... 124

Spectra B1.8.

1H and

13C Spectra for Compound 94ah ..................................................... 125

Spectra B1.9

1H and

13C Spectra for Compound 94ai ...................................................... 126

Spectra B1.10.

1H and

13C Spectra for Compound 94aj ...................................................... 127

Spectra B1.11.

1H and

13C Spectra for Compound 94ak ..................................................... 128

Spectra B1.12.

1H and

13C Spectra for Compound 94al ...................................................... 129

Spectra B1.13.

1H and

13C Spectra for Compound 94am .................................................... 130

Spectra B1.14.

1H and

13C Spectra for Compound 94an ..................................................... 131

Spectra B1.15.

1H and

13C Spectra for Compound 94ao ..................................................... 132

Spectra B1.16.

1H and

13C Spectra for Compound 94ap ..................................................... 133

Spectra B1.17.

1H and

13C Spectra for Compound 94aq ..................................................... 134

Spectra B1.18.

1H and

13C Spectra for Compound 94ar ...................................................... 135

Spectra B1.19.

1H and

13C Spectra for Compound 94as ..................................................... 136

Spectra B1.20.

1H and

13C Spectra for Compound 94at ...................................................... 137

Spectra B1.21.

1H and

13C Spectra for Compound 94au ..................................................... 138

Spectra B1.22.

1H and

13C Spectra for Compound 94av ..................................................... 139

Spectra B1.23.

1H and

13C Spectra for Compound 94ba ..................................................... 140

Spectra B1.24.

1H and

13C Spectra for Compound 94ca ..................................................... 141

viii


13C Spectra for Compound 94da ..................................................... 142

Spectra B1.26.

1H and

13C Spectra for Compound 94ja ...................................................... 143

Spectra B1.27.

1H and

13C Spectra for Compound 94ka ..................................................... 144

Spectra B1.28.

1H and

13C Spectra for Compound 94la ...................................................... 145

Spectra B1.29

1H and

13C Spectra for Compound 123 ....................................................... 146

Spectra B2.1.

1H and

13C Spectra for Compound 148a ..................................................... 147

Spectra B2.2.

1H and

13C Spectra for Compound 148b ..................................................... 149

Spectra B2.3.

1H and

13C Spectra for Compound 148c ..................................................... 151

Spectra B2.4.

1H and

13C Spectra for Compound 148d ..................................................... 153

Spectra B2.5.

1H and

13C Spectra for Compound 148e ..................................................... 155

Spectra B2.6.

1H and

13C Spectra for Compound 148f ...................................................... 157

Spectra B2.7.

1H and

13C Spectra for Compound 148g ..................................................... 159

Spectra B2.8.

1H and

13C Spectra for Compound 148h ..................................................... 161

Spectra B2.9.

1H and

13C Spectra for Compound 148i ...................................................... 163

Spectra B2.10. HPLC Spectra for Compound 159 .............................................................. 165

ix

ABSTRACT

Chiral molecules as with biological activity are plentiful in nature and the chemical literature;

however they represent a smaller portion of the pharmaceutical drug market. As asymmetric

methodologies grow more powerful, the tools are becoming available to synthesize chiral

molecules in an enantioselective and efficient manner.

Recent breakthroughs in our understanding of phosphoric acid now allow for Lewis acid

catalysis via pairing with alkaline earth metals. Using alkaline earth metals with chiral phosphates

is an emerging approach to asymmetric methodology, but already has an influential record.

The development of new conditions for the phosphoric acid-catalyzed highly enantioselective

ring-opening of meso-aziridines with a series of functionalized aromatic thiol nucleophiles is

described in this thesis. This methodology utilizes commercially available aromatic thiols, a series

of meso-aziridines, and a catalytic amount of VAPOL calcium phosphate to explore the substrate

scope of this highly enantioselective reaction.

Additionally, the development of new conditions for a catalytic asymmetric aza-Darzens

aziridine synthesis mediated by a vaulted biphenanthrol (VAPOL) magnesium phosphate salt is

described in this thesis. Using simple substrates, this methodology explores the scope and

reactivity of a new magnesium catalyst for an aziridination reaction capable of building chirality

and complexity simultaneously.

1

CHAPTER 1: ASYMMETRIC CATALYSIS, LIGANDS, AND CHIRAL

PHOSPHATE SALTS

1.1 Catalytic Asymmetric Induction

From Pasteur’s discovery of optically active L and D Tartaric acid in 1848, charity has

intrigued organic chemists. The human body can recognize different terpenoids with relative

ease, for example: the “R” enantiomer of carvone is the smell of peppermint, while the “S”

enantiomer is the smell of caraway fruit.1 For the preparation of enantiopure molecules there are

three fundamental paths; start with enantiopure molecules prepared by nature, chiral resolution of

a racemate, and asymmetric bond forming reactions. The most elegant and attractive of these

methods is to use a small amount of chiral compound to induce chirality through a transformation

or bond forming reaction. Asymmetric methodology is of paramount importance due to the chiral

recognition in biological systems; most biologically active nature products are optically active.2,3

Figure 1.1 Tartaric Acid and Carvone

The last 30 years has seen an explosion in the development of chiral catalysts for

asymmetric induction, although its roots are much older.4 When using small molecules which are

inexpensive and more stable in organic solvent then enzymes, research laboratories around the

world have started to observe certain outstanding organic catalysts. For the asymmetric bond

forming reactions those that demonstrate a wide scope have been of particular interest to

chemists. Known as “privileged ligands and catalysts,”5 some of these catalysts have shown a

particularly large range in scope, versatility and effectiveness for asymmetric bond formation.

2

When discussing the range of catalytic system chemists are interested in a single catalyst

capable of a wide variety of reactions, opposed to a unique catalyst for a singular reaction.

Certain small molecules of asymmetric catalysis often described as “privileged ligands and

catalysts” have demonstrated this fundamental property in the literature. Outlined in Figure 1.2:

we see 5 bisoxazoline,6 6 cinchona alkaloids,

7,8 7 thiourea,

9 8 salen,

10 9 TADDOL,

11-13 and 10

BINOL,14,15

these are just a few of the catalytic systems designed in recent years.5,16

Today many of chemists’ most useful chiral ligands were inspired by nature; bisoxazoline was

said to be inspired by the vitamin B12 core, while TADDOL is synthesized from tartaric acid.

Cinchona alkaloids have become popular in the literature for activations using the notably basic

nitrogen of quinine, which has medicinal properties dating back to the Spanish missionaries

integration with the Incan empire in the 1630’s.17

Thiourea’s functionality is similar to nature’s

urea with additional substituents to allow for a chiral environment and modulation of the

electronics. Salen was based on various oxidative enzymes which have a heme like core where

quatra-coordination to a central metal is present; salens are similar to porphyrins but accessed

more easily.5 BINOL is the exception in this regard; it was designed only to exploit C2 symmetry

operation and axial chirality caused by the restricted rotation around the central carbon-carbon

bond.

Figure 1.2 Privileged Ligands and Catalysts

3

Although the privileged ligands share similar functionalities, multiple heteroatoms and ridged

structures, it is not a trivial question as to why they have been so successful. What is clear is that

each catalyst is available to adopt multiple transition states, which allow for a variety of

activations in a chiral environment. While these catalysts have been used for different

functionalities over the years, our focus is on those reactions where the catalyst activates the

nucleophile/electrophile through coordination (Lewis acid/base); opposed to systems where the

catalyst forms a reactive intermediate or acts as a phase-transfer catalyst. In this thesis the

contribution to asymmetric methodology concerning BINOL Phosphate Salts of group two metals

is described.

1.2 BINOL as a Chiral Backbone

BINOL has shown great versatility as a chiral ligand in many reactions since its preparation

by Von Richter18

in 1873, and notably by Pummerer19

in 1926. In 1979 Noyori20

recognized

optically pure BINOL (preparation method from Jacques and Fouquey 1971)21

for its use as a

chiral auxiliary, taking advantage of its axial chirality to create nearly enantiopure products. In

2004 Terada22

and Akiyama,23

independently prepared and demonstrated the use of BINOL

phosphoric acid as a metal free organocatalyst. The phosphoric acid derivatization had been

used previously for the resolution of BINOLs and VAPOL but it wasn’t until 2004 that anyone had

used it directly for asymmetric organocatalysis. Their hope was to change the hydrogen bond

catalyst BINOL to a bifunctional catalyst able to activate a nucleophile and electrophile

simultaneously, a Lewis basic and Brønsted acid catalyst.

Figure 1.3 Developments in Modes of Activation

4

Besides the bifunctional nature and increased acidity, there is another important difference

between BINOL and the phosphoric acid derivative; there is an elongation from the reaction

center to the axial chirality. Curiously the wide variety of reactions which demonstrate

asymmetric control using BINOL or BINOL phosphoric acid, share little as far as their respective

mechanisms. Going forward these achievements by Akiyama and Terada were thought to be the

start of modern phosphoric acid chemistry.

Figure 1.4 Timeline for the Exploitation of BINOL Backbone

In recent years BINOL phosphates have been paired with metals to extend their utility, this

pairing can change the Brønsted acid activation to Lewis acid activation. However, the first

example of metal phosphate pairing was reported in 1990 when Alper serendipitously used

BINOL phosphoric acid as a ligand for Palladium catalyzed Hydrocarboxylation of Olefins.24

It is

interesting to note that phosphate salts of BINOL phosphoric acid were largely unappreciated and

underutilized in the literature until 20 years later and it would be another 14 years before Terada

and Akiyama published the catalytic use of phosphoric acids without the use of a metal.22,23

Pirrung followed up this work by demonstrating a cycloaddition reaction in 1992 with a rhodium

binaptholphosphate.25

Inanaga et al pioneered much of this area with a Yttrium phosphate Diels-

Alder 1995,26

Scandium phosphate catalyzed Michael addition in 200227

and Cerium phosphate

catalyzed hetero Diels-Alder in 2003.28

After Akiyama and Terada’s publications brought attention to phosphoric acid many other

metal BINOL phosphates were used to catalyze reactions, Copper,29

Sodium,30

Iridium,31

and

5

Aluminum32

all showed great utility. All of these phosphate salts were interesting but only made

up a small percentage of the BINOL phosphoric acid reactions being published during this time

period. Perhaps because of a lack of knowledge about the phosphate salts this area was largely

unexplored, with the exception of those mentioned, until 2010.

Figure 1.5 Functionality of BINOL Phosphoric Acid and Metal Salt

In 2010 Ishihara demonstrated that many of the phosphoric acid reactions in the literature

may have been phosphate salts of calcium, magnesium, and sodium.33

Ishihara also showed

that the impure phosphoric acid could be washed with HCl to remove salt impurities,34

and then

resubjected to alkoxide-metal salts to produce pure metal salt catalysts. List demonstrated that

these unrealized impurities had come from the silica gel used to purify the phosphoric acids after

being synthesized.35

Group one and two metals were largely ignored prior to this point under the

assumption that they were too weak to catalyze reactions; however they were the true catalyst for

many of the reactions between 2004 and 2010.

1.3 Electronics and Heteroatom Variants

The move from BINOL diol to phosphoric acid expanded the use of this scaffold, and while

much of the research done in this area has been with phosphoric acid, there have been other

achievements. Hoffman36

synthesized a Dithiophosphate (22) and Yamamoto37

an N-Triflyl

Phosphoramide (23) both with the design to make a more acidic catalyst then phosphoric acid.

List would later synthesize an N-Phosphinyl phosphoramide as well as several other

modifications to the coordination sites of the catalyst.38,39

BINOL Phosphoric acid’s pKa is 13-14 in acetonitrile40

(1 in H2O), while N-Triflyl

Phosphoramide’s pKa is 6-7 in acetonitrile.40

At least in acetonitrile we can see how the N-Triflyl

6

Phosphoramide will be much more acidic and thus have different reactivity when it comes to

activation of substrates.

For comparison thiourea’s pKa is 21 in DMSO, TADDOL’s pKa 28 in DMSO, BINOL diol’s

pKa is 17 in DMSO. Part of this additional acidity of BINOL has to do with the ability to share the

remaining proton between the two oxygens. Both approaches were to use the versatile structural

motif of the BINOL backbone and then change the electronic properties around the phosphorus to

make a more powerful catalyst.

There have been others interested in making more powerful Brønsted acids; however they

have seen little range of activation or use in the literature. List was able to produce a catalyst

demonstrating both Brønsted acid and Brønsted base motifs.38

It may be that BINOL phosphoric

acids have a pKa appropriate for hydrogen bonding but not so acidic that they produce ion

pairs,41

alternatively it could be caused by a lack of purification methods available until recently.

A phosphate metal salt of these stronger Brønsted acids would sure show different properties

then their phosphoric acid analogs. Terada has also attempted to make stronger acid catalysts

through modification of the aromatic skeleton to have a chiral bis-phosphoric acid.42

Regardless

of the reason these more acidic Brønsted acids have rarely been found to be the optimal catalyst.

Figure 1.6 Stronger Brønsted Acids

Recently Rueping43

has been able to grow a crystal of an N-Triflyl Phosphoramide

coordinated to calcium, which is the only one of its kind. It shows two N-triflyl phosphoramides

coordinated to single calcium in the presence of dioxane. As more is learned about the

coordination of these other phosphorus BINOL catalyst they may be a useful tool to control the

7

electronics of the catalyst system. Attempts at growing a crystal of BINOL based phosphate

calcium or magnesium, have not meet with success.

1.4 Axial Chirality as a Chiral Scaffold

Much has been done with the chiral scaffolding of BINOL Phosphoric acid in the 3, 3’

position. The majority of publications in the literature modify these positions to allow for facial

selectivity of various reactions via the modulation of sterics and electronics. Other positions on

BINOL have also been used, however 3, 3’ intuitively have the greatest effect on asymmetric

induction as they face toward the center of the catalytic pocket. It is clear that any change to the

3 and 3’ position can have a dramatic effect on the ratio of the enantiomers produced by the

reaction.

Figure 1.7 A Sample of 3, 3’ Substituted BINOL, VAPOL, and VANOL Phosphoric Acids

While there have been successful Phosphoric Acid derivatives of BINOL with substitutions in

the 3, 3’ positions some have seen more notoriety then others. The most prolific BINOL

8

Phosphoric acids in the literature all share aromatic rings in the 3, 3’ position. Much of the initial

success of both Akiyama23

and Terada22

was their realization that they needed to modify the 3, 3’

substitution.

Other notable structures exist such as Shibasaki’s44

linked dimeric BINOL from the 3

position. By mimicking crown ethers using two BINOL’s they hoped to coordinate metals with +3

oxidation states and larger atomic radii.

In Terada’s work with asymmetric Mannich reactions, he was able to show some trend in

sterics of the catalyst to enantioselectivity of the product formed (table 1.1). In this Mannich

reaction as the substituent grows in size from H to phenyl to biphenyl to 4-(naphthalen-2-

yl)phenyl the enantiomeric excess grows successively. It should be noted this is not always the

case and in fact more often than not literature cannot explain the enantioselectivity caused by the

optimal catalyst. In the future it will be possible to explain the enantioselectivity as we learn more

about these types of catalytic systems and computational methods become available to examine

the effect of various substituent patterns on a catalyst.45

Table 1.1 Catalyst Effect on Mannich Reactions

In 2006 Wulff and coworkers developed VANOL and VAPOL as chiral catalysts for Lewis acid

activation.46-48

They hoped to point the naphthalene rings toward the chiral pocket to directly

affect the reactions near the diol with the aromatic rings attached to the C2 symmetric carbons.

In 2005 Antilla and coworkers extended the ideas of Terada and Akiyama making the VAPOL

phosphoric acid and demonstrating it for a number of reactions.49-51

In 2011 Antilla and

9

coworkers expanded the work of Ishihara and List by coordinating VAPOL phosphoric acid to

group one and two metal phosphates for catalytic asymmetric bond forming reactions. 52-55

Figure 1.8 Development of Vaulted Binapthols and Vaulted Biphenanthrols

It is noteworthy that many 3 and 3’ position substitutions on BINOL have been developed but

scarce other C2 symmetric scaffolds like VAPOL and VANOL exist which can be produced

cheaply in enantiopure form. Some success has been seen with 2 linked BINOL motifs through

an alkyl chain in the 3 position, or through an imidodiphosphoric acid.39

A spirocycle backbone

has also been developed which can contain a phosphoric acid.56

Although not discussed here

hydrogenation of the two aromatic rings of BINOL not connected to the C2 axis is possible and

leads to the so called “H8 BINOL” which has been a fairly successful derivatization.

1.5 Alkaline Metals: Calcium and Magnesium

Alkaline earth metals found from the salt impurities produced very effective catalysts for

asymmetric methodologies and have attractive properties as group two elements. Alkaline earth

metals are common in seawater as well as other places in nature; in fact calcium and magnesium

are respectively the fifth and eight most common elements in the earth’s crust.57

Due to their

abundance not only in nature but also in the mammalian body, they are known to be less toxic to

humans and the environment then transition metals.58

Due to their availability, precious metals

are often more expensive than their alkaline earth metal cousins. Alkaline metals are far less

common in the literature then transition metals and this is especially true for asymmetric

catalysis.59,60

This is not to say they don’t have a clear mode of activation, alkaline earth metals

10

do show significant Lewis acidity and among them calcium shows the strongest Lewis acidity of

the alkaline earth metals.59

When compared to hydrogen bond catalysts like BINOL derived phosphoric acid, group two

metals with phosphate ligands have the added effect of creating a more well-defined three

dimensional chiral pocket than phosphoric acid, due to their bidentate nature (figure 1.9). The

stable oxidation state shared by calcium and magnesium at +2 allows them to create two

covalent bonds to anionic chiral phosphates.

Figure 1.9 BINOL Phosphoric Acid and BINOL Calcium Phosphate Salts

1.5.1 Calcium Phosphate Salts

Bis(oxazoline),61-63

BINOL diols64,65

and BINOL phosphate ligands have been used in recent

years with calcium to successfully promote a number of asymmetric reactions. Ishihara33

found

that calcium BINOL phosphates were excellent catalysts for carbon-carbon bond forming

Mannich type reactions.33

He demonstrated three interesting ideas; that the original 2004

publication of this reaction was most likely the phosphate salt, a high yield and enantioselectivity

could be achieved with the pure phosphate salt and that the reaction could be re-optimized to use

the true phosphoric acid if desired.

Figure 1.10 Calcium Phosphate Catalyzed Mannich Reaction

11

Reuping,66

and Antilla55

were also able to expand the scope of those calcium phosphate

catalyzed Mannich reactions. Reuping showed an interesting use of pyrone and 1,3-

cyclohexadione Mannich reactions with N-protected Boc imines. They were able to demonstrate

moderate yield and selectivity for these difficult substrates.

Figure 1.11 Calcium Phosphate Catalyzed Mannich Reaction and Amidation

Amidation of enamides by Zhu67

with BINOL calcium phosphates suggest that previous

activation of enamides by phosphoric acids68

may have been phosphate salts instead of the true

acids. However they did note that although the phosphoric acid was not the optimal catalyst it

was able to catalyze this reaction with lower enantioselectivity. Zhu was also able to demonstrate

that the products were easily converted to useful products: 2-hydrainoketones and 1,2 diamines.

The activation of oxindoles for Michael reactions by Antilla53,54

showed that the calcium

phosphates could be very useful for activation of 1, 3 diones. The optimal catalyst for all three

systems was VAPOL calcium phosphate suggesting a similar transition state for

benzoyloxylation, chlorination, the Michael reaction and perhaps a wider scope of catalytic

activation then described in the literature.

