Studies Toward the Total Synthesis of (±)-Α-Yohimbine by Double Annulation

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University of Kentucky UKnowledge

University of Kentucky Doctoral Dissertations Graduate School

2010

STUDIES TOWARD THE TOTAL SYNTHESIS OF (±)-α-YOHIMBINE BY DOUBLE ANNULATION

Raghu Ram Chamala University of Kentucky, [email protected]

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Recommended Citation Chamala, Raghu Ram, "STUDIES TOWARD THE TOTAL SYNTHESIS OF (±)-α-YOHIMBINE BY DOUBLE ANNULATION" (2010). University of Kentucky Doctoral Dissertations. 78. https://uknowledge.uky.edu/gradschool_diss/78

This Dissertation is brought to you for free and open access by the Graduate School at UKnowledge. It has been accepted for inclusion in University of Kentucky Doctoral Dissertations by an authorized administrator of UKnowledge. For more information, please contact [email protected]. ABSTRACT OF DISSERTATION

Raghu Ram Chamala

The Graduate School University of Kentucky 2010 STUDIES TOWARD THE TOTAL SYNTHESIS OF (±)-α-YOHIMBINE BY DOUBLE ANNULATION

ABSTRACT OF DISSERTATION

A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Arts and Sciences at the University of Kentucky

ABSTRACT OF DISSERTATION

STUDIES TOWARD THE TOTAL SYNTHESIS OF (±)-α-YOHIMBINE BY DOUBLE ANNULATION

The indole alkaloids, a class of natural products, have received much synthetic attention for years due to their diverse structures and interesting biological properties. We are particularly interested in synthesizing some of the yohimbine alkaloids extracted from the bark of a tall evergreen African tree (Corynanthe yohimbe, commonly known as fringe tree). Yohimbine and its stereoisomers have been tempting targets for synthetic organic chemists for more than fifty years. These compounds feature a pentacyclic ring system with two heteroatoms and five stereogenic centers.

Broadly, the fifteen different synthetic approaches that led to the successful completion of yohimbine alkaloids relied only on two basic synthetic strategies. In the first strategy, the last step almost always was the formation of the C(2)-C(3) bond by either Pictet-Spengler reaction or by Bischler-Napieralski reaction with the concomitant formation of the C ring. The second strategy involved the annulation of the D and E rings onto the intact ABC ring system.

With our double annulation methodology, herein, we report a completely different synthetic approach to access the yohimbine alkaloids, and our disconnections are not even remotely close to the synthetic designs used in the past. Our key steps include double Michael reaction to construct the E ring, an intramolecular cyclization to construct the D ring, and finally, the functionality on the D ring can be elaborated to form the C ring of the yohimbine alkaloids.

KEYWORDS: Yohimbehe, Yohimbine, Double Annulation, Double Michael Reaction, Total Synthesis

Raghu Ram Chamala Student‟s Signature

November 22, 2010. Date

STUDIES TOWARD THE TOTAL SYNTHESIS OF (±)-α-YOHIMBINE BY DOUBLE ANNULATION

By Raghu Ram Chamala

Dr. Robert B. Grossman, Ph.D Director of Dissertation

Dr. John E. Anthony, Ph.D Director of Graduate Studies

November 22, 2010. Date

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Name Date

DISSERTATION

Raghu Ram Chamala

The Graduate School University of Kentucky 2010

STUDIES TOWARD THE TOTAL SYNTHESIS OF (±)-α-YOHIMBINE BY DOUBLE ANNULATION

DISSERTATION

A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Arts and Sciences at the University of Kentucky

Dedicated With Love And Respect To My Dear Parents

Smt. RAJESHWARI CHAMALA And Shri. NARAYANA CHAMALA

ACKNOWLEDGEMENTS This is by far the most important part of my dissertation. This dissertation is a culmination of an amazing journey that wouldn‟t have been possible without the help and support of several people. So it is with tremendous gratitude that I write these acknowledgements to show my appreciation to the people who have helped me throughout the years. First and foremost, I wholeheartedly thank my advisor Dr. Robert B. Grossman for his unwavering support, enthusiasm, and general concern for my development as an organic chemist. I have immeasurably benefited from his wisdom, and his dedication and passion to produce “good science” are inspiring. It has been a great privilege to work under his tutelage. I also would like to thank my dissertation committee: Dr. Arthur Cammers, Dr. Folami Ladipo, and Dr. Jürgen Rohr. I especially like to thank Dr. Arthur Cammers, for teaching me a great deal about organic synthesis in his advanced synthetic chemistry class, for his thoughtful insights, and entertaining group meetings in the initial years of my graduate school. I only wished we continued our group meetings together and did more of those “Synthetic Challenge” assignments. I would also like to thank Dr. Robert Houtz for serving as my outside examiner. I thank Mr. John Layton for his assistance in obtaining several NMR spectra, and Dr. Sean Parkin for obtaining all of my crystal structures. I would like to thank Dr. Fitzgerald Bramwell and Dr. Manjiri Patwardhan for their help and support. I thank all the office and the technical staff, especially, the ever-energetic, Mr. Art Sebesta for providing the technical support to our lab. I am grateful to the Department of Chemistry, University of Kentucky for giving me an opportunity to pursue my graduate career. I gratefully acknowledge the financial assistance I received in support of my research from the Department of Chemistry, the Research Challenge Trust Fund, the National Institutes of Health, the National Science Foundation, and the Pearson Education. I would like to thank my former lab mates, Dr. Freddie Hughes Jr., Dr. Roxana Ciochina, Mr. Uma Prasad Mallik, Dr. Syed Raziullah Hussaini, Dr. Suresh Jayasekara, Mr. Ronghua Lu, and Mr. Sujit Pawar for all their help and support in the lab. I would like to thank all my childhood teachers, and special thanks to my organic chemistry teacher, Dr. Ashok (Professor, Department of Chemistry, Osmania University), for his unique and exhilarating teaching method that inspired and enabled me to choose my career path. Also, my special thanks to my guru-cum-friend, the ever-youthful, Mr. Srinivasa Rao Deshpande (fondly called “Master” garu). I will forever be grateful for all his help, support, and encouragement. Throughout my life, I am fortunate enough to have developed some great friendships that helped me define myself. One of my good friends, Mr. Gangadhara Srinivas Annambhotla, is the root cause for my liking and understanding of the basic organic chemistry. He kindled my interest by initiating and leading several months of daily peer study at his home. Gorging out oodles of scratch paper, we together learned drawing out organic reaction mechanisms, and all this effort consequently led me to pursue my PhD in organic chemistry. I will forever be grateful for his help. The caring and the mirthfully mischievous, Dr. Pramod Nednoor, was my classmate at University of Pune; since then, with the passing time, we travelled our individual career paths together,

