And 1,4‒Additions Enabled by Asymmetric Organocatalysis

STEREOSELECTIVE 1,2‒ AND 1,4‒ADDITIONS ENABLED BY ASYMMETRIC ORGANOCATALYSIS

Jennifer Lynn Fulton

A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry in the College of Arts and Sciences.

Chapel Hill 2020

Approved by:

Jeffrey Johnson

Marcey Waters

Frank Leibfarth

Jeffrey Aubé

Simon Meek

ABSTRACT

Jennifer Lynn Fulton: Stereoselective 1,2‒ and 1,4‒Additions Enabled by Asymmetric Organocatalysis (Under the direction of Jeffrey S. Johnson)

I. Enantio- and Diastereoselective Organocatalytic Conjugate Additions of Nitroalkanes to Enone Diesters

Enantio- and diastereoselective conjugate addition reactions between nitroethane or nitropropane and enone diesters are described. A bifunctional triaryliminophosphorane catalyzed the addition reaction with consistently excellent stereoselectivities and yields across a wide range of substrates. Using the geminal diester functional handle present in the adducts, local desymmetrization via diastereotopic group discrimination was demonstrated and a polyfunctionalized lactam with three contiguous stereocenters was synthesized.

II. Asymmetric Organocatalytic Sulfa-Michael Addition to Enone Diesters

iii An asymmetric sulfa-Michael addition of alkyl thiols to enone diesters is reported. The reaction is catalyzed by a bifunctional triaryliminophosphorane-thiourea organocatalyst and provides a range of α-sulfaketones in high yields and enantioselectivities. Leveraging the gem- diester functional handle via a subsequent diastereotopic group discrimination generates functionalized lactones with three contiguous stereocenters.

III. Efforts Towards the Reduction of α-Imino Esters via Dynamic Kinetic Resolution

Efforts toward the enantioconvergent trichlorosilane-mediated reduction of β- substituted α-imino esters are described. Chiral Lewis base catalysis enables the synthesis of

N-aryl unnatural amino esters with β-alkyl or β-halo substitution in moderate yields and stereoselectivities. Reactions of β-alkyl α-imino esters provided suffered from poor diastereoselectivity, whereas decomposition and product instability plagued the β-halo analogs. Additional complicating factors associated with dynamic kinetic resolution and imine chemistry are broadly discussed and noted in this work.

IV. Organocatalytic Iso-Pictet-Spengler Reaction for the Enantioconvergent Synthesis of Tetrahydro-γ-Carbolines

iv Progress towards an enantioconvergent iso-Pictet-Spengler reaction using thiourea/Brønsted acid co-catalysis is reported. Preliminary control studies demonstrated a significant difference in reactivity between α-substituted β-formyl amides and esters, with the latter proving amenable for asymmetric reaction development. Optimized conditions provide unprotected tetrahydro-γ-carbolines with two contiguous stereocenters, including an exocyclic stereogenic center and orthogonal ester functional handle. Finally, promising efforts to expand the substrate scope to include α- and β-keto esters are disclosed.

To Karen, David, and Robert Fulton, for the sacrifices you made to get me to this point.

and

To Joan Bierwirth & Nancie Blaine, for endless love and support here on earth, and in heaven.

ACKNOWLEDGEMENTS

First and foremost, I would like to thank my advisor Jeff Johnson for his mentorship.

Under your tutelage I have grown as a chemist, problem solver, and communicator, and I thank you for your patience and unending support when I have struggled. Through these actions, and countless others, you have demonstrated how I can be a better leader, advocate, and compassionate human being. I am so grateful to have had the opportunity to be a member of your lab, and for your guidance throughout my doctoral research. Moreover, as a graduate student and advocate for underrepresented groups, I would be remiss not to mention my gratitude for your leadership as chair of the department during these past five years. You have supported AM_WISE’s mission from day 1, and you helped us make our ambitions a reality.

I have witnessed the growth of this department under your direction, and I am even more proud to be a member of the UNC chemistry department than the day I arrived. Thank you for all you have done, and will do, to advocate for and support both your lab group, and the UNC chemistry community.

I would also like to thank my final defense committee: Professors Marcey Waters,

Frank Leibfarth, Simon Meek, and Jeff Aubé. Thank you for taking the time to serve on my committee, and for the conversations we have had over the years. You all have contributed to my growth as a chemist and leader, and I am grateful for your efforts. I would also like to thank

Professors Dave Nicewicz, Bo Li, and Alex Miller for serving on my preliminary oral exam committee.

vii To all of the past and present Johnson lab members: thank you, thank you, thank you.

I would not be the chemist or person I am today without all of you. You all have provided invaluable guidance for so many of my projects, presentations, and practical skills, and I am so thankful to have learned from each and every one of you. More importantly, thank you for making graduate school not just livable, but enjoyable. I will deeply miss all of our impromptu chemistry chats, random trips to Benny’s or Starbucks, daily zoom chats during quarantine, and countless other fun times we have had living life in lab. Thank you to Matt Horwitz and

Ericka Bruske for collaborating on the iminophosphorane-catalyzed projects, and to Matt especially for teaching me a great deal about asymmetric organocatalysis. Thank you to Blane

Zavesky for obtaining X-ray crystal structure data for the thiol addition product, and to Evan

Crawford for obtaining X-ray crystal structure data for the iso-Pictet-Spengler reaction product. Thank you to Laura Wonilowicz for being a fantastic mentee and partner for the trichlorosilane reduction chemistry. A huge thank you to Will Cassels for collaborating on the iso-Pictet-Spengler project, and for also being such a wonderful friend and labmate. Thank you to Jacob Robins and Pedro de Jesus Cruz for countless hours of wonderful conversation about anything and everything. You both are phenomenal chemists who work far too hard, and I have learned a great deal from the two of you. Thank you to Kim Alley for your wonderful sense of humor and passion for chemistry. Thank you to Desiree Matias for your support from day 1 of graduate school, and for a friendship that I would not trade for the world. Thank you to Jessica

Griswold for spending four years with me in Caudill 223, for your support and guidance, for loving cats as much as I do, for playing softball with me, and for a thousand other things. I am so grateful for the network of support among the women of the Johnson lab.

viii Thank you to every member of Allies for Minorities and Women in Science and

Engineering (AM_WISE), and to the faculty and staff who have helped us along the way.

Thank you to Leah Bowers for being an incredible co-president and even better friend. Thank you for being so passionate and determined to achieve even our most ambitious dreams, and for the blood, sweat, and tears it took to tackle our goals. Thank you to Morgan Clark and

Tayliz Rodriguez for taking up the mantle and leading AM_WISE to bigger and better things.

Thank you to Marcey Waters and Frank Leibfarth for their service as faculty advisors. You both give AM_WISE the freedom and independence to be truly graduate-run, but also dropped everything to support and defend us any time we asked for help.

Thank you to my mentors at Grinnell College and UC-Irvine, who helped me reach this point. Thank you to Professor Stephen Sieck for igniting my passion for organic chemistry, and for teaching me the value of independence and decision-making in research. Thank you to

Minna Mahlab for teaching me how to mentor students, but also for showing me how to advocate for underrepresented groups in science. Thank you to my extended lab family from the Rychnovsky lab at UC-Irvine (Alex Wagner, Jacob DeForest, Emily Gish, Ryan King).

You all showed me what a supportive and fun lab community looks like, and made me part of the team. A special thank you to Alex Wagner for teaching me countless practical skills at the hood, for helping me with graduate school applications, and for your continued mentorship.

Thank you to my Greenleaf Vineyard Church community. I am so grateful I found this church home to restore and grow my faith during my graduate studies, and I could never fully express my gratitude for all of the hugs, prayers, and words of encouragement you have given me.

ix I am especially grateful for the support of my amazing friends: Sara Musetti, Emily

Howe, and Samantha Pilicer. Sara, thank you for being the very best roommate-turned-best friend. It’s a true miracle we connected as strangers, and I am so blessed to have gone on this

PhD journey with you. Emily, thank you for encouraging and supporting me from Grinnell to

Chapel Hill, and everywhere in between. Sam, thank you for being one of my biggest cheerleaders, and for always picking up the phone when I call. Though we have been in different states, in different labs, I always know I can always look to you for encouragement, a good rant, laughter, or just to cry. I look forward to many, many more years of adventures with all three of you.

Thank you to my amazing Dungeons and Dragons crew in Raleigh (John, Jason, Evan,

Alex, Keith, and Kyle). Considering we met on Reddit, I did not anticipate finding a group of friends that I would laugh with nearly every week for the last 2.5 years. Thank you for all of our crazy adventures together, but also for the wonderful friendship we have built. I am especially grateful to John for bringing his random co-worker Kyle into our group.

Kyle Roberts I could not ask for a better partner in life. Your unending patience and calm demeanor has been a godsend during these chaotic, stressful months. Thank you for the countless seen and unseen ways you have supported me during my PhD. I love you so much, and I cannot wait to start our life in Colorado together.

A huge thank you to my family. I am so blessed to have an incredible extended family that has loved and supported me through every step of my education. Thank you for always cheering me on from afar, and for celebrating every trip I made back to Illinois. I love you all very much. An even bigger thank you to my parents, Karen and David, and brother Rob. I cannot begin to grasp all of the many sacrifices the three of you have made for me throughout

x my education. Specifically, thank you to my dad for introducing me to chemistry, for all of the hours helping with homework, and for always being eager to talk with me about my research on sticks and letters. Thank you to my mom for being my biggest cheerleader and best friend.

I cannot possibly list all of the things you did to help me get to this point – it would be a thesis on its own – but I am so grateful for all of it. Thank you especially for all of the ways you have cheered me on from afar these last 9 years as I moved around the country; thank you for every card and care package you have made, and our many, many phone calls. I am so blessed to have a mom, dad, and brother who love and support me as much as the three of you do, and I only hope I can return that love and support in equal measure.

Finally, thank you to my wonderful forever-kitten Inara, who I adopted my second semester of graduate school. She has been a constant source of comfort and laughter, and has endured every forced cuddle. I truly would not have survived graduate school without her unconditional love.

TABLE OF CONTENTS

LIST OF TABLES ...... xv

LIST OF FIGURES ...... xvi

LIST OF ABBREVIATIONS AND SYMBOLS ...... xx

CHAPTER ONE: ENANTIO- AND DIASTEREOSELECTIVE ORGANOCATALYTIC CONJUGATE ADDITION OF NITROALKANES TO ENONE DIESTERS ...... 1

1.1 Background ...... 1

1.1.1 The Development of Enantioselective Superbase Organocatalysis ...... 1

1.1.2 Organocatalyzed Addition of Nitroalkanes ...... 11

1.2 Development of a One-Pot Synthesis of Enone Diesters...... 13

1.3 Asymmetric Addition of Nitroalkenes ...... 15

1.3.1 Reaction Optimization for Asymmetric Addition of Nitroalkanes ...... 15

1.3.2 Reaction Scope...... 18

1.4 Local Desymmetrization of Nitro-Adducts ...... 21

1.5 Conclusion ...... 22

1.6 Acknowledgements ...... 22

1.7 Experimental Details ...... 23

REFERENCES ...... 48

xii CHAPTER TWO: ASYMMETRIC ORGANOCATALYTIC SULFA-MICHAEL ADDITION TO ENONE DIESTERS ...... 55

2.1 Background ...... 55

2.2 Asymmetric sulfa-Michael Addition ...... 56

2.2.1 Reaction Optimization ...... 57

2.2.2 Investigation of Side-Product Formation ...... 58

2.2.3 Sulfa-Michael Addition Scope ...... 62

2.3 Derivatization of Sulfa-Michael Addition Products ...... 65

2.4 Conclusion ...... 66

2.5 Acknowledgements ...... 66

2.6 Experimental Details ...... 67

REFERENCES ...... 86

CHAPTER THREE: EFFORTS TOWARDS THE REDUCTION OF α-IMINO ESTERS VIA DYNAMIC KINETIC RESOLUTION ...... 90

3.1 Overview of Dynamic Kinetic Resolution ...... 90

3.2 Motivation & Background ...... 99

3.2.1 Applications of Unnatural Amino Acids ...... 99

3.2.2 Synthetic Approaches to Unnatural Amino Acids ...... 100

3.2.3 Asymmetric Reductions with Trichlorosilane ...... 104

3.3 Challenges to Dynamic Kinetic Resolution with α-Imino Esters ...... 107

3.4 Results & Discussion ...... 110

3.4.1 Synthesis of β-Substituted α-Imino Esters ...... 110

xiii 3.4.2 Trichlorosilane-Mediated Reduction and DKR of β-Alkyl α-Imino Esters ...... 111

3.4.3 Trichlorosilane-Mediated Enantioconvergent Reduction of β-Halo α-Imino Esters ...... 114

3.5 Conclusions ...... 118

3.6 Experimental Details ...... 119

REFERENCES ...... 131

CHAPTER FOUR: ORGANOCATALYTIC ISO-PICTET-SPENGLER REACTION FOR THE ENANTIOCONVERGENT SYNTHESIS OF TETRAHYDRO-γ-CARBOLINES ...... 140

4.1 Motivation ...... 140

4.2 Background: Synthesis of Tetrahydro-γ-Carbolines ...... 143

4.3 Results and Discussion ...... 152

4.3.1 Preliminary Studies with α-Substituted β-Formyl Morpholine Amides ...... 152

4.3.2 Reaction Development and Optimization with α-Substituted β-Formyl Esters .. 154

4.3.3 Preliminary Investigations into Generating Quaternary Stereogenic Centers ..... 161

4.4 Conclusion ...... 162

4.5 Experimental Details ...... 163

REFERENCES ...... 184

xiv LIST OF TABLES

Table 1-1. Optimization of the Asymmetric Nitroalkane Conjugate Addition ...... 17

Table 2-1. Optimization of a Sulfa-Michael Addition to Enone Diesters ...... 58

Table 2-2. Formation of an Undesired Malonate in the Presence of Various Thiols ...... 59

Table 3-1. Additive Effects on Trichlorosilane-Mediated DKR ...... 114

Table 4-1. Control Studies with α-Substituted β-formyl Esters vs. Amides...... 155

Table 4-2. Catalyst Screen ...... 156

Table 4-3. Reaction Optimization for Ethyl α-Isopropyl β-Formyl Ester ...... 158

Table 4-4. Initial Substrate Scope ...... 159

Table 4-5. Re-Optimization of Iso-Pictet-Spengler Reaction for Non- Branched Substrates ...... 161

xv LIST OF FIGURES

Figure 1-1. Summation of publications containing the term ‘organocatalysis’ on Reaxys from the years 2000 to 2019...... 4

Figure 1-2. Bifunctional Brønsted Base Organocatalysis ...... 5

Figure 1-3. Basicities of Common Brønsted Base Organocatalysts ...... 6

Figure 1-4. Comparison of Bifunctionality for Cinchona Alkaloid Thioureas and Iminophosphoranes ...... 8

Figure 1-5. Modifiable Regions of a Bifunctional Iminophosphorane Organocatalyst ...... 10

Figure 1-6. Scope of Enone Diesters via One-Pot Procedure ...... 15

Figure 1-7. Asymmetric Conjugate Addition of Nitroalkanes...... 20

Figure 1-8. X-Ray Crystal Structure of para-Bromo Nitro Adduct 1.14d ...... 21

Figure 2-1. Formation of Malonate 2.7 as a Function of Thiol Acidity ...... 60

Figure 2-2. Asymmetric Conjugate Addition of Alkyl Thiols to Enone Diester 2.2a ...... 63

Figure 2-3. Asymmetric Conjugate Addition of 2-Propanethiol to Enone Diesters ...... 64

Figure 3-1. Select Chiral Organocatalysts for the Trichlorosilane Reduction of α-Imino Esters and Aliphatic Ketimines ...... 106

Figure 3-2. Challenges in Dynamic Kinetic Resolution with α-Imino Esters ...... 108

Figure 4-1. Carboline Nomenclature ...... 140

Figure 4-2. Carboline Natural Products ...... 141

Figure 4-3. Biologically Active Tetrahydro-γ-Carbolines ...... 142

Figure 4-4. Conformational Effects on the Reactivity of α-Substituted β-Formyl Esters and Morpholine Amides ...... 153

Figure 4-5. X-Ray Crystal Structure of Boc-Protected THγC 4.28a ...... 157

xvi LIST OF SCHEMES

Scheme 1-1. Seminal Organocatalyzed Asymmetric Reactions ...... 3

Scheme 1-2. Iminophosphorane-Catalyzed Asymmetric Reductive Coupling Between Aldehydes and Isatins ...... 7

Scheme 1-3. Synthesis of Dixon’s Bifunctional Triaryl Iminophosphorane Catalysts ...... 8

Scheme 1-4. Iminophosphorane-Catalyzed Asymmetric Addition of Nitromethane to Phosphinoyl Imines...... 9

Scheme 1-5. Asymmetric Addition of Dicarbonyls to β-Nitrostyrene by an Immobilized Iminophosphorane ...... 9

Scheme 1-6. Modified Iminophosphoranes for Asymmetric Organocatalysis ...... 11

Scheme 1-7. Asymmetric Reductive Coupling Between Aldehydes and Benzylidene Pyruvates ...... 11

Scheme 1-8. Asymmetric Conjugate Addition of Nitroalkanes ...... 13

Scheme 1-9. Three Step Synthesis of Aryl Enone Diesters (Srinivasan, 2014) ...... 14

Scheme 1-10. Synthesis of Ketomalonate Hydrates via CAN Oxidation (Kürti, 2017) ...... 14

Scheme 1-11. Gram-Scale Asymmetric Conjugate Addition Reaction ...... 21

Scheme 1-12. Local Desymmetrization via Transesterification and Diastereoselective Lactamization ...... 22

Scheme 2-1. Asymmetric Conjugate Addition Reactions ...... 56

Scheme 2-2. Proposed Pathways for Diminished Product Yields and Racemization ...... 61

Scheme 2-3. Crossover Experiment Under Optimized Reaction Conditions ...... 61

Scheme 2-4. Gram-Scale Asymmetric Sulfa-Michael Reaction ...... 65

Scheme 2-5. Local Desymmetrization via Diastereoselective Reduction and Lactonization ...... 66

Scheme 3-1. Example Methods for the Resolution of Racemic Substrates ...... 91

Scheme 3-2. Key Differences Between Kinetic Resolution and Dynamic Kinetic Resolution ...... 93

xvii Scheme 3-3. Transfer Hydrogenation DKR of β-Keto Esters ...... 95

Scheme 3-4. Ruthenium-Catalyzed Transfer Hydrogenation DKR of α-Keto Esters ...... 96

Scheme 3-5. Advances in DKR with Configurationally Labile α-Keto Esters ...... 97

Scheme 3-6. DKRs with Underexplored Substrates ...... 98

Scheme 3-7. Generating Amines via Dynamic Kinetic Resolution ...... 99

Scheme 3-8. Unnatural Amino Acids in Organocatalyst Synthesis ...... 100

Scheme 3-9. C-H Functionalization of Natural Amino Acids ...... 101

Scheme 3-10. Synthesis of UAAs via Bio- or Organocatalysis...... 102

Scheme 3-11. Rhodium-Catalyzed Asymmetric Hydrogenation of Enamides ...... 103

Scheme 3-12. Hantzsch Ester Reduction of α-Imino Esters ...... 104

Scheme 3-13. Reduction of Imines by Hexacoordinate Silicates ...... 104

Scheme 3-14. Formamide-Activated Trichlorosilane Reduction of Imines (Zhang, 2007) . 106

Scheme 3-15. Proposed Stereochemical Model for Ephedrine-Trichlorosilane Reduction of N-Aryl Ketimines ...... 106

Scheme 3-16. Generic Proposed DKR of α-Imino Esters ...... 109

Scheme 3-17. Staudinger Reaction for the Efficient Synthesis of α-Imino Esters ...... 111

Scheme 3-18. Racemic Reduction of a β-Substituted α-Imino Ester via DMF-HSiCl3 ...... 112

Scheme 3-19. Initial Ligand Screening for HSiCl3 DKR Reduction ...... 113

Scheme 3-20. Synthesis of and Initial Hit with β-Bromo α-Imino Ester ...... 115

Scheme 3-21. Side Product Formation and Temperature Dependence ...... 116

Scheme 3-22. Hypothetical Mechanism for Dehalogenated Side Product Formation ...... 116

Scheme 3-23. Ligand Screen for the DKR Reduction of a β-Bromo α-Imino Ester ...... 117

Scheme 3-24. Synthesis of Diverse β-Substituted α-Imino Esters ...... 118

Scheme 4-1. Access to THβCs vs. THγCs ...... 141

xviii Scheme 4-2. Synthesis of 1,1,3,3,5-Pentamethyl-Tetrahydro-γ-Carboline ...... 143

Scheme 4-3. Regioselectivity Challenges with the Fischer Indole Synthesis of Carbolines ...... 144

Scheme 4-4. Synthesis of THγCs via AAA (Bandini, 2006) ...... 145

Scheme 4-5. Asymmetric Synthesis of THγCs via Aza-Ylides ...... 145

Scheme 4-6. Iso-Pictet-Spengler Synthesis of an Opianic Acid-Derived THγC ...... 146

Scheme 4-7. Synthetic Approaches to Iso-Tryptamines ...... 147

Scheme 4-8. Synthesis of Enantioenriched THγCs using Chiral Auxiliaries ...... 148

Scheme 4-9. Enantioselective Iso-Pictet-Spengler Reaction ...... 149

Scheme 4-10. Thiourea-Catalyzed Enantioselective Acyl Pictet-Spengler ...... 149

Scheme 4-11. Asymmetric Protioiminium Iso-Pictet-Spengler Reactions ...... 150

Scheme 4-12. Prior Art and Current Work ...... 152

Scheme 4-13. Uncatalyzed Iso-Pictet-Spengler Reaction with α-Substituted β-Formyl Morpholine Amides ...... 153

Scheme 4-14. Co-Catalyzed Iso-Pictet-Spengler Reaction with α- and β-Keto Esters ...... 162

xix LIST OF ABBREVIATIONS AND SYMBOLS

 racemic

] optical rotation

δ chemical shift or partial charge

 heat

Å angstrom

L microliter

2,6-lutidine 2,6-dimethylpyridine

Ac acetate

Ac2O acetic anhydride

AcOH acetic acid

Ag2CO3 silver (II) carbonate app apparent

Ar aryl aq aqueous

ATH asymmetric transfer hydrogenation atm atmospheres

BF3•OEt2 boron trifluoride diethyl etherate

BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

Bn benzyl

Boc tert-butyloxycarbonyl

Boc2O di-tert-butylcarbonate br broad

xx br s broad singlet iBu iso-butyl tBu tert-butyl nBuLi n-butyllithium tBuOOH tert-butyl hydrogen peroxide

Bz benzoyl

BzOH benzoic acid

13C NMR carbon nuclear magnetic resonance spectroscopy cAA canonical amino acid

CAN cerium (IV) ammonium nitrate cat catalytic amount or catalyst

Cbz carboxybenzyl

CDI 1,1’-carbonyldiimidazole

CHCl3 chloroform

CH2Cl2 methylene chloride

CHO aldehyde

CPME cyclopentyl methyl ether

Cs2CO3 cesium carbonate

CsF cesium fluoride

CSP chiral stationary phase

CuPF6 copper (I) hexafluorophosphate

Cy cyclohexyl d doublet or days

xxi DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCM dichloromethane dd doublet of doublets

DIBAL-H diisobutylaluminum hydride

DIPEA ethyldiisopropylamine

L-(+)-DIPT (+)-Diisopropyl L-tartrate

DKR dynamic kinetic resolution

DMF N,N-dimethylformamide

L-DOPS L-dihydroxyphenylserine or droxidopa dq doublet of quartets dr diastereomeric ratio dt doublet of triplets ent enantiomer equiv equivalents er enantiomeric ratio

Et ethyl

Et2O diethyl ether

Et2Zn diethyl zinc

Et3N triethylamine

EtOAc ethyl acetate

EtOH ethanol

Fmoc Fluorenylmethyloxycarbonyl h hour

xxii 1H NMR proton nuclear magnetic resonance spectroscopy

H-bond hydrogen bond

HCl hydrochloric acid

HCN hydrogen cyanide

HCO2H formic acid

H2O2 hydrogen peroxide

H2SO4 sulfuric acid

HPLC high performance liquid chromatography

HRMS high resolution mass spectroscopy

HSiCl3 trichlorosilane

Hz hertz

IR infrared spectroscopy

J coupling constant

K2CO3 potassium carbonate krac rate of racemization kinv rate of interconversion

L ligand

L* chiral ligand

LA Lewis acid

LB Lewis base

LiAlH4 lithium aluminum hydride

Li2CO3 lithium carbonate

M metal or molarity

xxiii m multiplet

MAL methylaspartate ammonia lyase

Me methyl

MeCN acetonitrile

MeI methyl iodide

MeNO2 nitromethane

MeOH methanol mg milligram

Mg0 magnesium(0) turnings

MHz megahertz min minutes mL milliliter mmol millimole

MnO2 manganese oxide mol mole mp melting point n number of atoms n.a. not applicable n.d. not determined

NaBH4 sodium borohydride

NaN3 sodium azide

NaOH sodium hydroxide

NEt3 triethylamine

xxiv NH4OAc ammonium acetate

NOE nuclear Overhauser enhancement

NOESY nuclear Overhauser enhancement spectroscopy

NuH nucleophile

PG protecting group

Ph phenyl

PhH benzene

PhMe toluene

PMe3 trimethylphosphine

PMP p-methoxyphenyl

PPh3 triphenylphosphine ppm parts per million iPr iso-propyl psi pounds per square inch q quartet

R substituent

Rf retention factor

Rh2(OAc)4 rhodium tetraacetate rt room temperature s singlet

SOCl2 thionyl chloride t triplet tert tertiary

xxv TBS tert-butyldimethylsilyl

TBME tert-butyl methyl ether

TEA triethylamine

TFA trifluoroacetic acid

THβC tetrahydro-β-carboline

THγC tetrahydro-γ-carboline

THF tetrahydrofuran

i Ti(O Pr)4 titanium (IV) isopropoxide

TLC thin-layer chromatography

(S)-TRIP (R)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl

hydrogenphosphate

Ts p-toluenesulfonyl

TsCl p-toluenesulfonyl chloride

UAA unnatural amino acid

UV ultraviolet

X anionic ligand or halide

Zn(OTf)2 zinc(II) trifluoromethanesulfonate

xxvi

CHAPTER ONE: ENANTIO- AND DIASTEREOSELECTIVE ORGANOCATALYTIC CONJUGATE ADDITION OF NITROALKANES TO ENONE DIESTERS*

1.1 Background

1.1.1 The Development of Enantioselective Superbase Organocatalysis

Chiral small molecules are intrinsic to life, both biochemically and in our modern world as pharmaceuticals, agrochemicals, and materials.1 The importance and applications of chirality in naturally occurring compounds have been long investigated, beginning with the discovery of molecular chirality by Louis Pasteur and other scientists in the 19th century.1–4

This revolutionary finding inspired countless new areas of study, but the pursuit of asymmetric synthesis remains among the most influential in synthetic chemistry. Over the last two centuries, three general approaches for synthesizing chiral non-racemic compounds have been established: (1) chiral pool synthesis, (2) asymmetric catalysis, and (3) resolution.5–7

The first method, chiral pool synthesis, derives structurally and stereochemically complex products from a ‘pool’ of naturally abundant enantiopure molecules such as amino acids and sugars. Syntheses of countless natural products5,8,9, organocatalysts10, and ligands rely on the chiral pool for its dependable stereospecificity. Yet, the limited chemical space covered by chiral pool materials inherently restricts the scope and diversity of asymmetric products accessible via this approach.11 As a result, the development of alternative methods for synthesizing chiral compounds is a significant, ongoing challenge in the field of organic

1 synthesis. The latter two approaches to the synthesis of chiral non-racemic products, asymmetric catalysis and resolution, seek to address that gap. Resolution, and in particular dynamic kinetic resolution, will be discussed at length in Chapter 3. Meanwhile, the following research falls into the realm of asymmetric catalysis.

Asymmetric catalysis involves transformation of a racemic or achiral substrate to an enantioenriched product via a chiral, non-racemic catalyst. Catalysts take many forms, including enzymes12,13, metals14,15, organic molecules16–18, or some cooperative combination of the three.19–21 Irrespective of the catalyst the goal remains the same: generate enantioenriched product quickly and in high yield without catalyst degradation. The first half of my doctoral research focused on developing novel enantioselective transformations via organocatalysis, specifically using chiral superbases.

Organocatalysts have been employed since the late 19th century,22 but their potential for enantioinduction were not realized until the late 20th century (Scheme 1-1). Seminal work from Hajos and Parrish (Scheme 1-1A), Seebach, and Wynberg established the utility of chiral enamine catalysis and asymmetric bifunctional organocatalysis for conjugate additions to

Michael acceptors;23–25 however, little work was done to expand the field until the 1990’s and early 2000’s when the ‘gold rush’ of asymmetric organocatalysis began. From 1998 to 2000, pioneers such as and Jacobsen (Scheme 1-1B)26 and MacMillan (Scheme 1-1C)27,28 developed novel, robust chiral non-racemic organocatalysts that promoted unexplored asymmetric transformations.

2 Scheme 1-1. Seminal Organocatalyzed Asymmetric Reactions

In addition to the newly accessible enantioenriched products, these catalytic manifolds launched the rapid development of countless other organocatalysts and prompted investigations into other unexplored reactions. In 2000, MacMillan coined the term

‘organocatalysis’ in his first publication on the subject. Five years later, nearly 500 published articles referenced the term, and as of the end of 2019 more than 16,000 journal articles discuss organocatalysis (Figure 1-1).22

3 Figure 1-1. Summation of publications containing the term ‘organocatalysis’ on Reaxys from the years 2000 to 2019†

18000

15000

12000

9000 Publications

6000

3000

0 2000 2005 2010 2015 2019

Modern organocatalysis encompasses any small molecule catalyst that does not involve an active inorganic species.22 As the field continues to expand, additional classification systems have been developed to clarify an organocatalyst’s role and capabilities. The vast majority of chiral organocatalysts can be identified as Lewis acids, Lewis bases, Brønsted acids, or Brønsted bases.22 While catalysts are generally defined by their most active functionality, additional functional handles are frequently employed to activate both the nucleophile and electrophile. For example, Cinchona alkaloid-derived thiourea 1.3 is a bifunctional Brønsted base organocatalyst which has been employed in numerous asymmetric transformations (Figure 1-2).18,29,30 The Brønsted basic quinuclidine deprotonates a pronucleophile, while the second functionality, the Lewis acidic thiourea, activates the electrophile via hydrogen-bonding.17,31 These identifiers enable organic chemists to better

† Searched for the concept ‘organocatalysis’ in SciFinder. Results were refined to journals, preprints, and reports, then refined by the following years for each data point: (1980-2000, 1980-2005, 1980-2010, 1980-2015, 1980- 2019)

4 understand the proposed function of an organocatalyst and therefore assist in catalyst selection when investigating novel transformations.

Figure 1-2. Bifunctional Brønsted Base Organocatalysis

Although the system above provides nomenclature for central concerns such as reactivity and the number of functional handles, it fails to characterize the strength of an organocatalyst. For example, quinuclidine 1.3 and iminophosphorane 1.4 function as bifunctional Brønsted base organocatalysts (Figure 1-3); however, as the basicity of the quinuclidine and iminophosphorane differ by five orders of magnitude, it is unsurprising that the two perform quite differently.16 Consequently, to qualitatively differentiate between these two classes of Brønsted bases, the community adopted another identifier: superbase.32

The definition of the term superbase is somewhat arbitrary, but superbases are generally

16,32 uncharged species with a pKBH+ greater than proton sponge (18.2 in MeCN). Specifically, organosuperbase catalysis takes advantage of the high basicity and poor nucleophilicity of these compounds to activate poorly acidic pronucleophiles in previously unproductive reactions. Notable classes of chiral organosuperbases include iminophosphoranes (1.4), guanidines (1.5), and cyclopropenimines (1.6) (Figure 1-3).16,17,33 Each class is composed of structurally diverse catalysts, which span a wide range of basicities.

5 Figure 1-3. Basicities of Common Brønsted Base Organocatalysts

a pKBH+ values obtained in MeCN

Interest from the Johnson lab in the field of asymmetric superbase organocatalysis dates back to 2012, when we collaborated with the Ooi lab to develop a direct aldolization of α-alkyl

α-hydroxy phosphonoacetate using [5,5]-P-spirocyclic catalyst 1.7 (Scheme 1-2A).34 A subsequent collaboration with the Ooi lab employed the same catalyst to enable a reductive coupling of isatins and aldehydes (Scheme 1-2B).35 The iminophosphorane catalyst (1.7) proved highly effective in both transformations, providing the phosphate products in high stereoselectivity and yield. Unfortunately, the synthesis of iminophosphorane 1.7 is challenging, and the P-spirocyclic nature of these catalysts generally limits appendage identity, thereby prohibiting bifunctional catalysis.36 As such, as our lab considered other underexplored transformations, we sought to employ more accessible and diversifiable organosuperbases.

6 Scheme 1-2. Iminophosphorane-Catalyzed Asymmetric Reductive Coupling Between

Aldehydes and Isatins

In 2013, the lab of Darren Dixon debuted amino acid-derived bifunctional iminophosphorane catalyst 1.4.37 Similar to bifunctional Cinchona alkaloid-derived thiourea

1.3, this catalyst possesses the same Lewis acidic thiourea to coordinate and activate electrophiles for addition (Figure 1-4); however, in place of the quinuclidine moiety, this catalyst relies on a Brønsted basic triaryliminophosphorane. The catalyst backbone is derived from the N-Boc-protected tert-leucine amino alcohol (Scheme 1-3). Subsequent tosylation and azide substitution provides the key azido amine intermediate, which undergoes transformation at either end to provide a bifunctional organocatalyst. For iminophosphorane 1.4, addition of the amine to an aryl isocyanide generated the thiourea moiety, then Staudinger reaction with triphenylphosphine yielded the iminophosphorane base.

7 Figure 1-4. Comparison of Bifunctionality for Cinchona Alkaloid Thioureas and

Iminophosphoranes

Scheme 1-3. Synthesis of Dixon’s Bifunctional Triaryl Iminophosphorane Catalysts

Organocatalyst 1.4 proved highly effective when employed in the addition of nitromethane into N-phosphinoyl imines, providing the desired amine in high yield and enantioselectivity (Scheme 1-4).37 Notably, quinuclidine catalyst 1.3 failed to provide any product, confirming the necessity of the more basic iminophosphorane catalyst. Subsequent efforts proved that this same reaction could be catalyzed by immobilized, polystyrene- supported iminophosphorane 1.8.38 Moreover, the immobilized catalyst 1.8 promoted enantioselective additions of malonates and β-keto amides to β-nitrostyrene as well (Scheme

1-5).

8 Scheme 1-4. Iminophosphorane-Catalyzed Asymmetric Addition of Nitromethane to

Phosphinoyl Imines

Scheme 1-5. Asymmetric Addition of Dicarbonyls to β-Nitrostyrene by an Immobilized

Iminophosphorane

One advantage of bifunctional catalysts such as iminophosphorane 1.4 are their modularity, which expands opportunities for catalyst tuning and optimization.37,39 Generically, this class of catalysts contains three modifiable functionalities (Figure 1-5): (1) amino acid- derived catalyst backbone (red), (2) the H-bond donor (blue), and (3) the substitution on the aryl rings of the triaryliminophosphorane (green). The 2013 publication from Dixon explored variations at each of these points, leading to the selection of thiourea 1.4 for their nitro-

Mannich reaction. Altering the triaryliminophosphorane impacted catalyst basicity, with electron-donating substitution on the aryl ring increasing the pKBH+ and electron-withdrawing

9 37 groups decreasing the pKBH+. Altering the H-bond donor or backbone primarily impacted stereocontrol.

Figure 1-5. Modifiable Regions of a Bifunctional Iminophosphorane Organocatalyst

Tuning the basicity of these catalysts and exchanging functionalities can enable new chemistry. Recently, Dixon found that exchanging the thiourea for 1-naphthyl amide and adding methoxy substitution to the triaryliminophosphorane (1.9) enabled a direct aldol addition of aryl ketones to α-fluorinated ketones (Scheme 1-6A).40 Alternatively, amino acid- derived H-bond donors can provide a second stereogenic center. In 2015, Dixon introduced their “second-generation” bifunctional iminophosphorane organocatalyst (1.10), which promoted the enantioselective addition of thiols to unactivated α,β-unsaturated esters (Scheme

1-6B).41,42 Although no stereochemical models have been proposed for either the first or second generation catalysts, Dixon had previously observed37 the impact of the H-bond donor identity on stereocontrol37, and the second stereogenic center provided a significant boost to the stereoselectivity for this reaction.41

10 Scheme 1-6. Modified Iminophosphoranes for Asymmetric Organocatalysis

Intrigued by these catalysts, we investigated the applicability of a bifunctional iminophosphorane catalyst to the asymmetric reductive coupling between benzylidene pyruvates and aldehydes (Scheme 1-7).43 Catalyst 1.4 successfully promoted the reaction, generating complex products with two contiguous stereocenters in high diastereoselectivity and enantioselectivity. More recently, we investigated whether bifunctional iminophosphorane organocatalysis could enable the stereoselective addition of extended nitroalkanes (Chapter 1) and alkyl thiols (Chapter 2) to enone diester electrophiles.