12

Figure 1.12 Benzoyloxylation, Chlorination, and Michael Addition to Oxindole

1.5.2 Magnesium Phosphate Salts

While calcium and magnesium both have stable oxidation states that allow them to bind to

two phosphates; magnesium has a smaller ionic radius which will allow for a different set of

coordination sites but overall less volume in the coordination sphere. This smaller ionic radius

causes the distance between the chiral ligand’s steric groups to contract and inevitably the size of

the chiral pocket. The ionic radius of 114 pm for calcium and 72 pm for magnesium in their

respective +2 cations, however both are rather larger compared with some common transition

metals used for catalysis (Cu[II] 73, Pd[II] 86, and Rh[II] 60).69

While many of the calcium phosphate catalyzed reactions mentioned in section 1.4.1

screened magnesium phosphates as well, it was not found to be the optimal catalyst. The first

possible magnesium phosphate was likely by Lou in 2010,70

there is no characterization of this

catalyst but it could be inferred by the reaction conditions that there is coordination between the

phosphoric acid and the magnesium fluoride.

13

Figure 1.13 Synergistic Effects of Brønsted Acid and Lewis Acid

However in 2011 Antilla52

demonstrated the preparation of chiral phosphine oxides by

asymmetric phosphination with BINOL magnesium phosphates. This useful reaction showed

wide substrate scope with retention of enantioselectivity, while producing products that are both

synthetically and biologically interesting.

Figure 1.14 Preparation of Chiral Phosphine Oxides

Luo followed up this work in 2012 with what they called Binary acid catalyst,71

this work is the

phosphate analogs of Metal BINOLate complex chemistry.15,44,72

This is an excellent example of

stereospecific 1,5-hydrogen transfer catalyzed by the coordination of magnesium to the 1,3

dicarbonyl system.

Figure 1.15 Magnesium Catalyzed Aminocyclization

Interestingly in this paper Luo demonstrated that the reaction could not be catalyzed by

phosphoric acid and when the magnesium phosphate was prepared as described by Ishihara33

the reaction worked well however there was no enantioselectivity (table 1.2).

14

Table 1.2 Effects of Brønsted/Lewis Acid Pairings

15

CHAPTER 2: CATALYTIC ASYMMETRIC AZIRIDINE

DESYMMETRIZATION

2.1 Introduction to aziridine desymmetrization

Aziridine ring-opening chemistry allows for direct access to a variety of chiral amines, and are

useful precursors for the rapid construction production of advanced targets with structural

complexity.73

Concurrently new methodology for the ability to simultaneously set two

stereocenters of adjacent carbons continues to be of interest for its high synthetic utility.74

The

difficulty of enantioselective desymmetrization is the ability of the catalyst to differentiate between

the two enantiotopic centers, figure 2.1. When R1 and R2 61, are the same desymmetrization by

nucleophilic attack on aziridine carbons produce two enantiomers 60 and 62. Mukaiyama

showed as early as 1985 that epoxides could be opened to set two stereo-centers

simultaneously,75

however reactions of aziridines in the literature are far less prolific.

Figure 2.1 Nucleophilic Aziridine Desymmetrization

Nucleophilic ring-opening of aziridines commands attention today as a growing number of

nucleophiles can be activated by Brønsted or Lewis acids to allow for the preparation of a diverse

list of functionalized products in spite of the aziridine’s relatively lower reactivity.49,51-53,68,76-78

Ring-opening strategies which lack stereocontrol often relay on chiral resolution for the

separation of enantiomers; while this method has proven profitable for pharmaceutical companies

at best it can only lead to 50% yield.79

Stereocontrol can be realized in cases where chiral

catalysts allow for ring-opening desymmetrization reactions of meso-aziridines in up to 99%

16

stereoselectivity.51,80

Examples include the implementation of catalytic chiral metal complexes

that can allow for a high enantioselectivity of the resulting ring-opened product using primarily

azide or cyanide nucleophiles.81-85

Figure 2.2 Chiral Chromium Azide Complex for Desymmetrization

In 1999, Jacobsen and coworkers81

showed the desymmetrization of meso aziridines 63

could be accomplished by the nucleophilic addition of a chromenium azide, figure 2.2. The

limitation of this first approach was the requirement of the stoichiometric chromenium tridentate

Schiff base complex 64. This lead the way for other groups to attempt desymmetrizations with a

variety of catalytic asymmetric systems.

Figure 2.3 Yttrium Catalyzed Desymmetrization

In 2006 Shibasaki and coworkers83

reported the Yttrium catalyzed desymmetrization (figure

2.3) using a chiral ligand and allowing for the direct synthesis of Tamiflu, 64. While previous

reports catalyzed the desymmetrization this is considered to be the first sub-stoichiometric

example by employing catalytic amounts of Yttrium triisopropoxide and chiral phosphine oxide 67.

RajanBabu made significant scientific improvements on this method in three years later.85

17

Figure 2.4 Direct Synthesis of Tamiflu

After the initial report, Shibasaki demonstrated that a similar system using phosphine oxide

chiral ligands (71 and 72) that could also be used in conjunction with TMSCN.82

This system

required a precise ratio of ligand to metal to phenol to be successful in generating the active

catalyst; but was none the less inspirational, figure 2.5.86

Figure 2.5 Gadolinium Catalyzed Desymmetrization with TMSCN

In 2007 the Antilla and coworkers51

showed that this transformation could be performed in the

absence of Lanthanide metals. By replacing both the metal and the chiral phosphate oxide from

Shibasaki’s work with a Brønsted acid VAPOL phosphoric acid P11 figure 2.6, allowing for the

simultaneous activation of both the aziridine 74 and the nucleophile.

Figure 2.6 Organocatalytic Desymmetrization

This dual functionality concept was based understanding at the time and lead to the proposed

mechanism with support from NMR data. The catalyst P11 would first undergo proton exchange

18

with the trimethylsilyl azide to form 76. The silicon would then become pentacoordinate 77,87

similar to silicon mediated catalysis,88

with the carbonyl of the aziridine 74.

Figure 2.7 Proposed Mechanism for Organocatalytic Desymmetrization

The effect of drawing the electrons away from the carbon nitrogen bonds makes the carbons

of the aziridine more electrophilic. The chiral pocket created by VAPOL phosphoric acid prevents

the attack from one side of the aziridine, controlling stereochemistry by facial selectivity for the

ring opening (77 to 78). Protonation of the catalyst P11 and release of the diamine 78 product

allows for the continuation of the catalytic cycle. This mechanism was the working hypothesis for

the next several years,89

until a report by Ishihara and coworkers uncovered the possibilty that

these catalysts were not Brønsted acids but instead Lewis acid phosphate salts.33

2.2 Mercaptans in Desymmetrization

Azides are strong nucleophiles but in the absence of catalyst the aziridines described in

section 2.1 are unreactive.51

Mercaptans are similar in nucleophilic strength to that of azides and

when they are applied to the aziridines in section 2.1 we see low to zero reactivity, similar to the

results seen in azide chemistry. We postulated that if a suitable catalytic system could be

19

discovered to lower the energy of activation and create a chiral environment to impart

enantioselectivity, that mercaptans could undergo a similar reaction.

This expansion of substrate scope would allow for the preparation of interesting chiral β-

amino thioethers.90

Common chiral β-amino thioethers are found in various natural products

(figure 2.8) including Penicillin 79, Biotin 80 (Vitamin H) and as well as an extract from Nuphar

pumilum Chinese water lily 81.91-93

Figure 2.8 Common Chiral β-amino Thioethers

Chiral β-amino thioethers can undergo interesting structural modification after the addition of

the thiol to aziridine. Recently Choon-Hong Tan94

and coworkers were able to desymmetrize

meso-aziridines with a guanidine catalyst. They then took those beta-amino thioethers 82 on to

allylic amides 83 (figure 2.9) or in a separate experiment, beta-amino sulfonic acid.

Figure 2.9 Post Desymmetrization Structural Modification

At the start of our study the previous methodology reporting catalytic asymmetric ring-

opening desymmetrization reactions utilizing thiols were rare, with low enantiomeric excesses

being found. Although several examples existed with chiral perpetrations from stoichiometric

reagents were already known in the literature.95

The best results were found with 4.8 equivalents

of thiol, 3.0 equivalents of diethyl Zinc alkyltarterate 86 at zero degrees Celsius (figure 2.10). We

20

believed that although this method was ground breaking at its time, there was clearly room left for

improvement.

Figure 2.10 Zinc Dialkyl Tartrate Desymmetrization

One catalytic example from Tetrahedron: Asymmetry in 2007, figure 2.11, showed the

perpetration using meso-N-sulfonylaziridines 87 with a single example reaching 73%

enantiomeric excess 88 with cinchonine-derived chiral quaternary ammonium salts as the catalyst

89.96

One year later Wu97

and coworkers would simplify this method using Quinine 6; this method

is both effective and fast. We chose a modified version of these conditions to prepare the

racemic examples for HPLC traces for compounds detailed in tables 2.1-2.9.

Figure 2.11 Desymmetrizations with Cinchonine-derived Ammonium Salts and Quinine

However these and other methods like them suffered from moderate enantioselectivity,

narrow substrate scopes and reliance upon meso-N-sulfonylaziridines 87 and 90; with Acyl

aziridines Wu had reported between zero and 45% enantiomeric excess.

21

Late in our investigation using thiols, a publication by Della Sala89

described an

enantioselective ring-opening of meso-aziridines using (phenylthio)trimethylsilane (TMS-SPh) and

the catalyst system we reported in our previous azide chemistry. Interestingly, this report implied

that silylated nucleophiles were required, and the authors explained their chemistry by invoking

our previously postulated mechanism involving the importance of silicon being present on the

nucleophile. It has now been suggested that this mechanism maybe incorrect based on the work

of Ishihara33

and List.98

The Lewis acid phosphate salt would be unlikely to coordinate with the

silicon of the TMS group.

2.3 Organocatalytic aziridine desymmetrization

During our optimization process, we quickly became aware that silylated nucleophiles while

usfull were not necessary for the phosphoric acid-catalyzed thiophenol ring-opening reactions of

substituted N-benzoylaziridine substrates. We also noticed that the 3,5 dinitro substitution on N-

protected benzoylaziridines was necessary to achieve the best possible enantioselectivity,

although optimization could likely be done to promote selectivity under other protecting groups

under other catalytic conditions.

Table 2.1 entry 92a, 3,5 dinitro-N-benzoylaziridine allowed for the greatest selectivity for the

nucleophilic addition of thiophenol 93a to make product 94aa. Never the less we also examined

other types of N-benzoylaziridines for comparison, 92b was the most successful aziridine

protecting group for the phosphoric acid catalyzed ring opening with TMS-N3.51

However when

used for the addition of thiophenol 93a we found it to be significantly lower in selectivity, with only

43% enantiomeric excess. Entry 92c, is a commonly used in the older literature of aziridine ring

opening chemistry,82

here however both its product yield and ee are affected negatively when

compared to the 3,5 dinitro N-benzoylaziridine. Presumably the yield is affected by the change in

electron withdrawing capacities and the ee by the reduced steric environment.

22

Table 2.1 Effects of N-Substitution

More recently in an effort to probe the mechanism of this reaction a number of other N-

substituted aziridines were synthesized via the known literature procedure.83

Entry 92d, the

perfluorinated-N-benzoylaziridine, with significant electron withdrawing capability, produced no

23

desired product. Cbz and Boc (entries 92e and 92f respectively) were synthesized but again

showed no reactivity in our catalytic system due to the strength of the carbon nitrogen bond in the

aziridine. Entry 92g, the Ts protected aziridine showed no reactivity in the presence of aziridine

in spite of its popularity as a reagent of choice in much of the previous work presented in the

literature. Notably no reaction in was observed in Entry 92g which was the optimal N-protected

aziridine for both the quinine and the cinchonine-derived chiral quaternary ammonium salts for

aziridine ring opening.96,97

Lastly, entry 92h without a carbonyl81

present had the expected lack of

reactivity as well, indicating that it is of paramount importance to the mechanism.

While entries 92a and 92b show 3-7% yield of product over 24 hours at room temperature in

the absence of catalyst; aziridines in entries 4-8 of this table showed no product by thin layer

chromatography over a period of 24 hours in the presence of the optimal catalyst P11 for entry 1.

Table 2.2 Solvent Effects on Desymmetrization

24

From our solvent screening table we can see the effects that the polarity of the solvent has

on the reaction, table 2.2. Nonpolar solvents like hexanes and toluene provided moderate

enantioselectivity for the reaction and lower yield compared to other solvents (entries 1-2), Ortho

and Meta xylenes gave higher yields but lower enantioselectivities (entries 3-4). Freshly

redistilled Chlorobenzene gave an improvement in enantioselectivity up to 83%, entry 5. Both

methyl tert-butyl ether (entry 8) and diethyl ether (entry 6) were excellent solvents for the

thiophenol ring-opening, with the product found in these conditions having excellent yield and ee.

Diethyl ether was selected for the rest of the reactions involving thiols due to its ease of

purification and availability. Interestingly Diisopropyl Ether did not follow the same trend as the

other ethers, giving instead 59% yield and 70% ee (entry 7).

Table 2.3 Brønsted Acid Optimization

While dichloromethane (DCM) gave improved ee when compared to the non-polar solvents

(entry 10), it as well as dichloroethane (DCE) gave lower enantioselectivity (entry 11) and yield

25

compared to diethyl ether. Other polar solvents like EtOAc (entry 12), MeCN (entry 13), or

tetrahydrofuran (THF) gave much lower enantioselectivity (entry 9).

Several additional catalysts were screened, but those evaluated gave poor selectivity results

compared to VAPOL phosphoric acid (S)-P11 which was the optimal catalyst for a previous

desymmetrization in our group (Table 2.3).51

For example, with catalyst P1 or P2 the

enantioselectivities dropped to zero and the reactivity to 20% yield and 15% respectively. With

P4 and P5 reasonable product formation was observed however the enantioselectivities indicated

that multiple ring systems in the 3,3’ position were not effective for enantiocontrol.

Table 2.4 Initial Scope of Thiol Desymmetrization

Quinine 6 was effective for N-tosyl aziridines, proved ineffective for enantiocontrol of N-

benzyol aziridines. In the case of the NHTf substituted phosphines either no product was formed

26

(P15) or little more than background reaction was observed (P16). When VAPOL phosphoric

acid was used at 5 mol% the yield fell to 65% and the ee to 89%. At the time these reactions

were performed our understanding was that they were phosphoric acids with a pH of 1-2.98

With

our understanding of phosphate salt chemistry we were able to come back and re address this

issue later in our investigation.

Inspired by the high degree of catalytic activity and selectivity, we wanted to establish the

generality of this reaction. In table 2.4, we show the details of our investigations into varying the

thiol substrate. We found that the reaction was very general for arene thiols. For example, we

were able to perform the reaction with naphthyl-2-thiol (entry 93b) and a variety of ortho-, or para-

substituted thiophenols (entries 93c-g). When a methyl substituent was present in the two

position of the thiol the yield dropped slightly to 88% and 85% for entries 93d and 93e

respectively.

The para position of the thiol might be pointed out of the reaction center significantly enough

that it has no effect on the reaction based on the observation that the enantioselectivity is the

same for methyl, isopropyl, and tert-butyl, 93% ee (entries 93c, 93f and 93g). For these alkyl

substituted mercaptans we see there is a wide range of tolerance while displaying excellent yield

and selectivity for the reaction.

In table 2.5, electron-withdrawing substituents on the thiophenol were not detrimental to the

reactivity or selectivity as chloro and fluoro groups were all well tolerated (entries 93h-j).

Likewise, electron-donating substituents on the arene were shown to be compatible, with

methoxy, and methyl sulfide and hydroxyl groups in the para position (entries 93k-m). To our

pleasant surprise we found that esters were shown to be compatible with the ring-opening

chemistry (entry 93n). The ester group did give lower yield and enantioselectivity however the

rich chemistry of ester functionality in the literature made this an interesting substrate.

27

Table 2.5 Functionalized Thiols for Desymmetrization

Heteroatom aromatic thiols such as 2-methylfuran-3-thiol (entry 93o), benzo[d]thiazole-2-thiol

(entry 93u), and 1-phenyl-1H-tetrazole-5-thiol (entry 93p) produced desymmetrized products

albeit in moderate yield and selectivity. Unfortunately, the use of alkyl thiols also leads to lower

enantioselectivities. For example, while benzyl thiols were moderately good substrates (entries

93qand 93r), longer chain thiols like 2-phenylethanethiol (entry 93s) and n-hexanethiol (entry 93t)

28

were relatively poor reaction partners under these conditions. As we expanded the scope of the

reaction we found reduced enantioselectivity for the same set of optimized conditions. As a side

note other conditions for these reactions were never attempted and may well offer rejuvenation of

the enantioselectivity and yield.

Table 2.6 Exploration of Desymmetrization Scope

We continued the study by investigating the reaction with two additional meso-aziridines with

fused ring systems and two substrates with acyclic substituents. The fused cyclohexene-based

substrate was shown to be an excellent reaction partner with thiophenol 93a (entry 92k). A fused

cycloheptane was also a suitable substrate for the reaction (entry 92j) but required higher

temperature of 60 oC. The cyclooctene equivalent aziridine was unreactive up to 150

oC, it

seems that the ring strain of the fused ring system might help with the reactivity by lowering the

energy barrier of breaking the C-N bond. Alternatively the eight member ring may bend in a

manner that makes backside attack on the aziridine impossible. However to our surprise both

methyl (entry 92i) and n-propyl (entry 92l) 1,2-disubstituted meso-aziridines could be used in the

29

ring-opening chemistry, providing high yield and enantioselectivity of the respective products

using P11 as the catalyst.

Table 2.7 Modulation of Aziridine Sterics and Ring Strain

Our discovery that simple, nonsilylated aromatic thiols can be used for these chiral

phosphoric acid-catalyzed additions strongly suggests that a simpler hydrogen-bond activation of

the aziridine N-acyl moiety and the incoming thiol could be invoked to explain the mechanism.

This is in contrast to the previous phosphoric acid catalyzed methodology for aziridine ring-

openings that may be following a mechanism based on silicon catalysis.51,89

30

2.4 Aziridine Desymmetrization by Phosphate Salt

In work by List98

the elemental analysis of his phosphoric acid in two batches. Batch A

contained phosphoric acid purified by column chromatography. Batch B contains phosphoric acid

by that is the true acid. Ding and coworkers found that if you washed the columned product with

acid you would receive the true acid.34

In Batch A, the all the elements present could be

assumed to be exist as a phosphate salt with the exception of silicon. If the amounts of these

were totaled based on the molecular weight of the various coordination, List estimated that 81%

of Batch A was Phosphate salt, while only 1% of batch B is salt.

Table 2.8 Trace Element Analysis by ICP-OES (values in ppm)

When this was applied to the aziridine desymmetrization with mercaptans we found that like

many others the phosphoric acid was not the true catalyst. After the preparation of the true

phosphoric acid, the reaction was run under standard conditions and found to be racemic (entry

3, table 2.9). Calcium and magnesium have become the most prolific in the literature recently,

and based on the reaction of entries 1 and 2 we can assume that calcium phosphate is the true

catalyst for this reaction. Other Lewis acids were also prepared but no interesting trends of high

reactivity or enantioselectivity were observed.

Table 2.9 Evaluation of Catalyst P11

Batch Na K Mg Ca Al Si Fe Pd Zn

A 6151 29 3590 7482 <5 560 15 7 5

B 16 13 20 83 20 725 9 <5 <5

31

2.5 Mechanistic insights

With the knowledge that the phosphoric acid is not the true catalyst in this reaction we were

left without a proposed mechanism. At this point in the investigation none of the other

publications on this topic propose a credible mechanism. In summary of what we know about the

mechanism of action we looked at the aziridine first. We know that if the carbonyl is not present

on the N-protecting group, the product is not formed; this suggests that Lewis acid metal center is

coordinating to the carbonyl of the N-protecting group. Also if you remove the electron

withdrawing potential of the dinitro groups, reactivity decreases significantly.