iii

nurturing our springing relationship into an everlasting friendship. I thank him very much for that amazing time we spent at the University of Pune and at the University of Kentucky, and also for his substantial role in my career growth. I would like to thank my noble-hearted friend, Dr. Maruthi Krishna Prakash Chittapragada, for all his help, for his ever-witty chat, and of course for our Ghantasala singing sessions over the hostel roof (just a prudent practice to keep our “golden” voices away from the innocent people). Mr. Mayuresh Moghe, the ever-blissful, eased out the enormous stress in the initial years of my graduate school. I can never forget his friendship or those 2 AM-dinners, coffee at Huddle House (South Limestone/Maxwell) while solving assignments and studying for the exams. I thank him for those gleeful couple of years. I like to thank the powerhouse of largely undiscovered talent, Dr. Gururaj Joshi, and the inimitable, Mr. Navneeth Singh Daundikhed, for their friendship and also for satiating my music palate by introducing me to the legendary maestros of Ghazals. My friend, Smt. Laxmi Sirisha Sadhu, though submerged with loads of work, being a software professional, wife, and mother of cute little Prabhav, always finds time to call me up and know my well-being. I thank for her concern and words of encouragement. I thank Mr. Suman Kumar Pulusu, an expression of free spirit, for overwhelming this itinerant with his extremely gracious gesture of hospitality. I would like to thank Mr. Vinay Srinivas Adepu for his concern and ever- entertaining phone conversations. I also would like to thank all my other friends, especially, Mr. Venkata Rajni Srikanth Vemuri, Dr. Gnaneswar Yadav Duggeni, and Mr. Narayana Reddy Bongunuri, for their help and support. I and my family will forever be grateful and indebted to these extremely generous and magnanimous people, Smt. Vijayalakshmi Gone, Smt. Savithri Devi Meka and Smt. Venkata Vimala Devi Inuganti, for facilitating a conducive atmosphere for education and an absolutely cherishable childhood for me and my brother. I am nothing without my family and I thank all of them for being very supportive. By accomplishing the doctorate I am paying a rich tribute, to my ever-dynamic and loving maternal grandmother, Smt. Induvadana Janaki, to my calm and serene paternal grandmother, Smt. Raama Tulasamma Chamala, and to my kind and warmhearted grandfather, Shri. Pullaiah Gopi. They will always be fondly remembered for their unparalleled love and affection. I am grateful to my babai, Shri. Dr. Bhoomiah Kasarla, who with his words and thoughts, inspired me at every stage of my career. Although, at this juncture, when I am ready to unleash my happiness along with him, his absence is dearly felt. I would forever be grateful and indebted, to my peddanaanna, Shri. Vykuntam Chamala, to my babai lu, Shri. Krishna Chamala and Shri. Pandu Chamala, to my attamma lu, Smt. Chandrasena Namboru, Smt. Anasuya Kanneboyina and Smt. Subhadra Bhuvanagiri, to my pinnamma lu, Smt. Suseela Kasarla and Smt. Kamala Dasari, for their unwavering support and unconditional love and affection. I also would like to thank my cousins, Mr. Raja Sekhar, Mr. Chandra Sekhar and Mr. Ravi Sekhar Kasarla, for all their support and encouragement since childhood, and for being immensely helpful to amma and naanna when I am thousands of miles away from home in pursuit of graduate career. I am forever indebted to Appannapally family, especially my mother- and father- in-law, Smt. Saraswathi and Shri. Janardhan Reddy, for their unwavering support, and for embellishing me with Jayashree, their most precious jewel.

I would like to personally thank my incredibly soft-spoken brothers-in-law, Mr. Suresh Reddy and Mr. Ramesh Reddy, my wonderful sister Smt. Sailaja, and of course my cute little niece Supraja, who with her very existence brings bliss to the family. I am blessed to have an absolutely fabulous younger brother and the truest friend anybody could ever hope to find, Mr. Raja Ram Chamala (Jaya), the biggest pillar of support all through my life. Jaya, my pride and joy, with his spiritual approach to life and with his insatiable passion for the pursuit of knowledge, is always an inspiration to me. One of the sweetest persons I am bestowed in life is my beautiful and gracious wife, Smt. Jayashree Chamala. Except loving her for the rest of my life, I will not be able to give anything in return for her love, understanding, and patience during the past few years of my PhD. It is only her immense support and encouragement was in the end what made this dissertation possible and she deserves this PhD as much as I do. My family is never complete without the mention of my dear Sony, and I would forever love her for the enormous joy she gave me. I feel humbled with gratitude when I think of my parents, the two invaluable people in my life, who did everything in their power to make sure I succeed in life. My parents, Smt. Rajeshwari Chamala and Shri. Narayana Chamala, receive my deepest gratitude and love for gifting me this life. I could complete my doctoral studies, only because of their ineffable love, sacrifices, understanding, and patience. Amma and Naanna, I love you both forever for all your hard work all these years to see me accomplish, and for inculcating in me the values of hard work and humility. I fondly dedicate this dissertation to both of you.

TABLE OF CONTENTS

ACKNOWLEDGEMENTS ...... iii LIST OF FIGURES ...... ix LIST OF SCHEMES ...... xi LIST OF TABLES ...... xiv

Chapter 1 Introduction to Yohimbine and Stereoisomers ...... 1

1.1. Introduction ...... 1

1.2. Biological Activity ...... 6

1.3. Biosynthesis of Yohimbine ...... 8 1.3.1. Biosynthesis of Tryptophan ...... 8 1.3.2. Biosynthesis of Secologanin ...... 10 1.3.3. Probable Biosynthetic Pathway for the Formation of Yohimbine ...... 11