Scheme 1-7. Asymmetric Reductive Coupling Between Aldehydes and Benzylidene Pyruvates

1.1.2 Organocatalyzed Addition of Nitroalkanes

11 The prevalence of nitrogen-containing acyclic and heterocyclic scaffolds in bioactive molecules provides ongoing opportunities for the development of methodologies for their efficient construction. Asymmetric organocatalytic conjugate additions of nitroalkanes have enabled the rapid construction of small polyads possessing numerous functional handles for downstream transformations. Previous approaches utilizing Brønsted base organocatalysis have accomplished this transformation in a stereoselective manner.44–49 Although methods have been developed for the enantioselective addition of nitromethane, diastereocontrol with homologs has proven challenging in many contexts because of prochirality in both reaction partners.50–57 Furthermore, substrates bearing both acrylate and enone moieties have been found to undergo regioselective addition exclusively at the enone Michael acceptor (Scheme

1-8A), which limits the scope of products accessible through this reaction. We sought to meet the challenges of regioselectivity and stereoselectivity by using a bifunctional organocatalyst to orient and unite extended nitroalkanes with acylidene malonates. Herein, we report the enantio- and diastereoselective conjugate addition of nitroethane and nitropropane to enone diester electrophiles (Scheme 1-8B).

12 Scheme 1-8. Asymmetric Conjugate Addition of Nitroalkanes

1.2 Development of a One-Pot Synthesis of Enone Diesters

With the aim of exploiting these highly activated substrates and delivering useful functionality in the derived products, we initiated conjugate addition reaction studies with enone diesters. In 2014, Srinivasan published a three-step procedure for accessing aromatic enone diesters. Their route proceeded as follows: (1) conjugate addition of a malonate, (2) base-promoted halogenation/cyclopropanation, (3) Lewis acid-promoted ring-opening and elimination of the nitro group (Scheme 1-9).58 The authors were limited to aryl enone diesters as their third step proceeds via formation of a zwitterionic species that relies on resonance stabilization of a positive charge at the benzylic carbon. Seeking to expand the scope of enone

13 diesters for our investigations, we opted to investigate alternative routes for accessing these substrates.

Scheme 1-9. Three Step Synthesis of Aryl Enone Diesters (Srinivasan, 2014)

Prior reports indicated that Wittig olefination between a ketomalonate and stabilized ylide could rapidly provide the desired enone diester;59–61 however, no examples had been reported with the di-tert-butyl ketomalonate. This absence is likely due in part to limited commercial availability, and in part to the problematic hydration issues associated with isolating the ketomalonate.62–64 This latter fact has necessitated some creative solutions.

Contemporaneously with our studies, Kürti demonstrated that CAN oxidation of the malonate followed by intentional hydration yields a stable crystalline solid which can be employed in subsequent operations (Scheme 1-10).65 Although successful, the CAN oxidation is rather sluggish, requiring more than 48 h to provide the product in 68% yield.

Scheme 1-10. Synthesis of Ketomalonate Hydrates via CAN Oxidation (Kürti, 2017)

In an effort to circumvent the hydration issue altogether, we developed a one-pot reaction. Di-tert-butyl 2-diazomalonate 1.11 (accessible via the malonate in one step) was subjected to oxo transfer under the action of Rh(II)/propylene oxide,66 then the resulting ketone underwent Wittig olefination in-situ following addition of the stabilized ylide (Figure 1-6).

Using this telescoped reaction sequence, we synthesized a variety of enone diesters in good to

14 moderate yields. In addition to tolerating aryl (1.12a-j) substitution, heteroaryl (1.12k-m), and alkyl (1.12n-o) substitution were well-tolerated, contrasting with the approach reported by

Srinivasan.58

Figure 1-6. Scope of Enone Diesters via One-Pot Procedure

1.3 Asymmetric Addition of Nitroalkenes

1.3.1 Reaction Optimization for Asymmetric Addition of Nitroalkanes

Having established a synthetic path to access enone diesters 1.12, we initiated our investigation into the stereoselective addition of nitroalkanes. As previously mentioned,

15 Cinchona alkaloid bifunctional organocatalysts are well-precedented in the asymmetric conjugate addition of nitroalkanes;48,49,51,54,67,68 however, when thiourea 1.3 was employed in the addition of nitromethane (1.13) to enone diesters 1.12, we observed poor yield and little enantioinduction for nitro adduct 1.14 (entry 1, Table 1-1). Undeterred, we hypothesized that superbase organocatalysis could effect this transformation. Indeed, phenylglycine-derived iminophosphorane 1.15 prompted a substantial increase in both enantioselectivity and yield

(entry 2). Decreasing the temperature and extending the reaction time further improved the yield and stereoselectivity (entry 3). Additional catalyst screening commenced with the tert- leucine-derived thiourea (1.4), as well as a tert-leucine-derived variant of the second- generation catalyst developed by the Dixon lab bearing two chiral centers (1.16). Although iminophosphorane 1.4 provided comparable enantioinduction, the yield was diminished (entry

4); catalyst 1.16 provided only trace product at -60 °C, and poor yield even at room temperature

(entries 5, 6). Consequently, optimization continued with the decidedly superior catalyst, iminophosphorane 1.15.

Despite completion of catalyst selection, the reaction provided sub-optimal results at 88:12 er and 62% NMR yield (entry 3). A brief solvent screen revealed that benzene, dichloromethane and ethyl acetate provided diminished enantioselectivities (entries 7-9), while other ethereal solvents (Et2O) provided analogous results to THF (entry 10). Switching from the ethyl to tert-butyl ester resulted in an increase to enantioselectivity, but yield remained consistently low. Despite the moderate yield, the reaction proceeded cleanly as judged by 1H

NMR spectroscopy, and reaction yield and conversion were well-correlated. Unfortunately, diminished yields were of particular concern as tert-butyl enone diester 1.12 and the desired product (1.14) were inseparable under standard chromatographic conditions.

16 At present, the cause for poor conversion remains unclear. Increasing the catalyst loading to 20 mol % was ineffective at increasing conversion or yield, so we do not believe catalyst decomposition is a major factor. In an effort to increase conversion, we elected to employ a more acidic nitroalkane. Nitromethane has a pKa of 10.2, while extending the

‡ nitroalkane to nitroethane decreases the pKa to 8.57. Although this extended nitroalkane presented an additional challenge of diastereocontrol, we hypothesized that the more acidic substrate could facilitate reaction. Gratifyingly, we observed excellent diastereocontrol by employing catalyst 1.15, along with dramatic improvements to both enantioselectivity and yield.

Table 1-1. Optimization of the Asymmetric Nitroalkane Conjugate Addition

X temp catalyst time entry R solvent dr er yielda (equiv) (°C) (equiv) (h) 1 H (10.0) Et THF 23 1.3 (0.10) 8 n.a. 55:45 (18) 2 H (10.0) Et THF 23 1.15 (0.10) 8 n.a. 77:23 (40) 3 H (10.0) Et THF -60 1.15 (0.10) 21 n.a. 88:12 (62) 4 H (10.0) Et THF -60 1.4 (0.10) 21 n.a. 13:87 (41) 5 H (10.0) Et THF -60 1.16 (0.10) 21 n.a. n.d. trace

6 H (10.0) Et THF 23 1.16 (0.10) 19 n.a. n.d. (30)

7 H (10.0) Et CH2Cl2 -60 1.15 (0.10) 21 n.a. 78:22 (46) 8 H (10.0) Et PhH -60 1.15 (0.10) 21 n.a. 81:19 (48)

9 H (10.0) Et EtOAc -60 1.15 (0.10) 21 n.a. 85.5:14.5 (45)

10 H (10.0) Et Et2O -60 1.15 (0.10) 21 n.a. 89:11 (54)

‡ pKa values obtained via SciFinder

17 t 11 H (10.0) Bu Et2O -60 1.15 (0.10) 22 n.a. 93.5:6.5 (47) Me 12b tBu Et O -60 1.15 (0.20) 24 >20:1 97:3 88 (20.0) 2

a Yields in parentheses represent 1H NMR yields determined using 1,3,5-trimethoxybenzene as an internal standard. b The dr, er, and yield values for this entry are an average of two trials.

1.3.2 Reaction Scope

When the optimized conditions were applied to the parent substrate 1.12a, the reaction proceeded with >20:1 diastereoselection and 97:3 er in 88% isolated yield (Figure 1-7). We observed similar reaction outcomes with halogen-substituted arenes 1.14b−d. X-ray diffraction analysis of nitro adduct 1.14d allowed us to determine the absolute stereochemical outcome of the reaction (Figure 1-8).§ We observed that placing the bromo substituent at the ortho position resulted in the formation of an undesired and inseparable byproduct. Other electron-deficient enone diesters 1.14e-g provided the desired products in high stereoselectivity and yield. When we turned our attention to the electron-donating substituents present in 1.14h-j (piperonyl, 4-methoxy, 3-methoxy), we found similar results regardless of the specific substitution pattern. A study of furan (1.14k), thiophene (1.14l), and pyridine

(1.14m) heterocycles also provided products with nearly perfect stereoselectivities and high yields. Aliphatic enones 1.14n and 1.14o performed well in the reaction, giving >20:1 dr with high enantioselectivities and good yields. Finally, we investigated whether homologous nitroalkanes could be employed. A nitropropane addition product was prepared with high

§ CCDC 1563042 contains the supplementary crystallographic data for this structure. These data can be obtained free of charge from the Cambridge Crystallographic Centre via www.ccdc.cam.ac.ui/data_request/cif.

18 stereoselectivity and chemical yield (1.14p). On a 1 g scale, the reaction of enone diester 1.12a provided product 1.14a with nearly perfect stereoselectivity in 86% isolated yield (Scheme 1-

11).

19 Figure 1-7. Asymmetric Conjugate Addition of Nitroalkanes

a All of the reactions were conducted on a 0.1 mmol scale using 21.0 equiv of EtNO2 or 20.2 equiv of n-PrNO2.

Isolated yields are shown. All yields and dr and er values are the averages of two trials. b The er of 1.14a was determined by derivatization to dimethyl malonate 1.18a

20 Figure 1-8. X-Ray Crystal Structure of para-Bromo Nitro Adduct 1.14d

Scheme 1-11. Gram-Scale Asymmetric Conjugate Addition Reaction

1.4 Local Desymmetrization of Nitro-Adducts

Seeking to take advantage of the diastereotopic ester groups, we developed a three-step local desymmetrization69,70 protocol that enables the formation of a new stereogenic center with concomitant lactamization (Scheme 1-12). It was necessary to transform the di-tert-butyl malonate substructure into dimethyl malonate 1.18a to achieve ring closure during the nitro group reduction. The final lactam 1.19a was obtained with 9.1:1 dr in 45% yield over three steps while maintaining the same level of enantiopurity as the starting material 1.14a. On the basis of the absence of a H2 −H3 NOE, the three-bond coupling constant (J3) of 7.5 Hz in

71–74 CD3OD (or 8.2 Hz in CDCl3), and strong literature precedent , the benzoyl group and methyl ester were assigned as trans on the γ-butyrolactam ring.

21 Scheme 1-12. Local Desymmetrization via Transesterification and Diastereoselective

Lactamization

1.5 Conclusion

In summary, we have developed asymmetric organocatalytic conjugate additions of extended nitroalkanes to enone diester electrophiles. A chiral bifunctional iminophosphorane enabled the creation of two adjacent stereocenters with high levels of enantio- and diastereoselectivity. Through subsequent diastereotopic group selection, the establishment of a third stereogenic center during formation of a polyfunctional lactam was demonstrated.

1.6 Acknowledgements

The work described was supported by Award R35 GM118055 from the National

Institute of General Medical Sciences. J.L.F. was supported by an NSF Graduate Research

Fellowship. We thank Dr. Brandie Ehrmann and Evan McConnell (UNC Department of

Chemistry Mass Spectrometry Core Laboratory) for their assistance with mass spectrometry analysis and Dr. Roger Sommer (North Carolina State University X-ray Structure Facility) for

X-ray crystallographic analysis.

22 1.7 Experimental Details

Methods: Infrared (IR) spectra were obtained using a Jasco 460 Plus Fourier transform infrared spectrometer. Proton and carbon magnetic resonance spectra (1H NMR, 13C NMR, 19F

NMR) were recorded on a Bruker model DRX 400 or 600 (1H NMR at 400 MHz or 600 MHz,

13C NMR at 101 MHz or 151 MHz, 19F NMR at 376 MHz with solvent resonance as the internal

1 13 1 standard ( H NMR: CDCl3 at 7.26 ppm and C NMR: CDCl3 at 77.0 ppm). H NMR data are reported as follows: chemical shift, multiplicity (s = singlet, app s = apparent singlet, br s = broad singlet, d = doublet, dd = doublet of doublet, t = triplet, m = multiplet), coupling constants (Hz), and integration. High resolution mass spectra were obtained with a Thermo

Fisher Scientific FinniganTM LTQ-ICR FTTM (all samples prepared in methanol). Melting points were obtained using a Thomas Hoover UniMelt Capillary Melting Point Apparatus.

Analytical thin layer chromatography was carried out using Whatman 0.25 mm silica gel 60 plates, Sorbent Technologies 0.20 mm Silica Gel TLC plates. Visualization was allowed by

UV light, phosphomolybdic acid in ethanol, or aqueous ceric ammonium nitrate solution.

HPLC analysis was performed on a Perkin Elmer flexar photodiode array (PDA) system equipped with Daicel IA, IC, AD, and OD-H columns. Asymmetric reactions were carried out in a Thermo Sigma UCR-150N aluminum block UC reactor with stirring. Purification of the reaction products was carried out by using Siliaflash-P60 silica gel (40- 63μm) purchased from

Silicycle. Yields refer to isolated yields after flash column chromatography; some samples contain residual minor diastereomers. Optical rotations of enantioenriched products were taken after purification using silica flash column chromatography. Since all asymmetric trial results are the averages of two trials, the stereoisomer ratios listed in the text above may not exactly match those represented in the NMR and HPLC data below. The relative and absolute stereoconfiguration of 1.14d was determined using X-ray diffraction analysis, and the

23 stereochemistry of products 1.14 were assigned by analogy.

Materials: Diethyl ether (Et2O) was passed through a column of neutral alumina under nitrogen prior to use. Wittig reagents were prepared according to a literature procedure.75

Triaryliminophosphorane catalysts 1.4, 1.15-1.16 were prepared according to literature procedures.37,41 Commercially available nitroethane and nitropropane were used as received.

® ® Raney -Nickel 2800 (W.R. Grace and Co. Raney ) slurry in H2O was used as received.

General procedure for synthesis of enone diesters:

A modification of literature procedures was used.66,76 A flame-dried 100 mL round-bottomed flask equipped with a reflux condenser was charged with Rh2(OAc)4 (0.046 mmol, 0.02 equiv), toluene (10 mL), and propylene oxide (22.4 mmol, 10.0 equiv). The mixture was heated to

85 °C in an oil bath for 10 min. A solution of di-tert-butyl 2-diazomalonate77 (2.25 mmol, 1.0 equiv) in toluene (2 mL) was added dropwise. An additional volume of toluene (1 mL) was used as a rinse to complete the addition of the diazomalonate. The reaction was stirred at 85 °C for 1 h then allowed to return to room temperature. The reaction flask was placed in an ice bath. MgSO4 (500 mg) was added to the reaction, followed by the appropriate Wittig reagent

(3.37 mmol, 1.5 equiv). The reaction was allowed to slowly warm to room temperature and was stirred for 16 h. The crude mixture was filtered through a short silica plug with CH2Cl2 (to remove solids) and concentrated in vacuo. The crude materials thusly obtained were purified using flash column chromatography, with the gradient noted below.

Characterization data for enone diesters:

24 Di-tert-butyl 2-(2-oxo-2-phenylethylidene)malonate (1.12a): The

title compound was prepared on a larger scale according to the general

procedure. Di-tert-butyl 2-diazomalonate (8.49 g, 35.0 mmol) was used and all components of the general procedure were scaled proportionally. The crude material was purified using flash column chromatography, with a gradient from 95:5 hexanes/EtOAc to 85:15 hexanes/EtOAc. Yellow solid (8.53 g, 25.7 mmol, 73%), mp 89-

1 90 °C; H NMR (600 MHz, CDCl3) δ 8.01-7.99 (m, 2H), 7.68 (s, 1H), 7.65-7.62 (m, 1H),

13 7.53-7.51 (m, 2H), 1.57 (s, 9H), 1.49 (s, 9H); C NMR (151 MHz, CDCl3) δ189.6, 163.7,

162.2, 138.9, 136.3, 134.0, 133.2, 128.9, 128.9, 83.3, 83.0, 27.9, 27.8. IR (thin film) ν 2979,

1724, 1673, 1450, 1369, 1278, 1257, 1156, 1069, 866 cm-1. HRMS (ESI): Calcd. For

+ + C19H24NaO5 ([M+Na ]): 355.1516, found 355.1509. TLC (10:90 EtOAc/hexanes): Rf = 0.32.

Di-tert-butyl 2-(2-(4-fluorophenyl)-2-oxoethylidene)malonate

(1.12b): The title compound was prepared according to the general

procedure. The crude material was purified using flash column chromatography, with a gradient from pure hexanes to 95:5 hexanes/EtOAc. Yellow oil (544.0

1 mg, 1.55 mmol, 69%); H NMR (600 MHz, CDCl3) δ 8.04-8.02 (m, 2H), 7.64 (s, 1H), 7.20-

13 7.18 (m, 2H), 1.56 (s, 9H), 1.50 (s, 9H); C NMR (151 MHz, CDCl3) δ188.0, 166.3 (d, J =

256.8 Hz), 163.6, 162.1, 139.1, 132.9, 132.8 (d, J = 3.0 Hz), 131.6 (d, J = 9.4 Hz), 116.1 (d, J

19 = 22.1 Hz), 83.4, 83.1, 27.9, 27.8; F NMR (565 MHz, CDCl3) δ -103.18. IR (thin film) ν

3437, 2980, 1724, 1673, 1598, 1541, 1369, 1279, 1155, 1070 cm-1. HRMS (ESI): Calcd. For

+ + C19H23FNaO5 ([M+Na ]): 373.1422, found 373.1413. TLC (10:90 EtOAc/hexanes): Rf =

0.34.

Di-tert-butyl 2-(2-(4-chlorophenyl)-2-oxoethylidene)malonate

(1.12c): The title compound was prepared according to the

general procedure. The crude material was purified using flash column chromatography, with a gradient from pure hexanes to 95:5 hexanes/EtOAc. Yellow

1 solid (528.0 mg, 1.44 mmol, 64%), mp 63-64 °C; H NMR (600 MHz, CDCl3) δ 7.94 (d, J =

8.6 Hz, 2H), 7.63 (s, 1H), 7.49 (d, J = 8.6 Hz, 2H), 1.56 (s, 9H), 1.50 (s, 9H); 13C NMR (151

MHz, CDCl3) δ188.3, 163.6, 162.1, 140.6, 139.4, 134.7, 132.5, 130.2, 129.2, 83.5, 83.2, 27.9,

27.8. IR (thin film) ν 2979, 2934, 1725, 1673, 1589, 1369, 1258, 1158, 1092, 847 cm-1. HRMS

+ + (ESI): Calcd. For C19H23ClNaO5 ([M+Na ]): 389.1126, found 389.1119. TLC (10:90

EtOAc/hexanes): Rf = 0.34.

Di-tert-butyl 2-(2-(4-bromophenyl)-2-

oxoethylidene)malonate (1.12d): The title compound was

prepared according to the general procedure. The crude material was purified using flash column chromatography, with a gradient from pure hexanes to 95:5 hexanes/EtOAc. Light yellow solid (626.6 mg, 1.52 mmol, 68%), mp 73-74 °C; 1H NMR (600

MHz, CDCl3) δ 7.85 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.5 Hz, 1H), 7.62 (s, 1H), 1.56 (s, 9H),

13 1.50 (s, 9H); C NMR (151 MHz, CDCl3) δ 188.5, 163.6, 162.0, 139.5, 135.1, 132.4, 132.2,

130.3, 129.4, 83.5, 83.2, 27.9, 27.8. IR (thin film) ν 2979, 2933, 1725, 1672, 1586, 1569, 1369,

-1 + + 1278, 1159, 1071 cm . HRMS (ESI): Calcd. For C19H23BrNaO5 ([M+Na ]): 433.0621, found

433.0611. TLC (10:90 EtOAc/hexanes): Rf = 0.38.

26 Di-tert-butyl 2-(2-(4-cyanophenyl)-2-oxoethylidene)malonate

(1.12e): The title compound was prepared according to the

general procedure. The crude material was purified using flash column chromatography, with a gradient from pure hexanes to 90:10 hexanes/EtOAc. Yellow

1 solid (407.2 mg, 1.14 mmol, 51%), mp 72-73 °C; H NMR (600 MHz, CDCl3) δ 8.08 (d, J =

8.3 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H), 7.62 (s, 1H), 1.56 (s, 9H), 1.51 (s, 9H); 13C NMR (151

MHz, CDCl3) δ 188.3, 163.3, 161.8, 140.4, 139.2, 132.7, 131.6, 129.2, 117.8, 117.1, 83.7, 83.5,

27.9, 27.8. IR (thin film) ν 2980, 2935, 2232, 1725, 1677, 1370, 1279, 1158, 1071, 847 cm-1.

+ + HRMS (ESI): Calcd. For C20H23NNaO5 ([M+Na ]): 380.1468, found 380.1463. TLC (10:90

EtOAc/hexanes): Rf = 0.14.

Di-tert-butyl 2-(2-(4-nitrophenyl)-2-oxoethylidene)malonate

(1.12f): The title compound was prepared according to the

general procedure. The crude material was purified using flash column chromatography, with a gradient from pure hexanes to 85:15 hexanes/EtOAc. Yellow

1 solid (598.1 mg, 1.58 mmol, 70%), mp 77-78 °C; H NMR (600 MHz, CDCl3) δ 8.37 (d, J =

8.9 Hz, 2H), 8.16 (d, J = 8.9 Hz, 2H), 7.65 (s, 1H), 1.57 (s, 9H), 1.52 (s, 9H); 13C NMR (151

MHz, CDCl3) δ 188.0, 163.3, 161.8, 150.7, 140.7, 140.5, 131.5, 129.8, 124.1, 83.8, 83.5, 27.9,

27.8. IR (thin film) ν 2980, 2360, 1725, 1678, 1530, 1370, 1347, 1278, 1157, 847 cm-1. HRMS

+ + (ESI): Calcd. For C19H23NNaO7 ([M+Na ]): 400.1367, found 400.1358. TLC (10:90

EtOAc/hexanes): Rf = 0.28.

27 Di-tert-butyl 2-(2-oxo-2-(4-

(trifluoromethyl)phenyl)ethylidene)malonate (1.12g): The

title compound was prepared according to the general procedure. The crude material was purified using flash column chromatography, with a gradient from pure hexanes to 90:10 hexanes/EtOAc. Yellow oil (550.6 mg, 1.38 mmol, 61%);

1 H NMR (600 MHz, CDCl3) δ 8.10 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H), 7.66 (s, 1H),

13 1.60 (s, 9H), 1.51 (s, 9H); C NMR (151 MHz, CDCl3) δ 188.6, 163.4, 161.9, 140.0, 139.0,

135.1 (q, J = 32.8 Hz), 132.0, 129.1, 125.9 (q, J = 3.7 Hz), 123.4 (q, J = 273.0 Hz), 83.6, 83.3,

19 27.9, 27.8; F NMR (565 MHz, CDCl3) δ -63.19. IR (thin film) ν 2981, 1726, 1678, 1370,

-1 + 1326, 1279, 1258, 1161, 1067, 1032 cm . HRMS (ESI): Calcd. For C20H23F3NaO5

+ ([M+Na ]): 423.1390, found 423.1383. TLC (10:90 EtOAc/hexanes): Rf = 0.34.

Di-tert-butyl 2-(2-(benzo[d][1,3]dioxol-5-yl)-2-

oxoethylidene)malonate (1.12h): The title compound was

prepared according to the general procedure. The crude material was purified using flash column chromatography, with a gradient from pure hexanes to 80:20 hexanes/EtOAc. Yellow solid (506.0 mg, 1.34 mmol, 60%), mp 55-56 °C; 1H NMR (600 MHz,

CDCl3) δ 7.62 (s, 1H), 7.59 (d, J = 8.2, 1H), 7.48 (s, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.09 (s,

13 2H), 1.56 (s, 9H), 1.51 (s, 9H); C NMR (151 MHz, CDCl3) δ 187.5, 163.8, 162.3, 152.7,

148.6, 138.5, 133.4, 131.3, 126.0, 108.1, 108.1, 102.1, 83.2, 82.9, 27.9, 27.8. IR (thin film) ν

2979, 2933, 1723, 1664, 1603, 1505, 1446, 1369, 1259, 1161 cm-1. HRMS (ESI): Calcd. For

+ + C20H24NaO7 ([M+Na ]): 399.1414, found 399.1405. TLC (10:90 EtOAc/hexanes): Rf = 0.21.

28 Di-tert-butyl 2-(2-(4-methoxyphenyl)-2-

oxoethylidene)malonate (1.12i): The title compound was

prepared according to the general procedure. The crude material was purified using flash column chromatography, with a gradient from pure hexanes to 90:10 hexanes/EtOAc. White solid (612.8 mg, 1.69 mmol, 75%), mp 93-94 °C; 1H NMR (600 MHz,

CDCl3) δ 7.98 (d, J = 8.8 Hz, 2H), 7.67 (s, 1H), 6.98 (d, J = 8.8 Hz, 2H), 3.91 (s, 3H), 1.56 (s,

13 9H), 1.50 (s, 9H); C NMR (151 MHz, CDCl3) δ 187.9, 164.3, 163.9, 162.4, 138.3, 133.5,

131.3, 129.5, 114.1, 83.2, 82.8, 55.6, 27.9, 27.8. IR (thin film) ν 2979, 1724, 1666, 1599, 1512,

-1 + + 1369, 1281, 1257, 1161, 847 cm . HRMS (ESI): Calcd. For C20H26NaO6 ([M+Na ]):

385.1622, found 385.1613. TLC (10:90 EtOAc/hexanes): Rf = 0.14.

Di-tert-butyl 2-(2-(3-methoxyphenyl)-2-oxoethylidene)malonate

(1.12j): The title compound was prepared according to the general

procedure. The crude material was purified using flash column chromatography, with a gradient from pure hexanes to 90:10 hexanes/EtOAc. Yellow oil (617.3

1 mg, 1.70 mmol, 76%); H NMR (600 MHz, CDCl3) δ 7.66 (s, 1H), 7.58-7.56 (m, 1H), 7.52-

7.51 (m, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.19-7.17 (m, 1H), 3.88 (s, 3H), 1.56 (s, 9H), 1.50 (s,

13 9H); C NMR (151 MHz, CDCl3) δ 189.3, 163.7, 162.2, 160.0, 139.0, 137.7, 133.1, 129.8,

121.8, 121.0, 112.4, 83.3, 83.0, 55.5, 27.9, 27.8. IR (thin film) ν 2979, 1724, 1672, 1597, 1456,

-1 + + 1369, 1278, 1157, 1032, 848 cm . HRMS (ESI): Calcd. For C20H26NaO6 ([M+Na ]):

385.1622, found 385.1612. TLC (10:90 EtOAc/hexanes): Rf = 0.25.

29 Di-tert-butyl 2-(2-(furan-2-yl)-2-oxoethylidene)malonate (1.12k):

The title compound was prepared according to the general procedure.

The crude material was purified using flash column chromatography, with a gradient from pure hexanes to 80:20 hexanes/EtOAc. White solid (389.0 mg, 1.21 mmol,

1 54%), mp 67-68 °C; H NMR (600 MHz, CDCl3) δ 7.69 (m, 1H), 7.58 (s, 1H), 7.36 (d, J = 3.7

Hz, 1H), 6.62 (dd, J = 3.6 Hz, 1.6 Hz, 1H), 1.59 (s, 9H), 1.55 (s, 9H); 13C NMR (151 MHz,

CDCl3) δ 175.8, 163.9, 162.0, 152.7, 147.9, 140.0, 129.8, 119.6, 113.0, 83.4, 83.1, 27.9, 27.9.

IR (thin film) ν 2979, 1732, 1669, 1558, 1465, 1370, 1258, 1158, 1071, 846 cm-1. HRMS

+ + (ESI): Calcd. For C17H22NaO6 ([M+Na ]): 345.1309, found 345.1302. TLC (10:90

EtOAc/hexanes): Rf = 0.17.

Di-tert-butyl 2-(2-oxo-2-(thiophen-2-yl)ethylidene)malonate

(1.12): The title compound was prepared according to the general

procedure. The crude material was purified using flash column chromatography, with a gradient from pure hexanes to 90:10 hexanes/EtOAc. Off-white solid

1 (485.8 mg, 1.44 mmol, 64%), mp 84-85 °C; H NMR (600 MHz, CDCl3) δ 7.83 (dd, J = 3.9,

1.0 Hz, 1H), 7.76 (dd, J = 4.9, 1.0 Hz, 1H), 7.58 (s, 1H), 7.19 (dd, J = 4.9, 3.8 Hz, 1H), 1.56

13 (s, 18H); C NMR (151 MHz, CDCl3) δ 180.7, 163.7, 162.1, 144.2, 139.4, 135.8, 133.7,

131.2, 128.6, 83.4, 83.1, 27.9, 27.9. IR (thin film) ν 2979, 1726, 1656, 1516, 1415, 1369, 1282,

-1 + + 1257, 1156, 1066 cm . HRMS (ESI): Calcd. For C17H22NaO5S ([M+Na ]): 361.1080, found

361.1073. TLC (10:90 EtOAc/hexanes): Rf = 0.18.

30 Di-tert-butyl 2-(2-oxo-2-(pyridin-4-yl)ethylidene)malonate

(1.12m): The title compound was prepared according to the general

procedure, but better results were obtained on larger scale. Di-tert- butyl 2-diazomalonate (3.00 g, 12.4 mmol) was used and all components of the general procedure were scaled appropriately. The crude material was purified using flash column chromatography, with a gradient from 95:5 hexanes/EtOAc to 40:60 hexanes/EtOAc. Low-

1 melting red-brown solid (2.23 g, 6.70 mmol, 54%); H NMR (600 MHz, CDCl3) δ 8.87 (br s,

13 2H), 7.78 (br s, 2H), 7.61 (s, 1H), 1.57 (s, 9H), 1.52 (s, 9H); C NMR (151 MHz, CDCl3) δ

188.8, 163.3, 161.8, 151.2, 142.1, 140.7, 130.9, 121.4, 83.8, 83.5, 27.9, 27.8. IR (thin film) ν

2979, 1725, 1682, 1370, 1279, 1223, 1158, 1072, 1032, 847 cm-1. HRMS (ESI): Calcd. For

+ + C18H23NNaO5 ([M+Na ]): 356.1468, found 356.1452. TLC (40:60 EtOAc/hexanes): Rf =

0.35.

Di-tert-butyl 2-(2-oxopropylidene)malonate (1.12n): The title

compound was prepared according to the general procedure. The crude material was purified using flash column chromatography, with a gradient from pure hexanes

1 to 95:5 hexanes/EtOAc. Clear oil (282.4 mg, 1.04 mmol, 46%); H NMR (600 MHz, CDCl3)

13 δ 6.97 (s, 1H), 2.35 (s, 3H), 1.58 (s, 9H), 1.52 (s, 9H); C NMR (151 MHz, CDCl3) δ 196.4,

163.9, 162.0, 138.1, 133.5, 83.4, 83.1, 30.8, 27.9 (2C). IR (thin film) ν 2980, 2935, 1730, 1703,

-1 + + 1369, 1274, 1254, 1159, 1075, 848 cm . HRMS (ESI): Calcd. For C14H22NaO5 ([M+Na ]):

293.1359, found 293.1356. TLC (10:90 EtOAc/hexanes): Rf = 0.24.

31 Di-tert-butyl 2-(2-cyclopropyl-2-oxoethylidene)malonate (1.12o):

The title compound was prepared according to the general procedure.

The crude material was purified using flash column chromatography, with a gradient from pure hexanes to 95:5 hexanes/EtOAc. Clear oil (342.4 mg, 1.16 mmol, 51%); 1H NMR (600 MHz,

CDCl3) δ 7.11 (s, 1H), 2.14-2.09 (m, 1H), 1.56 (s, 9H), 1.53 (s, 9H), 1.22-1.19 (m, 2H), 1.07-

13 1.04 (m, 2H); C NMR (151 MHz, CDCl3) δ 198.7, 164.0, 162.2, 137.4, 133.6, 83.2, 82.9,

27.9, 27.9, 22.2, 12.6. IR (thin film) ν 2979, 1729, 1686, 1391, 1369, 1256, 1159, 1087, 1062,

-1 + + 917 cm . HRMS (ESI): Calcd. For C16H24NaO5 ([M+Na ]): 319.1516, found 319.1510. TLC

(10:90 EtOAc/hexanes): Rf = 0.29.

Optimization of asymmetric conjugate addition of nitroalkanes:

General procedure: A test tube was charged with enone diester (0.1 mmol, 1.0 equiv), nitroalkane (amount listed in Table 1-1), 1,3,5-trimethoxybenzene (0.1 mmol, 1.0 equiv; internal standard), and solvent (listed in Table 1-1). The reaction was cooled to -60 °C and catalyst (amount listed in Table 1-1) was added. The reaction was stirred for the listed amount of time and then quenched with 50 L of a 0.5 M TFA/toluene solution before flowing it through a short plug of SiO2 with diethyl ether. The filtrate was concentrated in vacuo to provide the crude product mixture, which was purified via flash column chromatography.

General procedure for asymmetric conjugate addition of nitroalkanes:

A flame-dried test tube was charged sequentially with enone diester (0.1 mmol, 1.0 equiv),

Et2O (1.0 mL), and nitroethane (2.1 mmol, 21.0 equiv). The reaction was stirred at -60 °C in a cryogenic cooling apparatus for 15 min, then triaryliminophosphorane catalyst 1.15 (0.02

32 mmol, 0.20 equiv) was added. The reaction was then stirred at -60 °C for 24 h. After this period, the reaction was quenched with a TFA solution in toluene (50 L, 0.5 M solution) at the same temperature. Additional Et2O was used to flush the reaction through a short plug of silica and the filtrate was concentrated in vacuo. The crude material thusly obtained was purified using flash column chromatography with a gradient from 97.5:2.5 hexanes/EtOAc to 90:10 hexanes/EtOAc unless otherwise noted.

Gram scale asymmetric conjugate addition reaction:

A flame-dried 100 mL round-bottomed flask was charged sequentially with enone diester 1.12a

(1.00 g, 3.01 mmol, 1.0 equiv), Et2O (30.0 mL), and nitroethane (4.50 mL, 62.6 mmol, 20.8 equiv). The reaction was stirred at -60 °C in a cryogenic cooling apparatus for 15 min, then triaryliminophosphorane catalyst 1.15 (401.7 mg, 0.60 mmol, 0.20 equiv) was added. The reaction was then stirred at -60 °C for 24 h. After this period, the reaction was quenched with a TFA solution in toluene (1.5 mL, 0.5M solution) at the same temperature. Additional Et2O was used to flush the reaction through a short plug of silica and the filtrate was concentrated in vacuo. The crude material thusly obtained was purified using flash column chromatography with a gradient from 97.5:2.5 hexanes/EtOAc to 90:10 hexanes/EtOAc, yielding 1.05 g (86%)

1.14a as a white solid in >20:1 dr and >99.5:0.5 er.

Characterization data for conjugate addition products:

33 Di-tert-butyl 2-((2S,3R)-3-nitro-1-oxo-1-phenylbutan-2-

yl)malonate (1.14a): The title compound was prepared according to

the general procedure. No minor diastereomer was observed in the 1H

NMR spectrum of the unpurified product. White solid (34.7 mg, 0.085 mmol, 85%), mp 93-

1 94 °C (decomp); H NMR (600 MHz, CDCl3) δ 7.99 (d, J = 7.4 Hz, 2H), 7.61 (t, 7.4 Hz, 1H),

7.5 (t, J = 7.8 Hz, 2H), 4.92-4.86 (m, 2H), 3.87 (d, J = 9.8 Hz, 1H), 1.52 (s, 9H), 1.47 (d, 6.7

13 Hz, 3H), 1.35 (s, 9H); C NMR (151 MHz, CDCl3) δ 197.3, 166.8, 166.2, 137.1, 133.9, 128.8,

128.6, 83.2, 83.0, 82.4, 55.0, 46.5, 27.8, 27.7, 15.3. IR (thin film) ν 2979, 1729, 1682, 1557,

-1 + + 1370, 1257, 1143, 842, 734, 692 cm . HRMS (ESI): Calcd. For C21H29NNaO7 ([M+Na ]):

430.1842, found 430.1831. HPLC Derivatized to 1.13a for determination of enantiopurity.