Two structures that we can imagine for the aziridine are from an energy minimized structure

(figure 2.12) which is similar to a crystal structure obtained by Lectka of aziridine 96.99

If we look

at these models (hydrogens omitted for clarity) we see that one face of the aziridine is clearly

inaccessible for an SN2 type reaction while the other face is readily available. Our two

enantiomers then are not based of facial selectivity but arise from selectivity between the two

carbons. We also can see how planer the molecule is though the aziridine carbons-nitrogen and

carbonyl.

Figure 2.12 7-azabicyclo[4.1.0]heptan-7-yl(4-(trifluoromethyl)phenyl)methanone

Therefore we would like to propose the following mechanism (figure 2.13). The Lewis acid

P112[Ca] catalyst first interacts with the carbonyl of the aziridine 92 through coordination. Then

the thiophenol comes in coordinates with either the carbonyl of the aziridine or one of the

32

phosphine oxygens 97. This adjusts the phenyl group with pi-pi stacking to the catalyst for

selectivity and allows nucleophilic attack on the carbon of the aziridine 98. Next the amide

nitrogen picks up the hydrogen as the beta-amino thioether leaves the reaction center 93. Thus

allowing for reformation of the catalyst by dissociation-association.

Figure 2.13 Proposed Mechanism

Based on this mechanism we predicted that a variety of nucleophiles could open this aziridine

selectively as long as they coordinate to either the carbonyl of the aziridine or the catalyst. Earlier

success with TMS-N3 suggests that TMS-CN, TMS-Cl or TPS-Cl might be suitable for this

chemistry. We tried a few variants of this chemistry with TMS-CN, but saw little to no selectivity.

We experimented with TMS-Cl and TPS-Cl extensively but seemed to reach a limit at 40% ee

33

that could not be overcome. The chlorination of N-acyl aziridines is uncontrollably fast and do to

a lack of hydrogen bond with the catalyst lead to failure. Much to our disappointment it seems

that the aromatic handle that was required for the mercaptan aziridine opening might be the norm

for this system rather than the exception.

In unpublished work by Kimberly Law under the direction of Dr. Emily Rowland, we saw that

there was low product formation of both phenols and alkyl alcohols. When product was formed it

was racemic or nearly racemic. However recently we did find that aniline was able to form

product in very high yield, even when uncatalyzed. In polar aprotic solvents we would expect the

phenoxide ion to be more nucleophilic then sulfoxide so based on our data we can assume that

thiols are still protonated at the time of reaction (thiophenol 10.3 pka in DMSO,100

aniline 30.6 pka

in DMSO,101

phenol 18 pka in DMSO102

).

All three of these share the electron withdrawing potential and steric hindrance of the

benzene ring, so we can explain the reactivity differences based on ability of each to interact with

the catalyst.

2.6 Aniline Addition

In the interest of exploring the reaction mechanism we turned to Aniline because it was clear

that it was nucleophilic enough to open a meso-aziridine and at the same time shared steric

properties that were at force in the thiophenol opening. Going back to 1994, Yamamoto was

interested in the ring opening of aziridines with amines in a catalytic method by using lanthanum

triflates.103

Figure 2.14 Tin Catalyzed Desymmetrization with Aniline

34

Singh and coworkers104

had discovered that an aziridine 100 could be opened by tin or

copper triflate in as little as 10 minutes (figure 2.14). In 2002, Singh expanded this work to

include silica gel as a catalyst for this reaction without the use of solvent.105

This allowed other groups to think about using Lewis acids to catalyze this reaction for the

formation of useful diamines (figure 2.15). B(C6F5)3 catalyzed 104,106

PBu3,107,108

BiCl3,10

DMSO

106,109

Sc(OTf)3 108,110

and even DABCO111

were all shown to be successful catalysts for the

ring opening of aziridines with anilines.

Figure 2.15 Lewis Acid Catalyzed Ring Openings

PBu3 and DABCO most likely didn’t act as Lewis acids, their activity was partially explained

by Yizhe Li et al in 2005.111

In figure 2.16 the desymmetrization with DABCO the ammonium 111

was stable enough for characterization (figure 2.15). When 111 was added directly as the

catalyst for the ring opening with 109 the same reactivity was observed, and no displacement (cis

product) was observed.

Figure 2.16 DABCO Catalyzed Ring Opening

35

This work is particularly interesting because as far as I can see in the literature there are few

examples of others taking advantage of this ring opening strategy. Based on what we know

about aziridines we would assume that DABCO was too week of a nucleophile to ring open an

aziridine.

2.7 Catalytic Asymmetric Aniline Addition

In 2007 Kobayashi112

disclosed results on a catalytic asymmetric aniline addition to aziridines;

in this work he exploited a known catalyst with Niobium in the metal center (figure 2.17, 114).

Later Kobayashi also showed that Zirconium113

and finally in 2009 Titanium112

(figure 2.17, 117)

were all suitable catalysts for this desymmetrization.

Figure 2.17 Niobium and Titanium BINOL Catalyzed Desymmetrization

Schneider’s earlier racemic work no doubt led him to explore an asymmetric possibilities and

in 200980

published an interesting procedure using titanium and unsubstituted BINOL similar to

Kobayashi’s but with simplified conditions and a simplified ligand, figure 2.18 119. This method

works so well and uses readily available reagents that is has become a benchmark in this area

even overshadowing Schneider’s more recent racemic work with other metals figure 2.18

121.114,115

The only real limitations to this chemistry are the high catalyst loading and the

36

temperature requirement at -40 degrees Celsius, which are both required to achieve high

enantioselectivity.

Figure 2.18 Various Metal Catalyzed openings by Schneider et al.

2.8 Recent Findings

When we attempted this reaction, we were presently surprised that across a variety of phosphate

salts we were able to achieve enantioselectivity. Initially we hoped that VAPOL calcium or

magnesium phosphate would be able to catalyze that reaction in the same way it had worked for

thiophenol. Unfortunately it appears based on figure 2.19, the chiral pocket does not allow for

direct correlation from thiophenol to aniline for enantioselective control. Unfortunately VAPOL’s

sterics are less tunable then BINOL.

Figure 2.19 VAPOL Phosphate Metal Salts for Aniline Ring Opening

37

However the optimization of the catalyst could continue with BINOL based metal phosphates;

when we move from VAPOL phosphate to BINOL phosphate we can change the “R” group on the

3, 3’ positions. When “R” equals H P1 in table 2.10, there is no ee for calcium or magnesium, as

the “R” group is enlarged to Ph P2 34% ee is found. When we add steric groups to crowd the

chiral pocket P3 and P8 the ee drops nearly to zero as well as lowering the reactivity. When we

extend the “R” group to Biphenol P9 we are able to achieve 56% ee with calcium, and if we add

steric groups to that back aromatic ring P10 we see continued improvement up to a useful 85%.

Table 2.10 VAPOL Phosphate Metal Salts for Aniline Ring Opening

This tells us that with either sulfur or nitrogen we can build a chiral pocket around the

aziridine allowing us to choose an appropriate catalyst to activate both the aziridine and

nucleophile. This also tells us that while calcium or magnesium phosphate may not be a strong

Lewis acid compared to Scandium triflate, they may be more useful then we know today. While

38

the reaction conditions from the mercaptan chemistry is not directly applicable to aniline, the

same catalyst system can be used however some re-optimization is necessary.

2.9 In Conclusions

In conclusion, we have discovered a catalytic enantioselective process for the ring-opening of

meso N-acyl aziridines in a high yielding, enantioselective manner. In comparison to known

methods,89,95-97,116

we believe our procedure is attractive due to the reactions procedural

simplicity and broad substrate scope, while taking advantage of commercially available

mercaptans. The reaction is the first of its type to tolerate a wide range of aromatic and

heteroaromatic thiols. Based on this type of activation we believe that the full scope of reactivity

for phosphate salts with aziridines has yet to be fully elucidated. Previously we thought

impossible to activate anilines with phosphate salts, but by modifying the chiral pocket we are

able to expand the scope of this reaction and allow an environment with enough space for both

hydrogen bonding and metal chelation.

39

CHAPTER 3: CATALYTIC ASYMMETRIC AZA-DARZENS REACTION

3.1 Background Information

Direct aziridine synthesis can be accomplished by three main methods from imines, while

these methods are analogous to epoxides they are far less explored in the literature.117

Synthesis

of aziridines from the addition of a nitrene to an olefin or intramolecular ring closing reactions can

also be performed. Paul Muller summarized the nitrene aziridination, including several catalytic

asymmetric examples in a notable review.118

Carbene mediated aziridination and ylide mediated

aziridination are well studied mechanisms and have been reported with asymmetric

organocatalytic methodologies.119

Figure 3.1 Aziridination from Imines

In two reports from 1999 and 2000, a breakthrough by Wulff46,47

in the area of catalytic

asymmetric aziridination of imines was accomplished (figure 3.2). The catalyst for Wulff’s

reaction, while initially believed to be a boron Lewis acid, was later proven to be a chiral Brønsted

acid after in depth mechanistic study by their group, 131 figure 3.2.119

This work encompassed

the first successful asymmetric catalytic method to make bith cis 136 and trans 134 disubstituted

aziridines selectively via the same method. Other methods can be selected to make either the cis

40

or the trans independently with high enantioselectively.120-127

A subset of this reaction which was

alluded to earlier was work done by Aggarwal on sulfur ylide chemistry.73,128-131

Figure 3.2 Brønsted Acid Catalyzed Aziridination

3.2 The Aza-Darzens reaction, a variant to the Darzens Epoxidation

The Darzens aziridine synthesis, first proposed by Deyrup,132

is a pathway to prepare

complex aziridines, with considerable synthetic utility from common synthetic building blocks.

The aza-Darzens reaction is a nitrogen variant of the Darzens glycidic ester condensation (figure

3.3).133

Examples where such aziridines are used as versatile intermediates are mainly through

their ring-opening reactions for the preparation of chiral amines.95,109,134

New catalytic asymmetric

methods of aziridine synthesis via the aza-Darzens reaction would be interesting due to this

synthetic potential.

Figure 3.3 Darzens Epoxidation

41

In addition to Wulff’s aziridination, Sweeney128,130,135

and Davis136

independently reported

asymmetric versions of the aza-Darzens reaction in 1999, using stoichiometric amounts of chiral

reagents. In other early studies, Johnston and co-workers published a triflic acid-catalyzed aza-

Darzens variant.127,137

A number of new Brønsted acid variants similar to these reactions were

subsequently published with highly enantioselective conditions being described.120,122,126,138-140

We believe that the use of typical aza-Darzens-type nucleophiles,141-146

like α-halo-1,3-dicarbonyl

compounds, could lead to functionalized aziridines which are tri-substituted rather than the

disubstitution pattern often produced by diazo compounds or sulfur ylides. Chiral phosphoric

acids or phosphate salts catalysts could be of particular interest for these reactions as they have

demonstrated excellent enantioselective induction in other imine activations.22,23,49-54,68,76-78,147-152

3.3 Aza-Darzens with α-halo-1,3-dicarbonyl Compounds

After some limited initial success while focusing on chiral phosphoric acids, we turned our

attention to chiral phosphate metal salts as viable catalyst for this reaction. We were attracted to

these catalysts after a report by Ishihara on similar Mannich reactions showed that metal

phosphate salts were superior catalysts when screening versus the free phosphoric acids.30,33,153

These investigations were supported by the findings of List,98

who showed that phosphoric acids

used directly after column chromatography woud be the neutralized mixtures of phosphate salt

impurities and acid, rather than just the pure acid. Aza-Darzens reactions in our lab were

plagued with reproducibility problems when salt mixtures were used, likely due to competing

catalysts producing different enantiomeric ratios of the desired product.

Figure 3.4 Catalysts for Aza-Darzens Reactions

42

Encouraged by recent reports that successfully demonstrated a variety of chiral phosphate

salts for catalytic asymmetric induction; the investigation was continued with phosphate salts as

the catalyst of choice.43,54,67,70,154

An asymmetric aza-Darzens reaction that employs α-chloro-1,3-

diketones as competent nucleophiles for addition to N-benzoyl imines, allowing access to

trisubstituted aziridines with good enantioselectivity was developed.

Table 3.1 Optimization of Catalytic System

As we began our screening, we found that re-acidified versions of common phosphoric acids

(table 3.1, entries 1−3) were relatively poor catalysts for this reaction. The reaction did however

carry a strong preference for P11, a phosphoric acid derived from (R)-(VAPOL) over those

derived from BINOL, figure 3.4. When P11 was used directly after purification on silica gel (entry

4), the enantiomeric excess was significantly higher than the re-acidified phosphoric acid (entry

3); this led to the obvious pursuit of a phosphate salt catalyst with a chiral backbone of VAPOL.

The description of the synthesis of enantiopure VAPOL phosphoric acid and associated

phosphate salts is outlined in appendix A.

43

To explore this new chiral phosphate system, we matched P11 with commerically available

alkali or alkaline earth metal alkoxide salts. Group 1 elements were not promising: lithium showed

excellent efficiency, leading to a high yield but low enantioselectivity (entry 5), while sodium

prevented the aza-Darzens reaction from occurring at all (entry 6). While all three of the group

two alkaline metals tested promoted the reaction with some enantioselectivity, the most selective

example was the pairing of P11 with magnesium (entries 7−9). This is not an exhaustive list of

group one and two elements however magnesium and calcium are the Lewis acids which we

would expect to be the stronger of the group two metals. Additionally we would expect that two

coordinate metals will have more steric hindrance then one coordinate metals while restricting

possible transition states that could coordinate to the metal.

From the comparison of the yields and selectivities of the various salts, it became clear that

magnesium VAPOL phosphate salt impurities originating from the silica gel were most likely

catalyzing the reaction in entry 4. To our knowledge, this is the first example of a magnesium

phosphate salt being the optimal catalyst for an enantioselective Mannich-type reaction.

Initially, we assumed that a ratio of two P11 to one magnesium would be optimal; to confirm,

a screening of other ratios of VAPOL phosphate and magnesium was performed. A significant

drop in yield and enantioselectivity was observed in comparison with the initial ratio (entries 10

and 11). Lastly, we wanted to determine if other common phosphoric acids could be as effective

as the P11 catalyst. Perhaps the Lewis acidity of the magnesium phosphate was the driving

force of the reaction and any chiral environment would do equally well.

After conversion to the corresponding magnesium phosphate salt, both catalysts derived from

P3 and P5 showed little enantioselectivity for the aza-Darzens reaction (entries 12 and 13).

These results confirm that VAPOL magnesium phosphate is ideal for promoting the aza-Darzens

reaction efficiently and with selectivity.

With the optimal conditions identified, we proceeded to examine various substituted imines

derived from their corresponding benzaldehydes (table 3.2). These aza-Darzens aziridine

products were formed with moderate yields and high enantioselectivities.

44

Table 3.2 Scope of Aza-Darzens Reaction

In example 148a, when the starting material is fully consumed the mass balance of the

reaction can be accounted for by incomplete conversion in the second ring-closing step. Various

substituents at the aryl ring were evaluated in the exploration of the substrate scope. Both

methoxy and methyl groups showed analogous tolerance and enantioselectivities regardless of

their position on the arene ring system (148b−148f). However, as the steric environment

45

increased around the center of chirality, the enantioselectivity decreased, clearly the result of the

substituent on the aryl ring. This is evident when observing the enantioselectivities of 148c and

148f compared to 148b and 148e, respectively. The presence of electron-withdrawing halogens

in the para position (148g−148i) gave comparable results with the electron-donating para-

substituted substrates.

3.4 Theoretical Study of the Aza-Darzens Reaction

While the active catalytic species involved in these phosphate salt-catalyzed reactions are

not yet definitively proven, we moved forward with a theoretical study using two biphenanthrol

phosphate ions coordinated to one magnesium cation. Catalyst structures were geometry-

optimized using the Q-Chem ab initio package155

and employing the B3LYP156,157

functional and

6-31+G* basis set.158,159

Figure 3.5 represents the lowest energy structure found.160

Interestingly,

the dihedral angle of the phenanthrene rings was found to be approximately 60°; the axial C2-

symmetry and is the key to the enantioselectivity of the products formed.

\

Figure 3.5 Low Enegry Structure of diVAPOL Phosphate Magnesium Salt

46

Two alternative catalyst conformations were located; these were higher in energy, relative to

figure 3.5 by 10 and 24 kcal/mol. Different coordination patterns of magnesium can partially

account for these energy differences (vide infra). In the lowest energy structure, figure 3.5, the

magnesium is coordinated to the four terminal phosphoryl oxygens. In contrast, the higher energy

conformers, had magnesium bound to either one or two phosphoryl ethers in conjunction with

three or two terminal oxygens. From the NBO analysis, energetics of these interactions indicate

that an approximate 5 kcal/mol penalty exists when binding phosphoryl ether compared to

terminal oxygen. However, this energetic penalty is compensated for by increased stabilization

via interactions with the adjacent terminal oxygen. Measuring the magnesium−oxygen distances

highlights this as the magnesium−ether oxygen distance is 2.1 Å compared to 1.9 Å for the

magnesium−terminal oxygen (figure 3.6).

Figure 3.6 Middle Enegry Structure of diVAPOL Phosphate Magnesium Salt

47

Figure 3.7 High Enegry Structure of diVAPOL Phosphate Magnesium Salt

In contrast, the lowest energy structure (figure 3.5) has magnesium−oxygen distances of

approximately 2.1 Å for all interactions. Clearly, the orbital interactions cannot explain the

energetic differences observed; however, large structural changes are evident based on the

interaction patterns. Therefore, a combination of steric repulsion, strain, and

hydrophobic/hydrophilic effects likely dictate the final structure.

These three structures indicate that the bonding of the magnesium to the oxygens may affect

the chiral environment by changing the distances and angles between the two VAPOL molecules

(figure 3.8). One could imagine a high energy structure 150 between the lower two structures

(149 and 151) that were found, which represents the saddle point on a 3 dimensional energy

diagram.

48

Figure 3.8 Possible Interconversion Between Figures 3.5-3.7

3.5 Transition State

In 2010, Ishihara proposed three transition states for the reaction of aldimines with 1,3-dicarbonyl

compounds catalyzed by phosphate salts (figure 3.9).33,146

Figure 3.9 Possible Transition States by Ishihara

Transition state 152 and 154 are from a reaction with a Lithium phosphate catalyst, and in

TS-B 153 the catalyst is calcium diphosphate. Transition state 152 and 153 are very similar with

the exception that the hydrogen of the enol is coordinated to the catalyst in 153. There is no

explanation of the effect of the carbonyl on the aldimine other than perhaps an electronic effect.

TS-B 153 was one of the first proposed phosphate salt transition states allowing for simultaneous

activation of the enol and the aldimine, while 152 and 154 are able to activate one reactant at a

time. TS-C 154 invokes the protonation of the aldimine and coordination of both carbonyls of the

49

enol to the lithium phosphate salt, these seem unlikely to happen in any of the group two metals

coordinated to two phosphates.

Using this structural information, we propose a possible transition state and mechanism to

explain the high enantioselectivity observed. Figure 3.10 shows coordination of the magnesium to

the carbonyls of the imine and diketone’s enol form 155. Additionally, the enol can hydrogen bond

to an oxygen on the catalyst thus activating the enol by the Brønsted basic phosphate oxygen.