Chapter 2 Syntheses of Yohimbine and Stereoisomers ...... 13

2.1. Syntheses Using Strategy I ...... 15 2.1.1. E-ring Core as a Precursor ...... 15

2.1.1.1. Van Tamelen‟s Approach via Diels-Alder Reaction ...... 15 2.1.1.2. Chatterjee‟s Approach via 3-Isochromanone Derivatives ...... 18 2.1.1.3. Brown‟s Approach via Secologanin ...... 20 2.1.2. D-ring Core as a Precursor ...... 22 2.1.2.1. Wenkert‟s Approach via N-alkylpyridinium salt ...... 22 2.1.2.2. Wenkert‟s Alternative Approach via N-alkylpyridinium salt ...... 28 2.1.2.3. Kuehne‟s Approach via Annulations of 1,2-dihydro-4-pyridones ...... 30 2.1.3. DE-ring Core as a Precursor ...... 33 2.1.3.1. Stork‟s Approach via Derivatives of Hydroisoquinolone Carboxylic Acids...... 33 2.1.3.2. Martin‟s Approach via Intramolecular Diels-Alder Reaction ...... 36 2.1.3.3. Momose‟s Approach via Asymmetric Intramolecular Michael Addition ...... 38 2.1.3.4. Aubé‟s Approach via Asymmetric Nitrogen-Insertion of Oxaziridine ...... 41

2.2. Syntheses Using Strategy II...... 44 vi

2.2.1. ABC-ring Core (β-carboline derivative) as a Precursor ...... 44 2.2.1.1. Szántay‟s Approach via Dieckmann Cyclization ...... 44 2.2.1.2. Kametani‟s Approach via Dieckmann Cyclization and Robinson-type Annulation...... 48 2.2.1.3. Ninomiya‟s Approach via Photocyclization of Enamide ...... 50 2.2.1.4. Jacobsen‟s Approach via Catalytic Asymmetric Acyl-Pictet-Spengler and Intramolecular Diels-Alder ...... 52

2.3. Synthesis Using an Alternative Strategy ...... 54 2.3.1. Kametani‟s Alternative Approach via Birch Reduction ...... 54

2.4. Grossman’s Approach via Double Annulation ...... 57

Chapter 3 Our Double Annulation Approach to Yohimbine Alkaloids ...... 58

3.1. Brief Introduction to Double Annulation Methodology ...... 58 3.1.1. A General Double Michael Reaction ...... 58 3.1.2. “Tethered Diacids” in the Formation of Carbocycles and Heterocycles ...... 59 3.1.3. Double Annulation Products ...... 60

3.2. Retrosynthetic Strategy ...... 62 3.2.1. Difference Between our Synthesis and all Other Syntheses ...... 62

3.3. Preparation of Tethered Diacid and Alkynone ...... 63 3.3.1. Synthesis of Indole Alkynone ...... 63 3.3.2. Synthesis of Tethered Diacid ...... 64

3.4. The Double Michael Reaction ...... 65 3.4.1. The Double Michael Reaction with the Tethered Diacid 178 ...... 65 3.4.2. Hypothesis on the Failure of the Double Michael Reaction with 178 ...... 65

3.5. The Double Michael Reaction with Silyl enol ether of Tethered Diacid 196 ..... 67 3.5.1. The Double Michael Reaction of the Alkynone 179 with 196 ...... 68

3.6. 1,2-Allylic Strain and the Double Michael Adduct ...... 71

3.6.1. A1,2 Strain in 2,3-dimethyl-1-butene ...... 71

3.6.2. A1,2 Strain in 1,6-dimethyl-1-cyclohexene ...... 71

3.6.3. Effect of A1,2 Strain on the Double Michael Adduct ...... 72 vii

3.7. The First Approach to DE-Ring Core ...... 73 3.7.1. Formation of Double Annulated Adduct 203 ...... 73 3.7.2. Desulfonylation of Double Annulated Adduct ...... 75 3.7.3. Hydrogenation of Enamine from the Convex Face and Subsequent Reactions .... 75

3.8. The Second Approach to DE-Ring Core ...... 76 3.8.1. Hydrogenation of the Double Annulated Adduct 203 ...... 76 3.8.2. Desulfonation After the Enamine Reduction ...... 77

3.9. Hydrogenation from the Sterically Encumbered Concave Face of 203 ...... 81 3.9.1. Steric and Stereoelectronic Factors Effecting Reduction from Convex Face of 203 81 3.9.2. Conformational Preference of 203 ...... 82 3.9.3. Catalytic Hydrogenation: Traditional Insertion vs. Ionic Mechanism...... 83 3.9.4. Ionic Protonation–Hydride-Transfer Mechanism ...... 83

3.10. Unsuccessful End-Game ...... 83

3.11. A Serendipitous Discovery – To End on an Optimistic Note ...... 84

3.12. Experimental Section ...... 86 3.12.1. Materials and Methods ...... 86 3.12.2. Preparative Procedures...... 87

Chapter 4 Conclusion ...... 146 Appendix ...... 147 References ...... 259 Vita ...... 265

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LIST OF FIGURES Figure 1.1. dl-yohimbane and dl-alloyohimbane ...... 5 Figure 1.2. General structure of yohimbine and stereoisomers ...... 6 Figure 2.1. Yohimbine and its major stereoisomers ...... 13 Figure 2.2. Deserpidine and raunescine ...... 26 Figure 3.1. Isomers of yohimbine ...... 58 Figure 3.2. Illustration of trans-perhydroisoquinoline substructure ...... 61 Figure 3.3. Various indole alkynones ...... 65 Figure 3.4. pKa‟s of phenylsulfonyl acetonitrile and ethyl acetoacetate ...... 66 Figure 3.5. Double Michael adducts ...... 68 Figure 3.6: X-ray crystal structure of 197 ...... 70 Figure 3.7: X-ray crystal structure of 203 ...... 74 Figure 3.8: X-ray crystal structure of 208 ...... 79 Figure 3.9: X-ray crystal structure of 209 ...... 80 Figure 3.10: Reduction from the convex face of conformers A and B ...... 82 Figure 3.11: X-ray crystal structure of 214 ...... 85 1 Figure 3.12: H NMR (400 MHz, CDCl3) of compound 186 ...... 91 13 Figure 3.13: C NMR (400 MHz, CDCl3) of compound 186 ...... 92 Figure 3.14: Infrared spectrum (neat) of compound 186 ...... 93 1 Figure 3.15: H NMR (400 MHz, CDCl3) of compound 187 ...... 95 1 Figure 3.16: H NMR (400 MHz, CDCl3) of compound 188 ...... 97 13 Figure 3.17: C NMR (400 MHz, CDCl3) of compound 188 ...... 98 Figure 3.18: Infrared spectrum (thin film/KBr) of compound 188 ...... 99 1 Figure 3.19: H NMR (400 MHz, CDCl3) of compound 189 ...... 101 13 Figure 3.20: C NMR (400 MHz, CDCl3) of compound 189 ...... 102 Figure 3.21: Infrared spectrum (neat) of compound 189 ...... 103 1 Figure 3.22: H NMR (400 MHz, CDCl3) of compound 190 ...... 105 13 Figure 3.23: C NMR (400 MHz, CDCl3) of compound 190 ...... 106 Figure 3.24: Infrared spectrum (neat) of compound 190 ...... 107 1 Figure 3.25: H NMR (400 MHz, CDCl3) of compound 196 ...... 109 13 Figure 3.26: C NMR (400 MHz, CDCl3) of compound 196 ...... 110