TLC (10:90 EtOAc/hexanes): Rf = 0.25. [α]D = +80.2 (c = 1.5, CHCl3).

Di-tert-butyl 2-((2S,3R)-1-(4-fluorophenyl)-3-nitro-1-

oxobutan-2-yl)malonate (1.14b): The title compound was

prepared according to the general procedure. The diastereomeric ratio was determined by 1H NMR spectroscopic analysis of the crude reaction mixture by comparison of the resonances at δ 3.92 (minor diastereomer) and δ 3.86 (major diastereomer).

The crude material was purified using flash column chromatography, with a gradient from

97.5:2.5 hexanes/EtOAc to 95:5 hexanes/EtOAc. White solid (34.9 mg, 0.082 mmol, 82%),

1 mp 89-90 °C (decomp); H NMR (600 MHz, CDCl3) δ 8.02 (dd, J = 8.8, 5.3 Hz, 2H), 7.17 (t,

J = 8.6 Hz, 2H), 4.88-4.83 (m, 2H), 3.87 (d, J = 9.9 Hz, 1H), 1.53 (s, 9H), 1.48 (d, J = 6 Hz,

13 3H), 1.36 (s, 9H); C NMR (151 MHz, CDCl3) δ 195.7, 166.7, 166.2, 166.2 (d, J = 256.7 Hz),

133.6, 131.3 (d, J = 9.1 Hz), 116.0 (d, J = 21.14 Hz), 83.3, 83.1, 82.4, 54.9, 46.4, 27.8, 27.8,

34 19 15.0; F NMR (565 MHz, CDCl3) δ -103.8. IR (thin film) ν 2980, 1729, 1683, 1599, 1557,

-1 + + 1394, 1370, 1257, 1158, 848 cm . HRMS (ESI): Calcd. For C21H28FNNaO7 ([M+Na ]):

448.1748, found 448.1729. HPLC Chiralpak AD column, Hex/iPrOH = 98:2, flow rate = 1.0 mL/min, λ = 210 nm, 9.0 min (minor isomer), 16.4 min (major isomer). TLC (10:90

EtOAc/hexanes): Rf = 0.16. [α]D = +75.2 (c = 1.5, CHCl3).

Di-tert-butyl 2-((2S,3R)-1-(4-chlorophenyl)-3-nitro-1-

oxobutan-2-yl)malonate (1.14c): The title compound was

The crude material was purified using flash column chromatography, with a gradient from

97.5:2.5 hexanes/EtOAc to 95:5 hexanes/EtOAc. White solid (39.0 mg, 0.088 mmol, 88%),

1 mp 83-84 °C (decomp); H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.6 Hz, 2H), 7.46 (d, J =

8.6 Hz, 2H), 4.89-4.81 (m, 2H), 3.86 (d, J = 9.9 Hz, 1H), 1.52 (s, 9H), 1.47 (d, J = 6.6 Hz, 3H),

13 1.36 (s, 9H); C NMR (151 MHz, CDCl3) δ 196.1, 166.6, 166.2, 140.4, 135.5, 130.0, 129.1,

83.3, 83.1, 82.4, 55.0, 46.4, 27.8, 27.7, 15.1. IR (thin film) ν 2980, 1728, 1683, 1557, 1370,

-1 + + 1258, 1163, 1093, 846, 736 cm . HRMS (ESI): Calcd. For C21H28ClNNaO7 ([M+Na ]):

464.1452, found 464.1435. HPLC Chiralpak AD column, Hex/iPrOH = 98:2, flow rate = 1.0 mL/min, λ = 210 nm, 9.1 min (minor isomer), 21.8 min (major isomer). TLC (10:90

EtOAc/hexanes): Rf = 0.28. [α]D = +68.6 (c = 1.5, CHCl3).

35 Di-tert-butyl 2-((2S,3R)-1-(4-bromophenyl)-3-nitro-1-

oxobutan-2-yl)malonate (1.14d): The title compound was

Some residual minor diastereomer was still present in the isolated material. The crude material was purified using flash column chromatography, with a gradient from 97.5:2.5 hexanes/EtOAc to 95:5 hexanes/EtOAc. White solid (41.1 mg, 0.085 mmol, 85%), mp 80-

1 81 °C (decomp); H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz,

2H), 4.88-4.81 (m, 2H), 3.86 (d, J = 10.1 Hz, 1H), 1.52 (s, 9H), 1.48 (d, J = 6.7 Hz, 3H), 1.36

13 (s, 9H); C NMR (151 MHz, CDCl3) δ 196.4, 166.6, 166.2, 135.9, 132.1, 130.1, 129.3, 83.3,

83.1, 82.4, 55.0, 46.4, 27.8, 27.7, 15.1. IR (thin film) ν 2979, 1728, 1683, 1557, 1370, 1258,

-1 + + 1144, 1072, 845, 738 cm . HRMS (ESI): Calcd. For C21H28BrNNaO7 ([M+Na ]): 508.0947, found 508.0928. HPLC Chiralpak AD column, Hex/iPrOH = 98:2, flow rate = 1.0 mL/min, λ

= 210 nm, 12.9 min (minor isomer), 32.9 min (major isomer). TLC (10:90 EtOAc/hexanes):

Rf = 0.31. [α]D = +61.4 (c = 1.5, CHCl3).

Di-tert-butyl 2-((2S,3R)-1-(4-cyanophenyl)-3-nitro-1-

oxobutan-2-yl)malonate (1.14e): The title compound was

prepared according to the general procedure. No minor diastereomer was observed in the 1H NMR spectrum of the unpurified product. The crude material was purified using flash column chromatography, with a gradient from 97.5:2.5 hexanes/EtOAc to 90:10 hexanes/EtOAc. White solid (41.3 mg, 0.95 mmol, 95%), mp 116-

36 1 117 °C (decomp); H NMR (600 MHz, CDCl3) δ 8.07 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz,

2H), 4.86-4.81 (m, 2H), 3.89 (d, J = 10.1 Hz, 1H), 1.54 (s, 9H), 1.50 (d, J = 6.7 Hz, 3H), 1.37

13 (s, 9H); C NMR (151 MHz, CDCl3) δ 196.5, 166.4, 166.3, 140.1, 132.6, 128.9, 117.9, 116.8,

83.6, 83.4, 82.3, 55.1, 46.4, 27.8, 27.7, 14.8. IR (thin film) ν 2980, 2360, 1727, 1688, 1557,

-1 + + 1370, 1294, 1257, 1143, 848 cm . HRMS (ESI): Calcd. For C22H28N2NaO7 ([M+Na ]):

455.1794, found 455.1782. HPLC Chiralpak IC column, Hex/iPrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, 41.1 min (minor isomer), 43.2 min (major isomer). TLC (10:90

EtOAc/hexanes): Rf = 0.11. [α]D = +47.5 (c = 1.5, CHCl3).

Di-tert-butyl 2-((2S,3R)-3-nitro-1-(4-nitrophenyl)-1-

oxobutan-2-yl)malonate (1.14f): The title compound was

1 110 °C (decomp); H NMR (600 MHz, CDCl3) δ 8.34 (d, J = 8.8 Hz, 2H), 8.14 (d, J = 8.7 Hz,

2H), 4.86 (d, J = 8.8 Hz, 2H), 3.90 (d, J = 10.1 Hz, 1H), 1.54 (s, 9H), 1.52 (d, J = 6.7 Hz, 3H),

13 1.38 (s, 9H); C NMR (151 MHz, CDCl3) δ 196.4, 166.4, 166.3, 150.5, 141.6, 129.6, 123.9,

83.6, 83.5, 82.3, 55.1, 46.7, 27.8, 27.7, 14.8. IR (thin film) ν 2980, 2936, 2349, 1727, 1530,

-1 + + 1346, 1258, 1144, 850, 734 cm . HRMS (ESI): Calcd. For C21H28N2NaO9 ([M+Na ]):

475.1693, found 475.1681. HPLC Chiralpak OD-H column, Hex/iPrOH = 99:1, flow rate =

1.0 mL/min, λ = 254 nm, 11.8 min (major isomer), 13.9 min (major isomer). TLC (10:90

EtOAc/hexanes): Rf = 0.28. [α]D = +47.2 (c = 1.5, CHCl3).

Di-tert-butyl 2-((2S,3R)-3-nitro-1-oxo-1-(4-

(trifluoromethyl)phenyl)butan-2-yl)malonate (1.14g): The

title compound was prepared according to the general procedure. No minor diastereomer was observed in the 1H NMR spectrum of the unpurified product. The crude material was purified using flash column chromatography, with a gradient from 97.5:2.5 hexanes/EtOAc to 90:10 hexanes/EtOAc. Yellow solid (46.0 mg, 0.097 mmol,

1 97%), mp 68-69 °C (decomp); H NMR (600 MHz, CDCl3) δ 8.09 (d, J = 8.2 Hz, 2H), 7.76

(d, J = 8.16 Hz, 2H), 4.87 (d, J = 7.7 Hz, 2H), 3.89 (d, 9.8 Hz, 1H), 1.53 (s, 9H), 1.50 (d, J =

13 6.1 Hz, 3H), 1.37 (s, 9H); C NMR (151 MHz, CDCl3) δ 196.7, 166.5, 166.3, 139.8, 134.8 (q,

J = 33.2 Hz), 128.9, 125.8 (q, J = 3 Hz), 123.5 (q, J = 273.3 Hz), 83.4, 83.3, 82.3, 55.0, 46.6,

19 27.8, 27.7, 15.0; F NMR (565 MHz, CDCl3) δ -63.2. IR (thin film) ν 2981, 2937, 1728, 1689,

-1 + 1558, 1371, 1325, 1169, 1067, 850 cm . HRMS (ESI): Calcd. For C22H28F3NNaO7

([M+Na+]): 498.1716, found 498.1696. HPLC Chiralpak AD column, Hex/iPrOH = 98:2, flow rate = 1.0 mL/min, λ = 215 nm, 6.5 min (minor isomer), 20.0 min (major isomer). TLC (10:90

EtOAc/hexanes): Rf = 0.29. [α]D = +67.1 (c = 1.5, CHCl3).

Di-tert-butyl 2-((2S,3R)-1-(benzo[d][1,3]dioxol-5-yl)-3-nitro-

1-oxobutan-2-yl)malonate (1.14h): The title compound was

prepared according to the general procedure. The diastereomeric ratio was determined by 1H NMR spectroscopic analysis of the crude reaction mixture by comparison of the resonances at δ 3.93 (minor diastereomer) and δ 3.85 (major diastereomer).

The crude material was purified using flash column chromatography, with a gradient from

38 97.5:2.5 hexanes/EtOAc to 90:10 hexanes/EtOAc. White solid (35.8 mg, 0.079 mmol, 79%),

1 mp 91-92 °C (decomp); H NMR (600 MHz, CDCl3) δ 7.61 (dd, J = 8.3, 1.7 Hz, 1H), 7.45 (d,

J = 1.6 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.08 (s, 2H), 4.88-4.83 (m, 1H), 4.79 (dd, J = 10.2,

5.3 Hz, 1H), 3.85 (d, J = 10.2 Hz), 1.52 (s, 9H), 1.47 (d, J = 6.8 Hz, 3H), 1.37 (s, 9H); 13C

NMR (151 MHz, CDCl3) δ 194.9, 166.8, 166.2, 152.6, 148.4, 131.9, 125.4, 108.2, 108.1,

102.1, 83.2, 82.9, 82.5, 55.0, 46.4, 27.8, 27.7, 15.2. IR (thin film) ν 3443, 2937, 2349, 1728,

-1 + 1673, 1556, 1444, 1260, 1144, 1038 cm . HRMS (ESI): Calcd. For C22H29NNaO9

([M+Na+]): 474.1740, found 474.1717. HPLC Chiralpak AD column, Hex/iPrOH = 96:4, flow rate = 1.0 mL/min, λ = 205 nm, 13.9 min (minor isomer), 18.5 min (major isomer). TLC (10:90

EtOAc/hexanes): Rf = 0.22. [α]D = +77.5 (c = 1.5, CHCl3).

Di-tert-butyl 2-((2S,3R)-1-(4-methoxyphenyl)-3-nitro-1-

oxobutan-2-yl)malonate (1.14i): The title compound was

(major diastereomer). Some residual minor diastereomer was still present in the isolated material. The crude material was purified using flash column chromatography, with a gradient from 97.5:2.5 hexanes/EtOAc to 90:10 hexanes/EtOAc. White solid (37.6 mg, 0.086 mmol,

1 86%), mp 63-64 °C (decomp); H NMR (600 MHz, CDCl3) δ 7.97 (d, J = 8.8 Hz, 2H), 6.96

(d, J = 8.8 Hz, 2H), 4.89-4.84 (m, 2H), 3.89 (s, 3H), 3.86 (d, J = 9.7 Hz, 1H), 1.52 (s, 9H), 1.47

13 (d, J = 6.5 Hz, 3H), 1.34 (s, 9H); C NMR (151 MHz, CDCl3) δ 195.3, 166.9, 166.2, 164.2,

131.0, 130.1, 114.0, 83.1, 82.8, 82.6, 55.5, 54.9, 46.3, 27.8, 27.7, 15.2. IR (thin film) ν 2979,

39 2360, 1729, 1672, 1601, 1556, 1263, 1168, 1030, 846 cm-1. HRMS (ESI): Calcd. For

+ + C22H31NNaO8 ([M+Na ]): 460.1948, found 460.1926. HPLC Chiralpak AD column,

Hex/iPrOH = 98:2, flow rate = 1.0 mL/min, λ = 210 nm, 20.3 min (minor isomer), 29.0 min

(major isomer). TLC (10:90 EtOAc/hexanes): Rf = 0.17. [α]D = +77.9 (c = 1.5, CHCl3).

Di-tert-butyl 2-((2S,3R)-1-(3-methoxyphenyl)-3-nitro-1-

oxobutan-2-yl)malonate (1.14j): The title compound was

1 81 °C (decomp); H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.40 (t,

J = 8.0 Hz, 1H), 7.15 (dd, J = 8.2, 2.0 Hz, 1H), 4.91-4.84 (m, 2H), 3.88 (s, 3H), 3.85 (d, signal overlap prevents J value calculation, 1H), 1.52 (s, 9H), 1.47 (d, J = 6.6 Hz, 3H), 1.35 (s, 9H);

13 C NMR (151 MHz, CDCl3) δ 196.9, 166.8, 166.2, 159.8, 138.3, 129.8, 121.4, 120.6, 112.5,

83.2, 83.0, 82.4, 55.5, 55.0, 46.7, 27.8, 27.7, 15.4. IR (thin film) ν 2979, 2937, 1729, 1683,

-1 + + 1557, 1456, 1370, 1270, 1144, 840 cm . HRMS (ESI): Calcd. For C22H31NNaO8 ([M+Na ]):

460.1948, found 460.1926. HPLC Chiralpak OD-H column, Hex/iPrOH = 95:5, flow rate =

1.0 mL/min, λ = 205 nm, 25.3 min (major isomer), 50.5 min (minor isomer). TLC (10:90

EtOAc/hexanes): Rf = 0.17. [α]D = +38.3 (c = 1.5, CHCl3).

40 Di-tert-butyl 2-((2S,3R)-1-(furan-2-yl)-3-nitro-1-oxobutan-2-

yl)malonate (1.14k): The title compound was prepared according to

the general procedure. The diastereomeric ratio was determined by 1H

NMR spectroscopic analysis of the crude reaction mixture by comparison of the resonances at

δ 3.93 (minor diastereomer) and δ 3.81 (major diastereomer). The crude material was purified using flash column chromatography, with a gradient from 97.5:2.5 hexanes/EtOAc to 90:10 hexanes/EtOAc. White solid (38.0 mg, 0.096 mmol, 96%), mp 88-89 °C (decomp); 1H NMR

(600 MHz, CDCl3) δ 7.65 (app s, 1H), 7.31 (d, J = 3.6 Hz, 1H), 6.59 (dd, J = 3.5, 2.7 Hz, 1H),

4.91-4.86 (m, 1H), 4.62 (dd, J = 10.4, 5.1 Hz, 1H), 3.82 (d, J = 10.4 Hz, 1H), 1.52 (d, signal overlap prevents J value calculation, 3H), 1.51 (s, 9H), 1.37 (s, 9H); 13C NMR (151 MHz,

CDCl3) δ 184.6, 166.5, 166.0, 152.5, 147.6, 118.9, 112.9, 83.2, 83.0, 82.3, 54.2, 47.6, 27.8,

27.7, 15.0. IR (thin film) ν 2980, 2359, 1730, 1674, 1558, 1466, 1296, 1144, 842, 768 cm-1.

+ + HRMS (ESI): Calcd. For C19H27NNaO8 ([M+Na ]): 420.1635, found 420.1623. HPLC

Chiralpak AD column, Hex/iPrOH = 96:4, flow rate = 1.0 mL/min, λ = 210 nm, 10.4 min

(minor isomer), 11.8 min (major isomer). TLC (10:90 EtOAc/hexanes): Rf = 0.15. [α]D = +65.2

(c = 1.5, CHCl3).

Di-tert-butyl 2-((2S,3R)-3-nitro-1-oxo-1-(thiophen-2-yl)butan-2-

yl)malonate (1.14l): The title compound was prepared according to

the general procedure. The diastereomeric ratio was determined by 1H

NMR spectroscopic analysis of the crude reaction mixture by comparison of the resonances at

δ 3.93 (minor diastereomer) and δ 3.83 (major diastereomer). The crude material was purified using flash column chromatography, with a gradient from 97.5:2.5 hexanes/EtOAc to 90:10

41 hexanes/EtOAc. White solid (39.4 mg, 0.095 mmol, 95%), mp 100-101 °C (decomp); 1H NMR

(400 MHz, CDCl3) δ 7.79 (dd, J = 3.8, 0.8 Hz, 1H), 7.72 (dd, J = 4.9, 0.9 Hz, 1H), 7.16 (dd, J

= 4.8, 4.0 Hz, 1H), 4.94-4.87 (m, 1H), 4.66 (dd, J = 10.2, 5.3 Hz, 1H), 3.82 (d, J = 10.2 Hz,

13 1H), 1.53 (d, J = 7.2 Hz, 3H), 1.51 (s, 9H), 1.35 (s, 9H); C NMR (151 MHz, CDCl3) δ 189.0,

166.6, 165.9, 144.4 135.7, 133.5, 128.6, 83.3, 83.0, 82.5, 54.6, 48.6, 27.8, 27.6, 15.2. IR (thin film) ν 2980, 1730, 1660, 1557, 1415, 1370, 1256, 1144, 838, 733 cm-1. HRMS (ESI): Calcd.

+ + For C19H27NNaO7S ([M+Na ]): 436.1406, found 436.1394. HPLC Chiralpak AD column,

Hex/iPrOH = 98:2, flow rate = 1.0 mL/min, λ = 215 nm, 14.1 min (minor isomer), 22.6 min

(major isomer). TLC (10:90 EtOAc/hexanes): Rf = 0.23. [α]D = +80.6 (c = 1.5, CHCl3).

Di-tert-butyl 2-((2S,3R)-3-nitro-1-oxo-1-(pyridin-4-yl)butan-2-

yl)malonate (1.14m): The title compound was prepared according to

the general procedure. No minor diastereomer was observed in the

1H NMR spectrum of the unpurified product. The crude material was purified using flash column chromatography with a gradient from 90:10 hexanes/EtOAc to 60:40 hexanes/EtOAc.

1 White solid (35.3 mg, 0.086 mmol, 86%), mp 95-96 °C (decomp); H NMR (600 MHz, CDCl3)

δ 8.84 (d, J = 4.6 Hz, 2H), 7.76 (d, J = 4.6 Hz, 2H), 4.88-4.84 (m, 1H), 4.79 (dd, J = 10.3, 5.0

Hz, 1H), 3.88 (d, J = 10.4 Hz, 1H), 1.53 (s, 9H), 1.51 (d, J = 6.9 Hz, 3H), 1.37 (s, 9H); 13C

NMR (151 MHz, CDCl3) δ 197.3, 166.4, 166.2, 151.0, 143.0, 121.3, 83.5 (2C), 82.3, 55.1,

46.4, 27.8, 27.7, 15.1. IR (thin film) ν 3438, 2980, 2935, 1727, 1696, 1557, 1370, 1257, 1144,

-1 + + 845 cm . HRMS (ESI): Calcd. For C20H29N2O7 ([M+H ]): 409.1974, found 409.1958. HPLC

Chiralpak IC column, Hex/iPrOH = 95:5, flow rate = 1.0 mL/min, λ = 225 nm, 12.1 min (minor isomer), 18.3 min (major isomer). TLC (20:80 EtOAc/hexanes): Rf = 0.19. [α]D = +55.5 (c =

42 1.5, CHCl3).

Di-tert-butyl 2-((2R,3S)-2-nitro-4-oxopentan-3-yl)malonate (1.14n):

The title compound was prepared according to the general procedure.

The diastereomeric ratio was determined by 1H NMR spectroscopic analysis of the crude reaction mixture by comparison of the resonances at δ 3.66 (minor diastereomer) and δ 3.60 (major diastereomer). The crude material was purified using flash column chromatography, with a gradient from 97.5:2.5 hexanes/EtOAc to 95:5 hexanes/EtOAc. Low-melting white solid (26.3 mg, 0.076 mmol, 76%); 1H NMR (600 MHz,

CDCl3) δ 4.73-4.69 (m, 1H), 4.02 (dd, J = 10.3, 4.7 Hz, 1H), 3.62 (d, J = 10.4 Hz, 1H), 2.30

13 (s, 3H), 1.50 (s, 12H), 1.45 (s, 9H); C NMR (151 MHz, CDCl3) δ 205.5, 166.6, 166.4, 83.2,

83.0, 82.0, 54.6, 52.0, 32.5, 27.8 (2C), 14.7. IR (thin film) ν 2980, 1724, 1557, 1477, 1458,

-1 + + 1395, 1316, 1144, 1256, 847 cm . HRMS (ESI): Calcd. For C16H27NNaO7 ([M+Na ]):

368.1685, found 368.1671. HPLC Chiralpak AD column, Hex/iPrOH = 99:1, flow rate = 1.0 mL/min, λ = 210 nm, 6.3 min (minor isomer), 10.2 min (major isomer). TLC (10:90

EtOAc/hexanes): Rf = 0.34. [α]D = +30.8 (c = 1.5, CHCl3).

Di-tert-butyl 2-((2S,3R)-1-cyclopropyl-3-nitro-1-oxobutan-2-

yl)malonate (1.14o): The title compound was prepared according to the

general procedure. The diastereomeric ratio was determined by 1H

NMR spectroscopic analysis of the crude reaction mixture by comparison of the resonances at

δ 3.77 (minor diastereomer) and δ 3.62 (major diastereomer). The crude material was purified using flash column chromatography, with a gradient from 97.5:2.5 hexanes/EtOAc to 95:5

43 hexanes/EtOAc. White solid (33.3 mg, 0.090 mmol, 90%), mp 64-65 °C (decomp); 1H NMR

(600 MHz, CDCl3) δ 4.76-4.72 (m, 1H), 4.32 (dd, J = 10.6, 4.7 Hz, 1H), 3.64 (d, J = 10.7 Hz,

1H), 2.02-1.98 (m, 1H), 1.50 (s, 9H), 1.48 (d, J = 6.9 Hz, 3H), 1.44 (s, 9H), 1.17-1.12 (m, 1H),

13 1.05-1.01 (m, 2H), 0.98-0.95 (m, 1H); C NMR (151 MHz, CDCl3) δ 207.2 166.7, 166.3,

83.1, 82.7, 81.7, 54.2, 53.3, 27.8 (2C), 22.7, 14.6, 13.3, 12.9. IR (thin film) ν 2980, 2359, 1730,

-1 + 1556, 1393, 1370, 1294, 1256, 1146, 843 cm . HRMS (ESI): Calcd. For C18H29NNaO7

([M+Na+]): 394.1842, found 394.1826. HPLC Chiralpak AD column, Hex/iPrOH = 99:1, flow rate = 1.0 mL/min, λ = 210 nm, 7.9 min (minor isomer), 30.1 min (major isomer). TLC (10:90

EtOAc/hexanes): Rf = 0.36. [α]D = +36.5 (c = 1.5, CHCl3).

Di-tert-butyl 2-((2S,3R)-3-nitro-1-oxo-1-phenylpentan-2-

yl)malonate (1.14p): The title compound was prepared according to

the general procedure. No minor diastereomer was observed in the 1H

NMR spectrum of the unpurified product. The crude material was purified using flash column chromatography, with a gradient from 97.5:2.5 hexanes/EtOAc to 90:10 hexanes/EtOAc.

White solid (41.7 mg, 0.099 mmol, 99%), mp 99-100 °C (decomp); 1H NMR (400 MHz,

CDCl3) δ 8.00 (d, J = 7.4 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 4.79 (dd,

J = 9.4, 6.0 Hz, 1H), 4.73-4.68 (m, 1H), 3.87 (d, J = 9.4 Hz, 1H), 1.94-1.82 (m, 1H), 1.78-1.68

13 (m, 1H), 1.51 (s, 9H), 1.35 (s, 9H), 0.88 (t, J = 7.2 Hz, 3H); C NMR (151 MHz, CDCl3) δ

197.3, 166.7, 166.2, 137.2, 133.8, 128.8, 128.6, 89.9, 83.1, 83.0, 55.2, 46.4, 27.8, 27.7, 23.5,

10.8. IR (thin film) ν 2979, 1741, 1683, 1556, 1370, 1258, 1144, 845, 735, 692 cm-1. HRMS

+ + (ESI): Calcd. For C22H31NNaO7 ([M+Na ]): 444.1999, found 444.1981. HPLC Chiralpak AD column, Hex/iPrOH = 98:2, flow rate = 1.0 mL/min, λ = 210 nm, 11.1 min (minor isomer),

44 14.1 min (major isomer). TLC (10:90 EtOAc/hexanes): Rf = 0.27. [α]D = +78.3 (c = 1.5,

CHCl3).

Procedure for transesterification of 1.14a:

A one-dram vial with a stir bar was charged with di-tert-butyl ester 1.14a (0.058 mmol, 1.0 equiv) and trifluoroacetic acid (0.5 mL). The reaction was stirred for 30 min, then placed under a stream of nitrogen to evaporate volatiles. The residue was dissolved in 3:2 toluene:MeOH (1 mL, 0.06 M) and cooled in an ice bath. A solution of TMSCHN2 (2.0 M in Et2O) was added dropwise until a yellow color persisted. The reaction was stirred for 30 min at room temperature then quenched dropwise with glacial acetic acid; the acid was added until the yellow color disappeared. After stirring for 30 min, ethyl acetate was used to dilute the crude reaction and the organic layer was washed with an aqueous saturated sodium bicarbonate solution. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude material thusly obtained was purified using flash column chromatography with a gradient from 97.5:2.5 hexanes/EtOAc to 90:10 hexanes/EtOAc.

Dimethyl 2-((2S,3R)-3-nitro-1-oxo-1-phenylbutan-2-yl)malonate

(1.18a): The diastereomeric ratio of the isolated material was

determined by 1H NMR spectroscopic analysis by comparison of the resonances at δ 4.22 (minor diastereomer) and δ 4.08 (major diastereomer). Clear oil (16.4 mg,

1 0.051 mmol, 87%); H NMR (600 MHz, CDCl3) δ 8.02 (d, J = 7.3 Hz, 2H), 7.65-7.63 (m, 1H),

7.54-7.51 (m, 2H), 4.98 (dd, J = 9.2, 6.5 Hz, 1H), 4.96-4.91 (m, 1H), 4.08 (d, J = 9.2 Hz, 1H),

45 13 3.80 (s, 3H), 3.69 (s, 3H), 1.47 (d, J = 6.8 Hz, 3H); C NMR (151 MHz, CDCl3) δ 197.3,

167.8, 167.7, 136.8, 134.1, 128.9, 128.7, 82.3, 53.3, 53.2, 52.6, 46.7, 16.5. IR (thin film) ν

2956, 1738, 1682, 1596, 1579, 1437, 1281, 1198, 968, 698 cm-1. HRMS (ESI): Calcd. For

+ + C15H17NNaO7 ([M+Na ]): 346.0897, found 346.0893. HPLC Chiralpak IC column,

Hex/iPrOH = 97:3, flow rate = 1.0 mL/min, λ = 210 nm, 27.3 min (major isomer), 44.1 min

(minor isomer). TLC (10:90 EtOAc/hexanes): Rf = 0.07. [α]D = +58.8 (c = 0.5, CHCl3).

Local desymmetrization sequence for transesterification/lactamization of 1.14a:

A scintillation vial with a stir bar was charged with di-tert-butyl ester 1.14a (0.25 mmol, 1.0 equiv) and cooled in an ice bath. Trifluoroacetic acid (1.25 mL) was added slowly and the reaction was stirred for 30 min in the ice bath. The reaction was then placed under a stream of nitrogen to evaporate volatiles. The residue was dissolved in 3:2 toluene:MeOH (2.5 mL, 0.1

M) and cooled in an ice bath. A solution of TMSCHN2 (2.0 M in Et2O) was added dropwise until a yellow color persisted. The reaction was stirred for 30 min at room temperature and then cooled in an ice bath while it was quenched dropwise with glacial acetic acid; the acid was added until the yellow color disappeared. The reaction was allowed to return to room temperature and stir for 30 min. Ethyl acetate was used to dilute the crude reaction and the organic layer was washed with an aqueous saturated sodium bicarbonate solution. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were dried with sodium sulfate, filtered, and concentrated in vacuo. 1H NMR analysis of this crude material indicated that it was >20:1 dr. The material was concentrated into a scintillation vial, where it was dissolved in EtOH (2.0 mL) and treated with Raney®-Nickel 2800 slurry in H2O (250 mg). The reaction was placed in a high pressure Parr reactor under H2 (60 psi); the vessel was

46 filled and purged three times before finally refilling and allowing the reaction to stir under H2

(60 psi) for 24 h at room temperature. The crude reaction was filtered through a Celite® plug with EtOH and concentrated in vacuo. The diastereomeric ratio could not be determined from the 1H NMR spectrum of the unpurified product. The crude material was purified using flash column chromatography, with a gradient from 60:40 hexanes/EtOAc to 40:60 hexanes/EtOAc to obtain the lactam product.

Methyl (3S,4S,5R)-4-benzoyl-5-methyl-2-oxopyrrolidine-3-

carboxylate (1.19a): The title compound was prepared according to

the above procedure. The diastereoselectivity could not be determined from the 1H NMR spectrum of the unpurified product. Once isolated, the product was found to be 9.1:1 dr, which was determined by comparing the signals in the 1H NMR spectrum at δ 1.38

(major) and δ 1.34 (minor). Clear oil (29.3 mg, 0.11 mmol, 45%); 1H NMR (600 MHz,

CD3OD) δ 8.01 (d, J = 7.6 Hz, 2H), 7.70-7.67 (m, 1H), 7.58-5.55 (m, 2H), 4.38 (dd, J = 7.4,

6.0 Hz, 1H), 3.89 (d, J = 7.5 Hz, 1H), 3.88-3.85 (m, 1H), 3.75 (s, 3H), 1.38 (d, J = 6.2 Hz, 3H);

13 C NMR (151 MHz, CD3OD) δ 197.8, 171.1, 169.8, 135.9, 133.7, 128.7, 128.4, 52.0, 51.9,

51.7, 51.7, 20.3. IR (thin film) ν 3231, 2954, 2359, 1705, 1596, 1448, 1381, 1264, 1219, 697

-1 + + cm . HRMS (ESI): Calcd. For C14H15NNaO4 ([M+Na ]): 284.0893, found 284.0895. HPLC

Chiralpak IA column, Hex/iPrOH = 92:8, flow rate = 1.0 mL/min, λ = 210 nm, 16.8 min (minor isomer), 22.7 min (major isomer). TLC (50:50 EtOAc/hexanes): Rf = 0.19. [α]D = +3.15 (c =

1.25, CHCl3).

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CHAPTER TWO: ASYMMETRIC ORGANOCATALYTIC SULFA-MICHAEL ADDITION TO ENONE DIESTERS *

2.1 Background

The conjugate addition of heteroatom nucleophiles to prochiral Michael acceptors offers an atom-economical entry into diverse scaffolds with concomitant construction of stereochemical complexity. The application of this reaction manifold to the installation of sulfur in organic frameworks has largely been driven by the prominence of sulfur in bioactive molecules1–5 and the established utility of thiol- and sulfide-derived functional handles.6–12 To that end, noteworthy advances have been made toward the development of the asymmetric sulfa-Michael reaction using a variety of catalytic systems.13–17 To advance the art, we sought to expand the range of products accessible through this reaction by studying substrates bearing multiple electrophilic sites on the Michael acceptor. Previous efforts in this direction have demonstrated that Michael acceptors possessing vicinal ester and ketone functionalities (γ-oxo acrylates) give addition exclusively at the ester α-carbon, and achieving high stereoselectivities remains challenging (Scheme 2-1A).18,19 We viewed this shortcoming of Cinchona alkaloid- based catalyst stereoselectivity as an opportunity to explore organosuperbase catalysts for this transformation. The Dixon group recently developed a tert-leucine and phenylglycine-derived triaryliminophosphorane catalyst which promoted the enantioselective addition of alkyl thiols to unactivated α,β−unsaturated esters (Scheme 2-1B).20 In addition, phenylglycine-based

55 triaryliminophosphorane catalyst 2.4, also developed by the Dixon group,21–27 was found to mediate the addition of nitroalkanes to enone diesters with high regio- and stereoselectivity

(Scheme 2-1C).28 By employing this catalyst system we sought to overcome the challenges of a highly regio- and enantioselective addition of sulfur nucleophiles to acylidene malonates

(Scheme 2-1D).

Scheme 2-1. Asymmetric Conjugate Addition Reactions

2.2 Asymmetric sulfa-Michael Addition

56 2.2.1 Reaction Optimization

We began our investigation by examining the reaction of enone diester 2.1a with benzyl thiol 2.2f (Table 2-1). Pleasingly, when triaryliminophosphorane organocatalyst 2.4 was added to a mixture of enone diester 2.1a and benzyl thiol at -60°C we obtained the desired product in high enantioselectivity, with addition exclusively to the alkylidene malonate (entry 1). Further optimization of the catalyst revealed that catalyst 2.4 was uniquely suited to providing enantioinduction, whereas use of iminophosphoranes 2.5 and 2.6 resulted in greatly diminished selectivities (entries 2-3). The failure of catalyst 2.5 to provide enantioinduction was particularly surprising, given its success in other sulfa-Michael additions.20,29

Further optimization proved necessary to broaden the thiol scope. When employing identical reaction conditions to entry 1, addition of ethanethiol yielded product with diminished enantioselectivities (entry 4). Moreover, products derived from substituted benzyl thiols such as para-chloro-substituted benzyl thiol were racemic (entry 5). Altering the order of addition remedied these stereoselectivity issues (see section 2.2.2 for a rationale). By adding the thiol after catalyst addition at -60 °C the ethanethiol addition product was obtained in 91:9 er (entry

6), and the enantiomeric ratio for the product derived from para-chloro-substituted benzyl thiol rose to 93:7 (entry 7). Further optimization revealed that isopropyl thiol further increased product yield and enantioenrichment (entry 8). Finally, much like the nitroalkane addition, we found that replacing the tert-butyl ester with the less bulky ethyl ester resulted in reduced enantioselectivity, providing the product in 86:14 er (entry 9).

57 Table 2-1. Optimization of a Sulfa-Michael Addition to Enone Diesters

thiol addition entry R1 (equiv) R2 catalyst er % yielda temp (°C) 1 23 Bn (5.1) tBu 2.4 90:10 n.d.c 2 23 Bn (5.1) tBu 2.5 59:41 (88) 3 23 Bn (5.1) tBu 2.6 55:45 (85) 4 23 Et (5.4) tBu 2.4 87:13 n.d.

5 23 4-Cl Bn (5.3) tBu 2.4 50:50 n.d. 6b -60 Et (5.4) tBu 2.4 91:9 92 7 b -60 4-Cl Bn (1.5) tBu 2.4 93:7 89 8b -60 iPr (5.4) tBu 2.4 97:3 93 9 -60 iPr (5.4) Et 2.4 86:14 n.d. a Yields in parentheses represent 1H NMR yields determined using 1,3,5-trimethoxybenzene (1.0 equiv) as an internal standard. b The er and yield values for this entry are an average of two trials. c n.d. = not determined.

2.2.2 Investigation of Side-Product Formation

Early in our investigations we observed an unexpected side product when thiol was added at room temperature, prior to cooling and catalyst addition. The side product was identified as the formal alkene reduction of 2.1 to give malonate 2.7 (Table 2-2). Although malonate 2.7 was not observed in our initial reactions employing benzyl thiol, substituted

58 benzyl thiols generated varying quantities of side product with concommitant reduction in enantioselectivity (entries 1-3). Thiol acidity correlated well with side product formation

(Figure 2-1), and the increased acidity of benzenethiol provided further evidence for this trend, generating the side product in a 1:2.7 ratio with desired product 2.3 (entry 4). Subsequent reactions revealed an additional dependence on thiol stoichiometry, with fewer equivalents providing less of the side product while maintaining complete conversion of the enone diester starting material (entry 5). Notably, we never observed any of malonate 2.7 when employing less acidic alkyl thiols (entries 6-7).