The catalyst can simultaneously activate the nucleophile and electrophile, while providing the

chiral environment for asymmetric induction.161

Figure 3.10 Proposed Transition State for Aza-Darzens Reaction

We surmised, therefore, that the enantioselectivity is a consequence of steric interactions

between the phenanthrene rings and the aromatic substituents of the imine, allowing for facial

selectivity. As the imine coordinates with the catalyst, its aryl rings align perpendicularly to the

plane of the catalyst while crossing the center to minimize the steric interactions with the

phenanthrenes. The validity of the proposed mechanism can be supported by its ability to predict

the absolute configuration of the major enantiomer.

The absolute configuration was unambiguously determined by HPLC comparison of the

dechlorinated β-amino carbonyl compound to the literature162

and the absolute configuration

corresponds with that of the (S) enantiomer for 148a.

50

Figure 3.11 Possible Transition States

We could draw 4 possible transition states all of which show the enolate attacking from the

back of the imine because of the C2 symmetry of the catalyst. In transition state 156 and 159 we

have the “cis” type imine, this causes the two phenyl rings on the imine to be far too close to each

other, and the steric hindrance should preclude these as a possibility. Transition state 158 has

the aromatic ring is in a pseudo axial position; additionally this ring is coming into contact with one

of the phenanthryl rings of the catalyst. It is difficult to imagine more than two coordination

possibilities for this TS3 158, whereas in TS2 157 we can imagine an additional oxygen to

magnesium coordination.

51

Figure 3.12 Three Dimensional Model of Transition State Two

When we model TS2 157 in 3D (figure 3.12 and figure 3.13) we want to bring the carbonyl of

the aldimine close enough to the metal center without steric interactions between the phenyl rings

and the catalyst phenanthryl rings. Then by pointing the enol into the metal center allows for

orbital overlap between sp2 hybridized carbons and hydrogen bonding between the phosphate

oxygen or the imine nitrogen.

Figure 3.13 Alternate View of Transition State Two

52

It is entirely possible that this is an oversimplified definition of the catalyst system. In a

demonstration by Dean Toste,163

halocyclization anion phase-transfer catalysis, significant

nonlinear effect was seen:

“100% ee catalyst: 96.3% and 96.5% ee product; 80% ee catalyst: 87.3% ee and 88.0% ee product; 60% ee catalyst: 78.4% and 75.1% ee product; 40% ee catalyst: 64.7% ee and 59.8% ee product; 20% ee catalyst: 31.4% and 32.1% ee product; 0% ee catalyst: 1.9% and 3.7% ee product.”

In one of the early observations of the nonlinear effect was that of Kagan and Agami’s

observation of the Sharpless Epoxidation and Adol reactions.164,165

The explained this effect with

the implication that two diethyl tartrates were present in the active catalyst during the Sharpless

Epoxidation.

53

CHAPTER 4: CONCLUSION

4.1 Conclusion

There continue to be new calcium phosphate catalyzed reactions that are not detailed here

published regularly in the literature; however magnesium phosphates continue to be less prolific.

One possibility reason is the stronger Lewis acidity of calcium when compared to magnesium.

While undoubtedly the realization of chiral BINOL based phosphate salts will be a windfall for

this area of asymmetric catalysis, there remains one major problem. Chiral induction by this type

of Lewis acid allows for a variety of possible transition states (based on coordination geometries)

and thus predicting activation of novel substrates is not trivial. Predicting the enantiomer of the

product formed by a reaction will continue to be difficult until more reactions have been disclosed.

When changing the steric groups in the 3,3’ positions the geometry orthogonal to the metal’s

coordination sphere can change drastically effecting the multiple possible transition states. Each

of those transition states might yield the same, opposite, or both enantiomers dependent of

sterics of the environment.

Regardless of the current limitations of this chemistry, the methods provided here outline a

significant scientific contribution to chemistry. Asymmetric formation of beta thio ethers, diamines

and unsymmetrical aziridines outline future directions for undiscovered metal phosphate

reactions.

An interesting side product isolated during this reaction is the attack of the carbonyl on the

chlorinated carbon rather than the nitrogen during the aza-Darzens reaction. Known as the Heine

reaction, there are no literature examples of concerted asymmetric Heine reactions and only a

few examples of one step synthesis described. However, during the optimization of the Heine

reaction described we moved away from chiral phosphates as catalyst, and thus it does not fit in

the scope of this dissertation.

We have demonstrated the utility of a chiral VAPOL magnesium phosphate salt catalyst and

described its first use in the enantioselective aza-Darzens reaction. This was accomplished while

54

simultaneously showing a new approach to the aza-Darzens reaction through the addition of α-

chloro-1,3-dicarbonyl compounds. These chiral phosphate salts represent a significant step

forward in our ability to tailor optimized catalytic systems to specific reactions. Further

experiments to evaluate the utility of VAPOL-derived phosphate salts are currently underway in

our laboratory.

55

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62

APPENDIX A. SUPPORTING INFORMATION

A1 Supporting Information for Chapter 2

A1.1 General Considerations

All reactions were carried out in flame-dried screw-cap test tubes fitted with a septum and

performed under a dry argon atmosphere with magnetic stirring. Anhydrous solvents were used

purchased from commercial sources; ether, dichloromethane, tetrahydrofuran, and toluene were

purified by passing the degassed solvent through a column of activated alumina prior to use in

reactions. Thiols were purchased from commercially available sources. Liquid thiols were

distilled under reduced pressure onto 4 Å molecular sieves directly before use. Solid thiols were

used directly with the exception of 2-naphthalenethiol, which was purified by sublimation to a

white solid.

Aniline was purchased from Sigma Aldrich, if used as is low reactivity and racemic

products were formed. When the brown colored aniline was distilled a clear lightly yellow liquid

was collected and stored at -20 0C for long periods of time, the recorded reactivity was observed.

Thin layer chromatography (TLC) was performed on Merck TLC plates (silica gel 60

F254). Flash column chromatography was performed with an Isco-Teledyne Companion 4X

chromatography system using Merck silica gel (230-400 mesh). Enantiomeric excess (ee) was

determined using a Varian Prostar HPLC system with a Prostar 210 binary pump and Prostar 335

diode-array detector with Daicel Chiralcel AS-H, AD-H, OJ-H or OD-H chiral column. Optical

rotations were performed on a Rudolph Research Analytical Autopol IV polarimeter (λ 589) using

a 700 μL cell with a path length of 1 dm. Melting points were determined using a MEL-TEMP 3.0

instrument and are uncorrected. 1H NMR and

13C NMR were recorded on Bruker Avance DPX-

250 (250 MHz), a Varian Inova 400 (400 MHz), or a Varian Inova 500 (500 MHz) instrument with

63

chemical shifts reported relative to residual solvent. The HRMS data were measured on an

Agilent 1100 series MSD/TOF mass spectrometer with electrospray ionization. Compounds

described in the literature were characterized by comparing their 1H NMR,

13C NMR, and melting

point (mp) to the reported values.

Yields reported for reactions are single runs that are representative of those results that

would be seen if performed by the average chemist with a background in anhydrous reaction

methods. On several examples multiple runs were performed showing similar results with those

of a single attempt. For example compound 94aa had an average yield of 96% over 4 runs

including that which is outlined in the exact information below. Assuming little to no water content

the enantiomeric excess should be identical from one run to the next. If a difference of greater

than 1% was observed starting materials would be purified and the reaction repeated. On

several occasions the results of 94aa were repeated by an undergraduate under close

supervision; those results aligned with what is detailed in chapter 2.

A1.2 Preparations of Compounds in Chapter 2

Aziridines were prepared by known literature procedures,82,83,166

characterization of aziridines

was identical to that reported. An example of the common steps of the synthesis is shown in

figure 4.1. Some aziridines were synthesized from their corresponding alkene for reasons of cost

or availability.

Figure A1 Example for the Preparation of Aziridines

In a deviation from the published preparation of these aziridines, the distillation of the

secondary aziridine off of the triphenyl phosphine allowed for more constant results and much

simpler purification of the final aziridine. Storage of this aziridine for long periods of time at -20

OC allows for preparation of various electron withdrawing groups on the nitrogen. Comparison of

64

these aziridines to their known 1H NMR was used for both purity and identification. No major

differences were noted from the published values.

VAPOL was synthesized according to the literature procedure.48

Other methods exist which

are able to prepare VAPOL in higher yield, however the ease and cost effectiveness of this

method developed by Wulff et. al. makes it very attractive.

Figure A2 Preparation of VAPOL by Wulff

Unless otherwise noted the phosphoric acids in chapter 2 are salt mixtures and were used as

is. Chiral BINOL was purchased from commercial sources and used without further purification.

Substituted BINOL phosphoric acids and phosphate salts were prepared according to literature

procedures.48,50,98,167

Pure phosphate salts of single known metals and pure acids were prepared

via methods by Ishihara33

and Ding34

respectively. This performed by acid wash with 6N HCl

while the phosphate salt is dissolved in DCM. Complexation with alkoxide substituted alkaline

earth metals is achieved by stirring at room temperature for at least 30 minutes at room

temperature under anhydrous conditions. Below is one example of the procedure used for the

preparation of substituted BINOL phosphoric acids.

65

Figure A3 Preparation of BINOL Phosphoric Acids, TRIP by List et al.98

A1.3 Preparation of Racemic Products by Desymmetrization

The aziridine (0.1 mmol), then phenylphosphinic acid, quinine, or a mixture of (R) and (S)

VAPOL phosphoric acid (10 mol%), were weighed into a screw cap test tube. The air was

removed under vacuum and replaced with argon three times. Ethanol or diethyl ether was added

(1.0 mL per 0.1 mmol of aziridine) followed by thiol (0.12 mmol) via a syringe to the test-tube.

The reaction was stirred at room temperature or 60 ºC until product formation was significant

which was monitored by TLC. The reaction was diluted with acetone, concentrated on silica gel

under reduced pressure, and purified by flash column chromatography.

A1.4 Procedure for the Desymmetrization of meso-Aziridines.

Figure A4 General Desymmetrization of meso-Aziridines

To a flame-dried screw cap test tube with septum, was added the aziridine (0.1 mmol) and

the acid catalyst (10 mol %). At this point, if the thiol was a solid it was also added (0.12 mmol).

The air was removed by vacuum and replaced with argon three times. Diethyl ether (1.0 mL per

0.1 mmol of aziridine) was added to the reaction by oven-dried syringe. If the thiol was a liquid it

was added at this point (0.12 mmol) by oven-dried syringe. The reaction was stirred at room

temperature for 20 hours and monitored by TLC for 20 hours. The reaction was diluted with

66

acetone, concentrated on silica gel under reduced pressure, and purified by flash column

chromatography with hexanes / EtOAc.

Alternatively the reaction can be applied directly to the top of a silica gel column when it has

be deemed complete by TLC, and eluted in a short amount of time via hexanes / EtOAc.

Full characterization of products including 94aa, 94ba, 94ca, 94ia, 94ja, 94ka and 94la was

reported by Della Sala and coworkers.89

Upon characterization of the beta amino thioethers we

found significant differences in melting point and chiral HPLC data to the data in reference by

Della Sala.

A1.5 Procedure for Desymmetrization of meso-Aziridines with Aniline

Figure A5 Desymmetrization of meso-Aziridines with Aniline

To a flame-dried screw cap test tube with septum, was added the aziridine (0.1 mmol) and

the calcium biphenyl substituted BINOL phosphate (5 mol %). The air was removed by vacuum

and replaced with argon three times. Toluene (1.0 mL per 0.1 mmol of aziridine) was added to the

reaction by syringe. The aniline was added at this point (0.12 mmol) by oven-dried syringe, the

reaction was stirred at room temperature and monitored by TLC for 20 hours. The reaction was

diluted with acetone, concentrated on silica gel under reduced pressure, and purified by flash

column chromatography with hexanes / EtOAc.

Alternatively the reaction can be applied directly to the top of a silica gel column when it has

be deemed complete by TLC, and eluted in a short amount of time via hexanes / EtOAc.

67

A1.6 Characterization of Beta Amino Thioethers and 1,2 Diamines

3,5-dinitro-N-(2-(phenylthio)cyclohexyl)benzamide (94aa) To a flame-dried test tube

was added 7-(3,5-Dinitrobenzoyl)-7-azabicyclo[4.1.0]heptane (0.0291 g, 0.10 mmol) and (S)-P11

(6.0 mg, 10 mol %). The air was removed under vacuum and replaced with argon. Diethyl ether

(1.0 mL) was added to the reaction by oven-dried syringe. At this point thiophenol was added

(0.0122 mL, 0.12 mmol) by oven-dried syringe. The reaction was stirred at room temperature

and monitored by TLC for 20 hours. The reaction was diluted with acetone, concentrated on

silica gel, and purified by flash column chromatography with hexanes / EtOAc. Recovered white

solid (0.0397 g, 93%). Mp = 197.7-199.5 °C. HPLC analysis: Chiralcel AD-H (hexane/iPrOH =

80/20, 1.0 mL/min), t r-minor 9.29 min, t r-major 7.64 min. 1H NMR (400 MHz, CDCl3): δ 9.11 (s, 1H),

8.73 (s, 1H), 8.72 (s, 1H), 7.39 (d, J = 8 Hz, 1H), 7.20 (t, J = 8 Hz, 1H), 7.15 (d, J = 8 Hz, 1H),

6.22 (m, 1H), 3.98 (m, 1H), 3.11 (m, 1H), 2.22 (m, 2H), 1.79 (m, 2H), 1.47 (m, 2H), 1.38 (m, 2H).

13C NMR (500 MHz, CDCl3): δ 162.0, 148.5, 137.9, 133.8, 132.5, 129.1, 127.4, 127.0, 120.9,

55.3, 51.6, 33.6, 33.1, 26.0, 24.6. HRMS (ESI) Calcd for C19H19N3O5S ([M+Na]+) 424.0938,

Found 424.0940. [α]29

D +93.6 (c = 0.5, CHCl3) (96% ee).

68

N-(2-(naphthalen-2-ylthio)cyclohexyl)-3,5-dinitrobenzamide (94ab) To a flame-dried

test tube was added 7-(3,5-Dinitrobenzoyl)-7-azabicyclo[4.1.0]heptane (0.0291 g, 0.10 mmol),

(S)-P11 (6.0 mg, 10 mol %) and 2-naphthalenethiol was added (0.0192 g, 0.12 mmol). The air

was removed under vacuum and replaced with argon. Diethyl ether (1.0 mL) was added to the

reaction by oven-dried syringe. The reaction was stirred at room temperature and monitored by

TLC for 20 hours. The reaction was diluted with acetone, concentrated on silica gel, and purified

by flash column chromatography with hexanes / EtOAc. Recovered yellow solid (0.0448 g, 99%).

Mp = 201.0-202.6 °C. HPLC analysis: Chiralcel AS-H (hexane/iPrOH = 80/20, 1.0 mL/min), t r-minor

13.95 min, t r-major 22.67 min. 1H NMR (400 MHz, CDCl3): δ 8.70 (s, 1H), 7.69 (s, 2H), 7.63 (s,

1H), 7.54 (d, J = 8 Hz 1H), 7.48 (dd, J = 20 Hz, J = 8 Hz 2H), 7.39 (d, J = 8 Hz 1H), 7.27 (m, 2H),

6.10 (m, 1H), 4.15 (m, 1H), 3.38 (m, 1H), 2.26 (m, 1H), 2.12 (m, 1H), 1.83 (m, 2H), 1.44(m, 4H).

13C NMR (400 MHz, CDCl3): δ 161.7, 148.0, 137.0, 133.5, 132.9, 131.9, 130.5, 129.2, 129.0,

127.5, 127.0, 127.0, 126.6, 126.5, 120.7, 57.1, 51.3, 34.0, 32.7, 26.3, 24.9. HRMS (ESI) Calcd

for C23H21N3O5S ([M+H]+) 452.1275, Found 452.1287. [α]

29D +104.2 (c = 0.5, CHCl3) (95% ee).

69

3,5-dinitro-N-2-(p-tolylthio)cyclohexyl)benzamide (94ac) To a flame-dried test tube



(1.0 mL) was added to the reaction by oven-dried syringe. At this point 4-methylbenzenethiol was

added (0.0129 mL, 0.12 mmol) by oven-dried syringe. The reaction was stirred at room

temperature and monitored by TLC for 20 hours. The reaction was diluted with acetone,

concentrated on silica gel, and purified by flash column chromatography with hexanes / EtOAc.

Recovered yellow solid (0.0390 g, 94%). Mp = 201.8-202.8 °C. HPLC analysis: Chiralcel AS-H

(hexane/iPrOH = 80/20, 1.0 mL/min), t r-minor 15.51 min, t r-major 20.27 min. 1H NMR (400 MHz,

CDCl3): δ 9.07 (s, 1H), 8.79 (s, 2H), 7.25 (d, J = 6.4 Hz, 2H), 6.99 (d, J = 6.4 Hz, 2H), 6.60 (s,

1H), 3.95 (m, 1H), 3.07 (m, 1H), 2.20 (m, 5H), 1.76 (m, 2H), 1.41(m, 4H). 13

C NMR (400 MHz,

CDCl3): δ 162.2, 148.6, 138.2, 138.0, 133.3, 130.0, 127.3, 121.0, 77.5, 77.2, 76.9, 55.3, 51.9,

33.8, 33.3, 26.2, 24.8, 21.1. HRMS (ESI) Calcd for C20H21N3O5S ([M+H]+) 416.1274, Found

416.1277. [α]29

D +80.4 (c = 1.0, CHCl3) (93% ee).

70

3,5-dinitro-N-(2-(o-tolylthio)cyclohexyl)benzamide (94ad) To a flame-dried test tube



(1.0 mL) was added to the reaction by oven-dried syringe. At this point 2-methylbenzenethiol was




Recovered tan solid (0.0363 g, 88%). Mp = 178.8-180.4 °C. HPLC analysis: Chiralcel AS-H


CDCl3): δ 9.08 (s, 1H), 8.67 (s, 1H), 8.67 (s, 1H), 7.40 (d, J = 8 Hz 1H), 7.07 (d, J = 8 Hz 1H),

6.24 (m, 1H), 4.07 (m, 1H), 3.17 (m, 1H), 2.31 (m, 5H), 1.80 (m, 2H), 1.38 (m, 4H). 13

C NMR

(500 MHz, CDCl3): δ 162.0, 148.3, 139.7, 137.8, 134.0, 131.6, 130.5, 127.1, 126.9, 126.5, 120.8,

55.7, 55.7, 51.1, 33.6, 32.9, 25.9, 24.6, 24.6, 20.9, 20.8. HRMS (ESI) Calcd for C20H21N3O5S

([M+H]+) 416.1275, Found 416.1294. [α]

29D +80.2 (c = 0.5, CHCl3) (94% ee).

71

N-2-(2,4-dimethylphenylthio)cyclohexyl)-3,5-dinitrobenzamide (94ae) To a flame-

dried test tube was added 7-(3,5-Dinitrobenzoyl)-7-azabicyclo[4.1.0]heptane (0.0291 g, 0.10

mmol) and (S)-P11 (6.0 mg, 10 mol %). The air was removed under vacuum and replaced with

argon. Diethyl ether (1.0 mL) was added to the reaction by oven-dried syringe. At this point 2,4-

dimethylbenzenethiol was added (0.0166 mL, 0.12 mmol) by oven-dried syringe. The reaction

was stirred at room temperature and monitored by TLC for 20 hours. The reaction was diluted

with acetone, concentrated on silica gel, and purified by flash column chromatography with

hexanes / EtOAc. Recovered yellow solid (0.0365 g, 85%). Mp = 189.2-189.5 °C. HPLC analysis:

Chiralcel AS-H (hexane/iPrOH = 80/20, 1.0 mL/min), t r-minor 11.43 min, t r-major 14.68 min. 1H NMR

(500 MHz, CDCl3): δ 9.05 (s, 1H), 8.73 (s, 2H), 7.24 (d, J = 8 Hz, 1H), 6.82 (m, 2H), 6.54 (s, 1H),

4.05 (m, 1H), 3.10 (m, 1H), 2.27 (s, 3H), 2.13 (s, 3H), 1.76 (m, 2H), 1.40 (m, 4H). 13

C NMR (400

MHz, CDCl3): δ 162.1, 148.5, 140.2, 138.0, 137.7, 132.8, 131.6, 130.3, 127.5, 127.2, 120.9, 56.2,

51.6, 33.8, 33.1, 26.1, 24.8, 21.0, 20.9. HRMS (ESI) Calcd for C21H23N3O5S ([M+H]+) 430.1431,

Found 430.1425. [α]29

D +67.3 (c = 1.01, CHCl3) (93% ee).