Figure 3.27: Infrared spectrum (neat) of compound 196 ...... 111 1 Figure 3.28: H NMR (400 MHz, CDCl3) of compound 197 ...... 113 13 Figure 3.29: C NMR (400 MHz, CDCl3) of compound 197 ...... 114 Figure 3.30: Infrared spectrum (neat) of compound 197 ...... 115 1 Figure 3.31: H NMR (400 MHz, CDCl3) of compound 198 ...... 117 13 Figure 3.32: C NMR (400 MHz, CDCl3) of compound 198 ...... 118 1 Figure 3.33: H NMR (400 MHz, CDCl3) of compound 199 ...... 120 13 Figure 3.34: C NMR (400 MHz, CDCl3) of compound 199 ...... 121 Figure 3.35: Infrared Spectrum (neat) of compound 199 ...... 122 1 Figure 3.36: H NMR (400 MHz, CDCl3) of compound 203 ...... 124 13 Figure 3.37: C NMR (400 MHz, CDCl3) of compound 203 ...... 125 Figure 3.38: Infrared spectrum (neat) of compound 203 ...... 126 1 Figure 3.39: H NMR (400 MHz, CDCl3) of compound 204a,b ...... 128 1 Figure 3.40: H NMR (400 MHz, CDCl3) of compound 205 ...... 130 1 Figure 3.41: H NMR (400 MHz, CDCl3) of compound 207 ...... 132 13 Figure 3.42: C NMR (400 MHz, CDCl3) of compound 207 ...... 133 1 Figure 3.43: H NMR (400 MHz, CDCl3) of compound 208 ...... 135 13 Figure 3.44: C NMR (400 MHz, CDCl3) of compound 208 ...... 136 Figure 3.45: Infrared spectrum (neat) of compound of 208 ...... 137 1 Figure 3.46: H NMR (400 MHz, CDCl3) of compound 209 ...... 139 13 Figure 3.47: C NMR (400 MHz, CDCl3) of compound 209 ...... 140 Figure 3.48: Infrared spectrum (KBr) of compound 209 ...... 141 1 Figure 3.49: H NMR (400 MHz, DMSO-d6) of compound 214 ...... 143 13 Figure 3.50: C NMR (400 MHz, DMSO-d6) of compound 214 ...... 144 Figure 3.51: Infrared spectrum (KBr) of compound 214 ...... 145

LIST OF SCHEMES Scheme 1.1: Condensation of tryptamine with secologanin ...... 8 Scheme 1.2: Biosynthesis of tryptophan/tryptamine ...... 9 Scheme 1.3: Mevalonic acid (MVA) pathway ...... 10 Scheme 1.4: Non-mevalonate (MEP) pathway ...... 10 Scheme 1.5: The biosynthesis of secologanin from isopentenyl diphosphate (IPP) ...... 11 Scheme 1.6: Probable biosynthetic pathway for the formation of yohimbine alkaloids . 12 Scheme 2.1: General Strategies towards Yohimbine and Stereoisomers ...... 15

Scheme 2.2: Van Tamelen‟s Retrosynthesis ...... 16

Scheme 2.3: Van Tamelen's Synthesis ...... 17 Scheme 2.4: Chatterjee‟s Retrosynthesis ...... 19 Scheme 2.5: Chatterjee‟s Synthesis ...... 19 Scheme 2.6: Brown‟s Retrosynthesis ...... 20 Scheme 2.7: Brown‟s Synthesis ...... 21 Scheme 2.8: Wenkert‟s Retrosynthesis I ...... 23 Scheme 2.9: Wenkert‟s Synthesis I ...... 24 Scheme 2.10: Wenkert‟s Synthesis II ...... 25 Scheme 2.11: Wenkert‟s Synthesis III ...... 26 Scheme 2.12: Wenkert‟s Synthesis IV...... 27 Scheme 2.13: Wenkert‟s Synthesis V ...... 28 Scheme 2.14: Wenkert‟s Retrosynthesis II ...... 29 Scheme 2.15: Wenkert‟s Synthesis VI...... 29 Scheme 2.16: Kuehne‟s Retrosynthesis ...... 30 Scheme 2.17: Kuehne‟s Synthesis ...... 31 Scheme 2.18: Stork‟s Retrosynthesis ...... 33 Scheme 2.19: Stork‟s Synthesis ...... 35 Scheme 2.20: Martin‟s Retrosynthesis ...... 36 Scheme 2.21: Martin‟s Synthesis ...... 37 Scheme 2.22: Momose‟s Retrosynthesis ...... 39 Scheme 2.23: Momose‟s Synthesis...... 40 Scheme 2.24: Aubé‟s Retrosynthesis ...... 41

Scheme 2.25: Aubé‟s Synthesis ...... 42 Scheme 2.26: Szántay‟s Retrosynthesis ...... 44 Scheme 2.27: Szántay‟s Synthesis I...... 45 Scheme 2.28: Szántay‟s Synthesis II ...... 46 Scheme 2.29: Szántay‟s Synthesis III ...... 47 Scheme 2.30: Szántay‟s Synthesis IV ...... 48 Scheme 2.31: Kametani‟s Retrosynthesis I ...... 48 Scheme 2.32: Kametani‟s Synthesis I ...... 49 Scheme 2.33: Ninomiya‟s Retrosynthesis ...... 50 Scheme 2.34: Ninomiya‟s Synthesis...... 51 Scheme 2.35: Jacobsen‟s Retrosynthesis ...... 53 Scheme 2.36: Jacobsen‟s Synthesis ...... 54 Scheme 2.37: Kametani‟s Retrosynthesis II ...... 55 Scheme 2.38: Kametani‟s Synthesis II ...... 56 Scheme 3.1: General representation of a double Michael reaction ...... 59 Scheme 3.2: Double Michael route to carbocycles ...... 59 Scheme 3.3: Double Michael route to heterocycles ...... 60 Scheme 3.4: Selected examples of double annulation products ...... 61 Scheme 3.5: Retrosynthetic strategy ...... 62 Scheme 3.6: Synthesis of indole alkynone ...... 64 Scheme 3.7: Synthesis of tethered diacid ...... 64 Scheme 3.8: Failed double Michael reaction with tethered diacid and various indole alkynones ...... 65 Scheme 3.9: Anticipated double Michael reaction with the tethered diacid ...... 66 Scheme 3.10: Presumed initial Michael reaction on the β-ketoester moiety and the failure of the double Michael reaction ...... 67 Scheme 3.11: Preparation of silyl enol ether ...... 67 Scheme 3.12: The double Michael adduct ...... 69 Scheme 3.13: 1,2-allylic strain in 2,3-dimethyl-1-butene...... 71 Scheme 3.14: 1,2-allylic strain in 1,6-dimethyl-1-cyclohexene ...... 72 Scheme 3.15: Effect of 1,2-allylic strain on the double Michael adduct ...... 72