Table 2-2. Formation of an Undesired Malonate in the Presence of Various Thiols

thiol addition R1 product ratioa entry er temp (°C) (equiv) (2.3:2.7) 1 23 4-OMe Bn (4.9) 7.9:1 68:32 2 23 4-tBu Bn (5.0) 6.5:1 79:21 3 23 4-Cl Bn (5.3) 5.5:1 50:50 4 23 Ph (4.9) 2.7:1 n.d.

5 23 Ph (1.1) 6.7:1 n.d. 6 23 iPr (5.0) 100:0 95:5

7 23 nPr (5.0) 100:0 89:11 8 -60 nPr (5.4) 100:0 92:8 9 -60 4-Cl Bn (1.5) 100:0 93:7 10 -60 4-Cl Bn (5.1) 100:0 n.d. a Product ratios determined by 1H NMR. Complete consumption of the enone diester starting material was observed in all cases (100% conversion).

59 Figure 2-1. Formation of Malonate 2.7 as a Function of Thiol Aciditya

30 PhSH 25

15 4-Cl BnSH 4-tBu BnSH 4-OMe BnSH

% Conversion to to Conversion % Reduction Product Product Reduction 5 iPrSH 0 6 8 10 12

Thiol pKa

a ® Predicted pKa values obtained from SciFinder .

While poor enantioselectivity could presumably result solely from uncatalyzed addition of the thiol nucleophile, formation of malonate 2.7 complicated this hypothesis. α-

Thio carbonyls can serve as electrophilic sources of sulfur to generate the disulfide under basic conditions.30–32 Consequently, in addition to uncatalyzed thiol addition, we propose that pathways A and B could be interfering with enantioenriched product formation (Scheme 2-2).

Pathway A would generate side product 2.7 via the reported disulfide formation, while

Pathway B provides an alternative hypothesis for racemic product generation via reversible disulfide formation.

60 Scheme 2-2. Proposed Pathways for Diminished Product Yields and Racemization

Scheme 2-3. Crossover Experiment Under Optimized Reaction Conditions

Addition of the thiol at -60 °C following catalyst addition successfully prevented side product formation and improved enantioselectivity for both alkyl thiols (Table 2-2, entry 8) and substituted benzyl thiols (entries 9-10). Additionally, we opted to continue with fewer equivalents in an attempt to mitigate any potential issues with other benzylic thiols. To further assess the impact of this revised procedure, we conducted a crossover experiment (Scheme 2-

3). Pleasingly, exposure of thiol addition product 2.3g to excess para-tbutyl benzyl thiol (2.2i) at -60 °C in the presence of iminophosphorane 2.4 failed to provide either the reduction product

(2.7) or crossover product (2.3i) after 24 hours. Consequently, we confirmed that pathway B is inactive at cryogenic temperatures.

61 2.2.3 Sulfa-Michael Addition Scope

With our optimized conditions in hand, we first examined the scope of the thiol nucleophile (Figure 2-2). Branched alkyl thiols (2.3a−c) performed well, providing the desired product in high yield and enantioselectivity. Products derived from linear alkyl thiols (2.3d−e) were obtained in similarly high yield, although enantioselectivity was slightly diminished.

Benzyl thiols (2.2f−2.2i) also proved to be competent reaction partners when fewer equivalents of the thiol were used in accordance with the findings reported above. Employing benzyl thiol

2.2f, the desired product (2.3f) was obtained in 91:9 er and 90% yield. Probing the impact of various para-substituents on the aromatic ring of the benzyl thiol, electron-withdrawing groups led to an increase in enantioselectivity (2.3g), while electron-donating groups had the opposite effect (2.3h−i).

62 Figure 2-2. Asymmetric Conjugate Addition of Alkyl Thiols to Enone Diester 2.2a

All of the reactions were conducted on a 0.1 mmol scale using 1.5−5.5 equiv of alkyl thiol 2. Isolated yields are shown. All yields and er values are the average of two trials.

Next, we investigated the scope of enone diesters that could be employed in this reaction (Figure 2-3). Enone diesters bearing an electron-releasing acyl substituent (2.1j−k,

4-methoxy, 3-methoxy, piperonyl) provided the desired products in excellent yield and enantioselectivity regardless of substitution pattern. Halogen-substituted arenes (2.1m−o) were similarly successful under these reaction conditions, as were other electron-poor enone

63 diesters (2.1p−q). Cyclopropyl enone diester 2.1r provided the desired product (2.3r) in 96% yield, although with diminished enantioselectivity (83.5:16.5 er). An exploration of heteroaromatic enone diesters revealed that furan 2.3s, thiophene 2.3t, and pyridine 2.3u could all be obtained in good yield and enantioselectivity. When examining the scalability of this transformation, we observed that on 1 g scale thiol 2.2a engaged acylidene malonate 2.1a, affording 1.21 g of α-sulfaketone 2.3a without any negative impact on yield or stereoselectivity

(Scheme 2-4).

Figure 2-3. Asymmetric Conjugate Addition of 2-Propanethiol to Enone Diesters

All of the reactions were conducted on a 0.1 mmol scale using 5.4 equiv of alkyl thiol 2.2a. Isolated yields are shown. All yields and er values are the average of two trials.

Scheme 2-4. Gram-Scale Asymmetric Sulfa-Michael Reaction

2.3 Derivatization of Sulfa-Michael Addition Products

Seeking to explore the synthetic utility of these products, we developed a two-step local desymmetrization that takes advantage of the diastereotopic ester groups (Scheme 3).33,34

Beginning with enantioenriched thioether 2.3a, reduction of the ketone with sodium borohydride35,36 provided the syn-hydroxy sulfide 2.8a in >20:1 dr and 89% yield. Subsequent acid-promoted cyclization provided lactone 2.9a with three contiguous stereocenters in >20:1 dr and 70% yield. Analogous results were obtained using benzyl thioether 2.3f, with both the reduction and lactonization proceeding in good diastereoselectivity and yield. Finally, an X- ray diffraction study revealed the absolute and relative stereochemistry of lactone 2.9f.†

† CCDC 1587179 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Centre via www.ccdc.cam.ac.uk/data_request/cif.

65 Scheme 2-5. Local Desymmetrization via Diastereoselective Reduction and Lactonization

2.4 Conclusion

In conclusion, we have developed an asymmetric organocatalyzed addition of alkyl thiols to enone diesters with unique regioselectivity that enables access to an unexplored class of enantioenriched sulfa-Michael adducts. The diester products were further manipulated via diastereoselective reduction and subsequent diastereotopic group selection to form stereochemically dense lactone products.

2.5 Acknowledgements

The work described was supported by Award R35 GM118055 from the National

Institute of General Medical Sciences. J.L.F. is an NSF Graduate Research Fellow. E.L.B. acknowledges support from the NSF REU program (CHE-1460874). We thank Dr. Brandie

Ehrmann and Evan McConnell (UNC Department of Chemistry Mass Spectrometry Core

Laboratory) for their assistance with mass spectrometry analysis and Blane Zavesky (UNC

Department of Chemistry X-ray Structure Facility) for X-ray crystallographic analysis.

66 2.6 Experimental Details

Methods: Infrared (IR) spectra were obtained using a Jasco 460 Plus Fourier transform infrared spectrometer. Proton and carbon magnetic resonance spectra (1H NMR, 13C NMR, 19F

NMR) were recorded on a Bruker model DRX 400 or 600 (1H NMR at 400 MHz or 600 MHz,

13C NMR at 101 MHz or 151 MHz, 19F NMR at 376 MHz with solvent resonance as the internal

1 13 1 standard ( H NMR: CDCl3 at 7.26 ppm and C NMR: CDCl3 at 77.0 ppm). H NMR data are reported as follows: chemical shift, multiplicity (s = singlet, br s = broad singlet, d = doublet, dd = doublet of doublet, t = triplet, m = multiplet), coupling constants (Hz), and integration.

High resolution mass spectra were obtained with a Thermo Fisher Scientific FinniganTM LTQ-

ICR FTTM (all samples prepared in methanol). Melting points were obtained using a Thomas

Hoover UniMelt Capillary Melting Point Apparatus. Analytical thin layer chromatography was carried out using Whatman 0.25 mm silica gel 60 plates, Sorbent Technologies 0.20 mm Silica

Gel TLC plates. Visualization was allowed by UV light, phosphomolybdic acid in ethanol, or aqueous ceric ammonium nitrate solution. HPLC analysis was performed on a Perkin Elmer flexar photodiode array (PDA) system equipped with Daicel IA, IC, and AD columns.

Asymmetric reactions were carried out in a Thermo Sigma UCR-150N aluminum block UC reactor with stirring. Purification of the reaction products was carried out by using Siliaflash-

P60 silica gel (40- 63μm) purchased from Silicycle. Yields refer to isolated yields after flash column chromatography. Optical rotations of enantioenriched products were taken after purification using silica flash column chromatography. Since all asymmetric trial results are the averages of two trials, the stereoisomer ratios listed in the text above may not exactly match those represented in the NMR and HPLC data below. The relative and absolute stereoconfiguration of 2.9f was determined via X-ray diffraction analysis, and the

67 stereochemistry of all other structures was assigned by analogy.

Materials: Diethyl ether (Et2O) was passed through a column of neutral alumina under nitrogen prior to use. The thiols employed were obtained from commercial sources and used as received. Enone diesters were prepared according to a literature procedure.28

Triaryliminophosphorane catalysts 2.4-2.6 were prepared according to a literature procedure.21,24 Racemic samples were obtained by employing the general procedure and using

2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) in place of organocatalyst 2.4.

Procedures employed during reaction optimization

General procedure A – Thiol addition at 23°C: A flame-dried test tube was charged sequentially with enone diester (0.1 mmol, 1.0 equiv), thiol (thiol identity and equivalents listed in table), and Et2O (1.0 mL). The reaction was stirred at -60 °C in a cryogenic cooling apparatus for 15 min, then the triaryliminophosphorane catalyst (0.01 mmol, 0.10 equiv) was added. The reaction was stirred at -60 °C for 24 h then quenched with a TFA solution in toluene

(50 L, 0.5 M solution) at the same temperature. The solvent was removed in vacuo, and the crude material was purified using flash column chromatography.

General procedure B – Thiol addition at -60°C: A flame-dried test tube was charged sequentially with enone diester (0.1 mmol, 1.0 equiv) and Et2O (1.0 mL). The reaction was stirred at -60 °C in a cryogenic cooling apparatus for 15 min, then triaryliminophosphorane catalyst 2.4 (0.01 mmol, 0.10 equiv) was added, followed by thiol (thiol identity and equivalents listed in table). The reaction was stirred at -60 °C for 24 h then quenched with a

68 TFA solution in toluene (50 L, 0.5 M solution) at the same temperature. The solvent was removed in vacuo, and the crude material was purified using flash column chromatography.

Optimized general procedure for the asymmetric conjugate addition of alkyl thiols. A flame-dried test tube was charged sequentially with enone diester 2.1 (0.1 mmol, 1.0 equiv) and Et2O (1.0 mL). The reaction was stirred at -60 °C in a cryogenic cooling apparatus for 15 min, then triaryliminophosphorane catalyst 2.4 (0.01 mmol, 0.10 equiv) was added, followed by thiol 2.2 (see below for thiol identity and equivalents). The reaction was stirred at -60 °C for 24 h then quenched with a TFA solution in toluene (50 L, 0.5 M solution) at the same temperature. The solvent was removed in vacuo, and the crude material was purified using flash column chromatography with 97.5/2.5 hexanes/EtOAc unless otherwise noted.

Gram scale asymmetric conjugate addition reaction with propane-2-thiol. A flame-dried test tube was charged sequentially with enone diester 2.1a (1.00 g, 3.01 mmol, 1.0 equiv) and

Et2O (30 mL). The reaction was stirred at -60 °C in a cryogenic cooling apparatus for 15 min, then triaryliminophosphorane catalyst 2.4 (201 mg, 0.30 mmol, 0.10 equiv) was added, followed by propane-2-thiol (1.51 mL, 16.3 mmol, 5.38 equiv). The reaction was stirred at -

60 °C for 24 h then quenched with a TFA solution in toluene (1.5 mL, 0.5 M solution) at the same temperature. The solvent was removed in vacuo, and the crude material was purified using flash column chromatography with 97.5/2.5 hexanes/EtOAc to yield 1.21 g (93%) of a low-melting white solid in 97:3 er.

69 Di-tert-butyl (S)-2-(1-(isopropylthio)-2-oxo-2-phenylethyl)malonate

(2.3a). The title compound was prepared using propane-2-thiol (0.05 mL,

0.54 mmol, 5.38 equiv) according to the general procedure. Low-melting

1 white solid (38.3 mg, 0.093 mmol, 93%); H NMR (600 MHz, CDCl3) δ 8.05 (d, J = 7.9 Hz,

2H; 7.58 (t, J = 7.3Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 4.76 (d, J = 11.6 Hz, 1H), 4.17 (d, J =

11.6 Hz, 1H), 2.96-2.89 (m, 1H), 1.55 (s, 9H), 1.39 (s, 9H), 1.23 (t, J = 6.8 Hz, 3H), 1.10 (t, J

13 = 6.8 Hz, 3H); C NMR (151 MHz, CDCl3) δ194.8, 167.0, 166.9, 135.9, 133.0, 128.7, 128.6,

82.4, 82.2, 55.8, 45.7, 34.6, 28.0, 27.8, 24.8, 24.2. IR (thin film) ν 3430, 2977, 2360, 1729,

-1 + + 1679, 1369, 1299, 1252, 1140, 690 cm . HRMS (ESI): Calcd. For C22H32O5SNa ([M+Na ]):

431.1868, found 431.1858. HPLC Chiralpak IC column, Hex/iPrOH = 98:2, flow rate = 1.0 mL/min, λ = 210 nm, tR (minor) 11.5 min, tR (major) 15.4 min. TLC (10/90 EtOAc/hexanes):

25 Rf = 0.41. [α]D = -65.9 (c = 2.0, CHCl3).

Di-tert-butyl (S)-2-(1-(tert-butylthio)-2-oxo-2-phenylethyl)malonate

(2.3b). The title compound was prepared using 2-methylpropane-2-thiol

(0.06 mL, 0.53 mmol, 5.32 equiv) according to the general procedure.

White solid (43.5 mg, 0.010 mmol, 100%), mp 76-78 °C (decomp); 1H NMR (600 MHz,

CDCl3) δ 8.06 (d, J = 7.7 Hz, 2H), 7.56 (t, J = 7.3 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 4.76 (d, J

= 11.8 Hz, 1H), 4.17 (d, J = 11.8 Hz, 1H), 1.55 (s, 9H), 1.38 (s, 9H), 1.18 (s, 9H); 13C NMR

(151 MHz, CDCl3) δ 198.2, 167.1 (2C), 136.9, 132.7, 129.1, 128.4, 82.5, 82.1, 57.0, 45.6, 45.4,

31.5, 28.0, 27.8. IR (thin film) ν 2979, 2360, 1739, 1682, 1368, 1290, 1252, 1138, 855, 695

-1 + + cm . HRMS (ESI): Calcd. For C23H34O5SNa ([M+Na ]): 445.2025, found 445.2016. HPLC

i Chiralpak IC column, Hex/ PrOH = 96:4, flow rate = 1.0 mL/min, λ = 210 nm, tR (minor) 7.6

70 25 min, tR (major) 10.4 min. TLC (10/90 EtOAc/hexanes): Rf = 0.42. [α]D = -89.2 (c = 2.0,

CHCl3).

Di-tert-butyl (S)-2-(1-(cyclohexylthio)-2-oxo-2-phenylethyl)malonate

(2.3c). The title compound was prepared using cyclohexanethiol (0.06 mL,

0.49 mmol, 4.90 equiv) according to the general procedure. White solid

1 (43.7 mg, 0.097 mmol, 97%), mp 53-55 °C (decomp); H NMR (600 MHz, CDCl3) δ 8.04 (d,

J = 7.9 Hz, 2H), 7.57 (t, J = 7.3 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 4.76 (d, J = 11.6 Hz, 1H),

4.15 (d, J = 11.6 Hz, 1H), 2.71-2.67 (m, 1 H), 1.95-1.89 (m, 1H), 1.73-1.64 (m, 2H), 1.63-1.57

(m, 1H), 1.55 (s, 9H), 1.53-1.48 (m, 1H), 1.38 (s, 9H), 1.32-1.26 (m, 2H), 1.25-1.19 (m, 1H),

13 1.18-1.11 (m, 2H); C NMR (151 MHz, CDCl3) δ 194.7, 167.0, 166.9, 135.9, 133.0, 128.7,

128.6, 82.4, 82.1, 55.8, 45.3, 42.4, 34.8, 34.4, 28.0, 27.8, 26.1, 26.0, 25.4. IR (thin film) ν

2978, 2931, 2853, 2360, 1741, 1680, 1369, 1299, 1139, 857 cm-1. HRMS (ESI): Calcd. For

+ + C25H36O5SNa ([M+Na ]): 471.2181, found 471.2171. HPLC Chiralpak IC column,

i Hex/ PrOH = 96:4, flow rate = 1.0 mL/min, λ = 230 nm, tR (minor) 6.8 min, tR (major) 9.8 min.

25 TLC (10/90 EtOAc/hexanes): Rf = 0.39. [α]D = -64.3 (c = 2.0, CHCl3).

Di-tert-butyl (S)-2-(1-(ethylthio)-2-oxo-2-phenylethyl)malonate (2.3d).

The title compound was prepared using ethanethiol (0.04 mL, 0.56 mmol,

5.52 equiv) according to the general procedure. Clear oil (36.5 mg, 0.092

1 mmol, 92%); H NMR (600 MHz, CDCl3) δ 8.05 (d, J = 7.9 Hz, 2H), 7.58 (t, J = 7.3 Hz, 1H),

7.50 (t, J = 7.5 Hz), 4.73 (d, J = 11.5 Hz, 1H), 4.14 (d, J = 11.5 Hz, 1H), 2.63-2.58 (m, 1H),

2.39-2.33 (m, 1H), 1.55 (s, 9H), 1.39 (s, 9H), 1.14 (t, J = 7.5 Hz, 3H); 13C NMR (151 MHz,

71 CDCl3) δ 193.1, 167.0, 166.8, 135.5, 133.1, 128.7, 128.6, 82.5, 82.2, 54.8, 44.9, 28.0, 27.8,

22.9, 13.8. IR (thin film) ν 3431, 2978, 1741, 1679, 1369, 1300, 1259, 1140, 856, 689 cm-1.

+ + HRMS (ESI): Calcd. For C21H30O5SNa ([M+Na ]): 417.1708, found 417.1701. HPLC

i Chiralpak IC column, Hex/ PrOH = 98:2, flow rate = 1.0 mL/min, λ = 210 nm, tR (minor) 9.5

25 min, tR (major) 14.8 min. TLC (10/90 EtOAc/hexanes): Rf = 0.39. [α]D = -44.2 (c = 2.0,

CHCl3).

Di-tert-butyl (S)-2-(2-oxo-2-phenyl-1-(propylthio)ethyl)malonate

(2.3e). The title compound was prepared using propane-1-thiol (0.05 mL,

0.54 mmol, 5.36 equiv) according to the general procedure. Clear oil (39.5

1 mg, 0.096 mmol, 96%); H NMR (600 MHz, CDCl3) δ 8.05 (d, J = 7.7 Hz, 2H), 7.58 (t, J =

7.3 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 4.73 (d, J = 11.5 Hz, 1H), 4.13 (d, J = 11.5 Hz, 1H), 2.58-

2.53 (m, 1H), 2.33-2.29 (m, 1H), 1.55 (s, 9H), 1.52-1.46 (m, 2H), 1.39 (s, 9H), 0.90 (t, J = 7.4

13 Hz, 3H); C NMR (151 MHz, CDCl3) δ 193.2, 166.9, 166.8, 135.5, 133.0, 128.7, 128.6, 82.4,

82.1, 54.8, 44.7, 30.6, 28.0, 27.8, 22.3, 13.6. IR (thin film) ν 3431, 2978, 2360, 1740, 1680,

-1 + + 1369, 1299, 1139, 856, 668 cm . HRMS (ESI): Calcd. For C22H32O5SNa ([M+Na ]):

431.1868, found 431.1858. HPLC Chiralpak IC column, Hex/iPrOH = 98:2, flow rate = 1.0 mL/min, λ = 210 nm, tR (minor) 6.6 min, tR (major) 9.4 min. TLC (10/90 EtOAc/hexanes): Rf

25 = 0.41. [α]D = -54.0 (c = 2.0, CHCl3).

Di-tert-butyl (S)-2-(1-(benzylthio)-2-oxo-2-phenylethyl)malonate

(2.3f). The title compound was prepared using phenylmethanethiol (0.02

mL, 0.17 mmol, 1.71 equiv) according to the general procedure. Low-

72 1 melting white solid (40.4 mg, 0.091 mmol, 91%); H NMR (600 MHz, CDCl3) δ 7.98 (d, J =

7.9 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.29-7.22 (m, 5H), 4.79 (d, J =

11.4 Hz, 1H), 4.26 (d, J = 11.4 Hz, 1H), 3.86 (d, J = 11.8 Hz, 1H), 3.55 (d, J = 11.8 Hz, 1H),

13 1.58 (s, 9H), 1.40 (s, 9H); C NMR (151 MHz, CDCl3) δ 193.2, 166.9 (2C), 136.2, 135.4,

133.1, 129.4, 128.7, 128.6, 128.5, 127.3, 82.6, 82.3, 55.0, 45.3, 33.7, 28.0, 27.8. IR (thin film)

ν 3431, 2978, 2360, 1727, 1678, 1369, 1300, 1252, 1157, 691 cm-1. HRMS (ESI): Calcd. For

+ + C26H32O5SNa ([M+Na ]): 479.1868, found 479.1858. HPLC Chiralpak IC column,

i Hex/ PrOH = 99:1, flow rate = 1.0 mL/min, λ = 210 nm, tR (major) 10.8 min, tR (minor) 12.3

25 min. TLC (10/90 EtOAc/hexanes): Rf = 0.36. [α]D = -50.6 (c = 2.0, CHCl3).

Di-tert-butyl (S)-2-(1-((4-chlorobenzyl)thio)-2-oxo-2-

phenylethyl)malonate (2.3g). The title compound was prepared using (4-

chlorophenyl)methanethiol (0.02 mL, 0.15 mmol, 1.51 equiv) according

to the general procedure. Low-melting white solid (44.4 mg, 0.089 mmol,

1 89%); H NMR (600 MHz, CDCl3) δ 7.94 (d, J = 7.9 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.47

(t, J = 7.7 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 4.76 (d, J = 11.5 Hz,

1H), 4.23 (d, J = 11.5 Hz, 1H), 3.81 (d, J = 12.1 Hz, 1H), 3.51 (d, J = 12.1 Hz, 1H), 1.57 (s,

13 9H), 1.38 (s, 9H); C NMR (151 MHz, CDCl3) δ 193.2, 166.8 (2C), 135.3, 134.9, 133.2, 133.1,

130.7, 128.7, 128.6 (2C), 82.7, 82.4, 55.0, 45.1, 33.1, 28.0, 27.8. IR (thin film) ν 3431, 2979,

2360, 1739, 1678, 1491, 1369, 1301, 1140, 690 cm-1. HRMS (ESI): Calcd. For

+ + C26H31ClO5SNa ([M+Na ]): 513.1479, found 513.1469. HPLC Chiralpak IC column,

i Hex/ PrOH = 98:2, flow rate = 1.0 mL/min, λ = 210 nm, tR (major) 9.1 min, tR (minor) 12.2

25 min. TLC (10/90 EtOAc/hexanes): Rf = 0.41. [α]D = -54.6 (c = 2.0, CHCl3).

Di-tert-butyl (S)-2-(1-((4-methoxybenzyl)thio)-2-oxo-2-

phenylethyl)malonate (2.3h). The title compound was prepared using (4-

methoxyphenyl)methanethiol (0.03 mL, 0.21 mmol, 2.15 equiv) according

to the general procedure. The crude material was purified via flash column chromatography using a gradient from 97.5/2.5 hexanes/EtOAc to 95/5 hexanes/EtOAc. Low-

1 melting white solid (45.2 mg, 0.094 mmol, 94%); H NMR (600 MHz, CDCl3) δ 7.97 (d, J =

7.9 Hz, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.79

(d, J = 8.4 Hz, 2H), 4.76 (d, J = 11.5 Hz, 1H), 4.26 (d, J = 11.5 Hz, 1H), 3.82 (d, J = 11.8 Hz,

1H), 3.78 (s, 3H), 3.50 (d, J = 11.8 Hz, 1H), 1.58 (s, 9H), 1.40 (s, 9H); 13C NMR (151 MHz,

CDCl3) δ 193.2, 166.9 (2C), 158.8, 135.4, 133.0, 130.5, 128.7, 128.6, 128.0, 113.9, 82.5, 82.3,

55.2, 54.5, 45.3, 33.2, 28.0, 27.8. IR (thin film) ν 3431, 2978, 2360, 1777, 1738, 1512, 1251,

-1 + + 1139, 833, 690 cm . HRMS (ESI): Calcd. For C27H34O6SNa ([M+Na ]): 509.1974, found

509.1967. HPLC Chiralpak IC column, Hex/iPrOH = 98:2, flow rate = 1.0 mL/min, λ = 210

25 nm, tR (major) 14.8 min, tR (minor) 18.1 min. TLC (10/90 EtOAc/hexanes): Rf = 0.25. [α]D =

-49.9 (c = 2.0, CHCl3).

Di-tert-butyl (S)-2-(1-((4-(tert-butyl)benzyl)thio)-2-oxo-2-

phenylethyl)malonate (2.3i). The title compound was prepared using (4-

tert-butylphenyl)methanethiol (0.03 mL, 0.16 mmol, 1.60 equiv)

according to the general procedure. Clear oil (44.4 mg, 0.086 mmol, 86%);

1 H NMR (600 MHz, CDCl3) δ 7.98 (d, J = 7.8 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.47 (t, J =

7.5 Hz, 2H), 7.28 (d, J = 7.9 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 4.79 (d, J = 11.4 Hz, 1H), 4.26

74 (d, J = 11.5 Hz, 1H), 3.86 (d, J = 11.8 Hz, 1H), 3.53 (d, J = 11.7 Hz, 1H), 1.59 (s, 9H), 1.41 (s,

13 9H), 1.30 (s, 9H); C NMR (151 MHz, CDCl3) δ 193.2, 166.9 (2C), 150.2, 135.5, 133.0 (2C),

129.0, 128.7, 128.6, 125.4, 82.5, 82.3, 54.9, 45.4, 34.5, 33.2, 31.3, 28.0, 27.8. IR (thin film) ν

3431, 2970, 2360, 1728, 1678, 1368, 1300, 1253, 1139, 851 cm-1. HRMS (ESI): Calcd. For

+ + C30H40O5SNa ([M+Na ]): 535.2494, found 535.2491. HPLC Chiralpak AD column,

i Hex/ PrOH = 99:1, flow rate = 1.0 mL/min, λ = 254 nm, tR (minor) 7.7 min, tR (major) 9.5 min.

25 TLC (10/90 EtOAc/hexanes): Rf = 0.39. [α]D = -48.3 (c = 2.0, CHCl3).

Di-tert-butyl (S)-2-(1-(isopropylthio)-2-(4-methoxyphenyl)-2-

oxoethyl)malonate (2.3j). The title compound was prepared

according to the general procedure using propane-2-thiol (0.05 mL,

0.54 mmol, 5.38 equiv). The crude material was purified via flash column chromatography using a gradient from 97.5/2.5 hexanes/EtOAc to 95/5 hexanes/EtOAc. Clear oil (43.6 mg,

1 0.099 mmol, 99%); H NMR (600 MHz, CDCl3) δ 8.04 (d, J = 8.9 Hz, 2H), 6.97 (d, J = 8.9

Hz, 2H), 4.73 (d, J = 11.6 Hz, 1H), 4.16 (d, J = 11.5 Hz, 1H), 3.89 (s, 3H), 2.97-2.90 (m, 1H),

1.55 (s, 9H), 1.38 (s, 9H), 1.24 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H); 13C NMR (151

MHz, CDCl3) δ 193.5, 167.1, 167.0, 163.5, 131.0, 128.6, 113.8, 82.3, 82.1, 55.8, 55.5, 45.3,

34.4, 28.0, 27.8, 24.8, 24.2. IR (thin film) ν 3431, 2978, 2360, 1739, 1669, 1602, 1369, 1260,

-1 + + 1142, 860 cm . HRMS (ESI): Calcd. For C23H34O6SNa ([M+Na ]): 461.1974, found

461.1964. HPLC Chiralpak IA column, Hex/iPrOH = 98:2, flow rate = 1.0 mL/min, λ = 210

25 nm, tR (major) 9.8 min, tR (minor) 10.7 min. TLC (10/90 EtOAc/hexanes): Rf = 0.29. [α]D =

-43.7 (c = 2.0, CHCl3).

75 Di-tert-butyl (S)-2-(1-(isopropylthio)-2-(3-methoxyphenyl)-2-

oxoethyl)malonate (2.3k). The title compound was prepared according to

the general procedure using propane-2-thiol (0.05 mL, 0.54 mmol, 5.38 equiv). The crude material was purified via flash column chromatography using a gradient from 97.5/2.5 hexanes/EtOAc to 95/5 hexanes/EtOAc. Clear oil (42.3 mg, 0.096 mmol, 96%);

1 H NMR (600 MHz, CDCl3) δ 7.64 (d, J = 7.7 Hz, 1H), 7.56 (dd, J = 2.4 Hz, 1.6 Hz, 1H), 7.40

(t, J = 8.0 Hz, 1H), 7.12 (dd, J = 8.2 Hz, 2.6 Hz, 1H), 4.73 (d, J = 11.6 Hz, 1H), 4.16 (d, J =

11.6 Hz, 1H), 2.96-2.89 (m, 1H), 1.55 (s, 9H), 1.39 (s, 9H), 1.23 (d, J = 6.8 Hz, 3H), 1.12 (d,

13 J =6.8 Hz, 3H); C NMR (151 MHz, CDCl3) δ 194.6, 166.9 (2C), 159.8, 137.3, 129.6, 121.2,

119.5, 113.1, 82.5, 82.2, 55.8, 55.4, 45.7, 34.7, 28.0, 27.8, 24.7, 24.2. IR (thin film) ν 3432,

2978, 2360, 1729, 1679, 1583, 1369, 1288, 1159, 761 cm-1. HRMS (ESI): Calcd. For

+ + C23H34O6SNa ([M+Na ]): 461.1974, found 461.1963. HPLC Chiralpak IA column,

i Hex/ PrOH = 96:4, flow rate = 1.0 mL/min, λ = 210 nm, tR (minor) 8.2 min, tR (major) 12.7

25 min. TLC (10/90 EtOAc/hexanes): Rf = 0.35. [α]D = -74.5 (c = 2.0, CHCl3).

Di-tert-butyl (S)-2-(2-(benzo[d][1,3]dioxol-5-yl)-1-(isopropylthio)-

2-oxoethyl)malonate (2.3l). The title compound was prepared

according to the general procedure using propane-2-thiol (0.05 mL,

0.54 mmol, 5.38 equiv). The crude material was purified via flash column chromatography using a gradient from 97.5/2.5 hexanes/EtOAc to 95/5 hexanes/EtOAc. Clear oil (42.3 mg,

1 0.093 mmol, 93%); H NMR (600 MHz, CDCl3) δ 7.68 (dd, J = 8.2 Hz, 1.7 Hz, 1H), 7.51 (d,

J = 1.7 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.06 (s, 2H), 4.67 (d, J = 11.6 Hz, 1H), 4.14 (d, J =

11.5 Hz, 1H), 2.97-2.90 (m, 1H), 1.54 (s, 9H), 1.38 (s, 9H), 1.24 (d, J = 6.9 Hz, 3H), 1.11 (d,

76 13 J = 6.8 Hz, 3H); C NMR (151 MHz, CDCl3) δ 193.0, 167.0, 166.9, 151.8, 148.1, 130.4,

124.8, 108.7, 108.0, 101.9, 82.4, 82.1, 55.9, 45.4, 34.5, 28.0, 27.8, 24.8, 24.2. IR (thin film) ν

3431, 2978, 1727, 1672, 1442, 1258, 1139, 1038, 850, 734 cm-1. HRMS (ESI): Calcd. For

+ + i C23H33O7S ([M+H ]): 453.1948, found 453.1940. HPLC Chiralpak IA column, Hex/ PrOH =

95:5, flow rate = 1.0 mL/min, λ = 210 nm, tR (major) 5.5 min, tR (minor) 6.2 min. TLC (10/90

25 EtOAc/hexanes): Rf = 0.30. [α]D = -51.8 (c = 2.0, CHCl3).

Di-tert-butyl (S)-2-(2-(4-bromophenyl)-1-(isopropylthio)-2-

oxoethyl)malonate (2.3m). The title compound was prepared

according to the general procedure using propane-2-thiol (0.05 mL,

0.54 mmol, 5.38 equiv). White solid (46.8 mg, 0.096 mmol, 96%), mp 73-75 °C (decomp); 1H

NMR (600 MHz, CDCl3) δ 7.92 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 4.69 (d, J = 11.6

Hz, 1H), 4.15 (d, J = 11.6 Hz, 1H), 2.94-2.87 (m, 1H), 1.55 (s, 9H), 1.39 (s, 9H), 1.24 (d, J =

13 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H); C NMR (151 MHz, CDCl3) δ 193.8, 167.0, 166.8,

134.7, 131.9, 130.2, 128.1, 82.6, 82.3, 55.7, 45.7, 34.7, 28.0, 27.8, 24.8, 24.2. IR (thin film) ν

3430, 2978, 2360, 1729, 1679, 1586, 1369, 1309, 1251, 1139 cm-1. HRMS (ESI): Calcd. For

+ + C22H31BrO5SNa ([M+Na ]): 509.0974, found 509.0963. HPLC Chiralpak IC column,

i Hex/ PrOH = 98:2, flow rate = 1.0 mL/min, λ = 210 nm, tR (minor) 5.8 min, tR (major) 8.0 min.

25 TLC (10/90 EtOAc/hexanes): Rf = 0.50. [α]D = -41.3 (c = 2.0, CHCl3).

Di-tert-butyl (S)-2-(2-(4-chlorophenyl)-1-(isopropylthio)-2-

oxoethyl)malonate (2.3n). The title compound was prepared

according to the general procedure using propane-2-thiol (0.05 mL,

77 0.54 mmol, 5.38 equiv). White solid (43.6 mg, 0.098 mmol, 98%), mp 64-66 °C (decomp); 1H

NMR (600 MHz, CDCl3) δ 7.99 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 4.69 (d, J = 11.6

Hz, 1H), 4.15 (d, J = 11.6 Hz, 1H), 2.94-2.87 (m, 1H), 1.55 (s, 9H), 1.39 (s, 9H), 1.24 (d, J =

13 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H); C NMR (151 MHz, CDCl3) δ 193.6, 167.0, 166.8,

139.4, 134.2, 130.1, 128.9, 82.6, 82.3, 55.7, 45.7, 34.6, 27.9, 27.8, 24.8, 24.2. IR (thin film) ν

3430, 2979, 1740, 1680, 1590, 1369, 1309, 1140, 1093, 861 cm-1. HRMS (ESI): Calcd. For

+ + C22H31ClO5SNa ([M+Na ]): 465.1479, found 465.1469. HPLC Chiralpak IC column,

i Hex/ PrOH = 98:2, flow rate = 1.0 mL/min, λ = 210 nm, tR (minor) 5.7 min, tR (major) 7.5 min.

25 TLC (10/90 EtOAc/hexanes): Rf = 0.47. [α]D = -53.0 (c = 2.0, CHCl3).

Di-tert-butyl (S)-2-(2-(4-fluorophenyl)-1-(isopropylthio)-2-

oxoethyl)malonate (2.3o). The title compound was prepared according

to the general procedure using propane-2-thiol (0.05 mL, 0.54 mmol,

5.38 equiv). White solid (39.2 mg, 0.093 mmol, 93%), mp 71-73 °C (decomp); 1H NMR (600

MHz, CDCl3) δ 8.10-8.07 (m, 2H), 7.17 (at, J = 8.6 Hz, 2H), 4.71 (d, J = 11.6 Hz, 1H), 4.16

(d, J = 11.5 Hz, 1H), 2.95-2.88 (m, 1H), 1.55 (s, 9H), 1.39 (s, 9H), 1.24 (d, J = 6.8 Hz, 3H),

13 1.09 (d, J = 6.8 Hz, 3H); C NMR (151 MHz, CDCl3) δ 193.3, 167.0, 166.8, 165.7 (d, J =

254.7 Hz), 132.2 (d, J = 3.0 Hz), 131.3 (d, J = 9.2 Hz), 115.7 (d, J = 21.9 Hz), 82.5, 82.2, 55.7,

19 45.7, 34.6, 27.9, 27.8, 24.8, 24.2; F NMR (376 MHz, CDCl3)δ -105.41. IR (thin film) ν 3431,

2979, 2360, 1728, 1678, 1598, 1369, 1308, 1157, 862 cm-1. HRMS (ESI): Calcd. For

+ + C22H31FO5SNa ([M+Na ]): 449.1774, found 449.1764. HPLC Chiralpak IC column,

i Hex/ PrOH = 98:2, flow rate = 1.0 mL/min, λ = 210 nm, tR (minor) 5.6 min, tR (major) 6.8 min.