72

N-2-(4-isopropylphenylthio)cyclohexyl)-3,5-dinitrobenzamide (94af) To a flame-dried

test tube was added 7-(3,5-Dinitrobenzoyl)-7-azabicyclo[4.1.0]heptane (0.0291 g, 0.10 mmol) and

(S)-P11 (6.0 mg, 10 mol %). The air was removed under vacuum and replaced with argon.

Diethyl ether (1.0 mL) was added to the reaction by oven-dried syringe. At this point 4-

isopropylbenzenethiol was added (0.0182 mL, 0.12 mmol) by oven-dried syringe. The reaction





(400 MHz, CDCl3): δ 9.08 (s, 1H), 8.88 (s, 2H), 7.29 (d, J = 8 Hz, 2H), 7.08 (d, J = 8 Hz, 2H), 6.71

(s, 1H), 3.95 (m, 1H), 3.03 (m, 1H), 2.77 (m, 1H), 2.26 (m, 1H), 2.18 (m, 1H), 1.75 (m, 2H), 1.38

(m, 5H), 1.13 (m, 6H). 13

C NMR (400 MHz, CDCl3): δ 162.4, 148.9, 148.7, 138.4, 133.5, 129.8,

127.7, 127.4, 121.0, 54.8, 52.0, 33.8, 33.5, 26.2, 24.8, 23.9, 23.9. HRMS (ESI) Calcd for

C22H25N3O5S ([M+H]+) 444.1588, Found 444.1591. [α]

29D +64.9 (c = 1.26, CHCl3) (93% ee).

73

N-(2-(4-tert-butylphenylthio)cyclohexyl)-3,5-dinitrobenzamide (94ag) To a flame-



argon. Diethyl ether (1.0 mL) was added to the reaction by oven-dried syringe. At this point 4-

tert-butylbenzenethiol was added (0.0199 mL, 0.12 mmol) by oven-dried syringe. The reaction





(400 MHz, CDCl3): δ 9.09 (s, 1H), 8.91 (s, 2H), 7.29 (dd, J = 20 Hz J = 8 Hz, 4H), 6.72 (s, 1H),

3.93 (m, 1H), 3.02 (m, 1H), 2.28 (m, 1H), 2.15 (m, 1H), 1.75 (m, 2H), 1.38 (m, 4H), 1.22 (s, 9H).

13C NMR (400 MHz, CDCl3): δ 162.2, 151.1, 148.5, 138.2, 133.1, 129.1, 127.2, 126.1, 120.9,

54.4, 51.8, 34.5, 33.6, 33.4, 31.1, 26.0, 24.6. HRMS (ESI) Calcd for C23H27N3O5S ([M+Na]+)

480.1564, Found 480.1560. [α]29

D +88.2 (c = 0.5, CHCl3) (93% ee).

74

N-(2-(3-chlorophenylthio)cyclohexyl)-3,5-dinitrobenzamide (94ah) To a flame-dried




chlorobenzenethiol was added (0.0215 mL, 0.12 mmol) by oven-dried syringe. The reaction was

stirred at room temperature and monitored by TLC for 20 hours. The reaction was diluted with

acetone, concentrated on silica gel, and purified by flash column chromatography with hexanes /

EtOAc. Recovered yellow solid (0.0378 g, 87%). Mp = 143.4-144.6 °C. HPLC analysis: Chiralcel

AS-H (hexane/iPrOH = 80/20, 1.0 mL/min), t r-minor 13.57 min, t r-major 17.99 min. 1H NMR (400

MHz, CDCl3): δ 9.09 (s, 1H), 8.78 (s, 2H), 7.29 (s, 1H), 7.26 (d, J = 8 Hz 2H), 7.14 (t, J = 8 Hz

1H), 7.06 (d, J = 8 Hz 1H), 6.54 (s, 1H), 4.05 (m, 1H), 3.18 (m, 1H), 2.20 (m, 2H), 1.79 (m, 2H),

1.43 (m, 4H). 13

C NMR (400 MHz, CDCl3): δ 162.2, 148.7, 137.9, 136.5, 134.8, 131.9, 130.4,

130.3, 127.5, 127.2, 121.1, 55.2, 52.1, 33.8, 33.2, 26.0, 24.8. HRMS (ESI) Calcd for

C19H18ClN3O5S ([M+NH4]+) 453.0994, Found 453.1007. [α]

29D +63.3 (c = 0.5, CHCl3) (96% ee).

75

N-(2-(2-chlorophenylthio)cyclohexyl)-3,5-dinitrobenzamide (94ai) To a flame-dried




chlorobenzenethiol was added (0.0141 mL, 0.12 mmol) by oven-dried syringe. The reaction was



EtOAc. Recovered white solid (0.0381 g, 99%). Mp = 169-171 °C. HPLC analysis: Chiralcel AS-

H (hexane/iPrOH = 80/20, 1.0 mL/min), t r-minor 19.47 min, t r-major 22.76 min. 1H NMR (400 MHz,

CDCl3): δ 9.07 (s, 1H), 8.84 (s, 1H), 8.84 (s, 1H), 7.49 (t, J = 8 Hz, 1H), 7.32 (t, J = 8 Hz, 1H),

7.13 (t, J = 8 Hz, 2H), 6.81 (m, 1H), 4.01 (m, 1H), 3.22 (m, 1H), 2.31 (m, 1H), 2.17 (m, 1H), 1.77

(m, 2H), 1.52 (m, 1H), 1.43 (m, 2H), 1.30 (m, 1H). 13

C NMR (400 MHz, CDCl3): δ 162.4, 148.6,

138.1, 137.2, 134.8, 133.2, 130.4, 129.1, 127.4, 127.3, 121.1, 54.9, 51.6, 33.7, 33.4, 26.0, 24.7.

HRMS (ESI) Calcd for C19H18ClN3O5S ([M+Na]+) 458.0548, Found 458.0554. [α]

29D +20.2 (c =

0.5, CHCl3) (98% ee).

76

N-(2-(4-fluorophenylthio)cyclohexyl)-3,5-dinitrobenzamide (94aj) To a flame-dried




fluorobenzenethiol was added (0.0184 mL, 0.12 mmol) by oven-dried syringe. The reaction was



EtOAc. Recovered white solid (0.0366 g, 85%). Mp = 182.3-183.3 °C. HPLC analysis: Chiralcel


MHz, CDCl3): δ 9.14 (s, 1H), 8.85 (s, 2H), 7.40 (s, 2H), 6.94 (m, 2H), 6.34 (t, J = 8 Hz, 2H), 3.94

(s, 1H), 2.98 (m, 1H), 2.26 (m, 1H), 2.11 (m, 1H), 1.77 (m, 2H), 1.37 (m, 4H). 13

C NMR (400

MHz, CDCl3): δ 164.1, 162.2, 148.8, 138.2, 136.1, 127.2, 121.2, 116.5, 116.3, 54.5, 52.3, 33.8,

33.2, 26.1, 24.7. HRMS (ESI) Calcd for C19H18FN3O5S ([M+H]+) 420.1024 Found 420.1032.

[α]29

D +82.0 (c = 0.5, CHCl3) (91% ee).

77

N-(2-(4-methoxyphenylthio)cyclohexyl)-3,5-dinitrobenzamide (94ak) To a flame-dried




methoxybenzenethiol was added (0.0191 mL, 0.12 mmol) by oven-dried syringe. The reaction



hexanes / EtOAc. Recovered orange solid (0.0428 g, 99%). Mp = 153.2-154.7 °C. HPLC

analysis: Chiralcel AD-H (hexane/iPrOH = 90/10, 1.0 mL/min), t r-minor 19.31 min, t r-major 36.41 min.

1H NMR (400 MHz, CDCl3): δ 9.11 (s, 1H), 8.80 (s, 2H), 7.67 (m, 1H), 7.51 (m, 1H), 7.33 (d, J = 8

Hz, 2H), 6.72 (m, J = 8 Hz 1H), 6.43 (s, 1H), 4.18 (m, 1H), 3.90 (m, 1H), 3.70 (s, 3H), 2.92 (m,

1H), 2.26 (m, 1H), 2.12 (m, 1H), 1.76 (m, 1H), 1.33 (m, 2H), 0.89 (m, 2H). 13

C NMR (500 MHz,

CDCl3): δ 161.9, 159.7, 148.5, 138.0, 135.8, 127.1, 123.1, 120.9, 114.6, 55.2, 55.1, 52.1, 33.6,

32.9, 26.0, 24.5. HRMS (ESI) Calcd for C20H21N3O6S ([M+H]+) 432.1224, Found 432.1220. [α]

29D

+53.2 (c = 0.5, CHCl3) (99% ee).

78

N-(2-(4-(methylthio)phenylthio)cyclohexyl)-3,5-dinitrobenzamide (94al) To a flame-




(methylsulfanyl)phenyl hydrosulfide was added (0.0187 mL, 0.12 mmol) by oven-dried syringe.

The reaction was stirred at room temperature and monitored by TLC for 20 hours. The reaction

was diluted with acetone, concentrated on silica gel, and purified by flash column

chromatography with hexanes / EtOAc. Recovered yellow solid (0.0348 g, 78%). Mp = 174.1-

175.8 °C. HPLC analysis: Chiralcel AS-H (hexane/iPrOH = 80/20, 1.0 mL/min), t r-minor 14.00 min, t

r-major 9.36 min. 1H NMR (400 MHz, CDCl3): δ 9.08 (s, 1H), 8.77 (s, 1H), 8.77 (s, 1H), 7.29 (d, J =

8 Hz, 2H), 6.99 (d, J = 8 Hz, 2H), 6.45 (m, 1H), 3.99 (m, 1H), 3.07 (m, 1H), 2.35 (s, 3H), 2.19 (m,

2H), 1.77 (m, 2H), 1.38 (m, 4H). 13

C NMR (400 MHz, CDCl3): δ 162.1, 148.6, 139.0, 138.0,

133.7, 129.6, 127.1, 126.5, 121.1, 55.5, 51.9, 33.9, 33.1, 26.1, 24.8, 15.3. HRMS (ESI) Calcd for

C20H21N3O5S2 ([M+H]+) 448.0995, Found 448.1013. [α]

29D +80.4 (c = 1.0, CHCl3) (90% ee).

79

N-(2-(4-hydroxyphenylthio)cyclohexyl)-3,5-dinitrobenzamide (94am) To a flame-




sulfanylphenol was added (0.0152 mL, 0.12 mmol) by oven-dried syringe. The reaction was




AS-H (hexane/iPrOH = 80/20, 1.0 mL/min), t r-minor 27.13 min, t r-major 9.61 min. 1H NMR (400 MHz,

(CD3)2CO): δ 9.03 (s, 1H), 8.98 (s, 2H), 8.42 (m, 1H), 8.31(m, 1H), 7.30 (d, J = 8 Hz, 2H), 6.82

(m, 1H), 6.67 (d, J = 8 Hz, 2H), 3.99 (m, 1H), 3.06 (m, 1H), 2.89 (m, 1H), 2.06 (m, 2H), 1.73 (m,

2H), 1.49 (m, 1H), 1.26 (m, 2H). 13

C NMR (400 MHz, (CD3)2CO): δ 161.6, 157.7, 148.8, 138.2,


C19H19N3O6S ([M+Na]+) 440.0887, Found 440.0895. [α]

29D +42.0 (c = 0.5, CHCl3) (89% ee).

80

Methyl 2-(2-(3,5-dinitrobenzamido)cyclohexylthio)benzoate (94an) To a flame-dried

test tube was added 7-(3,5-Dinitrobenzoyl)-7-azabicyclo[4.1.0]heptane (0.0291 g, 0.10 mmol),

(S)-P11 (6.0 mg, 10 mol %) and methyl 2-sulfanylbenzoate was added (0.0165 g, 0.12 mmol).

The air was removed under vacuum and replaced with argon. Diethyl ether (1.0 mL) was added

to the reaction by oven-dried syringe. The reaction was stirred at room temperature and

monitored by TLC for 20 hours. The reaction was diluted with acetone, concentrated on silica

gel, and purified by flash column chromatography with hexanes / EtOAc. Recovered white solid

(0.0339 g, 74%). Mp = 222.2-223.6 °C. HPLC analysis: Chiralcel AD-H (hexane/iPrOH = 80/20,

1.0 mL/min), t r-minor 9.23 min, t r-major 11.95 min. 1H NMR (400 MHz, CDCl3): δ 9.13 (s, 2H), 8.26

(s, 1H), 7.95 (d J = 8 Hz, 1H), 7.67 (d J = 8 Hz, 1H), 7.45 (t J = 4 Hz, 1H), 7.38 (t J = 4 Hz, 1H),

3.90 (s, 3H), 3.82 (m, 1H), 3.12 (t, J = 8 Hz 1H), 2.53 (d, J = 8 Hz 1H), 2.13 (d, J = 8 Hz 1H), 1.74

(s, 2H), 1.59 (m, 2H), 1.23 (m, 2H). 13

C NMR (400 MHz, DMSO): δ 167.1, 161.8, 148.7, 138.2,

137.5, 132.5, 131.5, 130.4, 130.1, 128.0, 125.6, 121.3, 53.6, 52.6, 50.1, 33.5, 33.2, 26.0, 25.0.

HRMS (ESI) Calcd for C21H21N3O7S ([M+H]+) 460.1173, Found 460.1177. [α]

29D +12.0 (c = 0.5,

CHCl3) (72% ee).

81

N-(2-(2-methylfuran-3-ylthio)cyclohexyl)-3,5-dinitrobenzamide (94ao) To a flame-




methyl-3-furanthiol was added (0.0122 mL, 0.12 mmol) by oven-dried syringe. The reaction was



EtOAc. Recovered yellow solid (0.0286 g, 99%). Mp = 113.3-114.3 °C. HPLC analysis: Chiralcel

AD-H (hexane/iPrOH = 80/20, 1.0 mL/min), t r-minor 6.31 min, t r-major 6.95 min. 1H NMR (400 MHz,

CDCl3): δ 9.07 (s, 1H), 8.69 (s, 1H), 8.68 (s, 1H), 7.39 (d, J = 8 Hz, 1H), 7.06 (m, 1H), 6.99 (s,

2H), 6.36 (m, 1H), 4.10 (m, 1H), 3.19 (m, 1H), 2.31 (s, 3H), 2.23 (m, 2H), 1.79 (m, 2H), 1.40 (m,

4H). 13

C NMR (400 MHz, CDCl3): δ 162.1, 148.6, 140.0, 138.0, 134.3, 132.1, 130.7, 127.1,

121.0, 56.2, 51.5, 33.8, 33.0, 26.1, 24.8, 21.1. HRMS (ESI) Calcd for C18H19N3O6S ([M+H]+)

406.1067, Found 406.1074. [α]29

D +83.6 (c = 0.5, CHCl3) (82% ee).

82

3,5-dinitro-N-(2-(1-phenyl-1H-tetrazol-5-ylthio)cyclohexyl)benzamide (94ap) To a

flame-dried test tube was added 7-(3,5-Dinitrobenzoyl)-7-azabicyclo[4.1.0]heptane (0.0291 g,

0.10 mmol), (S)-P11 (6.0 mg, 10 mol %) and 1-phenyl-1H-tetrazole-5-thiol was added (0.0213 g,

0.12 mmol). The air was removed under vacuum and replaced with argon. Diethyl ether (1.0 mL)

was added to the reaction by oven-dried syringe. The reaction was stirred at room temperature


silica gel, and purified by flash column chromatography with hexanes / EtOAc. Recovered yellow

solid (0.0356 g, 78%). Mp = 62.4-65.5 °C. HPLC analysis: Chiralcel OJ-H (hexane/iPrOH = 80/20,

1.0 mL/min), t r-minor 33.32 min, t r-major 23.65 min. 1H NMR (400 MHz, CDCl3): δ 9.08 (s, 1H), 8.96

(s, 2H), 8.59 (m, 1H), 7.52 (m, 3H), 7.48 (m, 2H), 4.18 (m, 1H), 3.99 (m, 1H), 2.44 (m, 1H), 2.29

(m, 1H), 1.87 (m, 1H), 1.68 (m, 1H), 1.48 (m, 2H), 1.23 (m, 1H). 13

C NMR (400 MHz, CDCl3): δ

162.4, 155.6, 148.9, 148.8, 137.8, 133.4, 130.6, 130.0, 127.5, 123.9, 121.1, 57.2, 52.8, 34.0,

33.7, 26.6, 24.5. HRMS (ESI) Calcd for C20H19N7O5S ([M+H]+) 470.1241, Found 470.1247. [α]

29D

+78.6 (c = 0.4, CHCl3) (61% ee).

83

N-(2-(benzylthio)cyclohexyl)-3,5-dinitrobenzamide (94aq) To a flame-dried test tube



(1.0 mL) was added to the reaction by oven-dried syringe. At this point benzyl hydrosulfide was




Recovered a gold colored solid (0.0369 g, 86%). Mp = 164.7-166.9 °C. HPLC analysis: Chiralcel


MHz, CDCl3): δ 9.09 (s, 1H), 8.84 (s, 2H), 8.83 (s, 1H), 7.51 (t, J = 8 Hz, 1H), 7.34 (t, J = 8 Hz,

1H), 7.14 (t, J = 8 Hz, 1H), 6.70 (m, 1H), 4.01 (m, 1H), 3.21 (m, 1H), 2.33 (m, 1H), 2.18 (m, 1H),

1.77 (m, 2H), 1.54 (m, 2H), 1.42 (m, 2H), 1.27 (m, 2H). 13

C NMR (400 MHz, CDCl3): δ 162.5,

148.7, 138.7, 138.5, 128.9, 128.8, 127.3, 121.1, 53.1, 48.5, 34.0, 33.8, 33.6, 26.2, 24.8. HRMS

(ESI) Calcd for C20H21N3O5S ([M+H]+) 416.1275, Found 416.1289. [α]

29D +31.9 (c = 0.5, CHCl3)

(59% ee).

84

N-(2-(2-chlorobenzylthio)cyclohexyl)-3,5-dinitrobenzamide (94ar) To a flame-dried



Diethyl ether (1.0 mL) was added to the reaction by oven-dried syringe. At this point (2-

chlorophenyl)methanethiol was added (0.0190 mL, 0.12 mmol) by oven-dried syringe. The

reaction was stirred at room temperature and monitored by TLC for 20 hours. The reaction was

diluted with acetone, concentrated on silica gel, and purified by flash column chromatography

with hexanes / EtOAc. Recovered white solid (0.0191 g, 43%). Mp = 137.3-139.3 °C. HPLC

analysis: Chiralcel AS-H (hexane/iPrOH = 80/20, 1.0 mL/min), t r-minor 17.49 min, t r-major 21.96 min.