xii

Scheme 3.16: The double annulated adduct ...... 73 Scheme 3.17: Desulfonylation of double annulated adduct...... 75 Scheme 3.18: Hydrogenation of enamine 204 from the convex face and subsequent reactions ...... 76 Scheme 3.19: Hydrogenation of the double annulated adduct ...... 77 Scheme 3.20: Desulfonation after the enamine reduction ...... 78 Scheme 3.21: Hydrogenation from the concave face – reported example ...... 81 Scheme 3.22: The major conformations of the doubly annulated adduct 203 ...... 82 Scheme 3.23: Preference of conformer A over conformer B ...... 82 Scheme 3.24: Ionic hydrogenation mechanism ...... 83 Scheme 3.25: The enol reduction ...... 84

xiii

LIST OF TABLES Table 1.1: Sources of yohimbine and stereoisomers ...... 2 Table 1.2: Determination of relative configuration of yohimbine and stereoisomers ...... 4 Table 1.3: Classification and relative configuration of yohimbine and stereoisomers ...... 6 Table 3.1: Summary of basic differences in synthetic strategies ...... 63

xiv

Chapter 1 Introduction to Yohimbine and Stereoisomers

1.1. Introduction

A Natural Product is considered to be “a chemical substance produced by a living organism; - a term used commonly in reference to chemical substances found in nature that have distinctive pharmacological effects. Such a substance is considered a natural product even if it can be prepared by total synthesis”. Of all the living systems, plants have always been a rich source of biologically active natural products serving to alleviate the ailments of the human race over the ages. Ayurveda, meaning “Science of Life”, which dates back to the Vedic period (first millennia BCE to the 6th century BCE) mentions the use of plants as medicinal sources.1 Records from China, traced to the Emperor Shen Nung (2700 B.C.), indicate the use of specific plant extracts to treat health disorders. The Ebers Papyrus, one of the oldest (1550 B.C.) preserved medical documents, indicates the use of many plants in Egyptian medicine. De Materia Medica by Dioscorides (77 A.D.) reported the uses of over 600 plants. Ibn Al-Baitar (1197- 1248) in his Corpus of Simples listed over 1400 medicinal plants. William Withering extracted an active ingredient, digitalis, from the foxglove extracts used to cure dropsy (swelling often caused by congestive heart failure). He published An Account of the Foxglove and its Medicinal Uses (1785) based on case histories, which also described the specific doses and administration instructions for herbal remedies. However, not until after the isolation of „active principles‟ of commonly used medicinal plants in the early 1800s, was the cure of ailments attributed to science rather than magic or witchcraft.2-3 Yohimbehe is the dried bark of the tall evergreen African tree, scientifically known as Pausinystalia yohimbe or Corynanthe yohimbe, and commonly known as the fringe tree. This tree is native to southwestern Nigeria, Cameroon, Gabon, and the Congo. Yohimbine constitutes about 10-15% of the total 6% alkaloid content of yohimbehe. Minor alkaloids like ajmalicine, alloyohimbine, corynanthine, and tetrahydromethyl corynanthine are also found in the bark. Yohimbehe and yohimbine have been used in folk medicine as a potent aphrodisiac.4-7 Usually, the decoction made by boiling the inner shavings of the bark in water was given to a patient to drink.

Traditionally, yohimbine bark was also used by natives of western Africa for curing leprosy, fevers, and cough.5,7 Yohimbehe poultices were used on skin as an antiseptic and for pain alleviation. Sniffing or smoking the powder provided the necessary stimulant for warriors before the battle. It was also used for mild hallucinogenic effects.4-5 Yohimbine and its stereoisomers were originally isolated from the bark of an African tree Pausinystalia yohimbe Pierre (Family: Rubiaceae) in the late nineteenth century, but were later found in many other plants of rubiaceae and apocynaceae (Table 1.1).8-9 However, the principal source of yohimbine is Pausinystalia yohimbe Pierre, and, true to its occurrence, the name yohimbine is derived from the name of its bark, yohimbehe.8-9

Table 1.1: Sources of yohimbine and stereoisomers

[α]D Alkaloid Synonyms MP ( oC) Occurrencea Type (pyridine) Quebrachine Aphrodine Yohimbine 235-236 +106 1-12 Corynine Hydroaergotocin Normal Corynanthine Rauhimbine -85 5,13

225-226 1,3,5,7,8,14, β-Yohimbine Amsonine -54 236-237 15

Pseudo- 268 +27 Pseudo 1,5 yohimbine

Table 1.1: Sources of yohimbine and stereoisomers, continued

epi-3- 252-256 -13 Synthetic Corynanthine

epi-3-β- 203-204 -83 Synthetic Yohimbine

Alloyohimbine 135-140 -84 1,5

Corynantheidine Allo Rauwolscine 1,5,6,13, α-Yohimbine -18 Isoyohimbine 235-236 16 Mesoyohimbine

epi-3- 224 +151 Synthetic Alloyohimbine

Epiallo epi-3- epi-3-α- Rawolscine 225 -104 5 Yohimbine Isorauhimbine

aNumbers refer to: 1. Pausinystalia yohimbe Pierre (Corynanthe johimbe K. Schum.) 2. P. trillesii Beille 3. Corynanthe Paniculata Welw. 4. C. macroceras K. Schum. 5. Rauwolfia spp. 6. Vinca spp. 7. Aspidosperma quebracho-blanco Schlecht. 8. Diplorhynchus condylocarpon Pich. 9. Alchorea floribunda Muell.-Arg.

10. Lochnera lancea K. Schum. 11. Pouteria sp. (Fam. Sapotaceae). 12. Hunteria eburnea Pich. 13. Pseudocinchona Africana A. Chev. 14. Amsonia elliptica Roem. et Schult. 15. Aspidosperma oblongum A.DC. 16. Alstonia constricta F. Muell.