25 TLC (10/90 EtOAc/hexanes): Rf = 0.43. [α]D = -70.0 (c = 2.0, CHCl3).

Di-tert-butyl (S)-2-(1-(isopropylthio)-2-(4-nitrophenyl)-2-

oxoethyl)malonate (2.3p). The title compound was prepared

according to the general procedure using propane-2-thiol (0.05 mL,

1 0.54 mmol, 5.38 equiv). Clear oil (42.0 mg, 0.093 mmol, 93%); H NMR (600 MHz, CDCl3)

δ 8.34 (d, J = 8.9 Hz, 2H), 8.20 (d, J = 8.9 Hz, 2H), 4.70 (d, J = 11.5 Hz, 1H), 4.16 (d, J = 11.5

Hz, 1H), 2.94-2.87 (m, 1H), 1.56 (s, 9H), 1.41 (s, 9H), 1.24 (d, J = 6.8 Hz, 3H), 1.10 (d, J =

13 6.8 Hz, 3H); C NMR (151 MHz, CDCl3) δ 193.1, 167.1, 166.6, 150.2, 141.1, 129.7, 123.8,

82.9, 82.5, 55.6, 46.4, 34.9, 27.9, 27.8, 24.8, 24.1. IR (thin film) ν 3439, 2978, 2931, 1738,

-1 + + 1685, 1530, 1307, 1139, 850, 702 cm . HRMS (ESI): Calcd. For C22H31NO7SNa ([M+Na ]):

476.1719, found 476.1712. HPLC Chiralpak IC column, Hex/iPrOH = 98:2, flow rate = 1.0 mL/min, λ = 210 nm, tR (minor) 9.6 min, tR (major) 13.0 min. TLC (10/90 EtOAc/hexanes): Rf

25 = 0.39. [α]D = -46.6 (c = 2.0, CHCl3).

Di-tert-butyl (S)-2-(2-(4-cyanophenyl)-1-(isopropylthio)-2-

oxoethyl)malonate (2.3q). The title compound was prepared

according to the general procedure using propane-2-thiol (0.05 mL,

0.54 mmol, 5.38 equiv). The crude material was purified via flash column chromatography using a gradient from 97.5/2.5 hexanes/EtOAc to 95/5 hexanes/EtOAc. White solid (38.8 mg,

1 0.091 mmol, 91%), mp 83-85 °C (decomp); H NMR (600 MHz, CDCl3) δ 8.13 (d, J = 8.4 Hz,

2H), 7.80 (d, J = 8.5 Hz, 2H), 4.67 (d, J = 11.6 Hz, 1H), 4.15 (d, J = 11.6 Hz, 1H), 2.92-2.86

(m, 1H), 1.55 (s, 9H), 1.40 (s, 9H), 1.23 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H); 13C NMR

(151 MHz, CDCl3) δ 193.3, 167.0, 166.6, 139.4, 132.4, 129.1, 118.0, 116.1, 82.8, 82.5, 55.6,

79 46.1, 34.8, 27.9, 27.8, 24.8, 24.1. IR (thin film) ν 2978, 2231, 1727, 1685, 1369, 1298, 1162,

-1 + + 1140, 866, 755 cm . HRMS (ESI): Calcd. For C23H31NO5SNa ([M+Na ]): 456.1821, found

456.1815. HPLC Chiralpak IC column, Hex/iPrOH = 96:4, flow rate = 1.0 mL/min, λ = 210

25 nm, tR (minor) 11.0 min, tR (major) 12.9 min. TLC (10/90 EtOAc/hexanes): Rf = 0.30. [α]D =

-51.0 (c = 2.0, CHCl3).

Di-tert-butyl (S)-2-(2-cyclopropyl-1-(isopropylthio)-2-

oxoethyl)malonate (2.3r). The title compound was prepared according to

the general procedure using propane-2-thiol (0.05 mL, 0.54 mmol, 5.38

1 equiv). Low-melting white solid (33.2 mg, 0.092 mmol, 92%); H NMR (600 MHz, CDCl3) δ

4.07 (d, J = 11.6 Hz, 1H), 3.88 (d, J = 11.6 Hz, 1H), 2.98-2.91 (m, 1H), 2.26-2.22 (m, 1H),

1.51 (s, 9H), 1.43 (s, 9H), 1.31 (d, J = 6.8 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H), 1.13-1.09 (m, 1H),

13 1.09-1.05 (m, 1H), 1.01-0.96 (m, 2H); C NMR (151 MHz, CDCl3) δ 204.7, 166.7, 166.7,

82.2, 82.0, 55.3, 51.2, 34.8, 27.9, 27.8, 24.8, 24.1, 19.5, 12.1, 11.2. IR (thin film) ν 3445, 2979,

-1 + 2931, 1732, 1609, 1369, 1255, 1141, 1054, 851 cm . HRMS (ESI): Calcd. For C19H32O5SNa

([M+Na+]): 395.1868, found 395.1858. HPLC Chiralpak AD column, Hex/iPrOH = 98:2, flow rate = 1.0 mL/min, λ = 210 nm, tR (major) 5.0 min, tR (minor) 10.5 min. TLC (10/90

25 EtOAc/hexanes): Rf = 0.40. [α]D = -103.6 (c = 1.5, CHCl3).

Di-tert-butyl (S)-2-(2-(furan-2-yl)-1-(isopropylthio)-2-

oxoethyl)malonate (2.3s). The title compound was prepared according to

the general procedure using propane-2-thiol (0.05 mL, 0.54 mmol, 5.38 equiv). The crude material was purified via flash column chromatography using a gradient

80 from 97.5/2.5 hexanes/EtOAc to 95/5 hexanes/EtOAc. White solid (36.9 mg, 0.091 mmol,

1 91%), mp 103-105 °C (decomp); H NMR (600 MHz, CDCl3) δ 7.62 (d, J = 0.9 Hz, 1H), 7.32

(d, J = 3.5 Hz, 1H), 6.58 (dd, J = 3.5 Hz, 1.6 Hz, 1H), 4.59 (d, J = 11.8 Hz, 1H), 4.11 (d, J =

11.8 Hz, 1H), 3.10-3.03 (m, 1H), 1.54 (s, 9H), 1.38 (s, 9H), 1.26 (d, J = 6.8 Hz, 3H), 1.19 (d,

13 J = 6.7 Hz, 3H); C NMR (151 MHz, CDCl3) δ 183.9, 166.8, 166.7, 151.3, 146.3, 118.0, 112.6,

82.5, 82.2, 55.3, 45.8, 35.1, 27.9, 27.8, 24.4, 24.0. IR (thin film) ν 3430, 2979, 2360, 1737,

-1 + + 1659, 1468, 1366, 1311, 1165, 1138 cm . HRMS (ESI): Calcd. For C20H30O6SNa ([M+Na ]):

421.1661, found 421.1650. HPLC Chiralpak IC column, Hex/iPrOH = 96:4, flow rate = 1.0 mL/min, λ = 210 nm, tR (minor) 12.1 min, tR (major) 17.5 min. TLC (10/90 EtOAc/hexanes):

25 Rf = 0.27. [α]D = -56.2 (c = 2.0, CHCl3).

Di-tert-butyl (S)-2-(2-(furan-2-yl)-1-(isopropylthio)-2-

oxoethyl)malonate (2.3t). The title compound was prepared according to

1 95%), mp 71-73 °C (decomp); H NMR (600 MHz, CDCl3) δ 7.86 (dd, J = 3.8 Hz, 1.1 Hz,

1H), 7.67 (dd, J = 4.9 Hz, 1.0 Hz, 1H), 7.17 (dd, J = 4.9 Hz, 3.8 Hz, 1H), 4.58 (d, J = 11.6 Hz,

1H), 4.13 (d, J = 11.6 Hz, 1H), 3.08-2.99 (m, 1H), 1.55 (s, 9H), 1.38 (s, 9H), 1.27 (d, J = 6.8

13 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H); C NMR (151 MHz, CDCl3) δ 187.9, 166.8, 166.7, 142.4,

133.8, 132.4, 128.2, 82.5, 82.2, 55.7, 47.1, 34.7, 27.9, 27.8, 24.7, 24.2. IR (thin film) ν 3431,

2978, 1730, 1659, 1415, 1369, 1304, 1161, 849, 724 cm-1. HRMS (ESI): Calcd. For

+ + C20H30O5S2Na ([M+Na ]): 437.1433, found 437.1423. HPLC Chiralpak IC column,

81 i Hex/ PrOH = 98:2, flow rate = 1.0 mL/min, λ = 210 nm, tR (minor) 10.7 min, tR (major) 15.7

25 min. TLC (10/90 EtOAc/hexanes): Rf = 0.33. [α]D = -60.5 (c = 2.0, CHCl3).

Di-tert-butyl (S)-2-(1-(isopropylthio)-2-oxo-2-(pyridin-4-

yl)ethyl)malonate (3.3u). The title compound was prepared according to

the general procedure using propane-2-thiol (0.05 mL, 0.54 mmol, 5.38 equiv). The crude material was purified via flash column chromatography using a gradient from 90/10 hexanes/EtOAc to 85/15 hexanes/EtOAc. White solid (37.3 mg, 0.090 mmol,

1 90%), mp 69-71 °C (decomp); H NMR (600 MHz, CDCl3) δ 8.82 (d, J = 5.9 Hz, 2H), 7.82

(dd, J = 4.4 Hz, 1.6 Hz, 2H), 4.64 (d, J = 11.6 Hz, 1H), 4.13 (d, J = 11.6 Hz, 1H), 2.92-2.85

(m, 1H), 1.54 (s, 9H), 1.40 (s, 9H), 1.23 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H); 13C NMR

(151 MHz, CDCl3) δ 193.8, 167.0, 166.5, 150.8, 142.5, 121.7, 82.9, 82.5, 55.4, 46.1, 34.9,

27.9, 27.8, 24.7, 24.1. IR (thin film) ν 3431, 2979, 2360, 1728, 1691, 1369, 1301, 1141, 861,

-1 + + 667 cm . HRMS (ESI): Calcd. For C21H32NO5S ([M+H ]): 410.2002, found 410.1990. HPLC

i Chiralpak IA column, Hex/ PrOH = 98:2, flow rate = 1.0 mL/min, λ = 225 nm, tR (major) 7.2

25 min, tR (minor) 8.5 min. TLC (25/75 EtOAc/hexanes): Rf = 0.32. [α]D = -65.5 (c = 2.0,

CHCl3).

General procedure for the reduction of 2.3. A vial under an N2 atmosphere was charged with

α-sulfaketone 2.3 (0.15 mmol, 1.0 equiv) followed by MeOH (1.5 mL). The reaction mixture was cooled to -20 °C, NaBH4 (10.3 mg, 1.75 equiv) was added, and stirring was continued at

-20 °C. After quenching with 1 M HCl (1.5 mL), the product was extracted with DCM (3x), dried with Na2SO4, and concentrated in vacuo. The crude material was purified via column

82 chromatography using a gradient from 97.5/2.5 hexanes/EtOAc to 95/5 hexanes/EtOAc.

Di-tert-butyl 2-((1S,2S)-2-hydroxy-1-(isopropylthio)-2-

phenylethyl)malonate (2.8a). The product was synthesized according to the general procedure, and quenched after 1 h. White solid (53.7 mg, 0.131 mmol, 87%), mp 85-

1 87 °C (decomp); H NMR (600 MHz, CDCl3) δ 7.46 (d, J = 7.5 Hz, 2H), 7.37 (t, J = 7.6 Hz,

2H), 7.29 (t, J = 7.3 Hz, 1H), 4.89 (d, J = 3.4 Hz, 1H), 3.54-3.49 (m, 2H), 2.39-2.32 (m, 1H),

1.52 (s, 9H), 1.51 (s, 9H), 1.11 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H); 13C NMR (151

MHz, CDCl3) δ 167.7, 167.0, 142.1, 128.2, 127.6, 126.1, 82.6, 82.0, 76.8, 73.0, 57.2, 53.5,

37.4, 28.0, 23.3 (2C). IR (thin film) ν 3434, 2979, 2089, 1725, 1645, 1454, 1628, 1251, 1155,

-1 + + 1139 cm . HRMS (ESI): Calcd. For C22H34O5SNa ([M+Na ]): 433.2025, found 433.2012.

i HPLC Chiralpak IA column, Hex/ PrOH = 97:3, flow rate = 1.0 mL/min, λ = 210 nm, tR (major)

25 7.3 min, tR (minor) 8.8 min. TLC (10/90 EtOAc/hexanes): Rf = 0.29. [α]D = -7.33 (c = 0.75,

CHCl3).

Di-tert-butyl 2-((1S,2S)-1-(benzylthio)-2-hydroxy-2-

phenylethyl)malonate (2.8f). The product was synthesized according to the general procedure, and quenched after 3 h. White solid (49.6 mg, 0.108 mmol, 74%), mp 81-

1 83 °C (decomp); H NMR (600 MHz, CDCl3) δ 7.43 (d, J = 7.4 Hz, 2H), 7.38 (t, J = 7.6 Hz,

2H), 7.32 (t, J = 7.3 Hz, 1H), 7.26-7.20 (m, 3H), 7.08 (d, J = 6.5 Hz, 2H), 4.94 (d, J = 1.9 Hz,

1H), 3.53-3.48 (m, 3H), 3.44 (br s, 1H), 3.29 (d, J = 12.2 Hz, 1H), 1.52 (s, 9H), 1.51 (s, 9H);

13 C NMR (151 MHz, CDCl3) δ 167.7, 166.9, 141.9, 137.4, 129.0, 128.4, 128.3, 127.7, 127.2,

126.1, 82.7, 82.2, 73.0, 57.0, 54.3, 38.6, 28.0 (2C). IR (thin film) ν 3459, 2979, 2359, 2341,

83 -1 + + 1731, 1455, 1369, 1254, 1140, 700 cm . HRMS (ESI): Calcd. For C26H34O5SNa ([M+Na ]):

481.2025, found 481.2011. HPLC Chiralpak IA column, Hex/iPrOH = 97:3, flow rate = 1.0 mL/min, λ = 210 nm, tR (major) 10.2 min, tR (minor) 14.4 min. TLC (10/90 EtOAc/hexanes):

25 Rf = 0.27. [α]D = +18.4 (c = 2.0, CHCl3).

tert-Butyl (3S,4S,5S)-4-(isopropylthio)-2-oxo-5-phenyltetrahydrofuran-3-

carboxylate (2.9a). A vial under an atmosphere of N2 was charged with 2.8a

(41.3 mg, 0.10 mmol, 1.0 equiv) and 1,4-dioxane (0.1 M). Then, 4 M HCl in 1,4-dioxane (0.1

M) was added dropwise at room temperature. The reaction was stirred for 5 h, then diluted with Et2O and H2O. The layers were separated, and the aqueous layer was extracted with Et2O.

The combined organic layers were dried with Na2SO4 and concentrated in vacuo. The crude material was then purified with flash column chromatography using 50/50 DCM/hexanes to give an off-white solid (25.5 mg, 0.075 mmol, 75%), mp 70-72 °C (decomp); 1H NMR (600

MHz, CDCl3) δ 7.43-7.39 (m, 3H), 7.29-7.28 (m, 2H), 5.81 (d, J = 7.4 Hz, 1H), 4.32 (t, J = 7.7

Hz, 1H), 3.68 (d, J = 7.9 Hz), 2.74-2.68 (m, 1H), 1.56 (s, 9H), 1.22 (d, J = 6.6 Hz, 3H), 1.18

13 (d, J = 6.8 Hz, 3H); C NMR (151 MHz, CDCl3) δ 170.9, 165.9, 134.9, 129.0, 128.3, 126.6,

83.7, 82.5, 55.5, 46.8, 35.5, 27.9, 23.5, 23.2. IR (thin film) ν 3436, 1783, 1732, 1647, 1636,

-1 + + 1456, 1135, 1271, 1034, 978 cm . HRMS (ESI): Calcd. For C18H24O4SNa ([M+Na ]):

359.1293, found 359.1285. HPLC Chiralpak IC column, Hex/iPrOH = 96:4, flow rate = 1.0 mL/min, λ = 210 nm, tR (minor) 11.4 min, tR (major) 12.6 min. TLC (10/90 EtOAc/hexanes):

25 Rf = 0.34. [α]D = -39.8 (c = 1.0, CHCl3).

84 tert-Butyl (3S,4S,5S)-4-(benzylthio)-2-oxo-5-phenyltetrahydrofuran-3-

carboxylate (2.9f). A vial under an atmosphere of N2 was charged with 2.8f

(41.3 mg, 0.10 mmol, 1.0 equiv) and 1,4-dioxane (0.05M). The reaction was stirred for 2 h, then diluted with Et2O and H2O. The layers were separated, and the aqueous layer was extracted with Et2O. The combined organic layers were dried with Na2SO4 and concentrated in vacuo. The crude material was then purified with flash column chromatography using 50/50

DCM/hexanes to give an off-white solid (25.5 mg, 0.067 mmol, 67%), mp 94-96 °C (decomp);

1 H NMR (600 MHz, CDCl3) δ 7.43-7.41 (m, 3H), 7.33 (t, J = 7.2 Hz, 2H), 7.29-7.27 (m, 3H),

7.21 (d, J = 7.0 Hz, 2H), 5.73 (d, J = 7.0 Hz, 1H), 4.11 (t, J = 6.8 Hz, 1H), 3.69 (d, J = 6.7 Hz,

1H), 3.49 (d, J = 13.1 Hz, 1H), 3.45 (d, J = 13.1 Hz, 1H), 1.55 (s, 9H); 13C NMR (151 MHz,

CDCl3) δ 170.6, 165.6, 136.8, 134.7, 129.1, 128.9, 128.7, 128.3, 127.5, 126.5, 83.8, 82.3, 55.3,

47.8, 36.2, 27.9. IR (thin film) ν 3437, 1783, 1731, 1636, 1456, 1370, 1138, 1004, 979, 699

-1 + + cm . HRMS (ESI): Calcd. For C22H24O4SNa ([M+Na ]): 407.1293, found 407.1286. HPLC

i Chiralpak IC column, Hex/ PrOH = 96:4, flow rate = 1.0 mL/min, λ = 210 nm, tR (major) 16.0

25 min, tR (minor) 18.2 min. TLC (10/90 EtOAc/hexanes): Rf = 0.29. [α]D = -49.3 (c = 1.0,

CHCl3).

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(11) Pellissier, H. Chiral Sulfur Ligands Asymmetric Catalysis; RSC Publishing: Campbridge U.K., 2009.

(12) Hoyle, C. E.; Bowman, C. N. Thiol-Ene Click Chemistry. Angew. Chemie Int. Ed. 2010, 49 (9), 1540–1573. https://doi.org/10.1002/anie.200903924.

(13) Enders, D.; Lüttgen, K.; Narine, A. A. Asymmetric Sulfa-Michael Additions. Synthesis (Stuttg). 2007, 2007 (7), 959–980. https://doi.org/10.1055/s-2007-965968.

86 (14) Chauhan, P.; Mahajan, S.; Enders, D. Organocatalytic Carbon-Sulfur Bond-Forming Reactions. Chem. Rev. 2014, 114 (18), 8807–8864. https://doi.org/10.1021/cr500235v.

(15) Fang, X.; Wang, C. J. Recent Advances in Asymmetric Organocatalysis Mediated by Bifunctional Amine-Thioureas Bearing Multiple Hydrogen-Bonding Donors. Chem. Commun. 2015, 51 (7), 1185–1197. https://doi.org/10.1039/c4cc07909d.

(16) Chatupheeraphat, A.; Liao, H. H.; Mader, S.; Sako, M.; Sasai, H.; Atodiresei, I.; Rueping, M. Asymmetric Brønsted Acid Catalyzed Substitution of Diaryl Methanols with Thiols and Alcohols for the Synthesis of Chiral Thioethers and Ethers. Angew. Chemie - Int. Ed. 2016, 55 (15), 4803–4807. https://doi.org/10.1002/anie.201511179.

(17) Guo, W.; Wu, B.; Zhou, X.; Chen, P.; Wang, X.; Zhou, Y. G.; Liu, Y.; Li, C. Formal Asymmetric Catalytic Thiolation with a Bifunctional Catalyst at a Water-Oil Interface: Synthesis of Benzyl Thiols. Angew. Chemie - Int. Ed. 2015, 54 (15), 4522–4526. https://doi.org/10.1002/anie.201409894.

(18) Zhao, F.; Zhang, W.; Yang, Y.; Pan, Y.; Chen, W.; Liu, H.; Yan, L.; Tan, C. H.; Jiang, Z. Synthesis of Sulfur-Substituted α-Stereogenic Amides and Ketones: Highly Enantioselective Sulfa-Michael Additions of 1,4-Dicarbonylbut-2-Enes. Adv. Synth. Catal. 2011, 353 (14–15), 2624–2630. https://doi.org/10.1002/adsc.201100227.

(19) Kowalczyk, R.; Wierzba, A. J.; Boratyński, P. J.; Ba¸kowicz, J. Enantioselective Conjugate Addition of Aliphatic Thiols to Divergently Activated Electron Poor Alkenes and Dienes. Tetrahedron 2014, 70 (35), 5834–5842. https://doi.org/10.1016/j.tet.2014.06.035.

(20) Yang, J.; Farley, A. J. M.; Dixon, D. J. Enantioselective Bifunctional Iminophosphorane Catalyzed Sulfa-Michael Addition of Alkyl Thiols to Unactivated β-Substituted-α,β- Unsaturated Esters. Chem. Sci. 2016, 8 (1), 606–610. https://doi.org/10.1039/c6sc02878k.

(21) Núñez, M. G.; Farley, A. J. M.; Dixon, D. J. Bifunctional Iminophosphorane Organocatalysts for Enantioselective Synthesis: Application to the Ketimine Nitro- Mannich Reaction. J. Am. Chem. Soc. 2013, 135 (44), 16348–16351. https://doi.org/10.1021/ja409121s.

(22) Goldys, A. M.; Dixon, D. J. Organocatalytic Ring-Opening Polymerization of Cyclic Esters Mediated by Highly Active Bifunctional Iminophosphorane Catalysts. Macromolecules 2014, 47 (4), 1277–1284. https://doi.org/10.1021/ma402258y.

(23) Goldys, A. M.; Núñez, M. G.; Dixon, D. J. Creation through Immobilization: A New Family of High Performance Heterogeneous Bifunctional Iminophosphorane (BIMP) Superbase Organocatalysts. Org. Lett. 2014, 16 (24), 6294–6297. https://doi.org/10.1021/ol5029942.

(24) Farley, A. J. M.; Sandford, C.; Dixon, D. J. Bifunctional Iminophosphorane Catalyzed Enantioselective Sulfa-Michael Addition to Unactivated α-Substituted Acrylate Esters.

87 J. Am. Chem. Soc. 2015, 137 (51), 15992–15995. https://doi.org/10.1021/jacs.5b10226.

(25) Robertson, G. P.; Farley, A. J. M.; Dixon, D. J. Bifunctional Iminophosphorane Catalyzed Enantioselective Ketimine Phospha-Mannich Reaction. Synlett 2016, 27 (1), 21–24. https://doi.org/10.1055/s-0035-1560530.

(26) Horwitz, M. A.; Zavesky, B. P.; Martinez-Alvarado, J. I.; Johnson, J. S. Asymmetric Organocatalytic Reductive Coupling Reactions between Benzylidene Pyruvates and Aldehydes Scheme 1. Asymmetric Reductive Multicomponent Coupling Reactions. Org. Lett 2016, 18 (1), 36–39. https://doi.org/10.1021/acs.orglett.5b03127.

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(28) Horwitz, M. A.; Fulton, J. L.; Johnson, J. S. Enantio- and Diastereoselective Organocatalytic Conjugate Additions of Nitroalkanes to Enone Diesters. Org. Lett. 2017, 19 (21), 5783–5785. https://doi.org/10.1021/acs.orglett.7b02735.

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CHAPTER THREE: EFFORTS TOWARDS THE REDUCTION OF α-IMINO ESTERS VIA DYNAMIC KINETIC RESOLUTION

3.1 Overview of Dynamic Kinetic Resolution

As discussed in chapter 1, an ongoing demand exists for enantiopure molecules with ever-increasing stereocomplexity. While chiral pool synthesis and asymmetric catalysis are essential methods for generating novel chiral structures, resolution remains a robust and widely used process for isolating enantioenriched compounds.1 Resolution involves the physical separation of enantiomers from a racemic mixture, and encompasses a broad array of approaches for accessing enantioenriched products (Scheme 3-1).2 Chief among these methods is classical resolution, which relies on stoichiometric quantities of a resolving agent (Scheme

3-1A). These resolving agents are generally chiral pool materials and bond either covalently or non-covalently to a racemic substrate to generate a pair of diastereomers. Following separation of the diastereomers, chemical-mediated decomplexation provides the enantioenriched material. Classical resolution is frequently employed, particularly in industry; however, the scope of substrates is generally limited to those which form ion pairs or who can engage in facile covalent connection and removal. Consequently, other methods of resolution have been developed to obviate formal complexation and decomplexation of the resolving agent.

Chiral chromatography is another effective means of resolution, whereby a chiral stationary phase (CSP) enables separation of the two enantiomers (Scheme 3-1B).3,4 Similar to classical resolution, the CSP interacts with the substrate non-covalently to form transient

90 diastereomers and promote separation of enantiomers. The nature of the interaction eliminates any need for subsequent decomplexation and CSPs can be reused for extensive periods of time.

Unfortunately, although CSPs are currently the most efficient means for quantitatively analyzing enantiomeric ratios, the broader utility of this process is limited to due to the high cost of even small scale CSP-packed columns, as well as the need for large quantities of solvent and long separation times.

Scheme 3-1. Example Methods for the Resolution of Racemic Substrates

A third general strategy within the resolution manifold is kinetic resolution. For example, the Sharpless asymmetric epoxidation kinetic resolution enables isolation of highly enantioenriched allylic alcohols (Scheme 3-1C).5 While the former two approaches require stoichiometric quantities of resolving agent or struggle with scale limitations, kinetic resolutions can proceed catalytically and are well-suited to large scale transformations. In a

91 kinetic resolution, enantiomers of a racemic substrate (S) are transformed at different rates (kR

2,6 and kS) to a product (P) (Scheme 3-2A). A successful kinetic resolution converts one enantiomer of substrate to product, while the other enantiomer is collected as unreacted substrate. The success of a kinetic resolution, or the ability to isolate highly enantioenriched material, is directly related to the difference in energy between the diastereomeric transition states (ΔΔG‡). Additionally, enantioenrichment changes as a function of conversion; therefore, optimal kinetic resolution involves full conversion of one enantiomer and no conversion of the opposite enantiomer. In this ideal scenario enantioenrichment is maximized, but the theoretical yield of one enantiomer of product is capped at 50%  much like classical resolution and chromatographic resolution. Moreover, separation of the resolved starting material and product can be challenging.

92 Scheme 3-2. Key Differences Between Kinetic Resolution and Dynamic Kinetic Resolution

Despite the reliability of resolution as a means for accessing enantioenriched material, a maximum theoretical yield of 50% limits the utility of this process and results in the abandonment of valuable material. Dynamic kinetic resolution (DKR) overcomes this barrier, by following the same general principles as kinetic resolution, but with simultaneous equilibration between the two enantiomers of starting material (Scheme 3-2B).2,6 Equilibration can proceed through a variety of means: chemical, enzymatic, or spontaneous.6 With sufficiently rapid racemization, the racemic substrate can be funneled through the faster asymmetric pathway, increasing the theoretical yield of a single enantiomer of product to

100%. Along with this significant improvement come some equally important requirements for success. The rate of equilibration (kinv) is crucial to this process. At a minimum, this rate

93 must be greater than the rate of reaction for the slower enantiomer (kinv > kR) as per Curtin

Hammett kinetics.1,6 Moreover, an optimal DKR requires that the rate of equilibration be greater than the rate of reaction for the faster enantiomer (kinv > kS), otherwise the demands on

1,6 enantioselectivity for the reaction increase dramatically (kS >>> kR). Finally, the resolution must be irreversible and the product cannot undergo racemization under the reaction conditions. These final two restrictions are true of any resolution, but particularly applicable to KR and DKR.

When the criteria outlined above are satisfied, dynamic kinetic resolutions can quickly and effectively provide enantioenriched product in high yield. Consequently, DKR has been a research area of interest for academia and industry alike. Perhaps the most influential and well- known DKR is Noyori’s development of a ruthenium-catalyzed hydrogenation of α-substituted

β-keto esters.7,8 Noyori contributed key theoretical and practical advances to the art of DKR through mathematical models9 and other studies10. Additionally, their initial 1989 publication included the stereoselective synthesis of a key intermediate of L-threo-3,4- dihydroxyphenylserine (L-DOPS), a norepinephrine prodrug that has been studied for more than three decades for the treatment of neurodegenerative diseases (Scheme 3-3A).7,11–14

Subsequent advances enabled chemical manufacturer Takasago to stereoselectively manufacture 4-acetoxyazetidinones – precursors in carbapenem antibiotic synthesis – on the scale of 150 tons/year (Scheme 3-3B).10,15

94 Scheme 3-3. Transfer Hydrogenation DKR of β-Keto Esters

For more than a decade, the Johnson lab has studied dynamic asymmetric processes. In particular, we have recently focused our pursuits on the dynamic kinetic resolutions of α-keto esters as a means for accessing diverse glycolate scaffolds.16 Initial efforts involved ruthenium- catalyzed asymmetric transfer hydrogenations (ATH), inspired by Noyori’s seminal DKR work with configurationally labile β-keto esters.7,8 We envisioned reducing the ketone of racemic α-keto ester 3.1 to generate alcohol 3.2 with two contiguous stereocenters (Scheme 3-

4). In 2012, we reported a DKR-ATH of malonate substrate 3.1a to generate alcohol 3.2a, which spontaneously cyclized after reduction to provide lactone 3.3a with a third contiguous stereocenter.17,18 This transformation proved to be extremely robust throughout subsequent investigations, generating chemically diverse and stereochemically complex products (3.2b-d) under nearly identical reaction conditions for all substrates.17–19

95 Scheme 3-4. Ruthenium-Catalyzed Transfer Hydrogenation DKR of α-Keto Esters

Following our DKR-ATH work, we began exploring C-C bond forming reactions for the enantioconvergent synthesis of increasingly complex glycolic acid scaffolds. The Johnson lab successfully adapted a variety of organocatalyzed and transition-metal catalyzed reactions to our α-keto ester DKR manifold, including the cross-benzoin condensation (Scheme 3-5A),20 alkyne addition (Scheme 3-5B),21 and Hayashi-Miyaura arylation (Scheme 3-5C),22 among others.

96 Scheme 3-5. Advances in DKR with Configurationally Labile α-Keto Esters

While continuing our investigations into α-keto ester dynamic kinetic resolutions, our ambitions also expanded to other substrate classes. In 2015, we published a DKR employing

α-substituted β-formyl amides, which were novel substrates for asymmetric catalytic transformation.23 Although these substrates resemble their β-keto ester counterparts, they are notable for their increased acidity at the α-position, particularly following enamine formation.

Careful substrate optimization was required to promote equilibration of the enamine to the imine. Ultimately, combination of these substrates with an allyl primary amine and chiral phosphoric acid catalyst yielded the aza-Cope rearrangement product in good yield and stereoselectivity (Scheme 3-6A). More recently, we published a stereoconvergent addition of

97 arylboronic acids to α-angelica lactone derivatives to provide enantioenriched γ-butyrolactones with two contiguous stereocenters (Scheme 3-6B).24 Racemization of the α-Angelica lactone proceeded via formation of the dienolate ‒ a novel racemization approach for our lab. This

DKR also overcame several obstacles, including polymerization, dimerization, and hydrolysis of the lactone.

Scheme 3-6. DKRs with Underexplored Substrates

Motivated and informed by these past efforts, we have sought to develop novel DKRs which provide access to stereochemically complex amines. The remainder of this chapter discusses my efforts to synthesize unnatural amino acids containing vicinal stereocenters via

DKR transformation of β-substituted α-imino esters (Scheme 3-7A). Subsequently, Chapter 4 discloses the successful development of an enantioconvergent iso-Pictet Spengler reaction with

α-alkyl β-formyl esters to provide γ-carbolines with two contiguous stereocenters (Scheme 3-

7B).

98 Scheme 3-7. Generating Amines via Dynamic Kinetic Resolution

3.2 Motivation & Background

3.2.1 Applications of Unnatural Amino Acids

The synthesis of unnatural amino acids (UAAs) is of great import to both the biological and chemical communities. Chemically, UAAs are often employed as chiral small molecule building blocks. For example, many asymmetric ligands and organocatalysts derive their chiral backbone from UAAs such as the commercially available25 UAA D-phenylglycine (Scheme

3-8).26–28 UAAs are also uniquely suited for myriad biological applications. Canonically, 22 amino acids (cAAs) comprise the vast majority of peptides and proteins, enabling fundamental cell functions.29 This small set of building blocks limits the scope of small molecules, peptides, and proteins, and as a result there is an ongoing impetus for the synthesis of novel amino acids.

The demand for UAAs arises from their unique biological properties and activities that enable bio-orthogonal chemistry, metabolic studies, studies on protein function and structure-activity relationships, and use as molecular probes.27,28,30–34 Finally, drug discovery efforts employ

UAAs as protein-small molecule linkages for antibody-drug complexes33,35, as well as in

99 peptidomimetic therapeutics such as Saralsin (hypertension) and Carbetocin (postpartum hemorrhaging).36

Scheme 3-8. Unnatural Amino Acids in Organocatalyst Synthesis

3.2.2 Synthetic Approaches to Unnatural Amino Acids

Numerous methods have been developed for the synthesis of enantioenriched UAAs.

The most robust syntheses of enantiopure unnatural amino acids diversify one of the canonical natural amino acids. Shi and Yu have both developed palladium-catalyzed methods for carrying out C-H functionalization of amino acids; although conversion of the AA’s carboxylic acid to a designer amide is required prior to reaction (Scheme 3-9A).37–41 Impressively, high diastereoselectivity is observed when installing the vicinal stereogenic center. White further expanded the library of amino acid-derived UAAs with their publication of an iron-catalyzed oxidative diversification of amino acids and peptides (Scheme 3-9B).42 While the utility of these approaches is undeniable, this chemistry relies on enantioenriched starting materials such as cAAs.

100 Scheme 3-9. C-H Functionalization of Natural Amino Acids

Biocatalytic approaches are an effective means of achieving excellent enantioselectivity in the synthesis of UAAs;30 however, establishing two stereocenters has proven extremely challenging. Engineered methylaspartate ammonia lyase (MAL) enzymes have found some application in the synthesis of aspartic acid analogs, but the substrate scope and yields were quite limited – a common issue for enzymes (Scheme 3-10A).43,44 Given the broader biochemical importance of enzymes, and particularly of transaminases, organic chemists have long sought to develop analogous processes using small molecule organocatalysis. Yet, organocatalytic asymmetric transamination has proven quite challenging and the literature contains relatively few examples. In 2011, Shi reported an asymmetric transamination of α-keto esters via a quinine-derived catalyst (Scheme 3-10B).45 Subsequent efforts improved the scope and enantioselectivity of this transformation.46–49 Spearheaded by

101 Dr. Blane Zavesky, our lab attempted to adapt this chemistry to the dynamic kinetic resolution of β-substituted α-keto esters, but these efforts did not bear fruit. More recently, Maruoka published an organocatalyzed transamination employing phase-transfer catalysis; but, this transformation was plagued by moderate enantioselectivities.50, a 2016 publication from Zhao disclosed a transamination of α-keto acids to generate unprotected, unnatural amino acids in a single step (Scheme 3-10C).51 Although my efforts focused on α-keto and α-imino esters, future work by members of the Johnson lab may seek to adapt these conditions to our synthetic interests.

Scheme 3-10. Synthesis of UAAs via Bio- or Organocatalysis

Historically, the vast majority of methods for synthesizing UAAs have proceeded via transformation of an α-imino ester. Initial efforts involved use of auxiliaries such as Ellman’s

102 sulfinamide or (R)-1-phenylethylamine;52 however, the evolution of asymmetric catalysis dramatically augmented the array of reactions employing achiral imine protecting groups.