1H NMR (400 MHz, CDCl3): δ 9.12 (s, 1H), 8.83 (s, 2H), 7.34 (d, J = 8 Hz, 1H), 7.30 (d, J = 8 Hz,

1H), 7.15 (m, 2H), 6.30 (d, J = 4 Hz, 1H), 3.86 (s, 2H), 2.59 (m, 1H), 2.35 (m, 2H), 1.80 (m, 2H),

1.65 (m, 1H), 1.44 (m, 1H), 1.29 (m, 3H). 13

C NMR (400 MHz, CDCl3): δ 162.57, 148.79, 138.55,

136.30, 134.05, 131.05, 130.06, 128.90, 127.33, 121.10, 53.37, 49.34, 34.11, 33.63, 31.76,

26.27, 24.80. HRMS (ESI) Calcd for C20H20ClN3O5S ([M+Na]+) 472.0704, Found 472.0680. [α]

29D

+45.4 (c = 0.5, CH3CN) (62% ee).

85

3,5-dinitro-N-(2-(phenethylthio)cyclohexyl)benzamide (94as) To a flame-dried test

tube was added 7-(3,5-Dinitrobenzoyl)-7-azabicyclo[4.1.0]heptane (0.0291 g, 0.10 mmol) and (S)-

P11 (6.0 mg, 10 mol %). The air was removed under vacuum and replaced with argon. Diethyl

ether (1.0 mL) was added to the reaction by oven-dried syringe. At this point 2-phenylethanethiol

was added (0.0166 mL 0.12 mmol) by oven-dried syringe. The reaction was stirred at room



Recovered white solid (0.0171 g, 40%). Mp = 148.3-149.1 °C. HPLC analysis: Chiralcel AS-H


CDCl3): δ 9.12 (s, 1H), 8.87 (s, 2H), 7.15(m, 5H), 6.38 (s, 1H), 3.84 (m, 1H), 2.81 (m, 4H), 2.55

(m, 1H), 2.35 (m, 1H), 2.19 (m, 1H), 1.78 (m, 2H), 1.56 (m, 1H), 1.41 (m, 1H), 1.27(m, 2H). 13

C

NMR (400 MHz, CDCl3): δ 162.5, 148.8, 140.4, 138.5, 128.6, 128.5, 127.3, 126.5, 121.0, 53.3,

48.9, 36.3, 33.5, 33.4, 30.3, 29.8, 26.1, 24.8. HRMS (ESI) Calcd for C21H23N3O5S ([M+Na]+)

452.1250, Found 452.1263. [α]29

D +24.6 (c = 0.5, CHCl3) (32% ee).

86

N-(2-(hexylthio)cyclohexyl)-3,5-dinitrobenzamide (94at) To a flame-dried test tube



(1.0 mL) was added to the reaction by oven-dried syringe. At this point 1-hexanethiol was added




solid (0.0061 g, 15%). Mp = 117.5-118.9 °C. HPLC analysis: Chiralcel Ad-H (hexane/iPrOH =

80/20, 1.0 mL/min), t r-minor 9.45 min, t r-major 11.47 min. 1H NMR (400 MHz, CDCl3): δ 9.13 (s,

1H), 8.93 (s, 1H), 8.93 (s, 1H), 6.50 (m, 1H), 3.83 (m, 1H), 2.62 (m, 1H), 2.51 (m, 2H), 2.38 (m,

1H), 2.18 (m, 1H), 1.80 (m, 2H), 1.51 (m, 4H), 1.34 (m, 4H), 1.23 (m, 4H), 0.82 (t, J = 8 Hz, 3H).

13C NMR (400 MHz, CDCl3): δ 162.6, 148.8, 138.6, 127.3, 121.1, 53.5, 48.8, 33.7, 33.5, 31.5,

30.0, 29.1, 28.8, 26.2, 24.8, 22.7, 14.1. HRMS (ESI) Calcd for C19H27N3O5S ([M+H]+) 410.1744,

Found 410.1737. [α]29

D +15.3 (c = 0.25, (CH3CN) (18% ee).

87

N-(2-(benzo[d]thiazol-2-ylthio)cyclohexyl)-3,5-dinitrobenzamide (94au) To a flame-


mmol), (S)-P11 (6.0 mg, 10 mol %) and 2-mercaptobenzothiazole was added (0.020 g, 0.12

mmol). The air was removed under vacuum and replaced with argon. Diethyl ether (1.0 mL) was

added to the reaction by oven-dried syringe. The reaction was stirred at room temperature and


gel, and purified by flash column chromatography with hexanes / EtOAc. Recovered yellow solid

(0.0345 g, 70%). Mp = 175.4-176.6 °C. HPLC analysis: Chiralcel AD-H (hexane/iPrOH = 80/20,

1.0 mL/min), t r-minor 8.12 min, t r-major 10.97 min. 1H NMR (400 MHz, CDCl3): δ 8.85 (m, 1H), 8.70

(s, 1H), 8.69 (s, 1H), 7.73 (d, J = 8 Hz, 1H), 7.64 (d, J = 8 Hz, 1H), 7.34 (t, J = 8 Hz, 1H), 7.26 (t,

J = 8 Hz, 1H), 4.01 (m, 1H), 2.51 (m, 1H), 2.32 (m, 1H), 1.90 (m, 1H), 1.65 (m, 1H), 1.50 (m, 1H).

13C NMR (400 MHz, CDCl3): δ 169.7, 163.1, 152.1, 148.4, 138.7, 135.1, 127.2, 126.7, 125.2,

121.3, 120.8, 120.6, 58.1, 51.6, 33.9, 33.0, 26.7, 24.5. HRMS (ESI) Calcd for C20H18N4O5S2

([M+Na]+) 481.0610, Found 481.0638. [α]

29D +69.8 (c = 0.5, CHCl3) (55% ee).

88

N-(2-(3,5-bis(trifluoromethyl)phenylthio)cyclohexyl)-3,5-dinitrobenzamide (94av) To

a flame-dried test tube was added 7-(3,5-Dinitrobenzoyl)-7-azabicyclo[4.1.0]heptane (0.0291 g,

0.10 mmol) and (S)-P11 (6.0 mg, 10 mol %). The air was removed under vacuum and replaced

with argon. Diethyl ether (1.0 mL) was added to the reaction by oven-dried syringe. At this point

3,5-bis(trifluoromethyl)benzenethiol was added (0.0202 mL, 0.12 mmol) by oven-dried syringe.

The reaction was stirred at room temperature and monitored by TLC for 20 hours. The reaction

was diluted with acetone, concentrated on silica gel, and purified by flash column

chromatography with hexanes / EtOAc. Recovered white solid (0.0378 g, 70%). Mp = 163.4-

164.3 °C. HPLC analysis: Chiralcel AD-H (hexane/iPrOH = 80/20, 1.0 mL/min), t r-minor 6.32 min, t

r-major 6.64 min. 1H NMR (400 MHz, CDCl3): δ 9.12 (s, 1H), 8.85 (s, 2H), 8.84 (s, 1H), 7.80 (s, 2H),

7.62 (s, 1H), 6.50 (m, 1H), 4.08 (m, 1H), 3.34 (m, 1H), 2.21 (m, 2H), 1.82 (m, 2H), 1.52 (m, 2H),

1.42 (m, 1H), 1.17 (m, 1H). 13

C NMR (400 MHz, CDCl3): δ 162.2, 148.8, 138.0, 137.8, 131.5,

127.2, 121.3, 120.9, 109.9, 54.1, 52.0, 33.5, 33.1, 25.7, 24.6. HRMS (ESI) Calcd for

C21H17F5N3O5S ([M+H]+) 538.0866, Found 538.0867. [α]

29D +36.4 (c = 0.5, CHCl3) (84% ee)

89

N-(2-(phenylthio)cyclohexyl)-3,5-bis(trifluoromethyl)benzamide (94ba) To a flame-

dried test tube was added 7-(3,5-Bis-trifluoromethylbenzoyl)-7-azabicyclo[3.1.0]heptane (0.0337

g, 0.10 mmol) and (S)-P11 (6.0 mg, 10 mol %). The air was removed under vacuum and

replaced with argon. Diethyl ether (1.0 mL) was added to the reaction by oven-dried syringe. At

this point thiophenol was added (0.0122 mL, 0.12 mmol) by oven-dried syringe. The reaction was




OD-H (hexane/iPrOH = 97.5/2.5, 1.0 mL/min), t r-minor 23.32 min, t r-major 28.56 min. 1H NMR (400

MHz, CDCl3): δ 8.02 (s, 2H), 7.93 (s, 1H), 7.39 (d, J = 8 Hz, 2H), 7.17 (m, 3H), 6.32 (d, J = 8 Hz,

1H), 3.97 (m, 1H), 3.09 (m, 1H), 2.21 (m, 2H), 1.76 (m, 2H), 1.35 (m, 4H). 13

C NMR (500 MHz,

CDCl3): δ 164.1, 136.9, 134.1, 132.8, 129.2, 127.7, 127.4, 125.0, 55.1, 51.9, 33.8, 33.3, 26.2,

24.7. HRMS (ESI) Calcd for C21H19F6NOS ([M+Na]+) 448.1164, Found 448.1179. [α]

29D +28.0 (c

= 0.5, CHCl3) (43% ee).

90

4-nitro-N-(2-(phenylthio)cyclohexyl)benzamide (94ca) To a flame-dried test tube was

added 7-(4-nitrobenzoyl)-7-azabicyclo[4.1.0]heptane (0.0246 g, 0.10 mmol) and (S)-P11 (6.0 mg,

10 mol %). The air was removed under vacuum and replaced with argon. Diethyl ether (1.0 mL)

was added to the reaction by oven-dried syringe. At this point thiophenol was added (0.0122 mL,

0.12 mmol) by oven-dried syringe. The reaction was stirred at room temperature and monitored

by TLC for 20 hours. The reaction was diluted with acetone, concentrated on silica gel, and

purified by flash column chromatography with hexanes / EtOAc. Recovered white solid (0.0223,

99%). Mp = 139.9-140.5 °C. HPLC analysis: Chiralcel AD-H (hexane/iPrOH = 80/20, 1.0 mL/min),

t r-minor 12.04 min, t r-major 17.24 min. 1H NMR (400 MHz, CDCl3): δ 8.19 (d, J = 8 Hz, 2H), 7.74 (d,

J = 8 Hz, 2H), 7.40 (d, J = 8 Hz, 2H), 7.24 (d, J = 8 Hz, 3H), 6.28 (d, J = 8 Hz, 1H), 3.90 (m, 1H),

3.06 (m, 1H), 2.29 (m, 1H), 2.14 (m, 1H), 1.75 (m, 2H), 1.45 (m, 2H), 1.31 (m, 2H). 13

C NMR

(400 MHz, CDCl3): δ 165.0, 140.5, 133.9, 132.9, 129.3, 128.3, 127.6, 123.8, 54.6, 51.8, 33.7,

33.3, 26.1, 24.7. HRMS (ESI) Calcd for C19H20N2O3S ([M+Na]+) 379.1087, Found 379.1087 [α]

20D

+30.5 (c = 0.5, CH3CN) (6.1% ee).

91

3,5-dinitro-N-(3-(phenylthio)butan-2-yl)benzamide (94ia) To a flame-dried test tube

was added cis-1-(3,5-Dinitrobenzoyl)-2,3-dimethylaziridine (0.0265 g, 0.10 mmol) and (S)-P11






solid (0.0374 g, 99%). Mp = 144.6-145.8 °C. HPLC analysis: Chiralcel AS-H (hexane/iPrOH =


1H), 8.85 (s, 1H), 8.85 (s, 1H), 7.46 (d, J = 8 Hz, 2H), 7.28 (t, J = 8 Hz, 2H), 7.21 (m, 1H), 6.51 (d,

J = 8 Hz, 2H), 4.42 (m, 1H), 3.52 (m, 1H), 1.37 (s, 6H). 13

C NMR (500 MHz, CDCl3): δ 162.4,


C17H17N3O5S ([M+H]+) 376.0961, Found 376.0974. [α]

29D +46.6 (c = 0.5, CHCl3) (95% ee).

92

3,5-dinitro-N-(2-(phenylthio)cycloheptyl)benzamide (94ja) To a flame-dried test tube

was added 8-(3,5-Dinitrobenzoyl)-8-azabicyclo[5.1.0]octane (0.0305 g, 0.10 mmol) and (S)-P11



(0.0122 mL, 0.12 mmol) by oven-dried syringe. The reaction was stirred at 60 °C and monitored

by TLC for 72 hours. The reaction was diluted with acetone, concentrated on silica gel, and

purified by flash column chromatography with hexanes / EtOAc. Recovered pale yellow solid

(0.0394, 95%). Mp = 164.3-165.0 °C. HPLC analysis: Chiralcel OJ-H (hexane/iPrOH = 80/20, 1.0

mL/min), t r-minor 8.28 min, t r-major 15.65 min. 1H NMR (400 MHz, CDCl3): δ 9.08 (s, 1H), 8.78 (s,

1H), 8.78 (s, 1H), 7.36 (d, J = 8 Hz, 2H), 7.23 (t, J = 8 Hz, 2H), 7.14 (t, J = 8 Hz, 1H), 6.55 (d, J =

8 Hz, 1H), 4.18 (m, 1H), 3.34 (m, 1H), 2.07 (m, 2H), 1.80 (m, 2H), 1.59 (m, 4H). 13

C NMR (400

MHz, CDCl3): δ 162.0, 148.7, 138.2, 134.8, 131.9, 129.3, 127.3, 127.2, 121.0, 57.4, 54.0, 33.8,

32.6, 28.0, 25.7, 24.2. HRMS (ESI) Calcd for C20H21N3O5S ([M+H]+) 416.1275, Found 416.1281

[α]20

D +44.6 (c = 0.5, CH3CN) (96% ee).

93

4-nitro-N-(2-(phenylthio)cyclohexyl)benzamide (94ka) To a flame-dried test tube was

added 7-(3,5-Dinitrobenzoyl)-7-azabicyclo[4.1.0]hept-3-ene (0.0289 g, 0.10 mmol) and (S)-P11





silica gel, and purified by flash column chromatography with hexanes / EtOAc. Recovered white

solid (0.0388, 97%). Mp = 171.8-172.8 °C. HPLC analysis: Chiralcel AS-H (hexane/iPrOH =


1H), 8.95 (s, 1H), 8.95 (s, 1H), 8.43 (d, J = 8 Hz, 2H), 7.47 (d, J = 8 Hz, 2H), 7.26 (t, J = 8 Hz,

2H), 7.17 (d, J = 8 Hz, 1H), 5.65 (s, 2H), 4.37 (m, 1H), 3.73 (m, 1H), 2.80 (m, 2H), 2.59 (m, 2H),

2.33 (m, 2H), 2.23 (m, 2H). 13

C NMR (400 MHz, CDCl3): δ 162.2, 148.8, 138.0, 134.9, 134.2,


C19H17N3O5S ([M+H]+) 400.0962, Found 400.0972. [α]

29D +37.6 (c = 0.5, (CH3)2CO) (95% ee).

94

3,5-dinitro-N-(5-(phenylthio)octan-4-yl)benzamide (94la) To a flame-dried test tube

was added cis-1-(3,5-Dinitrobenzoyl)-2,3-dipropylaziridine (0.0321 g, 0.10 mmol) and (S)-P11





silica gel, and purified by flash column chromatography with hexanes / EtOAc. Recovered gold

colored solid (0.0405 g, 94%). Mp = 96.2-97.2 °C. HPLC analysis: Chiralcel OD-H (hexane/iPrOH

= 80/20, 1.0 mL/min), t r-minor 15.16 min, t r-major 23.81 min. 1H NMR (400 MHz, CDCl3): δ 9.14 (s,

1H), 8.85 (s, 1H), 8.84 (s, 1H), 7.48 (d, J = 8 Hz, 2H), 7.31 (t, J = 8 Hz, 2H), 7.22 (m, 1H), 6.40 (d,

J = 8 Hz, 2H), 4.48 (m, 1H), 3.32 (m, 1H), 1.65 (m, 2H), 1.58 (m, 2H), 1.28 (m, 2H), 0.92 (m, 3H),

0.84 (m, 3H). 13

C NMR (500 MHz, CDCl3): δ 162.5, 148.9, 148.8, 138.1, 135.3, 132.1, 129.4,


C21H25N3O5S ([M+H]+) 432.1588, Found 432.1601 [α]

29D -46.2 (c = 0.5, CHCl3) (87% ee).

95

3,5-dinitro-N-(2-(phenylamino)cyclohexyl)benzamide (123) To a flame-dried test tube was

added 7-(3,5-Dinitrobenzoyl)-7-azabicyclo[4.1.0]heptane (0.0291 g, 0.10 mmol or 0.010 g, 0.03

mmol) and 5-10 mol % catalyst. The air was removed under vacuum and replaced with argon.

Toluene (1.0 mL) was added to the reaction by oven-dried syringe. At this point aniline was

added (1 equivalent) by oven-dried syringe. The reaction was stirred at room temperature and


gel, and purified by flash column chromatography or preparatory TLC plate with hexanes / EtOAc.

HPLC analysis: Chiralcel AS-H (hexane/iPrOH = 80/20, 1.0 mL/min), t r-minor 9.88 min, t r-major

16.99 min. 1H NMR (400 MHz, CDCl3): δ 9.06 (s, 1H), 8.65 (s, 2H), 7.01 (q, 2H), 6.54 (m, 3H),

4.02 (m, 1H), 3.77 (m, 1H), 3.34 (m, 1H), 2.17 (m, 2H), 1.86 (m, 2H), 1.58 (m, 2H), 1.44 (m, 2H),

13C NMR (500 MHz, CDCl3): δ 163.3, 148.2, 147.6, 137.8, 129.4, 126.9, 120.7, 117.3, 112.9,

77.3, 76.9, 76.6, 57.8, 55.9, 32.9, 32.6, 24.9, 24.8

96

A2 Supporting Information for Chapter 3

A2.1 General Reaction Conditions

All reactions were carried out in flame-dried screw-cap test tubes and were allowed to

proceed under a dry argon atmosphere with magnetic stirring. Anhydrous solvents were used

purchased from commercial sources; tetrahydrofuran was distilled from sodium and

benzophenone, dimethylformamide was used without further purification. 3-chloro-2,4-

pentanedione was purchased and purified by distillation; while 4-(Dimethylamino)pyridine was

purchased and used without further purification. (R)-2,2′-Diphenyl-3,3′-(4-biphenanthrol), VAPOL,

was synthesized according to the literature procedure discussed in section 4.1.48

(R)-(+)-1,1′-Bi(2-naphthol), BINOL, was purchased from commercial sources and used

without further purification. Phosphoric acids P11 and P12 were prepared according to literature

procedures.48,50,168

Substituted BINOL phosphoric acids (P1-P10, P13, and P14) were prepared

from BINOL according to known literature procedures as outlined in section 4.1. Chiral phosphate

salts, were prepared directly before use according to the known literature procedure.33

Thin layer

chromatography was performed on Merck TLC plates (silica gel 60 F254). Visualization was

accomplished UV light (256 nm), with the combination of ceric ammonium molybdate as indicator.

Flash column chromatography was performed with Merck silica gel (230-400 mesh).

Enantiomeric excess (ee) was determined using a Varian Prostar HPLC with a 210 binary

pump and a 335 diode array detector with Daicel Chiralcel AS-H, AD-H, OJ-H or OD-H chiral

column (eluent and flow rates shown below). The Melting points were determined using a MEL-

TEMP 3.0 instrument and are uncorrected. Optical rotations were performed on a Rudolph

Research Analytical Autopol IV polarimeter (λ 589) using a 700 μL cell with a path length of 1 dm.