In 1880, Hesse10 first isolated yohimbine from Aspidosperma quebracho-blanco, Schlecht., and it was later found to be the major alkaloid of Corynanthe yohimbe, Schum., by Spiegel11 in 1896. The correct constitution was suggested by Witkop12 in 1943. The information on the structure and stereochemistry of yohimbine stereoisomers were obtained by the mid-1950s. Although UV and IR spectra aided to some extent, the information was largely obtained by means of chemical methods.13 The information on skeletal structure was obtained by drastic degradation studies by Barger,14-16 Clemo,17-18 Field,14 Goutarel and Janot,19 Graser,20 Hahn and Werner,21 Julian, Karpel, Magnani, and Meyer,22-23 Raymond-Hamet,24 Schlittler and Speitel,25 Scholz,15-16,26 Swan,17-18,27 Walter and Winterstein,28 Warnat,29 Wilbaut and Mendlik,30 Witkop,20,31 and Woodward.31 The relative configuration of each of the yohimbine stereoisomers was also deduced by chemical methods by collective efforts of the following authors (Table 1.2).

Table 1.2: Determination of relative configuration of yohimbine and stereoisomers Alkaloid Author/s Year of Publication Yohimbine Witkop,32 Cookson,33 1949, 1953, 1954, 1956 34 35 Chatterjee, Van Tamelen Corynanthine Janot36 1952 β-Yohimbine Le Hir,37-38 Godtfredsen,39 1953, 1957,1958, 1961, 1965 Janot,40 Albright41-42 Pseudoyohimbine Janot,36 Wenkert43 1952, 1958

Table 1.2: Determination of relative configuration of yohimbine and stereoisomers, continued Alloyohimbine Woodward,44 Le Hir,45 1949, 1953, 1956, 1957, Wenkert,46 Stork,47 Töke48 1973 α-Yohimbine Le Hir,38,45 Janot40 1953, 1958, 1961 3-epi- α-Yohimbine Bader,49 Le Hir50 1954, 1955 3-epi-Corynanthine Le Hir45 1953 3-epi- β-Yohimbine Le Hir45 1953 3-epi-alloyohimbine Le Hir45 1953

The absolute configuration of yohimbine was first assigned by Klyne using molecular rotation calculations.51-52 Further corroboration of the initial assignment was provided by Djerassi53 and later on confirmed by Ban54 using chemical methods. Finally, in 1973, X-ray crystallographic analysis of yohimbine hydrochloride provided the expected stereochemistry of yohimbine.55 In 1954, the stereospecific synthesis of key degradation products dl-yohimbane35,56 and dl-alloyohimbane57 provided a major breakthrough in the evolution of the total synthesis of yohimbine alkaloids (Figure 1.1).

Figure 1.1. dl-yohimbane and dl-alloyohimbane

The generally accepted yohimbine numbering and the letter designation of the rings, as shown in the general structure of yohimbine alkaloid (Figure 1.2), will be followed throughout the course of this dissertation. With the absolute configuration at C(15) being invariably (S) with an α hydrogen, the yohimbine and stereoisomers (Table 1.3) are broadly divided into four groups, namely, normal, pseudo, allo, and epiallo depending on the relative configurations at C(3) and C(20). They are further subdivided depending on the relative configurations of the C(16) and C(17) substituents.13,58

Figure 1.2. General structure of yohimbine and stereoisomers Table 1.3: Classification and relative configuration of yohimbine and stereoisomers

Series C(3)-H C(20)-H C(16)-H C(17)-H Alkaloid β β Yohimbine (1) Normal α β α β Corynanthine (2) β α β-Yohimbine (3) β β Pseudoyohimbine (4) Pseudo β β α β 3-epi-Corynanthine (5) β α 3-epi-β-Yohimbine (6) α β α-Yohimbine (7) Allo α α β β Alloyohimbine (8) α β 3-epi-α-Yohimbine (9) Epiallo β α β β 3-epi-Alloyohimbine (10)

1.2. Biological Activity

Yohimbine, in the herbal extract form, has been used as an over-the-counter dietary supplement. In the late 1980s United States Food and Drug Administration (FDA) approved the purest form of yohimbine, yohimbine hydrochloride, as a prescription drug to treat erectile dysfunction. The approved dosage was 5.4 mg, three times a day for no longer than ten weeks.4 The pharmacological actions of yohimbine include selective blockage of α- adrenergic and serotonin (5-HT) receptors, central excitation leading to high blood pressure, rapid heart rate, increased motor activity, sweating, nausea, and antidiuresis due to vasopressin release.59 The selective affinity of yohimbine led to pharmacological studies unveiling more information about receptor distribution and their subtypes using

60-64 radiolabeled yohimbine and α-yohimbine. Yohimbine has high affinity for α2- adrenergic receptor, moderate affinity for the α1-adrenergic, 5-HT1A, 5-HT1B, 5-HT1D, 5-

HT1F, 5-HT2B, and D2 receptors, and weak affinity for the 5-HT1E, 5-HT2A, 5-HT5A, 5- 65 HT7, and D3 receptors. It acts as an antagonist at α1-adrenergic, α2-adrenergic, 5-HT1B, 65-68 5-HT1D, 5-HT2A, 5-HT2B, and D2, and as a partial agonist at 5-HT1A. The expression of functional α2-adrenergic receptors in human corpus cavernosum smooth muscle provided a credible mechanism for the improvement of erectile function in patients treated with yohimbine. The circulating catecholamines may activate postsynaptic α2- adrenergic receptors localized distally to adrenergic nerve terminals and induce contractility of the corporeal tissue. Selective adrenergic blockade with yohimbine would reverse the process to facilitate smooth muscle relaxation.69 Although yohimbine enjoyed a long-standing reputation as an aphrodisiac until the first half of the twentieth century, it was only after 1960s, yohimbine underwent extensive clinical studies.70 Clinical studies performed on animal and human population exhibited that yohimbine may indeed be used in treating erectile dysfunction.71-76 However, not all clinical studies showed yohimbine to be effective.77-78 The studies also found that the use of higher doses of yohimbine actually inhibited the sexual response.79- 80 Apart from its alleged use in treating erectile dysfunction, addition of yohimbine to fluoxetine or venlafaxine potentiated the antidepressant action of both of these agents.81 It was used to facilitate recall of traumatic memories in the treatment of post- traumatic stress disorder (PTSD),82 and also to effect significant fat loss in atheletes.83 Also, more recently, yohimbine was associated as a remedy for type-2 diabetes mellitus in animal and human models carrying polymorphisms of the α2A-adrenergic receptor gene.84 At much higher doses, the side effects of yohimbine include elevation of blood pressure, a slight anxiogenic action, and increased frequency of urination.85 Its chief toxicity was found to be renal.59