Rhodium-catalyzed hydrogenation of enamides is one of the oldest examples of asymmetric catalysis, dating back to Knowles in 1972.53 Only a few years later, advances in ligand development enabled the formation of two contiguous stereocenters with excellent enantioselectivity and diastereoselectivity (Scheme 3-11).54 Today, these Rh-catalyzed enamide hydrogenations tolerate a staggering array of substitution patterns and protecting groups;55,56 yet, as is common in transition metal chemistry, tolerance for substrates containing halogens is low. With an ever-growing list of halogen-dependent cross-coupling transformations57, enantioenriched β-halo-substituted unnatural amino acids could prove valuable.

Scheme 3-11. Rhodium-Catalyzed Asymmetric Hydrogenation of Enamides

Organocatalytic transfer hydrogenations with Hantzsch esters and benzothiazolines sought to overcome this substrate limitation, and specifically eliminate the need for precious transition metals and high pressures of H2. Despite achieving excellent results with aryl α- imino esters, these transformations exhibit low tolerance for aliphatic substitution (Scheme 3-

12A).52,58,59 Seeking to apply this chemistry to configurationally labile β-substituted α-imino esters, our preliminary investigations were fraught with poor reactivity and decomposition

(Scheme 3-12B). Consequently, we turned to a distinctly different approach to imine reduction: chiral Lewis-base activated trichlorosilane hydrosilylation.

103 Scheme 3-12. Hantzsch Ester Reduction of α-Imino Esters

3.2.3 Asymmetric Reductions with Trichlorosilane

Trichlorosilane is a well-established hydride source for the enantioselective reduction of C=N bonds.60 Predominantly used by the organosilicon industry, the clear, colorless liquid is a cheap, commodity chemical.60 As a reagent, trichlorosilane is not sufficiently hydridic to reduce carbonyls and imines on its own.61 Rather, dual coordination of a Lewis base (LB) generates a hypervalent, hexacoordinate silicate species, which is the active reductant (Scheme

3-13).62

Scheme 3-13. Reduction of Imines by Hexacoordinate Silicates

The racemic reduction of imines via trichlorosilane dates back to 1982, when Benkeser and Snyder synthesized N-benzyl anilines in refluxing acetonitrile.63 In 1996, Kobayashi identified trichlorosilane-DMF as an effective reducing reagent of ketones and confirmed the

104 presence of a six-coordinate silicon species via 29Si NMR.64 A catalytic reduction was subsequently reported by Matsumura using chiral formamide 3.10 (Figure 3-1), first to reduce ketones in 1999, then ketimines in 2001.65,66 Neither reaction exhibited good enantioselectivity, but the proof-of-concept prompted research and development of more effective chiral Lewis bases.

Independent contributions over the last two decades from Matsumura, Kocovsky, Sun, and Benaglia have given rise to a diverse library of chiral Lewis base organocatalysts;60–62 although very few have achieved broad substrate scopes with high levels of enantioinduction

(>90:10 er). A select number have successfully effected the asymmetric reduction of aryl α- imino esters and/or aliphatic ketimines, both of which were considered reasonable model substrates for our interests. In 2007, Zhang reported that ephedrine-based picolinamide 3.11 could asymmetrically reduce a variety of ketimines, including para-methoxy phenyl (PMP)- protected α-imino ester 3.18 and aliphatic ketimine 3.20 (Scheme 3-14).67 Unfortunately, stereoselectivities varied greatly (80:20 to 98:2 er), and products 3.18 and 3.20 were obtained with only modest enantioenrichment. Despite these mixed results, the ease with which this catalyst is synthesized prompted further optimization. Subsequent work from Benaglia demonstrated that chlorinated pyridyl 3.12 improved yields and stereoselectivities for a variety of ketimines.68 Related structure-activity investigations also informed the proposed stereochemical model, wherein the picolinamide activates trichlorosilane, while the secondary benzylic alcohol hydrogen bonds with the imine (Scheme 3-15).

105 Figure 3-1. Select Chiral Organocatalysts for the Trichlorosilane Reduction of α-Imino Esters and Aliphatic Ketimines

Scheme 3-14. Formamide-Activated Trichlorosilane Reduction of Imines (Zhang, 2007)

Scheme 3-15. Proposed Stereochemical Model for Ephedrine-Trichlorosilane Reduction of N-

Aryl Ketimines

Non-ephedrine-based systems have also shown great promise, although extended reaction sequences to arrive at the target structure have hampered attempts to expand the utility of these catalysts. Prolinols have long been employed as backbones for organocatalysts, and in

106 2008 Zhang developed a proline-derived picolinamide catalyst for the asymmetric reduction of β-enamino esters.69 The following year, Jones exchanged the pyridine for N-methyl imidazole to generate catalyst 3.14, which provided aliphatic amine 3.21 in high yield and good enantioselectivity.70 Finally, catalysts 3.15-3.17 all achieved excellent yields and enantioselectivities with 3.18.71–73 Unfortunately, 3.17 demonstrated very poor enantioselectivity with an aliphatic α-imino ester71, and our attempts to synthesize 3.16 were unsuccessful.73 As such, we settled on ephedrine, prolinol, and Cinchona alkaloid-derived

Lewis bases for our initial studies.

3.3 Challenges to Dynamic Kinetic Resolution with α-Imino Esters

With this prior literature front of mind, we sought to advance the art of dynamic kinetic resolution and expand the library of synthetically accessible unnatural amino acids by developing a DKR reduction of configurationally labile α-imino esters using trichlorosilane.

When initially considering this transformation, several key challenges quickly arose which required our attention as we moved forward. Naturally, all of the standard challenges of dynamic kinetic resolution were present, such as access to β-substituted α-imino ester substrates, rate of racemization, and stereoselective catalyst control; however, several additional complications arise when carrying out DKR with imines (Figure 3-2).

107 Figure 3-2. Challenges in Dynamic Kinetic Resolution with α-Imino Esters

The first complication is imine reactivity and stability, as these characteristics vary greatly with substrate structure and electronics. α-Imino esters are more electrophilic than ketimines due to the electron-withdrawing nature of the ester, and the pKa values for these two substrates reflects this difference.74 Consequently, α-imino esters benefit from heightened reactivity, as well as an increased propensity for racemization. As a result, we hypothesized that these substrates would be well-suited for DKR; however, this increased reactivity also amplifies the α-imino ester’s sensitivity to hydrolysis and other undesirable decomposition pathways. Careful tailoring of the N-protecting group and β-substituents is generally required to ensure sufficient stability of the α-imino ester starting material.

In addition to imine stability, the presence and equilibration of E/Z isomers for N- protected imines adds another challenging element. Sun and Hoveyda have independently observed that aliphatic ketimines and α-imino esters exist as a mixture of E/Z isomers.74,75 The two isomers readily interconvert, and the authors propose that selective reaction of a single

108 isomer is required for enantioselective transformation. Jacobsen noted a similar trend during mechanistic investigations of their enantioselective Strecker reaction, where the catalyst binding occurred exclusively with the Z-imine.76 Consequently, an ideal DKR would involve rapid E/Z imine equilibration as well as facile interconversion at the β-stereogenic center

(Scheme 3-16). Moreover, the optimal catalyst would select for only one of these four reactive species to stereoselectively provide product. This intense reliance on conformational control makes cyclic imines excellent candidates for asymmetric functionalization, and dynamic kinetic resolution in particular.77–81 A few impressive DKRs of cyclic β-imino esters and ketimines have been developed; however, unfortunately, no methods currently exist for the synthesis of cyclic α-imino esters and our attempts to develop a robust, accessible process proved unsuccessful.

Scheme 3-16. Generic Proposed DKR of α-Imino Esters

Ultimately, the factors above rely heavily on the identity of the nitrogen protecting group. A wide selection of amine protecting groups exist in the literature, and asymmetric catalysis has employed nearly all of them at one time or another; however, the vast majority of reactions accomplish enantioinduction with only a single class (e.g. carbamates, phosphinoyl,

109 sulfonyl, etc.) and broad tolerance is rarely observed. This is due to the unique electronic and structural features that each protecting group possesses to enable or disable reactivity and stereoselectivity.82,83 Additionally, many asymmetric transformations utilize amine substituents such as alkyl groups which are challenging, if not impossible, to remove. If the end goal of this endeavor is to synthesize UAAs, we must limit ourselves to amines that can be deprotected. All of these challenges must be overcome to develop a successful DKR transformation of α-imino esters with high yields and stereoselectivities.

3.4 Results & Discussion

3.4.1 Synthesis of β-Substituted α-Imino Esters

Our first task in developing an enantioconvergent trichlorosilane-mediated reduction of imines was accessing the requisite β-substituted α-imino ester starting material. In accordance with prior literature, we identified the para-methoxyphenyl (PMP) N-protecting group for the imine. Although these protecting groups are considerably more difficult to remove than alternatives such as carbamates, an abundance of trichlorosilane literature employs this protecting group.60 Moreover, the electron-donation of the PMP group serves to stabilize the imine C=N bond74 – a feature deemed critical for success after preliminary studies with electron-withdrawing groups (Cbz, Ts, Acyl) showed little to no isomerization of the enamide to the imine.

Traditionally, the synthesis of α-imino esters proceeds via condensation of a primary amine onto the α-keto ester. While this reaction is facile for aldimine synthesis, ketimine generation is considerably slower, and especially so when sterically encumbered (e.g. by β- substitution).74 Accordingly, the transformation generally suffers from long reaction times and

110 moderate yields. We sought to identify a faster, higher yielding method for accessing the desired starting material. In 2008, Hoveyda adapted a procedure from Palacios84 to generate aliphatic α-imino esters from aryl azides and α-keto esters via Staudinger reduction (Scheme

3-17A).74* Gratifyingly, we found that we could apply identical reaction conditions to generate

β-methyl, β-phenyl α-imino ester 3.22 in similarly high yield and a 5:1 E/Z ratio of imine isomers (Scheme 3-17B).

Scheme 3-17. Staudinger Reaction for the Efficient Synthesis of α-Imino Esters

3.4.2 Trichlorosilane-Mediated Reduction and DKR of β-Alkyl α-Imino Esters

With our desired starting material in hand, we established proof of concept using DMF as an achiral ligand64 in the presence of trichlorosilane and PMP-protected imino ester 3.22

(Scheme 3-18). DMF is considerably less activating than designer chiral ligands, but still succeeded in generating the desired amine (3.23) in 3.8:1 dr and 45% conversion after 21 h.

Following these encouraging results we opted to synthesize and screen an array of chiral organocatalysts.

* Hoveyda synthesized these imines for an asymmetric, Zr-catalyzed dialkyl zinc addition to generate quaternary stereocenters. Attempts to apply this to our system proved unsuccessful, resulting in uncatalyzed, racemic addition at the nitrogen center of the C=N bond. The reaction was abandoned in favor of more promising transformations.

111 Scheme 3-18. Racemic Reduction of a β-Substituted α-Imino Ester via DMF-HSiCl3

Applying catalyst ent-3.11 to our system, we observed promising enantioselectivity and diastereoselectivity despite moderate to low yield (Scheme 3-19). The 4-chloropicolinic acid derivative 3.12 provided a substantial increase in yield, but no dramatic improvements to stereoselectivity. Cinchona alkaloid catalyst 3.17 improved diastereoselectivity to 9:1 dr, but diminished enantioselectivity negated any advantages of exploring this ligand further. Finally, we observed racemic product when screening Sun’s tert-butyl sulfinamide catalyst (3.24).85

Ultimately, as in many reactions, the ephedrine-based ligands proved most promising. As such, we initiated optimization of that catalytic manifold.

We selected two areas of investigation for catalyst optimization: (1) the stereochemistry of the catalyst backbone, and (2) the nitrogen heterocycle. Like ephedrine, its diastereomers

(R,R) and (S,S)-pseudoephedrine are commercially available. Exchanging the backbone generated catalysts (R,R)-3.25 and (S,S)-3.26. Application of 3.25 and 3.26 in the model reaction resulted in increased yields and similar enantioselectivities relative to results obtained with 3.11. Catalyst 3.25 also increased the diastereoselectivity from 3.6:1 dr to 4:1 dr.

Simultaneous investigation of the N-heterocycle was motivated by differences observed between the unsubstituted (3.11) and 4-chloro (3.12) picolinic catalysts. We hypothesized that other nitrogen heterocycles could further improve stereoselectivities and yields. Unfortunately, both quinolyl ligand 3.27 and indole ligand 3.28 provided racemic product, and poor yields and diastereoselectivities.

112 Scheme 3-19. Initial Ligand Screening for HSiCl3 DKR Reduction

a Determined by 1H NMR analysis of the crude reaction mixture using an internal standard.

Although improvements to both yield and stereoselectivity were observed upon catalyst structure variation, the reaction outcomes remained suboptimal. Given that our enantioselectivity was thus far limited to 80:20 er, we hypothesized that perhaps the rate of racemization (krac) was not sufficiently fast. Traditionally, DKR of α-keto esters requires base to facilitate racemization, so we hypothesized that the DKR of α-imino esters could be enabled by the addition of acid or base. Reagent grade trichlorosilane generally contains trace quantities of HCl, and spontaneously reacts with water to generate hydrochloric acid and silicon polymer.86 Although distillation is possible, the presence of HCl in trichlorosilane reactions is somewhat inevitable.86,87 Kočovsky’s 2008 DKR synthesis of β-amino acids found that acetic

113 acid acted as a buffer to promote enamine/imine isomerization and improve reactivity.86 In an effort to strike a similar balance, we employed catalytic quantities of acids and bases (Table

3-1). Acetic acid performed as suspected by improving the yield dramatically, however stereoselectivity was slightly diminished (entry 2). In contrast, cesium carbonate had little effect (entry 3), while trialkylamines shutdown the reaction (entry 4) – likely due to displacement of the activating ligand by the amine61. Additives conclusively affected reactivity, yet poor stereoselectivity remained a serious issue.

Table 3-1. Additive Effects on Trichlorosilane-Mediated DKR

entry additive dr er yielda

1 none 3.6:1 81:19 48%

2 AcOH 3.4:1 77:23 89%

3 Cs2CO3 3.4:1 80:20 48%

4 DIPEA 2.4:1 - 20%

a Determined by 1H NMR analysis of the crude reaction mixture using an internal standard.

3.4.3 Trichlorosilane-Mediated Enantioconvergent Reduction of β-Halo α-Imino Esters

Concurrently with our additive screen, we began investigating whether β-halo α-imino esters might be more effective substrates in this transformation. Synthesis of β-bromo β-benzyl

α-imino ester 3.30 was accomplished using the same procedure as the β-alkyl substrates

(Scheme 3-20A). Subsequent exposure of the imine to the asymmetric trichlorosilane reduction conditions gave the desired secondary amine (3.31) in 20:1 dr and 80:20 er, although

114 yield was poor (Scheme 3-20B). Despite the moderate enantioselectivity and yield, the substantial improvement to diastereoselectivity led us to continue investigations exclusively with the β-halo substrates.

Scheme 3-20. Synthesis of and Initial Hit with β-Bromo α-Imino Ester

Although the β-halo α-imino esters proved synthetically accessible and sufficiently reactive, the improvements to diastereoselectivity were quickly accompanied by two new challenges. First, we found that this substrate was more susceptible to temperature-dependent decomposition. While preliminary trials 0 °C provided the product in moderate yield, warming the reaction to room temperature diminished the yield significantly (Scheme 3-21).

Additionally, the reaction conditions generated varying quantities (~5-10%) of dehalogenated side-product 3.32 (Scheme 3-22). This side product was observed in equal quantities at 0 °C and room temperature, suggesting additional pathways are responsible for the diminished yields at elevated temperature. We propose that initial aziridine formation could be followed by trichlorosilane-mediated reduction. No studies have previously reported this reactivity but we understand this outcome to be a logical outgrowth based on fundamental organic reactivity.

115 Scheme 3-21. Side Product Formation and Temperature Dependence

Scheme 3-22. Hypothetical Mechanism for Dehalogenated Side Product Formation

With these challenges in mind, we sought to minimize these decomposition pathways and maximize stereoselectivity by initiating a catalyst screen with β-bromo α-imino ester 3.30

(Scheme 3-23). Ephedrine and pseudoephedrine-derived catalysts ent-3.11, 3.25, and 3.26 all provided nearly identical results with regards to both stereoselectivity and yield, with enantioselectivity limited to 70:30 er. Inspired by a mechanistic investigation of trichlorosilane reductions from Jones in 2017, we began synthesizing ligands 3.33-3.36.88 Jones proposed that methylating the alcohol of their prolinol catalyst (3.36) could facilitate catalyst turnover; however, methylation of the pseudoephedrine-based catalyst to generate 3.33 proved less productive, diminishing product yield. Jones also found that their system benefited from the additional hydrogen-bonding capability of the imidazole relative to the picolinic functional group. However, our system performed quite differently when exposed to N-methylimidazole catalyst 3.34, with less than 15% NMR yield after stirring overnight. Proline-derived catalysts

3.35 and 3.36 provided further evidence of the stereochemical importance of the pyridine

116 moiety in this catalyst, while also indicating that stereoselectivity was not heavily dependent on the ephedrine-derived backbone.

Scheme 3-23. Ligand Screen for the DKR Reduction of a β-Bromo α-Imino Ester

a Determined by 1H NMR analysis of the crude reaction mixture using an internal standard.

Disheartened by these results, we made a final push to overcome the many obstacles of this transformation by attempting to synthesize alternative β-halo α-imino esters (Scheme 3-

24). Unfortunately, imine stability proved debilitating. Both β-chloro- and β-bromo-β-phenyl

α-iminoesters were observed to decompose under Staudinger reduction as reported for β-alkyl-

β-phenyl substrates (vide infra). Evidently, imine 3.30 was uniquely stable, and our initial concerns regarding β-halo imine instability were justified.

117 Scheme 3-24. Synthesis of Diverse β-Substituted α-Imino Esters

This final synthetic challenge proved insurmountable, and given the general complications this project faced, we opted to move away from this dynamic kinetic resolution.

With our improved understanding of asymmetric imine chemistry, we initiated an investigation into another imine-centered transformation developing an enantioconvergent iso-Pictet-

Spengler reaction.

3.5 Conclusions

In conclusion, we have reported efforts toward realizing a dynamic kinetic resolution of β-substituted α-imino esters. Ultimately, instability of both the imine starting material and

β-halogenated products diminished the yields of this transformation, while we suspect that slow racemization and suboptimal catalyst selectivity contributed to poor enantioenrichment.

Despite a lack of positive, publishable results, we identified two important lessons for application to future imine work: (1) Significant differences in diastereoselectivity were observed between the β-alkyl and β-halo α-imino esters, likely due to more facile group differentiation. (2) Our broader efforts to investigate the utility of PMP-protected imines, as well as other imines and enamides, in dynamic kinetic resolution shed light on the reactivity of α-imino esters. Other imine protecting groups (tosyl, acyl, carbamate) failed to generate any

118 product even under forcing conditions. PMP-protected imino esters successfully afforded the desired α-amino esters, but the nascent stereogenic centers were generated in poor selectivity.

The synthesis of unnatural amino acids via dynamic kinetic resolution is a challenging task, but a worthy one. We remain optimistic that our efforts will provide useful insight for future endeavors.

3.6 Experimental Details

Methods: Proton magnetic resonance spectra (1H NMR) were recorded on a Bruker model

DRX 400, 500, or 600 (1H NMR at 400 MHz, 500 MHz, or 600 MHz). 1H NMR data are reported as follows: chemical shift, multiplicity (s = singlet, app s = apparent singlet, br s = broad singlet, d = doublet, dd = doublet of doublet, t = triplet, m = multiplet), coupling constants (Hz), and integration. Analytical thin layer chromatography was carried out using

Whatman 0.25 mm silica gel 60 plates, Sorbent Technologies 0.20 mm Silica Gel TLC plates.

Visualization was allowed by UV light, phosphomolybdic acid in ethanol, aqueous ceric ammonium nitrate solution, ninhydrin solution, or KMnO4. HPLC analysis was performed on a Perkin Elmer flexar photodiode array (PDA) system equipped with a Daicel Chiralpak IC column. Asymmetric reactions at temperatures below 23 °C were carried out in a Thermo

Sigma UCR-150N aluminum block UC reactor with stirring. Purification of the reaction products was carried out by using Siliaflash-P60 silica gel (40- 63μm) purchased from

Silicycle. Yields refer to isolated yields after flash column chromatography. NMR yields were obtained using phenanthrene as an internal standard. Racemic traces were obtained using DMF as a racemic ligand (1 equiv as opposed to 10 mol %).

119 Materials: Solvents were passed through a column of neutral alumina under nitrogen prior to use. Reagents were obtained from Millipore Sigma, Fischer Scientific, or Oakwood Chemical

Supply and used as received.

Catalyst Synthesis

(R)-N-(2-hydroxybenzyl)-2-methylpropane-2-sulfinamide (3.24): The

title compound was synthesized as reported by Sun, et al.85 1H NMR spectroscopic data matches those reported.

(S)-(2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)(1-methyl-1H-imidazol-2-

yl)methanone (3.36): The title compound was synthesized as reported by Jones,

et al.70 1H NMR spectroscopic data matches those reported.

Ephedrine-Based Catalysts (ent-3.11, 3.12, 3.25-3.28): The catalysts below were synthesized via a modified procedure from Benaglia, et al.68

N-((1R,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methylpicolinamide

(ent-3.11): Picolinic acid (300 mg, 2.43 mmol, 1 equiv) was added to a flame- dried round bottom flask, then dissolved in SOCl2 (2.5 mL). The reaction was refluxed at 80 °C for 2 hours, then the solvent was removed in vacuo. In a separate flask, (1R,2S)-ephedrine (402 mg, 1 equiv) was dissolved in THF, followed by addition of triethylamine (1.02 mL, 3 equiv).

The acid chloride was dissolved in THF, added to the flask, and the reaction mixture was stirred at reflux overnight. The reaction was quenched with satd. aq. NaHCO3. The aqueous layer was

120 discarded, then the organics were washed with brine. The organics were collected and dried over Na2SO4, filtered, and concentrated. The crude material was purified using flash column chromatography (1% to 2.5% MeOH:DCM) to give a white solid. 1H NMR spectroscopic data matches those reported.68

N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methylpicolinamide

(3.25): Picolinic acid (123 mg, 1.00 mmol, 1 equiv) was added to a flame- dried round bottom flask, then dissolved in SOCl2 (1.0 mL). The reaction was refluxed at 80 °C for 2 hours, then the solvent was removed in vacuo. In a separate flask, (1S,2S)- pseudoephedrine (198 mg, 1.2 equiv) was dissolved in THF (3 mL), followed by addition of triethylamine (0.42 mL, 3 equiv). The acid chloride was dissolved in THF (2 mL) + DMF (2 drops), added to the flask, and the reaction mixture was stirred at reflux overnight. The reaction was quenched with satd. aq. NaHCO3. The aqueous layer was discarded, then the organics were washed with brine. The organics were collected and dried over Na2SO4, filtered, and concentrated. The crude material was purified using flash column chromatography (1% to

2.5% MeOH:DCM) to provide the product as a white solid (85 mg, 0.31 mmol, 31%). The product appeared as a 10:1 mixture of rotamers in the NMR spectrum. Major Rotamer: 1H

NMR (500 MHz, Chloroform-d) δ 8.73 (d, J = 4.8 Hz, 1H), 7.96 (td, J = 7.7, 1.7 Hz, 1H), 7.89

(d, J = 7.8 Hz, 1H), 7.53 (ddd, J = 7.6, 4.9, 1.3 Hz, 1H), 7.37 – 7.31 (m, 2H), 7.29 (d, J = 5.7

Hz, 3H), 4.61 (dd, J = 10.1, 8.4 Hz, 1H), 4.21 (dq, J = 10.2, 6.7 Hz, 1H), 3.19 (s, 3H), 0.95 (d,

J = 6.7 Hz, 3H). The alcohol proton was not observed.

121 N-((1R,2R)-1-hydroxy-1-phenylpropan-2-yl)-N-methylpicolinamide

(3.26): The title compound was synthesized in the same manner as reported for enantiomer 3.25. The product was obtained as a white solid (90 mg, 0.35 mmol, 35%), and appeared as a 10:1 mixture of rotamers in the NMR spectrum. Major Rotamer: 1H NMR (500

MHz, Chloroform-d) δ 8.73 (d, J = 4.8 Hz, 1H), 7.96 (td, J = 7.7, 1.7 Hz, 1H), 7.89 (d, J = 7.8

Hz, 1H), 7.53 (ddd, J = 7.6, 4.9, 1.3 Hz, 1H), 7.37 – 7.31 (m, 2H), 7.29 (d, J = 5.7 Hz, 3H),

4.61 (dd, J = 10.1, 8.4 Hz, 1H), 4.21 (dq, J = 10.2, 6.7 Hz, 1H), 3.19 (s, 3H), 0.95 (d, J = 6.7

Hz, 3H). The alcohol proton was not observed.

N-((1S,2S)-1-methoxy-1-phenylpropan-2-yl)-N-methylpicolinamide

(3.33): The title compound was synthesized via a modified procedure from

68 Benaglia. NaH was was added to a flame dried flask under N2. THF (5 mL, 0.17 M) was added, followed by addition of picolinamide 3.25 (215 mg, 0.80 mmol, 1 equiv) in a single portion. The mixture was stirred at room temperature for 2 h, then MeI (0.10 mL, 2 equiv) was added. The reaction was stirred for 20 h at room temperature, then quenched with satd. aq.

NH4Cl. The product was extracted with DCM (3x), then organics dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified using flash column chromatography (50% to 70% EtOAc:Hex) to provide the product as a clear, viscous oil (87 mg, 0.31 mmol, 39%). The product appeared as a 2.4:1 mixture of rotamers in the NMR spectrum. Major Rotamer: 1H NMR (400 MHz, Chloroform-d) δ 8.54 (d, J = 4.8 Hz, 1H), 7.74

(m, 1H), 7.39 (m, 2H), 7.36 – 7.21 (m, 5H), 4.12 (p, J = 7.2 Hz, 1H), 4.01 (d, J = 8.2 Hz, 1H),

3.13 (d, J = 2.0 Hz, 3H), 3.09 (d, J = 1.9 Hz, 3H), 1.14 – 1.06 (m, 3H). Minor Rotamer: 1H

NMR (400 MHz, Chloroform-d) δ 8.61 (d, J = 4.8 Hz, 1H), 7.74 (q, J = 7.9, 7.0 Hz, 1H), 7.48

122 (d, J = 7.9 Hz, 1H), 7.39 (m, 1H) 7.04 – 6.92 (m, 5H), 4.99 (bs, 1H), 4.32 (d, J = 8.4 Hz, 1H),

3.23 (d, J = 2.0 Hz, 3H), 2.91 (s, 3H), 1.14 – 1.06 (m, 3H).

4-chloro-N-((1R,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-

methylpicolinamide (3.12): A flame-dried round bottom flask was charged

with 4-chloro picolinic acid (158 mg, 1.00 mmol, 1 equiv), followed by SOCl2

(1 mL). The reaction was refluxed at 80 °C for 2 hours, then the solvent was removed in vacuo.

In a separate flask, (1R,2S)-ephedrine (198 mg, 1.2 equiv) was dissolved in THF (3 mL), followed by addition of triethylamine (0.42 mL, 3 equiv). The acid chloride was dissolved in

THF (2 mL) + DMF (2 drops), added to the flask, and the reaction mixture was refluxed overnight before aqueous quenching with satd. aq. NaHCO3. The aqueous layer was discarded, then the organics were washed with brine. The combined organics were collected and dried over Na2SO4, filtered, and concentrated. The crude material was purified using flash column chromatography (2% MeOH:DCM) to provide the product as a white solid (250 mg, 0.82 mmol, 82%). The product appeared as a 1.4:1 mixture of rotamers in the NMR spectrum. 1H

NMR spectroscopic data matches those reported.

N-((1R,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methylquinoline-2-

carboxamide (3.27): Quinoline 2-carboxylic acid (123 mg, 0.711 mmol,

1 equiv) was added to a flame-dried round bottom flask, then dissolved in SOCl2 (0.71 mL).

The reaction was refluxed at 80 °C for 3 hours, then the solvent was removed in vacuo. In a separate flask, (1R,2S)-ephedrine (141 mg, 1.2 equiv) was dissolved in THF (3 mL), followed by addition of triethylamine (0.30 mL, 3 equiv). The acid chloride was dissolved in THF (2

123 mL) + DMF (2 drops), added to the flask, and the reaction mixture was stirred at reflux overnight. The reaction was quenched with satd. aq. NaHCO3. The aqueous layer was discarded, then the organics were washed with brine. The organics were collected and dried over Na2SO4, filtered, and concentrated. The crude material was purified using flash column chromatography (1 to 3% MeOH:DCM) to give the product as a white solid (189 mg, 0.59 mmol, 83%). The product appeared as a 1.8:1 mixture of rotamers in the NMR spectrum. Major

Rotamer: 1H NMR (400 MHz, Chloroform-d) δ 8.30 (d, J = 8.6 Hz, 1H), 8.19 (d, J = 8.5 Hz,

1H), 7.91 (d, J = 8.2 Hz, 1H), 7.87-7.74 (m, 1H), 7.71-7.61 (m, 2H), 7.59-7.49 (m, 1H), 7.44

– 7.30 (m, 4H), 6.16 (bs, 1H), 4.93 (d, J = 4.6 Hz, 1H), 4.70 – 4.53 (m, 1H), 2.74 (s, 3H), 1.31

(d, J = 6.9 Hz, 3H). Minor Rotamer: 1H NMR (400 MHz, Chloroform-d) δ 8.27 (d, J = 8.6 Hz,

1H), 8.12 (d, J = 8.4 Hz, 1H), 7.87-7.74 (m, 2H), 7.71-7.61 (m, 1H), 7.59-7.49 (m, 1H), 7.46

– 7.31 (m, 5H), 5.18 (bs, 1H), 4.70 – 4.53 (m, 1H), 4.16 (bs, 1H), 2.93 (s, 3H), 1.43 (d, J = 7.0

Hz, 3H).

N-((1R,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methyl-1H-indole-2-

carboxamide (3.28): Indole 2-carboxylic acid (322 mg, 2.00 mmol, 1

equiv) was added to a flame-dried round bottom flask, then dissolved in

DCM (10 mL, 0.2 M). Oxalyl chloride (0.52 mL, 3 equiv) was added followed by 2 drops

DMF. The reaction was refluxed at 45 °C for 2 hours, then the solvent was removed in vacuo.

In a separate flask, (1R,2S)-ephedrine (397 mg, 1.2 equiv) was dissolved in THF (6 mL), followed by addition of triethylamine (0.30 mL, 3 equiv). The acid chloride was dissolved in

THF (4 mL) + DMF (2 drops), added to the flask, and the reaction mixture was stirred at reflux overnight. The reaction was quenched with satd. aq. NaHCO3. The aqueous layer was

124 discarded, then the organics were washed with brine. The organics were collected and dried over Na2SO4, filtered, and concentrated. The crude material was purified using flash column chromatography (30 to 40% EtOAc:Hex) to provide the product as a white solid (482 mg, 1.56 mmol, 78%). 1H NMR (500 MHz, Chloroform-d) δ 9.35 (s, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.44

(d, J = 8.3 Hz, 3H), 7.38 – 7.29 (m, 4H), 7.16 (ddd, J = 8.0, 6.9, 1.0 Hz, 1H), 6.84 (app s, 1H),

5.03 (app s, 1H), 4.73 (bs, 1H), 4.42 (s, 1H), 3.14 (app s, 3H), 1.40 (s, 3H).

N-((1R,2S)-1-hydroxy-1-phenylpropan-2-yl)-N,1-dimethyl-1H-

imidazole-2-carboxamide (3.34): N-methyl imidazole carboxylic acid (42 mg, 0.33 mmol, 1 equiv) was dissolved in DMF (1 mL, 0.33 M), and HBTU (126 mg, 1 equiv),

DIPEA (0.12 mL, 2.0 equiv), and (1R,2S)-ephedrine were added sequentially. The reaction was stirred overnight at room temperature, then quenched with water. The mixture was extracted with EtOAc (3x), then the organics were washed with brine (2x), dried over Na2SO4, and concentrated in vacuo. The crude material was purified using flash column chromatography (2% to 4% MeOH:DCM) to provide the product as a white solid (65 mg, 0.24 mmol, 71%). The product appeared as a 3:1 ratio of rotamers in the NMR spectrum. Major

Rotamer: 1H NMR (600 MHz, Chloroform-d) δ 7.38 – 7.19 (m, 4H), 7.02 (s, 1H), 6.91 (s, 1H),

5.10 (dt, J = 12.0, 6.0 Hz, 1H), 4.75 (d, J = 4.9 Hz, 1H), 3.66 (s, 3H), 2.51 (s, 3H), 1.30 (d, J

= 7.0 Hz, 3H). Minor Rotamer: 1H NMR (600 MHz, Chloroform-d) δ 7.42 (d, J = 6.9 Hz, 3H),

7.38 – 7.18 (m, 1H), 6.94 (s, 1H), 6.88 (s, 1H), 4.95 (app s, 1H), 4.60 (app s, 1H), 3.70 (s, 3H),

3.09 (s, 3H), 1.30 (d, J = 7.0 Hz, 3H).

125 (S)-[2-(Hydroxydiphenylmethyl)pyrrolidin-1-yl](pyridin-2-yl) methanone

(3.35): The title compound was synthesized via a modified procedure from Jones,

et al.88 Picolinic acid (300 mg, 2.44 mmol, 1.25 equiv) was added to a flame dried flask under N2 and dissolved in DCM (7.4 mL). Oxalyl chloride (0.63 mL, 3.8 equiv) was added dropwise and the reaction was stirred at rt for 4 h. The volatiles were removed in vacuo, then the residual material was dissolved in DCM (9.8 mL). In a separate flask, (S)-diphenyl prolinol (494 mg, 1.95 mmol, 1.0 equiv) was dissolved in toluene (9.8 mL), then the solution of acid chloride in DCM was added slowly. The reaction mixture was stirred overnight, then quenched with satd. aq. NH4Cl. The layers were separated, and the product was extracted with

EtOAc (3x). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified via flash column chromatography (column 1: 80% to

100% EtOAc:Hex, column 2: 1.5% to 3% MeOH:DCM) to provide the product as a white solid

(138 mg, 0.39 mmol, 16%). 1H NMR spectroscopic data matches those reported.88

N-((R)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-

vinylquinuclidin-2-yl)methyl)picolinamide (3.17): The quinidine

primary amine was synthesized as reported by Melchiorre, et al.89 The picolinic acid derivative was synthesized using a modified procedure from Benaglia, et al.90

Picolinic acid (123 mg, 1.00 mmol, 1 equiv) was added to a flame dried flask, dissolved in

SOCl2 (1 mL), and refluxed at 80 °C for 2 hours. The solution was concentrated in vacuo and the acid chloride was dissolved in THF (5.6 mL). The solution was cooled to 0 °C, then TEA

(0.17 mL, 1.2 equiv) was added, followed by dropwise addition of a solution of primary amine

(257 mg, 0.83 equiv) in THF (5.5 mL). The reaction was warmed to room temperature and

126 stirred overnight before quenching with satd. aq. NaHCO3 (3 mL). The biphasic solution was rotary evaporated to remove THF, then DCM was added and the layers were separated. The aqueous phase was extracted with DCM (5x), then the combined organics were dried over

Na2SO4, filtered, and concentrated in vacuo. The crude material was purified using flash column chromatography (100% DCM to 15% MeOH:DCM) to provide the product as a light brown solid (~95% purity) (308 mg, 0.72 mmol, 87%). 1H NMR spectroscopic data matches those reported.90

Synthesis of α-imino esters

1-azido-4-methoxybenzene: The title compound was synthesized as reported by

Fokin, et al.91 The crude material was purified via flash column chromatography (5%

to 10% EtOAc:Hex) to provide the product as a red oil (10.0g, 68 mmol, 90% yield).

The product was stored in the freezer in a vial wrapped with aluminum foil to mitigate safety concerns. 1H NMR (600 MHz, Chloroform-d) δ 6.98 (d, J = 9.0 Hz, 2H), 6.92 (d, J = 8.9 Hz,

2H), 3.82 (s, 3H).

ethyl 2-oxo-3-phenylbutanoate: The title compound was prepared as reported

by Johnson, et al.21 1H NMR spectroscopic data matches those reported.

ethyl 3-bromo-2-oxo-4-phenylbutanoate: Prepared as reported by

Hoffman, et al.92 1H NMR spectroscopic data matches those reported.

127 General procedure for PMP-protected imines: A flame dried flask was charged with 1- azido-4-methoxybenzene (1 equiv) and placed under N2. Dry DCM (0.05 M) was added, and the reaction was cooled to 0 °C. Trimethylphosphine (1.0 M in PhMe, 1 equiv) was added dropwise, then the reaction was warmed to room temperature and stirred for 30 minutes. A solution of α-keto ester (0.5 M in dry DCM, 1 equiv) was subsequently added to the pale yellow, room temperature solution of iminophosphorane. Stirring was continued for 1 hour, then the reaction was quenched with H2O. The organic layer was separated, and the aqueous layer was extracted with DCM (3x). The combined organics were dried over Na2SO4, filtered, and concentrated. The crude material was purified using flash column chromatography.