1H NMR and

13C NMR were recorded on a Varian Inova-400 spectrometer with chemical

shifts reported relative to tetramethylsilane (TMS). Known compounds and were characterized by

comparing their 1H NMR and

13C NMR values to the reported values. H3PO4 was used as an

31P NMR. The HRMS data was measured on an Agilent 1100 series

MSD/TOF mass spectrometer with electrospray ionization. Elemental analysis was conducted by

97

Atlantic Micro Labs and Micro-Analysis Inc. 3D Images were generated using CYLview, 1.0b;

Legault, C. Y., Université de Sherbrooke, 2009 (http://www.cylview.org)

A2.2 Preparation of N-Acyl Imines

All the N-acyl imines were prepared according to the reported method and their data are

identical with those in the corresponding literatures.129,169,170

Figure A6 Preparations of N-Acyl Imines

Purification of N-Acyl Imines by distillation was found to be very difficult, so imines were

purified by sublimation with heating in an oil bath and collection on a cold finger chilled with ice.

Collection of imine off the cold finger allowed for pure NMR for purity and identification free of

impurities or decomposition. Imines were stored at room temperature or at 0 0C, but inside of an

airtight desiccator.

4.2.3 Preparation and Characterization of Catalyst

H[P11] (VAPOL-PA) was purified on silica gel without acidification after preparation according

to the reported literature procedure.168

H[P1-10 and P12-14] were prepared in a similar manner

to the reported literature procedure168

but after purification by silica gel column chromatography

they were acidified in AcOEt or DCM with an aqueous solution of 6N HCl. The organic phase was

separated, and the removal of volatiles was performed under reduced pressure obtaining a white

solid.33

Catalysts M[P1-14]n were prepared in a similar manor to the in situ literature procedure.33

To

prepare M[P1-14]n (1.25–5 mol %) in situ, Li(OiPr) (5 mol %), NaOMe (5 mol %), Mg(OtBu)2

(1.25-5 mol %), Ca(OMe)2 (2.5 mol %), and Ba(OiPr)2 (2.5 mol %) were respectively used with

[P1-14] (5 mol %) in 1 mL each of CH2Cl2 and MeOH. The solution was stirred at room

temperature for 30 minutes in a flame dried, argon filled, screw-cap reaction tube loaded with a

stir bar. After 30 minutes the volatile solvents were removed in vacuo and the desired M[P1-14]n

98

was obtained as a white solid. The screw-cap tube was then used directly for the aza-Darzens

reaction.

A2.4 Characterization of Magnesium(II) salt of (R)-2,2′-Diphenyl-3,3′-biphenanthryl-4,4′-

diyl phosphate (Mg[P11]2)

1H NMR (400 MHz, DMSO) δ 9.95-9.93 (d, J = 8.0 Hz, 2H), 8.00-7.98 (d, J = 7.5 Hz, 2H),

7.87-7.80 (q, J = 8.6 Hz, 4H), 7.69-7.63 (p, J = 6.5 Hz, 4H), 7.49 (s, 2H), 7.07-7.04 (t, J = 7.1 Hz,

2H), 6.92-6.89 (t, J = 7.4 Hz, 4H), 6.42-6.40 (d, J = 7.7 Hz, 4H). 13C NMR (100 MHz, DMSO) δ

140.5, 139.8, 133.6, 132.6, 129.8, 128.9, 128.8, 128.2, 128.0, 127.3, 127.1, 127.0, 126.6, 126.3,

126.3, 124.8, 121.6. 31P NMR (121.5 MHz, DMSO) δ 1.23. C80H48MgO8P2·10xH20 F.W. 1403.64

g/mol, Analytical Calculated: (C and H) 68.45 and 4.88. Found: (C and H) 68.40 and 4.60.

A2.5 General Procedure for the Enantioselective aza-Darzens Reaction

The air was removed and back filled with argon three times to screw-cap reaction tube

preloaded with a stir bar, catalyst (R [P3]2Mg, 0.025 mmol) and N-acyl imine (1.5 mmol). Dry

tetrahydrofuran (1 mL) and freshly distilled 3-chloro-2,4-pentanedione (0.1 mmol) were added via

syringe. The reaction mixture was stirred overnight at room temperature. Solvent was then

removed in vacuo, followed immediately by the addition of 4-(Dimethylamino)pyridine (2.0 mmol),

dimethylformamide (1.0 mL), and lastly flushed with argon. The reaction was allowed to stir for

another 48 hours at room temperature while being monitored by TLC. The crude product was

concentrated on to silica gel under reduced pressure, and then loaded on a silica gel column. The

aziridine product was then purified by flash chromatography using ethyl acetate and hexanes,

and enantiomeric excess was determined by chiral HPLC.

A2.6 General Procedure for the Racemic aza-Darzens Reaction

All the racemic products were prepared according to the general procedure above but using

racemic [P11]2Mg in replacement of the R enantiomer.

A2.7 Absolute Configuration of aza-Darzens Products

99

Figure A7 Determination of the Absolute Configuration of aza-Darzens Products

Absolute configuration was determined before ring closing of the chlorinated β-amino

carbonyl compound by dechlorination with zinc and acetic acid. The air was removed and back

filled with argon three times to screw-cap reaction tube preloaded with a stir bar, catalyst

([P11]2Mg 0.025 mmol) and N-acyl imine (1.5 mmol). Dry tetrahydrofuran (1 mL) and freshly

distilled 3- chloro-2,4-pentanedione (0.1 mmol) were added via syringe. The reaction mixture was

stirred overnight at room temperature. Solvent was then removed in vacuo. Zinc washed with

HCL and deionized water was added (19.5 mg), followed by acetic acid (1 mL). The reaction was

allowed to stir at room temperature for 3 hours, followed by flash chromatography (hexane:ethyl

acetate). Comparison of the 1H NMR and HPLC analysis matched that of the S enantiomer from

the literature.162,171

White Solid, 1H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 9.2 Hz, 1H), 7.84-7.76

(m, 2H), 7.49-7.48 (m, 1H), 7.41 (m, 2H), 7.31-7.30 (d, J = 4.2 Hz, 3H), 6.04 (dd, J = 9.3, 6.5 Hz,

1H), 4.38 (m, 1H), 2.30 (s, 3H), 2.10 (s, 3H). 13

C NMR (100 MHz, CDCl3): δ 205.0, 166.7, 132.0,

131.8, 128.8, 128.6, 127.7, 127.1, 127.0, 126.2, 70.0, 52.2, 31.6, 29.7. Chiralpak AD-H (hexane:

isopropanol, 85:15, 1.0 mL/min), MS (ESI): C19H19NO3 m/z calcd. for ([M+H]+) 309.1, found

309.1; m/z calcd. for ([M+Na]+) 332.1 found 332.1. Mp: 157.3-159.3 ºC, tmajor = 20.09 min,

tminor = 23.51 min, ee = 93%. 80% yield for two steps.

100

A2.8 Cartesian Coordinates for the Lowest Energy Catalyst

C 6.72745 1.53931 -0.77999 C 6.65916 2.91354 -0.94277 C 5.68150 0.90017 -0.05216 C 4.61266 1.67717 0.39586 C 4.53318 3.08982 0.28828 C 5.61145 3.69862 -0.42469 C 6.77950 -2.53472 1.14130 C 6.78213 -1.15802 0.98564 C 5.77673 -3.36736 0.60853 C 4.67691 -2.80777 -0.11177 C 4.68824 -1.39238 -0.21207 C 5.71420 -0.56689 0.24952 O 3.56465 0.98047 1.01896 O 3.61483 -0.74376 -0.84283 P 2.58291 0.09395 0.08375 C 7.84074 0.80454 -1.44306 C 7.85176 -0.37261 1.66228 C 3.46829 3.94011 0.82511 C 3.50710 5.34071 0.53115 C 4.59152 5.89378 -0.22560 C 5.60842 5.11163 -0.66659 C 2.40608 3.48544 1.64876 C 1.42412 4.34580 2.10956 C 1.44892 5.71039 1.77788 C 2.48598 6.19453 1.00697 C 5.84104 -4.78030 0.84197 C 4.86744 -5.60860 0.38728 C 3.76339 -5.10433 -0.37509 C 3.65877 -3.70559 -0.66171 C 2.78760 -6.00348 -0.86267 C 1.73347 -5.56555 -1.63797 C 1.64502 -4.20190 -1.96269 C 2.58198 -3.29825 -1.49121 C 7.59377 -0.29714 -2.27834 C 8.63765 -0.92358 -2.95780 C 9.94754 -0.46048 -2.81848 C 10.20588 0.63548 -1.99348 C 9.16232 1.26153 -1.31324 C 7.54277 0.71005 2.50192 C 8.54849 1.38520 3.19215 C 9.88131 0.99070 3.05956 C 10.20116 -0.08613 2.23098 C 9.19571 -0.76129 1.54046 C -6.58137 -1.43464 -1.05588 C -6.50548 -2.79915 -1.28448 C -5.56326 -0.83331 -0.25992 C -4.50941 -1.63126 0.18574 C -4.42406 -3.03654 0.01078 C -5.47537 -3.60919 -0.76936 C -6.69977 2.54055 1.06397 C -6.69483 1.17248 0.84516 C -5.68527 3.39789 0.59593 C -4.56484 2.87273 -0.11861 C -4.56955 1.46353 -0.28271

101

C -5.60659 0.61733 0.11137 O -3.48238 -0.96346 0.87278 O -3.47645 0.84464 -0.90979 P -2.47314 -0.03872 0.00567 C -7.66824 -0.66552 -1.72402 C -7.77661 0.35193 1.45776 C -3.37637 -3.91148 0.54068 C -3.39849 -5.29459 0.17230 C -4.45392 -5.80968 -0.64945 C -5.45858 -5.00787 -1.08348 C -2.34791 -3.49816 1.42650 C -1.37891 -4.37881 1.87625 C -1.38434 -5.72364 1.47082 C -2.39069 -6.16937 0.63852 C -5.75943 4.79904 0.88990 C -4.77689 5.64832 0.49709 C -3.65192 5.18022 -0.25768 C -3.53530 3.79549 -0.60188 C -2.66699 6.10178 -0.68099 C -1.59191 5.70033 -1.44723 C -1.49090 4.35231 -1.82853 C -2.43641 3.42697 -1.42044 C -8.99486 -1.12214 -1.66449 C -10.01110 -0.45940 -2.35152 C -9.71977 0.67325 -3.11354 C -8.40419 1.13575 -3.18379 C -7.38774 0.47249 -2.49780 C -7.47971 -0.76033 2.26234 C -8.49691 -1.47391 2.89457 C -9.82999 -1.08983 2.73614 C -10.13790 0.01633 1.94250 C -9.12060 0.73132 1.31156 Mg 0.05490 0.01683 0.06093 H 7.42603 3.41002 -1.53048 H 7.56402 -2.99604 1.73447 H 4.58830 6.96269 -0.42457 H 6.43794 5.53679 -1.22551 H 2.36593 2.45101 1.95058 H 0.62812 3.95451 2.73709 H 0.66780 6.37579 2.13465 H 2.54092 7.25180 0.75797 H 6.68558 -5.16752 1.40596 H 4.91437 -6.67758 0.58020 H 2.89122 -7.05831 -0.61875 H 0.98781 -6.26597 -2.00353 H 0.83540 -3.84555 -2.59355 H 2.49522 -2.26572 -1.78969 H 6.57664 -0.65016 -2.41486 H 8.42410 -1.76998 -3.60530 H 10.75980 -0.94927 -3.35011 H 11.22248 1.00064 -1.87274 H 9.37037 2.09703 -0.65085 H 6.50784 1.00964 2.63303 H 8.28753 2.21599 3.84248 H 10.66372 1.51736 3.59968 H 11.23590 -0.39824 2.11577

102

H 9.45095 -1.58185 0.87589 H -7.24871 -3.26491 -1.92538 H -7.50138 2.97324 1.65600 H -4.43958 -6.86668 -0.90383 H -6.26643 -5.40504 -1.69251 H -2.32528 -2.48140 1.78544 H -0.60866 -4.01948 2.55317 H -0.61301 -6.40458 1.81950 H -2.43171 -7.21224 0.33251 H -6.61933 5.15966 1.44834 H -4.83198 6.70776 0.73521 H -2.78032 7.14490 -0.39463 H -0.83946 6.41778 -1.76231 H -0.66457 4.02519 -2.45345 H -2.33877 2.40864 -1.76155 H -9.22987 -1.98728 -1.05087 H -11.03248 -0.82534 -2.28541 H -10.51073 1.19056 -3.65023 H -8.16443 2.01079 -3.78220 H -6.36494 0.82609 -2.58130 H -6.44527 -1.05309 2.41203 H -8.24524 -2.32720 3.51888 H -10.62196 -1.64688 3.22984 H -11.17253 0.32127 1.80851 H -9.36602 1.57631 0.67447 O 1.69244 -0.74741 1.00005 O 1.65990 0.88666 -0.84308 O -1.60523 0.75483 0.98394 O -1.52825 -0.79524 -0.92987

A2.9 Cartesian Coordinates for the Middle Energy Catalyst

C 5.54255 1.20346 0.95408 C 5.81320 2.50694 1.33580 C 4.38954 0.98039 0.14989 C 3.64410 2.07609 -0.28334 C 3.87160 3.41904 0.11406 C 5.00960 3.60131 0.96215 C 3.27984 -2.64639 0.34299 C 3.59422 -1.36493 0.76898 C 3.30908 -3.03246 -1.01175 C 3.64692 -2.09010 -2.03314 C 3.90124 -0.76774 -1.57540 C 3.93855 -0.39845 -0.22297 O 2.59412 1.76108 -1.16161 O 4.18158 0.24707 -2.48889 P 2.98643 1.33288 -2.80131 C 6.49752 0.12960 1.34276 C 3.51427 -1.05700 2.22481 C 3.06385 4.58694 -0.24469 C 3.46820 5.86924 0.24934 C 4.63303 5.99714 1.07366 C 5.36884 4.91153 1.41854 C 1.88680 4.54716 -1.03350 C 1.16162 5.69062 -1.32046 C 1.57481 6.94309 -0.83899

103

C 2.71396 7.02215 -0.06428 C 2.94941 -4.37549 -1.36025 C 2.93661 -4.77967 -2.65488 C 3.31851 -3.89147 -3.71269 C 3.69988 -2.54158 -3.42483 C 3.33808 -4.36595 -5.04334 C 3.74446 -3.55688 -6.08483 C 4.15791 -2.24349 -5.80856 C 4.13843 -1.74837 -4.51582 C 7.01684 -0.76546 0.39315 C 7.96512 -1.71992 0.75907 C 8.41536 -1.79644 2.07857 C 7.91146 -0.90874 3.03075 C 6.96207 0.04463 2.66544 C 2.78530 0.03887 2.71557 C 2.66924 0.26398 4.08717 C 3.28003 -0.60143 4.99728 C 4.00755 -1.69473 4.52354 C 4.12172 -1.91987 3.15183 C -5.38059 -1.89302 0.40443 C -5.19686 -3.21883 0.76054 C -4.29414 -0.99082 0.59892 C -3.08311 -1.49565 1.07663 C -2.89356 -2.82396 1.53895 C -4.00248 -3.70032 1.32840 C -5.50630 2.60938 0.53125 C -5.38702 1.29571 0.95638 C -4.72949 3.15480 -0.50991 C -3.74256 2.36170 -1.17239 C -3.62215 1.03578 -0.68475 C -4.43270 0.46910 0.29604 O -2.00108 -0.59525 1.12315 O -2.63329 0.19042 -1.20932 P -1.34231 -0.08708 -0.26572 C -6.67094 -1.50269 -0.23069 C -6.19881 0.84544 2.12069 C -1.70030 -3.34473 2.20766 C -1.64373 -4.74486 2.50189 C -2.75091 -5.59809 2.18476 C -3.89059 -5.09314 1.65007 C -0.61611 -2.54724 2.65348 C 0.46711 -3.10020 3.31578 C 0.53376 -4.48306 3.55530 C -0.51288 -5.28763 3.15252 C -4.89275 4.53534 -0.85982 C -4.11548 5.11259 -1.81044 C -3.13320 4.35249 -2.52657 C -2.95108 2.96093 -2.24728 C -2.35798 4.98135 -3.52818 C -1.42734 4.27449 -4.26394 C -1.27292 2.89680 -4.03064 C -2.02146 2.25681 -3.05681 C -7.88658 -1.88217 0.36117 C -9.10385 -1.58177 -0.24912 C -9.12861 -0.89884 -1.46596 C -7.92653 -0.52399 -2.06966

104

C -6.70945 -0.82405 -1.45938 C -5.60467 0.20652 3.22132 C -6.36405 -0.14479 4.33641 C -7.73106 0.13690 4.37465 C -8.33283 0.77560 3.28912 C -7.57342 1.12703 2.17395 H 6.70425 2.70722 1.92420 H 2.96095 -3.38092 1.07692 H 4.91085 6.98870 1.42260 H 6.24932 5.01018 2.04795 H 1.52878 3.61048 -1.42529 H 0.26474 5.60585 -1.92736 H 1.00315 7.83752 -1.07138 H 3.05186 7.98005 0.32418 H 2.67151 -5.05534 -0.55961 H 2.64790 -5.79523 -2.91391 H 3.03211 -5.39274 -5.22902 H 3.75529 -3.93399 -7.10375 H 4.50045 -1.60091 -6.61488 H 4.48651 -0.74193 -4.34501 H 6.69609 -0.69666 -0.64154 H 8.36056 -2.39838 0.00771 H 9.15519 -2.54078 2.36119 H 8.25202 -0.96177 4.06158 H 6.54980 0.71475 3.41457 H 2.28847 0.71632 2.02718 H 2.09322 1.11411 4.44217 H 3.18893 -0.42452 6.06555 H 4.49510 -2.37065 5.22115 H 4.71047 -2.75717 2.78860 H -5.99652 -3.92906 0.57013 H -6.19934 3.26705 1.04834 H -2.66791 -6.65748 2.41464 H -4.74253 -5.73541 1.44319 H -0.63629 -1.47863 2.50446 H 1.26662 -2.45182 3.65837 H 1.39160 -4.90946 4.06856 H -0.49580 -6.35667 3.35170 H -5.64444 5.11302 -0.32853 H -4.23229 6.16522 -2.05641 H -2.51802 6.04092 -3.71437 H -0.83278 4.77041 -5.02593 H -0.56263 2.32073 -4.61692 H -1.90873 1.18979 -2.94129 H -7.87214 -2.38909 1.32172 H -10.03342 -1.87631 0.23103 H -10.07660 -0.66362 -1.94258 H -7.93339 -0.00281 -3.02326 H -5.78113 -0.54821 -1.94939 H -4.53820 0.00518 3.21345 H -5.88318 -0.63197 5.18065 H -8.32189 -0.13736 5.24465 H -9.39717 0.99526 3.30628 H -8.05044 1.59890 1.31961 O 1.66812 0.58271 -3.04142 O 3.49080 2.44223 -3.62321

105

O -0.50143 1.16607 0.00004 O -0.44312 -1.07809 -1.00405 Mg 0.94086 0.41936 -1.23283