Rauwolscine or α-yohimbine also functions primarily as a α2-adrenergic receptor antagonist and has a similar function as yohimbine in inhibiting the norepinephrine- induced contraction in corpus cavernosum.86 Corynanthine acts as an antagonist at both

α1- and α2-adrenergic receptors, but it has a 10-fold selectivity for the former over the latter.87-88 1.3. Biosynthesis of Yohimbine

Yohimbine, a member of class I alkaloids (Corynanthe-Strychnos type), is a monoterpenoid derived indole alkaloid formed from the initial condensation of tryptamine with an unrearranged secologanin (Scheme 1.1). The tryptamine portion of the alkaloid is derived from the decarboxylation of tryptophan with tryptophan decarboxylase enzyme.89 The independent studies by Wenkert and Thomas lead to the proposals of monoterpenoid origin of the non-tryptophan portion of the indole alkaloids.90-91 Further labeling experiments established secologanin as the specific precursor involved in the biosynthetic pathway.92-94 It is the ultimate precursor for the non-tryptophan portion (C9-C10 moiety) of the indole alkaloids.

Scheme 1.1: Condensation of tryptamine with secologanin

1.3.1. Biosynthesis of Tryptophan

The biosynthesis of tryptophan/tryptamine (indole pathway) is well understood (Scheme 1.2). Shikimic acid plays a key role in the biosynthesis of various aromatic amino acids, including tryptophan. The aldol type reaction of erythrose-4-phosphate with phosphoenol pyruvate affords 3-deoxy-D-arabinoheptulosonic acid-7-phosphate (DAHP). The cyclization of DAHP forms dehydroquinate (DHQ); mechanistically, NAD+ 8

promoted oxidation at C(5) facilitates β-elimination of phosphate to give an enol ether; then, reduction of C(5) back to the alcohol, ring opening, and intramolecular aldol reaction affords DHQ. Dehydration and reduction of DHQ produces shikimate, which then transforms to chorismate. Chorismate reacts with glutamine by an SN2ˈ -like reaction, and elimination of pyruvate and amide hydrolysis gives anthranilate. Anthranilate then reacts with phosphoribosylpyrophosphate (PRPP) to give N-(5- phospho-β-D-ribosyl)-anthranilate 11. The intermediate 12, formed after the ribose ring- opening, reductive decarboxylation and dehydration, looses glyceraldehyde-3-phosphate to form indole, which in turn reacts with serine to form tryptophan. Decarboxylation of the later, in the presence of tryptophan decarboxylase, forms tryptamine.95

Scheme 1.2: Biosynthesis of tryptophan/tryptamine

1.3.2. Biosynthesis of Secologanin

Isopentenyl diphosphate (IPP), the precursor for secologanin, is produced by the classical mevalonic acid (MVA) pathway (Scheme 1.3)95 and the recently discovered non-mevalonate/triose phosphate/pyruvate/deoxyxylulose 5-phosphate/2-C-methyl-D- erythritol 4-phosphate (MEP) pathway (Scheme 1.4). Although MVA pathway was considered the major source of precursors in biosynthesis of secologanin, the recent feeding studies with cell cultures of Catharanthus roseus and Ophiorrhiza pumila suggests MEP as the major pathway.96-99

Scheme 1.3: Mevalonic acid (MVA) pathway

Scheme 1.4: Non-mevalonate (MEP) pathway

The geraniol derived from IPP is hydroxylated to 10-hydroxygeraniol which subsequently transforms in to iridodial and then iridotrial (Scheme 1.5). The iridotrial undergoes a series of biosynthetic transformations to form deoxyloganin. Deoxyloganin undergoes hydroxylation to form loganin, the latter undergoes oxidative cleavage in the presence of the enzyme secologanin synthase to form secologanin.

Scheme 1.5: The biosynthesis of secologanin from isopentenyl diphosphate (IPP)

1.3.3. Probable Biosynthetic Pathway for the Formation of Yohimbine

The initial step is the condensation secologanin with tryptamine in the presence of strictosidine synthase to form strictosidine with “S” configuration at C(3). Strictosidine, after deglycosylation with glycosidase, through a series of reactive intermediates affords 4,21-dehydrocorynantheine aldehyde. The latter then undergoes isomerization, an intramolecular attack of vinylidene on acrylate, and reduction to afford yohimbine (Scheme 1.6).95

Scheme 1.6: Probable biosynthetic pathway for the formation of yohimbine alkaloids

Chapter 2 Syntheses of Yohimbine and Stereoisomers

Yohimbine 1 features a pentacyclic ring system with twenty-one compactly arranged skeletal atoms of which two are N atoms. It also comprises a total of five stereogenic centers of which four are contiguous and present on the E ring (Figure 2.1). Various synthetic approaches were designed to conquer these biologically significant natural products with intriguing structures and stereochemical complexity.

Figure 2.1. Yohimbine and its major stereoisomers Historically, two fundamental synthetic strategies have provided access to yohimbine alkaloids, as illustrated in a general retrosynthetic format (Scheme 2.1). During a period of more than half a century, starting from 1958, to the best of my knowledge, fifteen different synthetic approaches have led to the successful completion of total syntheses of yohimbine and its stereoisomers. Almost all of the syntheses, except one (Kametani‟s alternative approach via Birch reduction), have utilized either of the two fundamental strategies to synthesize yohimbine and isomers. Strategy I is the most widely employed. In this approach, the cyclization of seco- derivative 13 occurs by formation of the C(2)-C(3) bond as the final step with concomitant formation of the C ring to furnish the pentacyclic framework. The preparation of seco-derivative 13 is achieved by coupling of appropriate tryptophyl intermediate 14 with D ring synthon 15 possessing appropriate substituents at C(15) and C(20) for the eventual formation of E ring, or E ring synthon 16 with suitable C(15) and C(20) substituents for coupling and concomitant D ring formation or a fully substituted 13

DE ring compound 17. Alternatively, strategy II features a stepwise annulation of D and E rings onto the intact ABC ring system 18 by combining with the synthons of type 19 or 20. Although several outstanding general reviews58,100-104 are available on yohimboid alkaloids (a general term extended to all those natural products with the skeletal framework of yohimbine), this review, in relation to my dissertation topic, specifically focuses on detailing various synthetic designs and syntheses used for the successful construction of yohimbine and its stereoisomers. This is an attempt to survey a period of over fifty years of accomplishments, commencing from Van Tamelen‟s first synthesis (1958) and covering until Jacobsen‟s synthesis (2008). The review is basically divided into three main sections according to the strategy used. Each section again is divided into subsections based on the synthetic precursor, and contains strategies and syntheses arranged in a chronological order.