Ethyl 2-((4-methoxyphenyl)imino)-3-phenylbutanoate (3.22): The title

compound was synthesized from ethyl 2-oxo-3-phenylbutanoate (413 mg,

2.0 mmol, 1 equiv). The crude material was purified using flash column chromatography (2.5% to 5% EtOAc:Hex) to provide the product as a bright yellow oil (527 mg, 1.69 mmol, 85%). The product was obtained as a 5:1 ratio of E/Z isomers, which was calculated using proton resonances at 1.69 ppm (major) and 1.62 ppm (minor). 1H NMR (400

MHz, Chloroform-d) δ 7.34 (d, J = 2.8 Hz, 1H), 7.33 (app s, 2H), 7.28 (app s, 2H), 6.84 (app s, 4H), 4.13 (q, J = 7.0 Hz, 1H), 3.82 (d, J = 7.1 Hz, 2H), 3.80 (s, 3H), 1.62 (d, J = 7.0 Hz, 3H),

0.80 (t, J = 7.1 Hz, 3H).

Ethyl 3-bromo-2-((4-methoxyphenyl)imino)-4-phenylbutanoate

(3.30): The title compound was synthesized from ethyl 3-bromo-2-oxo-4-

phenylbutanoate (570 mg, 2.0 mmol, 1 equiv). The crude material was

128 purified using flash column chromatography (2.5% EtOAc:Hex) to provide the product as a bright orange solid (709 mg, 1.82 mmol, 91%). The product was obtained as a 2.6:1 ratio of

E/Z isomers, which was calculated using proton resonances at 1.05 ppm (major) and 1.48 ppm

(minor). 1H NMR (400 MHz, Chloroform-d) δ 7.36 (app s, 7.36) 7.35 (app s, 2H), 7.31-7.28

(m, 1H), 6.86 (d, J = 8.9 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H), 5.07 (dd, J = 8.5, 6.6 Hz, 1H), 4.12

(q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 3.79 (dd, J = 16.3, 8.2 Hz, 5H), 3.43 (dd, J = 14.5, 8.5 Hz,

1H), 1.05 (t, J = 7.1 Hz, 3H).

General procedure for the asymmetric trichlorosilane-mediated reduction of PMP- protected imines: The title compounds were synthesized via a modified procedure from

Hoveyda, et al.74 PMP-protected imine (0.10 mmol, 1 equiv) was added to a flame dried vial, placed under N2, and dissolved in dry DCM (1 mL, 0.1 M). The reaction was cooled to the appropriate temperature (see tables above for conditions), then catalyst (0.01 mmol, 10 mol %) was added, followed by HSiCl3 (30L, 0.30 mmol, 3 equiv). After stirring overnight at the same temperature, the reaction was quenched with satd. aq. NaHCO3. The mixture was extracted with DCM (3x), then the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified using flash column chromatography.

Ethyl 2-((4-methoxyphenyl)amino)-3-phenylbutanoate (3.23): The

title compound was obtained using PMP-protected imino ester 3.22. The

diastereomeric ratio was calculated using proton resonances at 3.30 ppm

(minor) and 3.19 ppm (major). 1H NMR (500 MHz, Chloroform-d) δ 7.38 – 7.22 (m, 5H), 6.75

(d, J = 8.9 Hz, 2H), 6.56 (d, J = 8.9 Hz, 2H), 4.07 (d, J = 6.9 Hz, 1H), 3.96 (q, J = 6.9 Hz, 2H),

129 3.75 (s, 3H), 3.19 (p, J = 7.0 Hz, 1H), 1.48 (d, J = 7.1 Hz, 3H), 1.03 (t, J = 7.1 Hz, 3H). HPLC

i (98:2 hexanes: PrOH, Daicel Chiralpak IC Column, flow rate = 1.0 mL/min, λ = 210 nm): tR

(major diastereomer) = 13.5, 14.5 min, tR (minor diastereomer) = 10.5 min, 12.2 min.

Ethyl 3-bromo-2-((4-methoxyphenyl)amino)-4-phenylbutanoate

(3.31): The title compound was obtained using PMP-protected imino ester

3.30. The crude material was purified using flash column chromatography

(60 to 70% DCM:Hexanes). 1H NMR (500 MHz, Chloroform-d) δ 7.42 – 7.36 (m, 2H), 7.36

– 7.30 (m, 3H), 6.76 – 6.70 (m, 2H), 6.49 – 6.41 (m, 2H), 4.48 (td, J = 7.7, 2.8 Hz, 1H), 4.37

– 4.26 (m, 2H), 4.27 – 4.23 (m, 1H), 3.75 (s, 3H), 3.54 (dd, J = 14.1, 7.7 Hz, 1H), 3.31 (dd, J

= 14.2, 7.6 Hz, 1H), 1.37 (t, J = 7.1 Hz, 3H). HPLC (97:3 hexanes:iPrOH, Daicel Chiralpak

IC Column, flow rate = 1.0 mL/min, λ = 210 nm): tR = 11 min, 12 min.

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139

CHAPTER FOUR: ORGANOCATALYTIC ISO-PICTET-SPENGLER REACTION FOR THE ENANTIOCONVERGENT SYNTHESIS OF TETRAHYDRO-γ- CARBOLINES

4.1 Motivation

Carbolines represent a broad class of chemically and biologically interesting natural and synthetic alkaloids, encompassing both constitutional isomers and hydrogenated derivatives.1–3 Structurally, carbolines contain a fused indole and pyridine fragment, with location of the pyrido nitrogen determining its identity as an α-, β-, γ-, or δ-carboline (Figure

4-1A).1,2 In addition to the fully aromatic species, dihydro-, tetrahydro-, and hexahydro- variants abound (Figure 4-1B).

Figure 4-1. Carboline Nomenclature

Both β- and γ-carbolines have demonstrated broad biological activity,1,2,4 and γ- carbolines have even outperformed their β-carboline counterparts in some cases;5,6 however, investigations of β-carboline scaffolds are made easier by their natural abundance and comparative ease of synthesis relative to γ-carbolines. An expansive array of aromatic and saturated β-carbolines are readily found in nature, including several bioactive compounds such

140 as reserpine, harmane, and ajmalicine (Figure 4-2A).7–17 In contrast, only three γ-carboline natural products have been reported to date, all of which are saturated variants (Figure 4-

2B).18,19 Synthetically, access to both tetrahydro-β- and γ-carbolines can be achieved in a single synthetic step via the Pictet-Spengler reaction;20–24 however, β-carbolines can be derived from naturally abundant sources such as tryptamine and tryptophan, while the synthesis of γ- carbolines requires costly iso-tryptamines (Scheme 4-1). Consequently, the library of γ- carbolines available for investigations of biological activity is quite small compared to β- carbolines.

Figure 4-2. Carboline Natural Products

Scheme 4-1. Access to THβCs vs. THγCs

Despite the limited scope of known γ-carbolines, myriad drug discovery efforts have investigated this scaffold (Figure 4-3). In particular, tetrahydro-γ-carbolines (THγCs) display a wide array of biological activities.1,4 For example, tetrahydro-γ-carboline dimebon progressed through phase III clinical trials as a treatment for Alzheimer’s disease (AD), but

141 ultimately failed to sufficiently ameliorate memory loss.4 Significant effort has since been devoted to scaffold optimization and diversification, seeking to maximize neuroprotective activities such as acetylcholinesterase antagonism, radical scavenging, and regulation of mitochondria.6,25–30 Setipiprant, another THγC, was investigated in two different clinical trials, one of which is ongoing. Early work with Setipiprant identified it as a CRTH2 antagonist, leading to Phase II and Phase III trials for asthma and seasonal allergic rhinitis, respectively.31

More recently, the compound has been revived by Allergan and placed in Phase II trials for androgenetic alopecia in males.32 Promising new THγC drug candidates include Tubastatin A, which has received significant attention in the literature as a selective inhibitor of histone deacetylases 6 and 10 (HDAC-6, HDAC-10).33,34 Finally, the 1-oxo-tetrahydro-γ-carboline

Alosetron is one of many γ-carboline antagonists of 5-HT serotonin receptors28,35–38 and an

FDA approved treatment for irritable bowel syndrome (IBS) in females.4

Figure 4-3. Biologically Active Tetrahydro-γ-Carbolines

These pharmacological hits suggest that increased accessibility to novel γ-carboline scaffolds could improve existing therapeutic activities, and enable new activity as well. In a

2018 review of γ-carboline syntheses and biological activities, Dai and co-workers argued that work is needed to provide access to functionalized and diversifiable γ-carbolines.1 Specifically, while development of more active γ-carbolines is ongoing, there is an increasing demand for

142 greater target specificity. One potential approach to improving both target binding and selectivity is to incorporate stereogenic elements39, which are noticeably absent in the γ- carbolines depicted above (Figure 4-3), as well as the broader medicinal chemistry literature.

4.2 Background: Synthesis of Tetrahydro-γ-Carbolines

The first synthesis of a tetrahydro-γ-carboline was accomplished using a classic organic chemistry reaction: the Fischer indole synthesis.4,40,41 This transformation was applied to the synthesis of indoles as early as 1883,42 and applied to the synthesis of THγCs in 1924 by

Robinson and Thornley (Scheme 4-2).43 Combination of hydrazine 4.1 and piperidone 4.2 in acetic acid generated hydrazone 4.3, and subsequent addition of dilute sulfuric acid provided the desired THγC (4.4).

Scheme 4-2. Synthesis of 1,1,3,3,5-Pentamethyl-Tetrahydro-γ-Carboline

The Fischer indole synthesis has been a robust method for generating an array of γ- carbolines; however, the transformation suffers from two limitations when considering its application to the synthesis of more diverse, densely substituted tetrahydro-γ-carbolines: (1)

The reaction is highly sensitive to functionalities on the piperid-4-one. Non-symmetrical substitution of the piperid-4-one can result in mixtures of regioisomers (Scheme 4-3A), while substituents like phenyl or benzyl groups adjacent to the carbonyl generate side products

(Scheme 4-3B).3,44,45 (2) If any stereogenic centers are desired for the final carboline product, they must be preset on the piperid-4-one starting material.3 Moreover, even if the enantioenriched piperid-4-one can be obtained, the mechanism of the transformation prohibits

143 stereogenic centers adjacent to the carbonyl, as they would likely undergo racemization under the reaction conditions. Consequently, the synthesis of stereochemically and structurally complex THγCs typically requires alternative methods.

Scheme 4-3. Regioselectivity Challenges with the Fischer Indole Synthesis of Carbolines

Although the Fischer indole reaction is not amenable to the asymmetric synthesis of tetrahydro-γ-carbolines, other enantioselective approaches have been reported.1,3 In 2006, the first asymmetric synthesis of THγCs was accomplished via a palladium-catalyzed, intramolecular asymmetric allylic alkylation (AAA) (Scheme 4-4).46 More recently, [3+3] cycloadditions have been employed to generate densely functionalized products with stereogenic centers. In 2016, Shi reported a chiral phosphoric acid (CPA)-catalyzed cycloaddition of 2-indolylmethanols to provide THγCs with a stereogenic center at the β- position (Scheme 4-5A).47 Yang published a copper-catalyzed [3+3] cycloaddition between azomethine ylides and 2-indolylnitroethylenes to afford products containing three stereogenic centers in high stereoselectivity and yield (Scheme 4-5B).48 Three years later, Wang extended this methodology to a cascade reaction, using an iridium catalyst for a stereodivergent AAA, followed by stereospecific iso-Pictet-Spengler reaction (Scheme 4-5C).49 Like the Fischer

144 indole synthesis, this latter transformation is an essential method for generating tetrahydro-γ- carbolines.

Scheme 4-4. Synthesis of THγCs via AAA (Bandini, 2006)

Scheme 4-5. Asymmetric Synthesis of THγCs via Aza-Ylides

145 In 1911, Pictet and Spengler transformed β-phenethylamine and aldehydes to generate quinolines under acidic conditions.50 Tatsui then extended this methodology to indoles in 1928, employing aldehydes and tryptamine to generate tetrahydro-β-carbolines (THβCs).51,52 The first reported Pictet-Spengler approach to generating tetrahydro-γ-carbolines was not reported until 1976, when iso-tryptamine analog 4.10 and opianic acid 4.11 were combined with sulfuric acid to provide THγC 4.12 (Scheme 4-6).53 This 50-year gap between the synthesis of β- and

γ-carbolines via the Pictet-Spengler reaction is partially attributed to the difficulty of synthesizing the requisite iso-tryptamine starting material.

Scheme 4-6. Iso-Pictet-Spengler Synthesis of an Opianic Acid-Derived THγC

Access to iso-tryptamines has, and continues to be, a limiting factor in generating novel tetrahydro-γ-carbolines. In 1957, Schindler reported the first synthesis of iso-tryptamine in 5 steps from indole 2-carboxylic acid.54 Homologation was achieved via sodium cyanide and an in situ generated 2-indolyl trimethylmethanammonium. The transformation proceeded in moderate yield, and subsequent reduction to the primary amine required forcing conditions, including stoichiometric Raney-Nickel heated to 190 °C under 120 atm. of hydrogen gas

(Scheme 4-7A). The synthesis has since been modified on several occasions, with most contemporary investigations using an approach published in 1998 by Tarzia and co-workers.55

Redox manipulations generated the requisite benzylic indole aldehyde which is homologated

146 by condensation of nitromethane. Subsequent reduction of the vinyl nitroindole provides the primary amine (Scheme 4-7B).

Scheme 4-7. Synthetic Approaches to Iso-Tryptamines

a Yields represent those obtained from the Johnson lab synthesis of iso-tryptamine. Yields not reported by Tarzia et. al.

Improved access to iso-tryptamines has helped to dramatically expand the scope of iso-

Pictet-Spengler products; however, asymmetric synthesis of THγCs via the Pictet-Spengler reaction remains underexplored1 relative to the vast body of literature on generating enantioenriched THβCs.52,56–59 In 2010, Fandrick and co-workers reported the first example of an iso-Pictet-Spengler reaction generating an enantioenriched THγC (Scheme 4-8A).60 After obtaining chiral iso-tryptamine 4.13 through use of a chiral auxiliary, exposure to aldehyde

4.14 under dehydrating conditions enabled the diastereoselective iso-Pictet-Spengler reaction to provide enantioenriched carboline 4.15 in >10:1 dr. In 2016, Yus expanded the scope of products by employing diverse, chiral iso-tryptamines and aldehydes in the presence of TFA to generate enantioenriched THγCs (Scheme 4-8B).61

147 Scheme 4-8. Synthesis of Enantioenriched THγCs using Chiral Auxiliaries

In 2011, Jacobsen reported the sole extant enantioselective iso-Pictet-Spengler reaction.62 Employing chiral thiourea 4.16 and benzoic acid co-catalysts, the rapid synthesis of tetrahydro-γ-carbolines 4.17 was accomplished in high yield and enantioselectivity (Scheme

4-9A). Further trituration or recrystallization of the Boc-protected carboline provided enantiopure material. This report also included the first example of a THγC bearing a quaternary stereogenic center at the δ-position (4.18), although this substrate required an extended reaction time and increased catalyst loadings (Scheme 4-9B).

148 Scheme 4-9. Enantioselective Iso-Pictet-Spengler Reaction

Jacobsen’s asymmetric iso-Pictet-Spengler reaction evolved out of a large body of work applying enantioselective thiourea organocatalysis to the synthesis of carbolines, as well as other stereochemically complex products.63 Between 1998 and 2002, Jacobsen published foundational studies revealing the utility of ureas and thioureas as asymmetric hydrogen bond donor catalysts.64–66 Jacobsen’s early investigations included an enantioselective acyl-Pictet-

Spengler catalyzed by thiourea 4.19 to generate acyl-protected THβCs (Scheme 4-10).67

Although enantioselectivity depended greatly on the identity of the acylating reagent, the importance of the acetyl chloride was not fully realized until 2007 when subsequent investigations demonstrated the importance of an anion-binding mechanism in enantiodetermination.68,69

Scheme 4-10. Thiourea-Catalyzed Enantioselective Acyl Pictet-Spengler

149 Initial examples of enantioselective anion-binding focused on iminium or oxocarbenium halide complexes; however, in 2009, Jacobsen demonstrated that protioiminium intermediates could be employed in a similar capacity for an asymmetric Pictet-Spengler reaction (Scheme 4-11A).70 Thiourea 4.20 and benzoic acid catalyzed the transformation between aldehydes and activated tryptamines in good yield and high enantioselectivity.

Although this report heavily informed Jacobsen’s subsequent iso-Pictet-Spengler publication, the original method required activated substrates and long reaction times. In an effort to increase the electrophilicity of the protioiminium species, Seidel employed his bifunctional thiourea/Brønsted acid catalysis 4.21 to enable use of unactivated tryptamines in the asymmetric Pictet-Spengler reaction.71 Seidel proposed that catalyst acidity would increase and promote reactivity due to stabilization of the conjugate carboxylate base. Stabilization is achieved via intramolecular thiourea anion-binding. The reaction successful provided enantioenriched THβCs, although aliphatic aldehydes failed to provide the product in high yield or enantioselectivity (Scheme 4-11B).

Scheme 4-11. Asymmetric Protioiminium Iso-Pictet-Spengler Reactions

150 With this precedent in mind, we sought to expand the library of synthetic THγCs by adapting enantioselective thiourea/Brønsted acid co-catalysis to a dynamic kinetic resolution

(DKR) iso-Pictet-Spengler reaction (Scheme 4-12A). Dixon reported the sole examples of

DKR Pictet-Spengler reactions in 2009 and 2010 using a chiral phosphoric acid-catalyzed N- acyliminium cyclization cascade.72,73 Their first publication employed tryptamines and enol lactones to provide enantioenriched fused tetracycles bearing two contiguous stereocenters. A follow-up study applied γ-keto acids to the same transformation, generating fused pentacycles

(Scheme 4-12B). We hypothesized that enantioconvergent reaction of iso-tryptamine with α- substituted β-formyl and β-keto carbonyls could provide enantioenriched tetrahydro-γ- carbolines bearing two contiguous stereocenters, including one exocyclic stereogenic center and a carbonyl functional handle for downstream diversification (Scheme 4-12C). Moreover, our approach would provide immediate access to the unprotected indole and piperidine, which are critical sites for manipulation in SAR studies.1,27,74

151 Scheme 4-12. Prior Art and Current Work

4.3 Results and Discussion

4.3.1 Preliminary Studies with α-Substituted β-Formyl Morpholine Amides

Motivated by the ongoing demand for diverse, enantioenriched THγCs, we initiated development of an enantioconvergent iso-Pictet-Spengler reaction using configurationally labile aldehydes. In 2015, our lab published an enantioconvergent 2-aza-Cope reaction using

α-substituted β-formyl morpholine amides.75 Morpholine amides provided superior results relative to the analogous α-substituted β-formyl ester due to the allylic strain imposed by the morpholine amide during enamine formation (Figure 4-4). This strain shifted the imine/enamine equilibrium towards the reactive species, the imine. Given these insights, we

152 opted to apply the same substrate to our system. When iso-tryptamine 4.23 and α-methyl β- formyl morpholine amide 4.24 were mixed in deuterated chloroform, we observed complete conversion to the tetrahydro-γ-carboline product 4.25 in 30 min with quantitative yield

(Scheme 4-13). Identical results were observed using dry DCM, and the background reaction even proceeded in C6D6, albeit at a much slower rate (47% conversion after 1.5 h).

Figure 4-4. Conformational Effects on the Reactivity of α-Substituted β-Formyl Esters and

Morpholine Amides

Scheme 4-13. Uncatalyzed Iso-Pictet-Spengler Reaction with α-Substituted β-Formyl

Morpholine Amides

These preliminary results suggested that β-formyl amides could be competent in this reaction, but a variety of analytical issues arose due to both the background reaction and product polarity. These analytical challenges were compounded by an inability to quickly and effectively quench the reaction and evaluate stereoselectivity. Aqueous quenching was problematic due to the high solubility of both product and reactants in aqueous solution under a range of pH conditions. Reductive quenching with LiAlH4 or DIBAL-H provided complex product mixtures. Finally, attempts to obtain a racemic HPLC trace of the highly polar amide

153 proved extremely challenging, even after N-protection of the carboline. While this latter issue could likely be overcome with reverse phase chromatography or mobile phase additives76, the perceived advantage of high reactivity was quickly becoming a barrier to success.

4.3.2 Reaction Development and Optimization with α-Substituted β-Formyl Esters

Considering the reactivity and analytical issues outlined above, we sought to investigate an alternative substrate for the enantioconvergent iso-Pictet-Spengler reaction.

Specifically, we wanted to slow or eliminate the background reaction observed with the β- formyl amides, and reduce polarity of the THγC product by exchanging the morpholine ring.

As previously discussed, our 2015 aza-Cope rearrangement75 revealed that β-formyl morpholine amides were significantly more reactive than β-formyl esters. We hypothesized that if β-formyl esters participated in the iso-Pictet-Spengler reaction, the rate of the background reaction would be diminished significantly. Additionally, substitution of the morpholine amide for an aliphatic ester would decrease the polarity of the THγC product.

A control study combining iso-tryptamine 4.23, α-isopropyl β-formyl ethyl ester 4.26a and CDCl3 confirmed our hypothesis, with a considerably slower background reaction relative to the morpholine amide (Table 4-1). In contrast to the fast-reacting morpholine amide, we exclusively observed enamine 4.27a after 2 h (entry 1), and only trace product after 19 h (entry

2). Even after nearly 3 d, only a 66:34 ratio of enamine:THγC was observed (entry 3).

Subsequent Boc-protection of THγC 4.28a provided a significantly less polar product relative to the analogous morpholine amide, enabling analysis via chiral HPLC.

154 Table 4-1. Control Studies with α-Substituted β-formyl Esters vs. Amides

entry time (h) 4.27a : 4.28a

1 2 100:0

2 19 97:3 3 67 66:34 a Ratio of enamine to THγC is determined by 1H

NMR peak integrations.

The preliminary studies suggested that use of α-substituted β-formyl esters enabled improved control of the background reaction and access to less polar THγCs (Table 4-2).

Therefore, we began investigating the enantioconvergent iso-Pictet-Spengler reaction employing these new substrates. The addition of catalytic quantities of acids accelerated the reaction in DCM and PhMe (entries 1-4), lending credence to the hypothesis that these less reactive esters could participate as active iminium electrophiles under general acid catalysis.

Exposure of iso-tryptamine and β-formyl ester 4.26a to valine-derived thiourea 4.20 and benzoic acid in DCM at room temperature yielded THγC 4.28a in 76% NMR yield, >16:1 dr and 90:10 er (entry 5). X-ray diffraction analysis of the Boc-protected product provided the absolute and relative stereochemistry (Figure 4-5).

155 Table 4-2. Catalyst Screen

thiourea acid T entry solvent yielda dr erb (mol %) (mol %) (°C) 1 4.29 (10) - DCM 23 91% 3.2:1 -

2 4.29 (10) - PhMe 23 82% 3.7:1 -

3 - BzOH (20) DCM 23 67% 4.7:1 - 4 - BzOH (20) PhMe 23 41% 5.0:1 - 5 4.20 (20) BzOH (10) DCM 23 76% >16:1 90:10 6 4.20 (20) BzOH (10) PhMe 23 32% - - 7 4.20 (20) BzOH (10) PhMe 35 83% >16:1 91:9 8 4.20 (20) BzOH (10) DCM 35 78% >16:1 88:12

9 4.30 (20) BzOH (10) PhMe 35 91% 20:1 95:5 10 4.16 (20) BzOH (10) PhMe 35 92% 17:1 96:4 11 4.31 (20) BzOH (10) PhMe 35 89% 17:1 96:4 aDetermined by 1H NMR analysis of the crude reaction mixture using an internal standard. bDetermined by chiral

HPLC analysis after Boc-protection. Represents the enantiomeric ratio of the major diastereomer.

156 Figure 4-5. X-Ray Crystal Structure of Boc-Protected THγC 4.28a*

Subsequent optimization of the reaction conditions revealed that use of toluene as a solvent delivered poor product yields at room temperature (entry 6); however, increasing the temperature to 35 °C generated THγC 4.28a in 83% yield and similar stereoselectivities as those obtained with DCM at room temperature (entry 7). Product 4.28a was obtained in diminished enantioselectivity when the reaction was conducted in refluxing DCM (entry 8).

A survey of catalyst structures resulted in further improvements to yield and stereoselectivity. Generally, stereocontrol for these thiourea catalysts is dictated by substitution on the terminal amide and the amino acid from which the catalyst is derived.62,70 Consequently, we began by exchanging the valine-derived isopropyl group for tert-butyl substitution, providing catalyst 4.30. This exchange significantly increased enantioselectivity, and dramatically improved yields by reducing the formation of side products (entry 9). We also probed the effect of adding a second phenyl group to the benzyl substituent (4.16), as well as the impact of fusing those aryl groups (4.31). The former catalyst provided a modest increase to enantioselectivity and yield (entry 10), while we observed slightly diminished yields with the latter catalyst (entry 11).

* CCDC 2005290 contains the supplementary crystallographic data for this structure. These data can be obtained free of charge from the Cambridge Crystallographic Centre via www.ccdc.cam.ac.ui/data_request/cif.

157 With optimized yields and stereoselectivities in hand, we next investigated lower catalyst loadings (Table 4-3). Gratifyingly, we found that with catalyst 4.16, we could decrease the loading of both catalysts to 5 mol % without any loss of stereoselectivity, and only slightly diminished yield (entry 1). Increasing the loadings of the thiourea and benzoic acid to 20 mol

% increased the yield (entry 2); however, the same yield could be achieved by reducing the thiourea loading to 5 mol % while maintaining a 20 mol % loading for benzoic acid (entry 3).

Finally, we found that heating the reaction further to 65 °C had little effect on stereoselectivity, but slightly diminished yields relative to results at 35 °C (entry 4). Ultimately, given the low cost of benzoic acid and higher yields we selected the reaction conditions employed in entry 3 for substrate scope investigations.

Table 4-3. Reaction Optimization for Ethyl α-Isopropyl β-Formyl Ester

thiourea BzOH T entry loading loading yielda dr erb (°C) (mol %) (mol %) 1 5 5 35 89% 21:1 95.5:5.5 2 20 20 35 96% 16:1 96:4

3 5 20 35 97% 19:1 95:5 4 5 5 65 85% 23:1 95.5:5.5 a Determined by 1H NMR analysis of the crude reaction mixture using an internal standard. b Determined by chiral HPLC analysis after Boc-protection. Represents the enantiomeric ratio of the major diastereomer.

158 Upon initiating investigations into the substrate scope for this transformation we quickly found that unbranched substrates performed quite differently from α-isopropyl substrate 4.26a (Table 4-4). Using α-methyl β-formyl ester 4.26b we obtained THγC 4.28b in

33% yield, 1.7:1 dr, and 85:15 er. Hoping the α-methyl aldehyde 4.26b was an outlier, we also synthesized the octanoic acid- and hydrocinnamic acid-derived β-formyl esters. α-Substituted

β-formyl esters 4.26c and 4.26d provided the desired THγC products 4.28c and 4.28d in slightly improved diastereoselectivities and yields relative to the methyl case, but even further diminished enantioselectivities.

Table 4-4. Initial Substrate Scope

aDetermined by 1H NMR analysis of the crude reaction mixture using an internal standard. bDetermined by chiral

HPLC analysis after Boc-protection. Represents the enantiomeric ratio of the major diastereomer.

Given these poor yields and stereoselectivities, we re-initiated optimization using α- benzyl β-formyl ester 4.28d (Table 4-5). Increasing the thiourea loading to 20 mol % slightly improved stereoselectivity (entry 1), but the most substantial improvement arose from

159 switching back to DCM at room temperature (entry 2). Under those conditions, THγC 4.28d was obtained in 6.3:1 dr and 92:8 er with 95% conversion, but only 59% NMR yield. Close examination revealed two side products: double condensation product 4.32 and an unidentified compound.

Seeking to limit formation of these undesired products and maintain stereoselectivity, we began screening alternative acid co-catalysts with varying pKa values. Specifically, we hypothesized acid strength could play a role in inhibiting over-condensation product formation.

In general, yield decreased as acidity increased, and improved yields were obtained using acetic acid or p-methoxy benzoic acid (entries 3 and 4). Diastereoselectivity was maximized with benzoic acid, and suffered greatly when p-nitro benzoic acid or trifluoroacetic acid were employed (entries 5 and 6); however, impurities were still observed in all cases, and yields remained good to moderate.

Acid co-catalyst identity appeared to only minimally affect yield, so we instead looked to new thiourea catalysts to improve yield and stereoselectivity. Catalyst 4.33 had previously resulted in improved stereoselectivities for Jacobsen’s iso-Pictet-Spengler reaction, presumably due to an increased barrier to amide bond rotation. Thioureas 4.16 and 4.33 generated THγC 4.28d with nearly identical enantioselectivity and diastereoselectivity was diminished; however, catalyst 4.33 increased the yield from 59% (entry 2) to 90% (entry 7).

We synthesized an even bulkier thiourea (4.34) to further explore the impact of steric bulk on catalyst selectivity, but observed diminished yields and enantioselectivities (entry 8). Finally, we employed a bifunctional catalyst developed by Seidel71 (4.21) that successfully provided

THγC product 4.28d in 77% yield, but without any diastereocontrol (entry 9). Additional optimization efforts are ongoing, but 4.33 appears to be the ideal catalyst.

160 Table 4-5. Re-Optimization of Iso-Pictet-Spengler Reaction for Non-Branched Substrates

entry thiourea acid (pKa) conversiona yieldb dr erc

1d 4.16 BzOH (4.20) 92% 68% 5.4:1 87:13

2 4.16 BzOH (4.20) 95% 59% 6.3:1 92:8

3 4.16 AcOH (4.76) 82% 69% 4.3:1 92:8 4 4.16 4-MeO-BzOH (4.47) 92% 74% 5.9:1 91:9

e 5 4.16 4-NO2-BzOH (3.44) 95% 62% 3.8:1 n.d.

6 4.16 CF3CO2H (-0.25) 63% 48% 2.0:1 73:27 7 4.33 BzOH (4.20) 89% 90% 5.3:1 91.5:8.5 8 4.34 BzOH (4.20) 90% 85% 6.2:1 89.5:10.5

9 4.21 - 77% n.d. 1:1 n.d. a Conversion estimates determined by 1H NMR peak integrations. bDetermined by 1H NMR analysis of the crude reaction mixture using an internal standard. cDetermined by chiral HPLC analysis after Boc-protection.

Represents the enantiomeric ratio of the major diastereomer. dRun with PhMe as solvent at 35 °C.

4.3.3 Preliminary Investigations into Generating Quaternary Stereogenic Centers

161 While the bulk of our efforts have focused on employing configurationally labile aldehydes in the enantioconvergent iso-Pictet-Spengler reaction, preliminary studies suggest ketones may also be viable. Under co-catalytic conditions with thiourea 4.16 and benzoic acid in toluene, α-methyl β-keto ester 4.35 provided THγC 4.36 in 69% yield and 3.4:1 dr (Scheme

4-14A). Increasing the temperature to 75 °C improved the yield, but lowered diastereoselectivity. α-Keto ester 4.37 also participated in the iso-Pictet-Spengler reaction under these conditions, generating THγC 4.38 in 79% yield and 3.2:1 dr at 35 °C, with similar results obtain at 75 °C (Scheme 4-14B). Unfortunately, our attempts to Boc-protect these products have been unsuccessful thus far, and as a result, the product remains too polar for

HPLC analysis. Still, these preliminary results suggest we can provide access to an array of

THγCs bearing a quaternary stereogenic center, and efforts to N-protect the substrate, analyze enantioenrichment, and optimize the reaction are ongoing.

Scheme 4-14. Co-Catalyzed Iso-Pictet-Spengler Reaction with α- and β-Keto Esters

4.4 Conclusion

162 In conclusion, we have developed an enantioconvergent protioiminium iso-Pictet-

Spengler reaction using Brønsted acid‒thiourea co-catalysis. Using α-substituted β-formyl ethyl esters, the transformation provides access to enantioenriched and unprotected tetrahydro-

γ-carbolines bearing two contiguous stereocenters, including an exocyclic stereogenic center and an orthogonal ester functional handle for downstream diversification. Future work will include further optimization of the scope of α-substituted β-formyl ethyl esters, as well as efforts to enantioselectively establish a quaternary stereogenic center in the iso-Pictet-Spengler reaction with α- and β-keto esters.

4.5 Experimental Details

Methods: Proton magnetic resonance spectra (1H NMR) were recorded on a Bruker model

Whatman 0.25 mm silica gel 60 plates, Sorbent Technologies 0.20 mm Silica Gel TLC plates.

Visualization was allowed by UV light, phosphomolybdic acid in ethanol, aqueous ceric ammonium nitrate solution, ninhydrin solution, or KMnO4. HPLC analysis was performed on a Perkin Elmer flexar photodiode array (PDA) system equipped with a Daicel Chiralpak IC column. Aluminum bead baths were used to heat reaction vessels. Purification of the reaction products was carried out by using Siliaflash-P60 silica gel (40-63μm) purchased from

Silicycle. Yields refer to isolated yields after flash column chromatography. NMR yields were obtained using phenanthrene as an internal standard. The relative and absolute

163 stereoconfiguration of Boc-protected 4.28a was determined using X-ray diffraction analysis, and the stereochemistry of products 4.28 was assigned by analogy.

Materials: Solvents were used as received, unless noted otherwise as dry. Dry solvents were passed through a column of neutral alumina under a stream of nitrogen prior to use. Reagents were obtained from Millipore Sigma, Fischer Scientific, or Oakwood Chemical Supply and used as received. Ethyl 2-methyl-3-oxobutanoate (4.35) was purchased and used as received.

Catalyst Synthesis

(S)-N-Benzyl-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-N,3-

dimethylbutanamide (4.20): The title compound was

synthesized as reported by Jacobsen, et al.70 1H NMR spectroscopic data matches those reported.

(S)-N-Benzyl-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-N,3,3-

trimethylbutanamide (4.30): The title compound was

synthesized as reported by Jacobsen, et al.68 1H NMR spectroscopic data matches those reported.

(S)-N-Benzhydryl-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-N,3,3-

trimethylbutanamide (4.16): The title compound was

synthesized as reported by Jacobsen, et al.68,77 1H NMR spectroscopic data matches those reported.77

164

(S)-N-(Bis(3,5-dimethylphenyl)methyl)-2-(3-(3,5-

bis(trifluoromethyl)phenyl)thioureido)-N,3,3-

trimethylbutanamide (4.33): The title compound was

synthesized as reported by Jacobsen, et al.62,68 1H NMR spectroscopic data matches those reported.62

1-((1R,2R)-2-Aminocyclohexyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea: The title

compound was synthesized as reported by Kang, et al.,64 and purified

according to Falck, et al.78,79 (1R,2R)-Cyclohexane-1,2-diamine was prepared as reported by Rawal, et al.80 1H NMR spectroscopic data matches those reported.79

2-(((1R,2R)-2-(3-(3,5-Bis(trifluoromethyl)phenyl)thioureido)cyclohexyl)carbamoyl)-

3,4,5,6-tetrabromobenzoic acid (4.21): The title compound

was synthesized as reported by Seidel, et al.71,81 1H NMR

spectroscopic data matches those reported.81

165 N-Methyl-9H-fluoren-9-amine: The title compound was prepared via a

modified procedure from Bhattacharyya, et al.82 A solution of methanamine (8.4

M in EtOH, 33.0 mmol, 3 equiv) was dissolved in MeOH (37 mL). Titanium (IV) isopropoxide

(4.3 mL, 14.5 mmol, 1.32 equiv) was added, followed by 9H-fluoren-9-one (1.98 g, 11.0 mmol,

1.0 equiv). The reaction mixture was stirred for 5 h at room temperature, then NaBH4 (416 mg,

11.0 mmol, 1.0 equiv) was added and the mixture was stirred for another 2 h. The reaction was quenched with water, and the inorganic precipitate was filtered through Celite and washed with

Et2O. The layers were separated, then the aqueous layer was extracted with Et2O (2x). The combined organics were washed with 2 M HCl (2x), and the aqueous layers were basified to pH = 10 by slow addition of 2.5 M NaOH. The aqueous mixture was extracted with Et2O (2x) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo.

The crude material was purified via flash column chromatography to provide pure product. 1H

NMR (400 MHz, Chloroform-d) δ 7.74 (dt, J = 7.5, 1.0 Hz, 2H), 7.62 (dq, J = 7.3, 0.8 Hz,

2H), 7.41 (tdd, J = 7.4, 1.3, 0.6 Hz, 2H), 7.35 (td, J = 7.4, 1.2 Hz, 2H), 4.94 (s, 1H), 2.23 (s,

3H), 1.91 (s, 1H).

tert-Butyl (S)-(1-((9H-fluoren-9-yl)(methyl)amino)-3,3-dimethyl-1-

oxobutan-2-yl)carbamate: The title compound was prepared via a

modified procedure from Jacobsen, et al.83 A flame-dried flask under a stream of N2 was charged with (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid

(1.39 g, 6.0 mmol, 1.0 equiv) and dissolved in DCM (12 mL). Then, HBTU (2.5 g, 6.6 mmol,

1.1 equiv), N-methyl-9H-fluoren-9-amine (1.63 g, 8.4 mmol, 1.4 equiv), and DIPEA (2.1 mL,

12.0 mmol, 2.0 equiv) were added sequentially. The reaction was stirred at room temperature

166 for 3 days, then the resulting orange mixture was diluted with Et2O and washed with 1 M HCl

(2x), satd. aq. NaHCO3, and brine. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via flash column chromatography (10% to 30% EtOAc:Hex) to provide the desired product (2.2 g, 88% yield).