A2.10 Cartesian Coordinates the High Energy Catalyst

H -7.95264 -3.26564 2.54971 H -7.62968 -1.70452 0.63866 C -7.01341 -3.25822 2.00301 C -6.83012 -2.37870 0.93419 C -5.98393 -4.13007 2.36197 H -6.11473 -4.81626 3.19466 C -5.62628 -2.36759 0.23169 H -5.50340 -1.70046 -0.61553 C -4.78013 -4.12054 1.65848 C -4.58083 -3.23637 0.58614 H -5.28469 5.88844 -0.78151 C -5.08718 4.95182 -1.29749 C -5.34656 4.82836 -2.64736 H -5.74405 5.66770 -3.21155 H -4.59349 4.98944 1.31063 C -4.36766 4.02562 0.86134 C -4.57583 3.86868 -0.54776 C -5.10736 3.59696 -3.27887 C -3.92148 2.99551 1.62274 H -3.87199 -1.19708 3.75536 H -5.32755 3.47658 -4.33595 C -4.59676 2.52241 -2.57094 H -3.78566 3.11188 2.69486 C -4.29220 2.62022 -1.18910 H -3.97375 -4.78590 1.95419 C -3.60493 1.72682 1.03460 C -3.74697 1.53226 -0.37421 H -4.45592 1.58747 -3.08867 C -3.12677 0.68823 1.85673 C -2.96779 -1.76660 3.56123 H -3.06401 -2.81417 5.43583 C -3.33125 -3.29239 -0.22079 H -3.40297 -5.41981 -0.35770 H -3.00563 0.89169 2.91664 C -3.33154 0.25894 -0.84622 C -2.51983 -2.69068 4.50317 C -2.78235 -0.56587 1.37472 C -2.87013 -4.52169 -0.65708 C -2.90291 -0.79050 -0.02960 O -3.40812 -0.03227 -2.20828 H -2.02343 6.47530 -2.89193 C -2.29324 -1.58834 2.34140 C -2.61484 -2.13245 -0.63312 C -1.32137 5.97421 -2.23215 H -0.81840 4.41969 -3.65287 H -1.85317 -6.83002 -1.41838 C -1.38859 -3.46474 4.24230 C -1.75716 -4.66636 -1.50670 C -0.65518 4.81333 -2.65456

106

H -1.52033 7.40605 -0.64569 P -2.04425 -0.09385 -3.09612 C -1.58964 -2.27367 -1.57179 C -1.05124 6.48284 -0.97769 C -1.31747 -5.98722 -1.84708 C -1.14768 -2.36288 2.10001 O -2.30437 -0.72052 -4.40089 H -1.04126 -4.19213 4.97129 C -0.70530 -3.29508 3.03716 C -1.09491 -3.51837 -2.04754 O -1.04295 -1.05928 -2.03815 O -1.20815 1.18264 -2.90077 C 0.22422 4.15764 -1.81033 H -0.59211 -2.23573 1.17667 C -0.15557 5.83360 -0.09886 C -0.25415 -6.18038 -2.66558 H -1.10927 1.85362 4.44286 H 0.77092 3.32007 -2.20833 C 0.47001 4.60494 -0.48880 H -0.32233 7.38119 1.41337 H 0.17966 -3.88837 2.82299 H 0.08703 -7.18454 -2.90503 C 0.15201 6.43504 1.16470 C 0.01450 -3.72759 -2.98293 C 0.43657 -5.07068 -3.25087 C -0.25183 1.19278 4.53987 Mg 0.31837 0.54901 -1.88631 H 0.17673 1.24268 2.43937 H -0.47480 0.94978 6.67275 C 1.31634 3.91776 0.48963 C 0.48379 0.85442 3.40493 C 0.10251 0.68510 5.79087 C 1.03969 5.86057 2.01432 C 0.71944 -2.69789 -3.65295 H 0.40909 -1.67442 -3.54742 O 1.55557 1.81739 -0.75177 C 1.62504 4.58692 1.71551 C 1.53173 -5.31464 -4.10959 C 1.83096 2.59800 0.38855 O 2.13492 0.32835 -2.54743 H 1.30134 6.33532 2.95614 H 1.82488 -6.34665 -4.28766 P 2.88496 1.46288 -1.82884 C 1.79304 -2.96049 -4.48540 C 1.20321 -0.16578 5.89789 C 1.60113 0.00939 3.49909 O 3.42478 2.65000 -2.51053 C 2.21451 -4.27923 -4.71472 C 2.51017 4.00430 2.64225 C 2.58667 1.96031 1.37633 C 1.94352 -0.49643 4.76474 C 2.39514 -0.40798 2.30920 H 1.49557 -0.56360 6.86608 C 2.84771 0.48592 1.29130 C 3.02119 2.72610 2.49781 H 2.30417 -2.12943 -4.96177

107

H 2.81504 4.59842 3.49897 C 2.70264 -1.75317 2.16976 H 2.32805 -2.45218 2.91145 C 3.55714 -0.03943 0.20823 O 3.95948 0.88708 -0.75521 H 2.94048 2.91739 5.21055 H 3.05867 -4.48120 -5.36776 C 3.45065 -2.26887 1.09459 H 2.82155 -1.12795 4.86151 C 3.93616 -1.40087 0.06910 C 4.02882 2.23675 3.47745 C 3.85933 2.46082 4.85370 C 3.69280 -3.68010 1.02029 H 3.29392 -4.31076 1.81082 C 4.75349 -1.96478 -1.00799 C 4.38895 -4.21488 -0.01400 H 5.34657 -0.12866 -1.99644 C 5.40615 -1.20478 -2.01178 C 4.94359 -3.38353 -1.04124 C 4.83913 2.07360 5.76648 C 5.21420 1.62107 3.04245 H 4.68356 2.24807 6.82801 H 5.37877 1.46840 1.98050 H 4.55684 -5.28734 -0.07343 C 6.15700 -1.80809 -3.00617 C 5.70585 -3.97350 -2.07467 C 6.30179 -3.20401 -3.05315 H 6.63997 -1.18557 -3.75421 C 6.00999 1.45722 5.32163 C 6.19385 1.23404 3.95575 H 5.82286 -5.05465 -2.07622 H 6.88735 -3.67027 -3.84078 H 6.77414 1.15583 6.03328 H 7.10656 0.76630 3.59634

108

A2.11 Characterization of Aza-Darzens Products

N

O

Me

O

OMe

1-(2-Acetyl-1-benzoyl-3-phenyl-aziridin-2-yl)-ethanone (148a)

Following the general procedure for the of aza-Darzens reaction of N-acyl imines with 1,3-

diketones, the title compound was isolated as the major product obtained by flash

chromatography as a clear oil, 16.3 mg, 53% yield. HPLC analysis: Chiralcel AD-H

(hexane/iPrOH = 90/10, 1.0 mL/min), tminor = 10.81 min, tmajor = 9.24 min, ee = 88%. -

119 (c 1.01, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.14-8.13 (d, J = 8.1 Hz, 2H), 7.59-7.55 (t, J =

7.6 Hz, 1H), 7.51-7.47 (t, J = 7.5 Hz, 2H), 7.30-7.23 (m, J = 7.3 Hz, 5H), 6.03 (s, 1H), 2.31 (s,

3H), 1.72 (s, 3H). 13

C NMR (100 MHz, CDCl3): δ 201.6, 201.4, 162.3, 136.2, 132.3, 128.7, 128.5,

128.5, 128.3, 127.8, 126.3, 99.9, 75.2, 27.1, 26.5. HRMS (ESI) Calcd for C19H17NO3 ([M+H]+)

308.1281, Found 308.1272.

109

N

O

Me

O

OMe

Me

1-(2-Acetyl-1-benzoyl-3-m-tolyl-aziridin-2-yl)-ethanone (148b)




(hexane/iPrOH = 90/10, 1.0 mL/min), tmajor = 16.67 min, tminor = 20.12 min, ee = 73%.

-127 (c 1.01, CHCl3).

1H NMR (400 MHz, CDCl3): δ 8.15-8.13 (d, J = 7.7 Hz, 2H), 7.60-

7.56 (q, J = 7.2 Hz, 1H), 7.52-7.48 (m, 1H), 7.19-7.15 (m, 1H), 7.06-7.03 (m, 3H), 5.99 (s, 1H),

2.31 (s, 3H), 2.28 (s, 3H), 1.73 (s, 3H). 13

C NMR (100 MHz, CDCl3): δ 201.8, 201.3, 162.2, 138.2,

136.1, 132.3, 129.0, 128.7, 128.5, 128.4, 128.4, 126.3, 124.9, 100.0, 75.3, 27.1, 26.5, 21.3.

HRMS (ESI) Calcd for C20H19NO3 ([M+Na]+) 344.1257, Found 344.1267.

110

N

O

Me

O

OMeMe

1-(2-Acetyl-1-benzoyl-3-p-tolyl-aziridin-2-yl)-ethanone (148c)




(hexane/iPrOH = 90/10, 1.0 mL/min), tminor = 14.11 min, tmajor = 15.58 min, ee = 92%. -116 (c

1.01, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.08-8.07 (d, J = 8.1 Hz, 2H), 7.54-7.50 (t, J = 7.5

Hz, 1H), 7.46- 7.42 (t, J = 7.4 Hz, 2H), 7.07-7.02 (q, J = 7.0 Hz, 4H), 5.93 (s, 1H), 2.26 (s, 3H),

2.23 (s, 3H), 1.68 (s, 3H). 13

C NMR (100 MHz, CDCl3): δ 201.8, 201.4, 162.2, 138.1, 133.1,


C20H19NO3 ([M+H]+) 322.1438, Found 322.1448

111

N

O

Me

O

OMe

OMe

1-[2-Acetyl-1-benzoyl-3-(2-methoxy-phenyl)-aziridin-2-yl]-ethanone (148d)




(hexane/iPrOH = 95/5, 1.0 mL/min), tminor = 19.64 min, tmajor = 12.56 min, ee = 57%. -54.95

(c = 1.01, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.12-8.11 (d, J = 8.1 Hz, 2H), 7.57-7.53 (t, J =

7.6 Hz, 1H), 7.49-7.45 (t, J = 7.5 Hz, 2H), 7.25-7.22 (t, J = 7.2 Hz, 1H), 7.09-7.07 (d, J = 7.1 Hz,

1H), 6.89-6.81 (m, 2H), 6.31 (s, 1H), 3.78 (s, 3H), 2.35 (s, 3H), 1.81 (s, 3H). 13

C NMR (100 MHz,

CDCl3): δ 201.1, 200.6, 162.6, 156.7, 132.1, 129.8, 129.0, 128.7, 128.6, 128.5, 126.5, 124.8,

120.8, 120.6, 110.8, 99.6, 70.2, 55.2, 27.1, 26.1. HRMS (ESI) Calcd for C20H19NO4 ([M+H]+)

322.1438, Found 322.1448.

112

N

O

Me

O

OMe

MeO

1-[2-Acetyl-1-benzoyl-3-(3-methoxy-phenyl)-aziridin-2-yl]-ethanone (148e)






Hz, 1H), 7.50-7.46 (t, J = 7.5 Hz, 2H), 7.15-7.13 (d, J = 7.1 Hz, 2H), 6.81-6.79 (d, J = 6.8 Hz, 2H),

5.96 (s, 1H), 3.73 (s, 3H), 2.29 (s, 3H), 1.74 (s, 3H). 13

C NMR (100 MHz, CDCl3): δ 201.8, 201.3,

162.1, 159.5, 132.3, 129.0, 128.6, 128.5, 128.0, 126.3, 113.9, 99.9, 74.9, 55.1, 27.1, 26.5.

HRMS (ESI) Calcd for C20H19NO4 ([M+H]+) 338.1387, Found 338.1382.

113

N

O

Me

O

OMeMeO

1-[2-Acetyl-1-benzoyl-3-(4-methoxy-phenyl)-aziridin-2-yl]-ethanone (148f)







5.96 (s, 1H), 3.70 (s, 3H), 2.27 (s, 3H), 1.73 (s, 3H). 13

C NMR (100 MHz, CDCl3): δ 201.7, 201.3,

162.1, 159.5, 132.2, 129.0, 128.6, 128.5, 128.1, 126.4, 113.8, 99.9, 74.8, 55.1, 27.1, 26.5.

HRMS (ESI) Calcd for C20H19NO4 ([M+Na]+) 360.1206, Found 260.1211.

114

N

O

Me

O

OMeF

1-[2-Acetyl-1-benzoyl-3-(4-fluoro-phenyl)-aziridin-2-yl]-ethanone (148g)




(hexane/iPrOH = 90/10, 1.0 mL/min), tminor = 17.69 min, tmajor = 22.31 min, ee = 89%. -116

(c 1.01, CHCl3). 1H NMR (400 MHz, CDCl3): δ 8.12-8.10 (d, J = 7.6 Hz, 2H), 7.58-7.54 (t, J = 7.2

Hz, 1H), 7.50-7.46 (t, J = 7.5 Hz, 2H), 7.24-7.20 (t, J = 7.9 Hz, 2H), 6.98-6.94 (t, J = 8.5 Hz, 2H),

6.00 (s, 1H), 2.29 (s, 3H), 1.74 (s, 3H). 13

C NMR (100 MHz, CDCl3): δ 201.4, 163.7, 162.4 (d, J =

150 Hz), 161.3, 132.4, 132.1, 129.6, 129.5, 128.7, 128.5, 126.2, 115.5, 115.3, 99.6, 74.5, 29.6,

27.1, 26.5. HRMS (ESI) Calcd for C19H16FNO3 ([M+Na]+) 348.1006, Found 348.1000.

115

N

O

Me

O

OMeCl

1-[2-Acetyl-1-benzoyl-3-(4-chloro-phenyl)-aziridin-2-yl]-ethanone (148h)



chromatography as a clear oil, 21.2 mg, 62% yield. HPLC analysis: Chiralcel OD-H




6.00 (s, 1H), 2.31 (s, 3H), 1.76 (s, 3H). 13

C NMR (100 MHz, CDCl3): δ 201.4, 201.2, 162.6, 134.8,


C19H16ClNO3 ([M+H]+) 342.0892, Found 342.0882.

116

N

O

Me

O

OMeBr

1-[2-Acetyl-1-benzoyl-3-(4-bromo-phenyl)-aziridin-2-yl]-ethanone (148i)




(hexane/iPrOH = 90/10, 1.0 mL/min), tminor = 9.89 min, tmajor = 13.36 min, ee = 84%. -98.7 (c



5.98 (s, 1H), 2.31 (s, 3H), 1.76 (s, 3H). 13

C NMR (100 MHz, CDCl3): δ 201.4, 201.2, 162.6, 135.3,


C19H16BrNO3 ([M+H]+) 386.0386, Found 386.0381

117

APPENDIX B: 1H AND 13C SPECTRA

B1 1H and

13C Spectra for Compounds in Chapter 2

118


13C Spectra for Compound 94aa

(94aa)

119


13C Spectra for Compound 94ab

(94ab)

)

120


13C Spectra for Compound 94ac

(94ac)

(6ac)

121


13C Spectra for Compound 94ad

(94ad)

(6ac)

122


13C Spectra for Compound 94ae

(94ae)

(6ac)

123


13C Spectra for Compound 94af

(94af)

(6ac)

124

Spectra B1.7 1H and

13C Spectra for Compound 94ag

(94ag)

(6ac)

125


13C Spectra for Compound 94ah

(94ah)

(6ac)

126

Spectra B1.9 1H and

13C Spectra for Compound 94ai

(94ai)

(6ac)

127


13C Spectra for Compound 94aj

(94aj)

(6ac)

128


13C Spectra for Compound 94ak

(94ak)

(6ac)

129


13C Spectra for Compound 94al

(94al)

(6ac)

130


13C Spectra for Compound 94am

(94am)

(6ac)

131


13C Spectra for Compound 94an

(94an)

(6ac)

132


13C Spectra for Compound 94ao

(94ao)

(6ac)

133


13C Spectra for Compound 94ap

(94ap)

(6ac)

134


13C Spectra for Compound 94aq

(94aq)

(6ac)

135


13C Spectra for Compound 94ar

(94ar)

(6ac)

136


13C Spectra for Compound 94as

(94as)

(6ac)

137


13C Spectra for Compound 94at

(94at)

(6ac)

138


13C Spectra for Compound 94au

(94au)

(6ac)

139


13C Spectra for Compound 94av

(94av)

(6ac)

140


13C Spectra for Compound 94ba

(94ba)

(6ac)

141


13C Spectra for Compound 94ca

(94ca)

(6ac)

142


13C Spectra for Compound 94da

(94da)

(6ac)

143


13C Spectra for Compound 94ja

(94ia)

(6ac)

(94ja)

(6ac)

144


13C Spectra for Compound 94ka

(94ka)

(6ac)

145


13C Spectra for Compound 94la

(94la)

(6ac)

146


13C Spectra for Compound 123

(123)

(6ac)

147

B2 1H and

13C Spectra for Compounds in Chapter 3


13C Spectra for Compound 148a

148a

N

O

Me O

Me

O

148

N

O

Me O

Me

O

148a

149


13C Spectra for Compound 148b

N

O

Me O

Me

O

Me

148b

150

N

O

Me O

Me

O

Me

148b

151


13C Spectra for Compound 148c

N

O

Me O

Me

O

Me

148c

152

N

O

Me O

Me

O

Me

3

c

148c


13C Spectra for Compound 148d

N

O

Me O

Me

O

OMe

3

d

148d

154

N

O

Me O

Me

O

OMe

148d

155


13C Spectra for Compound 148e

N

O

Me O

Me

O

OMe 148e

156

N

O

Me O

Me

O

OMe

3

e

148e

157


13C Spectra for Compound 148f

3

f

148f

N

O

Me O

Me

O

MeO

158

148f

N

O

Me O

Me

O

MeO

159


13C Spectra for Compound 148g

N

O

Me O

Me

O

F148f

160

N

O

Me O

Me

O

F

148f

161


13C Spectra for Compound 148h

148h

N

O

Me O

Me

O

Cl

162

N

O

Me O

Me

O

Cl

3

h

163


13C Spectra for Compound 148i

N

O

Me O

Me

O

Br

148i

164

N

O

Me O

Me

O

Br

3

i

148i

165

B3 Spectra HPLC Spectra for Compound 159

Spectra B3.1. HPLC Spectra for Compound 159

166

APPENDIX C. PERMISSIONS

Title: Chiral Phosphoric Acid-Catalyzed Desymmetrization of meso-Aziridines with Functionalized

Mercaptans

Author: Shawn E. Larson, Juan C. Baso, Guilong Li, and Jon C. Antilla

Publication: Organic Letters

Publisher: American Chemical Society

Date: Nov 1, 2009

Copyright © 2009, American Chemical Society

Title: Catalytic Asymmetric Aza-Darzens Reaction with a Vaulted Biphenanthrol Magnesium

Phosphate Salt

Author: Shawn E. Larson, Guilong Li, Gerald B. Rowland, Denise Junge, Rongcai Huang, H. Lee

Woodcock, and Jon C. Antilla

Publication: Organic Letters

Publisher: American Chemical Society

Date: May 1, 2011

Copyright © 2011, Am erican Chem ical Society

PERMISSION/LICENSE IS GRANTED FOR YOUR ORDER AT NO CHARGE

This type of permission/license, instead of the standard Terms & Conditions, is sent to you

because no fee is being charged for your order. Please note the following: Permission is granted

for your request in both print and electronic formats, and translations.

ABOUT THE AUTHOR

Shawn Larson was born December 13 1983 in upstate New York outside of Rochester, to

Roger and Sandra Larson. Shawn was the second child, his brother Scott died when Shawn was

in high school. While growing up in Gananda Shawn came to enjoy science and mathematics.

He went to SUNY Oswego for his undergraduate work in chemistry (ACS certified) and graduated

in 2006 with a B.S. in chemistry. During his degree he worked for two summers as a researcher

at Summit Lubricants making greases. While at Oswego he was residence assistant, chemistry

mentor, chemistry tutor, and the founding president of the Oswego paintball club.

After graduation he moved to Florida to pursue his future wife; while there he worked at

Coca-Cola North America in the research department of Minute Maid juice division. While at

Coca-Cola he enjoyed the work but needed more education to be competitive.

He returned to education at the University of South Florida in the fall of 2007 where he joined

the group of Jon Antilla. In 2009 he married his wife Dianne in a ceremony in Detroit Michigan

with many of his closest chemistry, college and hometown friends in attendance. Shawn

completed his Doctorate of Philosophy of chemistry in the fall of 2012.

enantioselective brønsted and lewis acid-catalyzed

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