The title compound appeared as a 5:1 mixture of rotamers in the NMR spectrum. Major

Rotamer: 1H NMR (600 MHz, Chloroform-d) δ 7.80 – 7.70 (m, 2H), 7.49 – 7.37 (m, 4H), 7.37

– 7.30 (m, 2H), 6.93 (s, 1H), 5.45 (d, J = 9.9 Hz, 1H), 4.62 (d, J = 9.9 Hz, 1H), 2.53 (s, 3H),

1.57 (s, 9H), 1.16 (s, 9H).

(S)-2-(3-(3,5-Bis(trifluoromethyl)phenyl)thioureido)-N-

(9H-fluoren-9-yl)-N,3,3-trimethylbutanamide (4.31): The

title compound was prepared via a modified procedure from

68,83 Jacobsen, et al. A flask was flame dried, cooled under a stream of N2, and charged with tert-butyl (S)-(1-((9H-fluoren-9-yl)(methyl)amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

(2.16 g, 5.28 mmol, 1.0 equiv) and 4 M HCl in dioxane (8.6 mL, 34.3 mmol, 6.5 equiv). The reaction was stirred at rt for 2 h, then the solution was concentrated in vacuo. The crude primary amine was subsequently dissolved in DCM (26 mL), followed by addition of TEA (2.21 mL,

15.8 mmol, 3 equiv) and 1-isothiocyanato-3,5-bis(trifluoromethyl)benzene (1.1 mL, 5.81 mmol, 1.1 equiv). The reaction was stirred at rt for 4 h, then the mixture was concentrated in vacuo. The crude material was purified via flash column chromatography (30% EtOAc:Hex) to provide pure product. The title compound appeared as an 8.3:1 mixture of rotamers in the

NMR spectrum. Major Rotamer: 1H NMR (400 MHz, Chloroform-d) δ 9.33 (s, 1H), 8.03 –

7.92 (m, 2H), 7.84 – 7.68 (m, 3H), 7.62 (s, 1H), 7.42 – 7.32 (m, 3H), 7.24 – 7.17 (m, 1H), 7.17

167 – 7.09 (m, 1H), 6.82 (s, 1H), 5.69 (d, J = 9.0 Hz, 1H), 2.69 (s, 3H), 1.28 (d, J = 1.8 Hz, 9H).

Bis(3,5-di-tert-butylphenyl)methanone: The title compound was

prepared via modified procedures from Liu and Marchese.84,85 A two-

necked flask was charged with magnesium turnings (1.35 g, 55.5 mmol,

3.0 equiv), flame-dried under vacuum, and cooled under a stream of N2. Enough THF was added to cover the magnesium turnings, followed by addition of an iodine crystal. A small portion of 1-bromo-3,5-di-tert-butylbenzene (1.2 g, 4.4 mmol, 0.24 equiv) was added portionwise until the yellow reaction mixture turned colorless, indicating initiation of the

Grignard reaction. Alternating portionwise additions of THF (90 mL) and 1-bromo-3,5-di-tert- butylbenzene (11.95g, 44.4 mmol, 2.4 equiv total) were completed, then the reaction was stirred at 70 °C for 4 h before cooling to rt. In a separate flask CDI (3.00 g, 18.5 mmol, 1 equiv) was dissolved in THF (90 mL, 0.5 M) and cooled to -78 °C. The Grignard reagent was added dropwise via syringe, then stirred at -78 °C for 30 min and room temperature for 1 h. The mixture was quenched with 1 M HCl, then extracted with EtOAc (3x). The combined organic

168 extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Baseline impurities removed via flash column chromatography (100% Hex to 10% EtOAc:Hex) to provide product with sufficient purity for the subsequent step. 1H NMR (500 MHz, Chloroform-d) δ 7.71 –

7.69 (m, 4H), 7.69 – 7.66 (m, 2H), 1.38 (s, 36H).

1,1-Bis(3,5-di-tert-butylphenyl)-N-methylmethanamine: The title

compound was prepared via a modified procedure from Bhattacharyya,

et al.82 A solution of methanamine (8.4 M in EtOH, 1.8 mL, 15.0 mmol,

3.0 equiv) was dissolved in MeOH (5.6 mL). Titanium (IV) isopropoxide (2.0 mL, 6.6 mmol,

1.32 equiv) was added, followed by bis(3,5-di-tert-butylphenyl)methanone (2.03 g, 5.0 mmol,

1.0 equiv). The reaction mixture was stirred for 16 h at room temperature, then NaBH4 (189 mg, 5.0 mmol, 1.0 equiv) was added and the mixture was stirred for another 2 h, then additional

NaBH4 (189 mg, 5.0 mmol, 1.0 equiv) was added and the reaction mixture was stirred for an additional 3 h. The reaction was quenched with water, and the precipitate was filtered through

Celite and washed with Et2O. The layers were separated, then the aqueous layer was extracted with Et2O (2x). The combined organics were washed with 2 M HCl (2x), and the aqueous layers were basified to pH = 10 by slow addition of 2.5 M NaOH. The aqueous mixture was extracted with Et2O (2x) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified using flash column chromatography (0% to 2.5% MeOH:DCM) to provide a fluffy white solid (1.19 g, 56% yield).

1H NMR (500 MHz, Chloroform-d) δ 7.31 – 7.30 (m, 4H), 7.28 – 7.26 (m, 2H), 4.69 (s, 1H),

2.44 (s, 3H), 1.32 (s, 36H).

169 tert-Butyl (S)-(1-((bis(3,5-di-tert-butylphenyl)methyl)(methyl)amino)-3,3-dimethyl-1-

oxobutan-2-yl)carbamate: The title compound was prepared via a

modified procedure from Jacobsen, et al.83 A flame-dried flask under

N2 was charged with (S)-2-((tert-butoxycarbonyl)amino)-3,3- dimethylbutanoic acid (435 mg, 1.9 mmol, 1.0 equiv) and dissolved in DCM (3.8 mL). Then,

HBTU (784 mg, 2.1 mmol, 1.1 equiv), 1,1-bis(3,5-di-tert-butylphenyl)-N-methylmethanamine

(1.19 g, 2.8 mmol, 1.5 equiv), and DIPEA (0.66 mL, 3.8 mmol, 2.0 equiv) were added sequentially. The reaction was stirred at rt for 3 days, then the resulting orange mixture was diluted with Et2O and washed with 1 M HCl (2x), satd. aq. NaHCO3, and brine. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via flash column chromatography (column 1: 5% to 25% Et2O:Hex, column 2: 0% to 2% MeOH:DCM) to provide a white solid (1.12 g, 94% yield). The product appeared as a 4.2:1 mixture of rotamers in the NMR spectrum. Major Rotamer: 1H NMR (500

MHz, Chloroform-d) δ 7.36 – 7.31 (m, 2H), 7.18 (s, 1H), 7.06 – 7.03 (m, 2H), 7.03 – 7.00 (m,

2H), 5.40 (d, J = 9.8 Hz, 1H), 4.64 (d, J = 9.9 Hz, 1H), 2.90 (s, 3H), 1.45 (s, 9H), 1.30 (s, 18H),

1.29 (s, 18H), 1.06 (s, 9H).

(S)-2-Amino-N-(bis(3,5-di-tert-butylphenyl)methyl)-N,3,3-trimethylbutanamide: The

title compound was prepared via a modified procedure from Jacobsen,

83 et al. A flame-dried flask under N2 was charged with tert-butyl (S)-

(1-((bis(3,5-di-tert-butylphenyl)methyl)(methyl)amino)-3,3-dimethyl-

1-oxobutan-2-yl)carbamate (1.12 g, 1.73 mmol, 1.0 equiv) and dry DCM (8.7 mL) was added.

Then, TEA (0.48 mL, 3.47 mmol, 2.0 equiv) was added, and the reaction was cooled to 0 °C

170 before dropwise addition of TMSOTf (1.9 mL, 10.4 mmol, 6 equiv). The solution was stirred at 0 °C for 1 h, then the mixture was treated slowly with satd. aq. NaHCO3. The mixture was transferred to a separatory funnel and diluted with satd. aq. NaHCO3 and DCM. The layers were mixed with venting, then separated. The aqueous layer was extracted with DCM, then the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in DCM and filtered through a silica plug (1:1:0.4 DCM:Et2O:MeOH) to remove baseline impurities, providing the primary amine (877 mg, 1.73 mmol, 95% yield) in sufficient purity for the next step. The product appeared as a 3:1 mixture of rotamers in the

NMR spectrum. Major Rotamer: 1H NMR (400 MHz, Chloroform-d) δ 7.34 – 7.32 (m, 1H),

7.31 – 7.30 (m, 1H), 7.16 (s, 1H), 7.07 – 7.04 (m, 2H), 7.03 – 7.01 (m, 2H), 5.30 (s, 1H), 2.85

(s, 3H), 1.28 (s, 18H), 1.26 (s, 18H), 1.02 (s, 9H).

(S)-N-(Bis(3,5-di-tert-butylphenyl)methyl)-2-(3-(3,5-

bis(trifluoromethyl)phenyl)thioureido)-N,3,3-

trimethylbutanamide (4.34): The title compound was

prepared via a modified procedure from Jacobsen, et

68,83 al. A flask was flame dried, cooled under a stream of N2, and charged with (S)-2-amino-N-

(bis(3,5-di-tert-butylphenyl)methyl)-N,3,3-trimethylbutanamide (877 mg, 1.64 mmol, 1.0 equiv). DCM (5.1 mL) was added, followed by 1-isothiocyanato-3,5- bis(trifluoromethyl)benzene (0.30 mL, 1.66 mmol, 1.0 equiv). The reaction was stirred at rt for

2 h, then the mixture was concentrated in vacuo. The crude material was purified via flash column chromatography to provide pure product (1.16 g, 88% yield). The product appeared as a 7:1 mixture of rotamers in the NMR spectrum. Major Rotamer: 1H NMR (400 MHz,

171 Chloroform-d) δ 9.28 (s, 1H), 7.96 (s, 2H), 7.62 (s, 1H), 7.37 – 7.34 (m, 1H), 7.28 – 7.26 (m,

1H), 7.08 (s, 1H), 7.07 – 7.03 (m, 2H), 6.96 – 6.90 (m, 2H), 5.66 (d, J = 9.3 Hz, 1H), 3.04 (s,

3H), 1.29 (s, 18H), 1.25 (s, 18H), 1.10 (s, 9H).

Starting Material Synthesis

See Scheme 4-7 for synthetic route to iso-tryptamine.

(1H-Indol-2-yl)methanol: The title compound was synthesized as reported by

Jaitak, et al. starting from ethyl 1H-indole-2-carboxylate.86 1H NMR spectroscopic data matches those reported.

(E)-2-(2-Nitrovinyl)-1H-indole: The title compound was synthesized as reported by Tarzia,

et al. starting from (1H-indol-2-yl)methanol.55 1H NMR spectroscopic data

matches those reported.87

2-(1H-Indol-2-yl)ethan-1-amine (4.23): The title compound was synthesized as reported by

Cossy, et al.88 1H NMR spectroscopic data matches those reported. Note that if

reaction time is extended, over-reduction to the indoline can occur.

2-Methyl-3-morpholino-3-oxopropanal (4.24): The title compound was

synthesized as reported by Johnson, et al.75 1H NMR spectroscopic data matches those reported.

172 Ethyl 2-oxo-3-phenylbutanoate (4.37): The title compound was synthesized

as reported by Johnson, et al.89 1H NMR spectroscopic data matches those reported.

General procedure A ‒ Synthesis of α-substituted β-formyl ethyl esters: The title compounds were synthesized according to an adapted procedure from Tius, et al.90 A flame- dried flask was cooled under a stream of N2 and charged with ester (1.0 equiv), ethyl formate

(30 equiv), and dry DCM (0.6 M). The solution was cooled to 0 °C, then TiCl4 (2.0 equiv) and

TEA (2.4 equiv) were added dropwise. The reaction mixture was stirred at 0 °C for 1 h, then warmed to room temperature and stirred for another 1 h. The mixture was then poured onto ice-cold water and the aqueous layer was extracted with DCM (3x). The combined organic layers were washed with water and brine, then dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via flash column chromatography.

Ethyl 2-formyl-3-methylbutanoate (4.26a): The title compound was

synthesized according to General Procedure A from ethyl 3-methylbutanoate

(3.00 mL, 19.9 mmol, 1.0 equiv). The product was obtained as a 1.4:1 mixture of aldehyde:enol. Aldehyde: 1H NMR (400 MHz, Chloroform-d) δ 9.73 (d, J = 3.9 Hz, 1H), 4.31

– 4.25 (m, 2H), 2.99 (dd, J = 8.0, 3.9 Hz, 1H), 2.52 – 2.39 (m, 1H), 1.31 (t, J = 6.1 Hz, 3H),

1.05 (dd, J = 6.8, 1.6 Hz, 7H). Enol: 1H NMR (400 MHz, Chloroform-d) δ 11.64 (d, J = 12.3

Hz, 1H), 7.06 (d, J = 12.3 Hz, 1H), 4.28 – 4.21 (m, 2H), 2.68 – 2.56 (m, 1H), 1.33 (t, J = 6.8

Hz, 3H), 1.11 (d, J = 6.9 Hz, 6H).

173 Ethyl 2-methyl-3-oxopropanoate (4.26b): The title compound was

synthesized according to General Procedure A using ethyl propionate (0.8 mL,

6.93 mmol, 1.0 equiv). Removal of baseline impurities removed via flash column chromatography (20% Et2O:Pet Ether) provided the product in approximately 81% purity after flash column chromatography. The product was isolated as a 2.2:1 mixture of enol:aldehyde.

Enol: 1H NMR (500 MHz, Chloroform-d) δ 11.36 (d, J = 12.5 Hz, 1H), 7.03 (d, J = 12.4 Hz,

1H), 4.27 (q, J = 7.2 Hz, 3H), 1.70 (d, J = 1.2 Hz, 3H), 1.40 – 1.27 (m, 3H). Aldehyde: 1H

NMR (500 MHz, Chloroform-d) δ 9.82 (d, J = 1.5 Hz, 1H), 4.06 (q, J = 7.0 Hz, 2H), 3.41 (qd,

J = 7.2, 1.5 Hz, 1H), 1.76 (d, J = 1.2 Hz, 4H), 1.41 – 1.25 (m, 6H).

Ethyl 2-formyloctanoate (4.26c): The title compound was synthesized

according to General Procedure A using ethyl octanoate (0.80 mL, 4.00 mmol,

1.0 equiv). The product was obtained as a 1.5:1 mixture of enol:aldehyde. Enol: 1H NMR (500

MHz, Chloroform-d) δ 11.47 (d, J = 12.4 Hz, 1H), 7.02 (d, J = 12.4 Hz, 1H), 4.32 – 4.22 (m,

2H), 2.07 (t, J = 7.5 Hz, 2H), 1.45 – 1.23 (m, 9H), 0.91 (td, J = 7.0, 2.8 Hz, 5H). Aldehyde: 1H

NMR (500 MHz, Chloroform-d) δ 9.72 (d, J = 2.6 Hz, 1H), 4.32 – 4.23 (m, 2H), 3.27 (td, J =

7.2, 2.5 Hz, 1H), 1.95 – 1.85 (m, 2H), 1.46 – 1.24 (m, 9H), 0.96 – 0.84 (td, J = 7.0, 2.8 Hz,

4H).

Ethyl 2-methyl-3-oxopropanoate (4.26d): The title compound was synthesized

according to General Procedure A using ethyl 3-phenyl propanoate (0.69 mL,

8.42 mmol, 1.0 equiv). The crude material was purified via flash column chromatography

(2.5% to 5% EtOAc:Hex) to provide the product an oil (333 mg, 58% yield). The product was

174 isolated as a 3:1 mixture of enol:aldehyde. Enol: 1H NMR (500 MHz, Chloroform-d) δ 11.56

(d, J = 12.5 Hz, 1H), 7.33 – 7.28 (m, 3H), 7.24 – 7.19 (m, 2H), 7.10 (d, J = 12.5 Hz, 1H), 4.20

(q, J = 7.0 Hz, 2H), 3.43 (s, 2H), 1.25 (t, J = 7.1 Hz, 3H). Aldehyde: 1H NMR (500 MHz,

Chloroform-d) δ 9.78 (d, J = 1.9 Hz, 1H), 7.34 – 7.31 (m, 3H), 7.28 – 7.24 (m, 2H), 4.24 –

4.17 (m, 3H), 3.26 (dd, J = 14.2, 6.7 Hz, 1H), 3.21 (dd, J = 14.2, 8.0 Hz, 1H), 1.30 – 1.25 (m,

3H).

Enantioconvergent iso-Pictet Spengler Reaction

1-morpholino-2-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-

yl)propan-1-one (4.25): A one-dram vial was charged with iso-tryptamine

(147 mg, 0.10 mmol, 1.0 equiv), 2-methyl-3-morpholino-3-oxopropanal

(138 mg, 0.10 mmol, 1.0 equiv), and CHCl3 (1.0 mL). The reaction was stirred for 1 h at rt then concentrated in vacuo. Analysis by 1H NMR spectroscopy showed 100% conversion to product. The diastereomeric ratio was calculated using proton resonances at 4.50 ppm (major) and 4.79 ppm (minor). 1H NMR (500 MHz, Chloroform-d) δ 8.23 (bs, 1H), 7.42 (d, J = 7.9

Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 4.50 (d, J

= 5.3 Hz, 1H), 3.63 – 3.49 (m, 6H), 3.50 – 3.41 (m, 1H), 3.40 – 3.35 (m, 1H), 3.34 – 3.22 (m,

2H), 3.22 – 3.15 (m, 1H), 2.98 – 2.87 (m, 1H), 2.87 – 2.77 (m, 1H), 1.20 (d, J = 6.8 Hz, 3H).

General procedure B ‒ Enantioconvergent iso-Pictet-Spengler reaction: A 1-dram vial was charged with iso-tryptamine (0.08 mmol, 1.0 equiv) and a thiourea catalyst,a, b then the solids were dissolved in DCM or PhMe (0.60 mL). Acidc (0.5 M in PhMe) was subsequently added, followed by addition of α-substituted β-formyl ester or amide (0.4 M in DCM or PhMe,

175 0.088 mmol, 1.1 equiv). The vial was capped and stirred overnight at room temperature for 16-

26 h then quenched with satd. aq. NaHCO3 and diluted with DCM or EtOAc. The layers were separated and aqueous layer was extracted (3x). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude material was purified via flash column chromatography.

General procedure C ‒ One-pot enantioconvergent iso-Pictet-Spengler reaction and Boc- protection: A 1-dram vial was charged with iso-tryptamine (0.08 mmol, 1.0 equiv) and a thiourea catalyst,a, b then the solids were dissolved in DCM or PhMe (0.60 mL). An acidc (0.5

M in PhMe) was subsequently added, followed by addition of α-substituted β-formyl ester or amide (0.4 M in DCM or PhMe, 0.088 mmol, 1.1 equiv). The vial was capped and stirred overnight at room temperature. After 16-26 h, satd. aq. NaHCO3 (150 μL) and Boc2O (25 μL,

0.11 mmol, 1.33 equiv) were added and the reaction was stirred at room temperature for 1 h.

The layers were separated, and the aqueous layer was extracted with DCM or EtOAc (3x). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude material was purified via flash column chromatography. a For catalyst loadings and reaction times see tables in section 4.4. b Racemic reactions accomplished using either diphenylphosphinic acid (10 mol %) or benzoic acid (10 mol %) and Schreiner’s thiourea (N,N′−bis[3,5−bis(trifluoromethyl)phenyl]−thiourea)

(20 mol %). c BzOH, AcOH, and TFA were added as a solution. p-NO2 and p-OMe benzoic acids were added neat due to poor solubility in DCM or PhMe. See Table 4-5 for acid screen.

176 General Procedure D ‒ Boc-protection: Tetrahydro-γ-carboline (0.08 mmol, 1.0 equiv) was dissolved in a 2:1 mixture of EtOAc:satd. aq. NaHCO3 (0.45 mL). Boc2O (25 μL, 0.11 mmol,

1.33 equiv) was subsequently added and the reaction was stirred at rt for 1 h. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via flash column chromatography.

Ethyl 3-methyl-2-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-

yl)butanoate (4.28a): The title compound was synthesized according to

General Procedure B from iso-tryptamine (12.8 mg, 0.080 mmol, 1.0 equiv) and ethyl 2-formyl-3-methylbutanoate (0.088 mmol, 15.5 mg, 1.10 equiv). The product was purified using flash column chromatography (100% DCM to 30% MeOH:DCM). The product was recrystallized for X-ray diffraction analysis by dissolution in minimal hot ethyl acetate, followed by vapor diffusion with pentanes for at least 48 h. The diastereomeric ratio was calculated using proton resonances at 0.63 ppm (major) and 0.88 ppm (minor). 1H NMR (500

MHz, Chloroform-d) δ 8.49 (bs, 1H), 7.58 – 7.52 (m, 1H), 7.31 – 7.25 (m, 1H), 7.17 – 7.06

(m, 2H), 4.57 (app s, 1H), 3.86 – 3.78 (m, 1H), 3.76 – 3.68 (m, 1H), 3.53 – 3.40 (m, 1H), 3.17

– 3.02 (m, 2H), 2.94 – 2.85 (m, 1H), 2.77 – 2.67 (m, 1H), 2.59 (d, J = 15.8 Hz, 1H), 2.50 –

2.39 (m, 1H), 1.23 (d, J = 6.6 Hz, 3H), 1.05 (d, J = 6.6 Hz, 3H), 0.63 (t, J = 7.1 Hz, 3H). The enantiomeric ratio was determined using the Boc-protected product.

177 tert-Butyl 1-(1-ethoxy-3-methyl-1-oxobutan-2-yl)-1,3,4,5-tetrahydro-

2H-pyrido[4,3-b]indole-2-carboxylate: The title compound was

synthesized according to General Procedure D from ethyl 3-methyl-2-

(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-yl)butanoate (32.0 mg, 0.08 mmol, 1.0 equiv).

The crude material was purified using flash column chromatography (100% DCM then 10% to 30% EtOAc:Hex). The product appeared as a 1.3:1 mixture of rotamers in the 1H NMR spectrum. Major: 1H NMR (400 MHz, Chloroform-d) δ 8.20 (s, 1H), 7.57 (t, J = 8.4 Hz, 1H),

7.37 – 7.30 (m, 1H), 7.22 – 7.01 (m, 2H), 5.73 (d, J = 8.9 Hz, 1H), 4.48 (dd, J = 14.0, 6.7 Hz,

1H), 4.19 – 3.91 (m, 2H), 3.48 (td, J = 12.8, 4.8 Hz, 1H), 3.02 – 2.83 (m, 2H), 2.64 (d, J = 4.6

Hz, 1H), 2.26 (dp, J = 13.3, 6.7 Hz, 1H), 1.49 (s, 9H), 1.35 – 1.24 (m, 6H), 1.16 (t, J = 7.1 Hz,

3H). Minor: 1H NMR (400 MHz, Chloroform-d) δ 8.09 (s, 1H), 7.57 (t, J = 8.4 Hz, 1H), 7.34

– 7.29 (m, 1H), 7.21 – 7.05 (m, 2H), 5.88 (d, J = 9.1 Hz, 1H), 4.27 (dd, J = 14.1, 6.5 Hz, 1H),

4.22 – 3.89 (m, 2H), 3.63 (td, J = 13.1, 4.6 Hz, 1H), 3.02 – 2.85 (m, 2H), 2.60 (d, J = 4.7 Hz,

1H), 2.26 (dp, J = 13.3, 6.7 Hz, 1H), 1.11 – 1.00 (m, 9H). HPLC (91:9 hexanes:iPrOH, Daicel

Chiralpak IC Column, flow rate = 1.0 mL/min, λ = 210 nm): tR (major diastereomer) = 13.5,

14.5 min, tR (minor diastereomer) = 10.5 min, 12.2 min.

Ethyl 2-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-yl)propanoate

(4.28b): The title compound was synthesized according to General Procedure

B using iso-tryptamine (12.9 mg, 0.08 mmol, 1.0 equiv) and ethyl 2-methyl-

3-oxopropanoate (12.7 mg, 0.088 mmol, 1.1 equiv). The crude material was purified using flash column chromatography (0% to 5% MeOH:DCM). The purified material was taken directly onto Boc-protection without NMR analysis.

178

tert-Butyl 1-(1-ethoxy-1-oxopropan-2-yl)-1,3,4,5-tetrahydro-2H-

pyrido[4,3-b]indole-2-carboxylate: The title compound was synthesized

according to General Procedure D from ethyl 2-(2,3,4,5-tetrahydro-1H- pyrido[4,3-b]indol-1-yl)propanoate (29.8 mg, 0.08 mmol, 1.0 equiv). The crude material was purified using flash column chromatography (100% DCM then 10% to 20% EtOAc:Hex). The product was isolated as a 1.6:1 mixture of diastereomers, and appeared as a 1.3:1 mixture of rotamers in the 1H NMR spectrum. For the 1H NMR spectrum, all peaks are reported as observed (as opposed to ratio-resolved) due to numerous overlapping peaks. 1H NMR (400

MHz, Chloroform-d) δ 8.05 (s, 1H), 8.01 (s, 1H), 7.98 (s, 1H), 7.62 – 7.54 (m, 2H), 7.54 – 7.45

(m, 2H), 7.36 – 7.26 (m, 3H), 7.22 – 7.02 (m, 6H), 5.80 (d, J = 6.9 Hz, 1H), 5.67 (d, J = 9.3

Hz, 1H), 5.58 (d, J = 8.6 Hz, 1H), 5.53 (d, J = 8.5 Hz, 1H), 4.59 (dd, J = 13.7, 6.4 Hz, 1H),

4.53 (dd, J = 13.9, 6.6 Hz, 1H), 4.39 (dd, J = 13.6, 6.0 Hz, 1H), 4.32 (dd, J = 14.0, 6.3 Hz, 1H),

4.23 – 4.00 (m, 6H), 4.00 – 3.87 (m, 1H), 3.63 – 3.51 (m, 1H), 3.51 – 3.33 (m, 2H), 3.24 (td, J

= 12.8, 4.6 Hz, 1H), 3.12 – 3.00 (m, 3H), 3.00 – 2.83 (m, 3H), 2.76 – 2.60 (m, 3H), 1.50 (s,

11H), 1.47 (s, 11H), 1.45 – 1.40 (m, 1H), 1.38 (d, J = 7.0 Hz, 2H), 1.33 – 1.25 (m, 5H). HPLC

i (91:9 hexanes: PrOH, Daicel Chiralpak IC Column, flow rate = 1.0 mL/min, λ = 210 nm): tR

(diastereomer 1) = 9, 10 min, tR (diastereomer 2) = 11, 12 min.

Ethyl 2-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-yl)octanoate

(4.28c): The title compound was synthesized according to General Procedure

B using iso-tryptamine (12.9 mg, 0.08 mmol, 1.0 equiv) and ethyl 2- formyloctanoate (19.6 mg, 0.088 mmol, 1.1 equiv). The crude material was purified using flash

179 column chromatography (0% to 5% MeOH:DCM). The diastereomeric ratio was calculated using proton resonances at 4.47 ppm (major) and 4.63 ppm (minor). Major: 1H NMR (400

MHz, Chloroform-d) δ 8.17 (s, 1H), 7.61 – 7.49 (m, 1H), 7.37 – 7.27 (m, 1H), 7.22 – 7.05 (m,

2H), 4.47 (d, J = 6.4 Hz, 1H), 4.22 – 4.11 (m, 1H), 4.06 – 3.87 (m, 2H), 3.57 – 3.43 (m, 1H),

3.31 – 3.22 (m, 1H), 3.12 – 3.00 (m, 1H), 2.79 – 2.63 (m, 1H), 2.08 (s, 1H), 1.93 – 1.73 (m,

2H), 1.46 – 1.22 (m, 7H), 0.97 – 0.85 (m, 4H).

tert-Butyl 1-(1-ethoxy-1-oxooctan-2-yl)-1,3,4,5-tetrahydro-2H-

pyrido[4,3-b]indole-2-carboxylate: The title compound was synthesized

according to General Procedure D from ethyl 2-(2,3,4,5-tetrahydro-1H- pyrido[4,3-b]indol-1-yl)octanoate (35.4 mg, 0.08 mmol, 1.0 equiv). The crude material was purified using flash column chromatography (100% DCM then 10% to 20% EtOAc:Hex). The product was isolated as a 5:1 mixture of diastereomers, and appeared as a 1.4:1 mixture of rotamers in the 1H NMR spectrum. Major rotamer: 1H NMR (400 MHz, Chloroform-d) δ 7.92

(s, 1H), 7.59 (t, J = 7.6 Hz, 1H), 7.40 – 7.30 (m, 1H), 7.24 – 7.02 (m, 2H), 5.51 (d, J = 9.0 Hz,

1H), 4.51 (dd, J = 13.8, 6.6 Hz, 1H), 4.21 – 3.99 (m, 2H), 3.54 – 3.42 (m, 1H), 3.07 – 2.84 (m,

2H), 2.71 – 1.67 (s, 1H), 2.09 – 1.86 (m, 2H), 1.46 (s, 9H), 1.34 – 1.07 (m, 11H), 0.85 (t, J =

6.7 Hz, 3H). Minor rotamer: 1H NMR (400 MHz, Chloroform-d) δ 7.86 (s, 1H), 7.59 (t, J =

7.6 Hz, 1H), 7.39 – 7.30 (m, 1H), 7.24 – 7.02 (m, 2H), 5.68 (d, J = 9.3 Hz, 1H), 4.35 – 4.25

(m, 1H), 4.21 – 3.98 (m, 2H), 3.65 – 3.55 (m, 1H), 3.08 – 2.78 (m, 2H), 2.67 – 2.60 (m, 1H),

1.85 – 1.68 (m, 2H), 1.46 (s, 9H), 1.36 – 1.09 (m, 11H), 0.85 (t, J = 6.7 Hz, 3H).

180 Ethyl 3-phenyl-2-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-

yl)propanoate (4.28d): The title compound was synthesized according to

General Procedure C using iso-tryptamine (12.9 mg, 0.08 mmol, 1.0 equiv) and ethyl 2-formyloctanoate (20.1 mg, 0.088 mmol, 1.1 equiv). The crude material was purified using flash column chromatography (0% to 0.2% to 5% MeOH:DCM). The diastereomeric ratio was calculated using proton resonances at 4.52 ppm (major) and 4.63 ppm

(minor). 1H NMR (400 MHz, Chloroform-d) δ 8.01 (s, 1H), 7.63 – 7.60 (m, 1H), 7.33 – 7.12

(m, 9H), 4.52 (d, J = 6.6 Hz, 1H), 3.94 – 3.77 (m, 2H), 3.60 – 3.54 (m, 1H), 3.51 – 3.45 (m,

1H), 3.37 – 3.28 (m, 1H), 3.25 – 3.17 (m, 1H), 3.15 – 3.04 (m, 1H), 2.81 – 2.61 (m, 2H), 2.33

(s, 1H), 0.77 (t, J = 7.1 Hz, 3H).

tert-Butyl 1-(1-ethoxy-1-oxo-3-phenylpropan-2-yl)-1,3,4,5-tetrahydro-

2H-pyrido[4,3-b]indole-2-carboxylate: The title compound was

synthesized according to General Procedure D from ethyl 3-phenyl-2-

(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-yl)propanoate (35.8 mg, 0.08 mmol, 1.0 equiv).

The crude material was purified using flash column chromatography (100% DCM then 10% to 20% EtOAc:Hex). The product appeared as a 1.3:1 mixture of rotamers in the 1H NMR spectrum. When General Procedure C was used, the diastereomeric ratio was calculated by adding peaks at 4.54 and 4.34, then dividing by the summation of peaks at 4.66 and 4.44. For the 1H NMR data, all peaks are reported as observed (as opposed to ratio-resolved) due to numerous overlapping peaks. 1H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 8.05 (s, 1H),

7.69 (d, J = 7.4 Hz, 1H), 7.65 (d, J = 6.0 Hz, 1H), 7.40 – 7.28 (m, 2H), 7.28 – 7.06 (m, 12H),

5.75 – 5.57 (m, 1H), 4.54 (dd, J = 14.0, 6.7 Hz, 1H), 4.34 (dd, J = 14.3, 6.3 Hz, 1H), 4.05 –

181 3.79 (m, 4H), 3.68 – 3.57 (m, 1H), 3.56 – 3.43 (m, 1H), 3.33 – 3.20 (m, 4H), 3.14 (t, J = 10.2

Hz, 1H), 3.07 – 2.86 (m, 2H), 2.71 (d, J = 4.7 Hz, 1H), 2.67 (d, J = 4.7 Hz, 1H), 1.48 (s, 14H),

1.01 – 0.82 (m, 8H). HPLC (93:7 hexanes:iPrOH, Daicel Chiralpak IC Column, flow rate =

1.0 mL/min, λ = 210 nm): tR (diastereomer 1) = 9, 15 min, tR (diastereomer 2) = 11, 13 min.

Ethyl 3-phenyl-2-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-

yl)propanoate (4.36): A 1-dram vial was charged with iso-tryptamine (10.0

mg, 0.062 mmol, 1.0 equiv) and ethyl 2-methyl-3-oxobutanoate (7.3 mg,

0.0124 mmol, 0.20 equiv) then the solids were dissolved in PhMe (0.60 mL). Benzoic acid (0.5

M in PhMe, 12.5 μL, 6.25 μmol, 0.10 equiv) was subsequently added, followed by ethyl 2- methyl-3-oxobutanoate (0.4 M in PhMe, 0.20 mL, 0.075 mmol, 1.2 equiv). The vial was capped and stirred overnight at the appropriate temperature for 26 h (see Scheme 4-14). The reaction was quenched with satd. aq. NaHCO3 and diluted with EtOAc. The layers were separated and aqueous layer was extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via flash column chromatography (5% to 15% EtOAc:Hex). The diastereomeric ratio was calculated using proton resonances at 0.58 ppm (major) and 1.00 ppm (minor). Major: 1H

NMR (400 MHz, Chloroform-d) δ 8.08 (s, 2H), 7.56 (d, J = 7.9 Hz, 1H), 7.36 – 7.26 (m, 1H),

7.18 – 7.06 (m, 2H), 4.21 (q, J = 7.1 Hz, 1H), 3.84 – 3.73 (m, 1H), 3.72 – 3.61 (m, 1H), 3.48

– 3.39 (m, 2H), 3.15 – 3.05 (m, 1H), 2.73 (dd, J = 9.6, 5.6 Hz, 1H), 2.69 – 2.65 (m, 1H), 1.63

(s, 3H), 1.44 (d, J = 7.2 Hz, 3H), 0.58 (t, J = 7.1 Hz, 3H).

182 Ethyl 3-phenyl-2-(2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-

yl)propanoate (4.38): A 1-dram vial was charged with iso-tryptamine (10.0

mg, 0.062 mmol, 1.0 equiv) and ethyl 2-oxo-3-phenylbutanoate (7.3 mg,

0.0124 mmol, 0.20 equiv) then the solids were dissolved in PhMe (0.60 mL). Benzoic acid (0.5

M in PhMe, 12.5 μL, 6.25 μmol, 0.10 equiv) was subsequently added, followed by addition of ethyl 2-oxo-3-phenylbutanoate (0.4 M in PhMe, 0.20 mL, 0.075 mmol, 1.2 equiv). The vial was capped and stirred overnight at the appropriate temperature for 26 h (Scheme 4-14). The reaction was quenched with satd. aq. NaHCO3 and diluted with EtOAc. The layers were separated and aqueous layer was extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via flash column chromatography (5% to 15% EtOAc:Hex). The diastereomeric ratio was calculated using proton resonances at 1.07 ppm (major) and 1.38 ppm (minor). Major: 1H

NMR (600 MHz, Chloroform-d) δ 8.19 – 8.11 (m, 1H), 7.97 (s, 1H), 7.39 (d, J = 8.2 Hz, 2H),

7.37 – 7.32 (m, 3H), 7.27 – 7.14 (m, 3H), 4.24 (q, J = 7.0 Hz, 1H), 4.15 – 4.07 (m, 1H), 4.04

– 3.94 (m, 1H), 3.28 – 3.21 (m, 1H), 3.21 – 3.14 (m, 2H), 3.03 – 2.93 (m, 1H), 2.58 (dd, J =

15.1, 2.2 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H), 1.07 (d, J = 7.1 Hz, 3H).

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