Scheme 2.1: General Strategies towards Yohimbine and Stereoisomers

2.1. Syntheses Using Strategy I

2.1.1. E-ring Core as a Precursor

2.1.1.1. Van Tamelen’s Approach via Diels-Alder Reaction

Only a couple of years after the structure of yohimbine 1 was elucidated in 1956, the first total synthesis of yohimbine was communicated by Van Tamelen and

coworkers.6,105 The first step and the key step in the synthesis is the stereoselective construction of the functionally rich E ring by a Diels-Alder reaction, which closely followed the first step in Woodward‟s classic reserpine synthesis.106-107 Of the total of five stereocenters, two of the contiguous stereocenters (C(15) and C(16)) were formed by this crucial reaction. The CD rings of yohimbine 1 were made in one step from the dialdehyde 21 (Scheme 2.2). The dialdehyde 21 was made from oxidative cleavage of alkene and the reduction of C(17) ketone in 22, which in turn was made from 23 by oxidation of aldehyde to acyl chloride and combining with tryptamine. The aldehyde 23 was made from the Diels-Alder reaction of 1,4-benzoquinone and butadiene.

Scheme 2.2: Van Tamelen’s Retrosynthesis

The octahydronaphthalene dione 24 was prepared from the selective reduction of quinone-butadiene adduct 25, which in turn was prepared from the Diels-Alder reaction of 1,4-benzoquinone and butadiene (Scheme 2.3). The adduct 25 was then converted to the glycidic ester 26 using Darzens reaction. Also, a base-promoted epimerization of 25 occurred concomitantly under Darzens conditions, forming a trans ring fusion in 26. The glycidic ester 26 on saponifiction followed by decarboxylation afforded an unsaturated keto-aldehyde 23. The keto-aldehyde 23 was oxidized to keto-acid 27 and subsequently to the corresponding acid chloride, which was used to acylate tryptamine to form the keto-amide 28. At this point the keto-amide 28 possesses three stereocenters, which are under thermodynamic control, and ultimately corresponds to the trans DE ring fusion and

C(16) substituent of yohimbine. The dihydroxylation of 28 with osmium tetroxide gave the corresponding diol, which on catalytic hydrogenation resulted in the triol 29 with the requisite C(17)-OH axial orientation. The subsequent cleavage of the vicinal diol in 29 with periodic acid followed by cyclization with hot phosphoric acid gave lactol lactam 32. The formation of 32 was presumed to go through an N-acylalkanolamine intermediate 30 followed by the dehydration to result in an acyliminium salt 31. The iminium bond in 31 then undergoes an intramolecular nucleophilic addition of the indole from the axial direction to form C(2)-C(3) bond, providing entry into the pseudoyohimbine series. Acid-catalyzed methanolysis of 32 followed by the reduction with lithium aluminum hydride gave lactol ether base 33. Acid catalyzed deprotection of 33 was followed by the acetylation of lactol OH group, and the acetylated lactol when subjected to pyrolytic conditions gave enol ether 34. Oxidative degradation of enol ether 34 gave the O-formate of pseudoyohimbaldehyde 35, which on further oxidation produced the natural product pseudoyohimbine 4. The latter was then resolved with (-)- camphorsulphonic acid to (+)-pseudoyohimbine. Since the conversion pseudoyohimbine 4 to yohimbine 1 via C(3) epimerization was known,6,105 a formal total synthesis of yohimbine was completed.

Scheme 2.3: Van Tamelen's Synthesis

2.1.1.2. Chatterjee’s Approach via 3-Isochromanone Derivatives

Chatterjee efficiently used the functional groups on 3-isochromanone derivatives to generate the pentacyclic yohimbine skeleton.108 Alloyohimbine 8 was made from the intermediate 36 by Birch reduction, demethylation of the intermediate enol ether, syn hydrogenation of C(15)-C(20) double bond, regioselective carbomethoxylation at C(16) and the reduction of C(17) ketone (Scheme 2.4). The intermediate 36 was made from 37

by Bischler-Napieralski cyclization-reduction sequence, and the latter was made from the addition of tryptamine to 6-methoxyisochromanone 38.

Scheme 2.4: Chatterjee’s Retrosynthesis

The synthesis began with the condensation of tryptamine with 6-methoxy isochromanone 38 to afford a tricyclic amide 37 (Scheme 2.5). The tricyclic amide 37 after cyclization with phosphorus oxychloride followed by reduction with NaBH4 afforded pentacyclic yohimbane 36. The compound 36 when subjected to Birch reduction conditions followed by acid hydrolysis gave ketone 39. Syn hydrogenation of the C(15)-C(20) double bond, regioselective carbomethoxylation at C(16), and stereospecific reduction of the C(17) ketone to α-C(17)-OH furnished alloyohimbine 8. The base catalyzed epimerization of C(16) stereocenter furnished α-yohimbine (rawolscine) 7.

Scheme 2.5: Chatterjee’s Synthesis

2.1.1.3. Brown’s Approach via Secologanin

Brown‟s approach featured a biomimetic analogy to synthesize normal and pseudo stereoisomers of yohimbine.109 The formation of the C(2)-C(3) bond and generation of C(3) stereocenter in 1 was effected by concomitant formation of C and D rings via deprotection of acetal in 40 and the subsequent cyclization of the resultant aldehyde in a Pictet-Spengler reaction. Compound 40 was formed from reductive amination of aldehyde 41, which in turn is formed from hydrolysis and rearrangement of secologanin.

Scheme 2.6: Brown’s Retrosynthesis

Acetylation of secologanin followed by protection of aldehyde and subsequent Zemplen deacetylation afforded ethylene acetal 42 (Scheme 2.7). The hydrolysis of 42 with β-glucosidase in pH 7.0 buffer for four days, followed by a vinylogous aldol

cyclization, afforded cyclohexene aldehyde 41 as the only stereoisomer in 70% yield with trans-trans C(7)-C(8) and trans-trans C(8)-C(9) stereochemistry. The reductive amination of aldehyde 41 with tryptamine gave secondary amine 40. The deprotection of the acetal in 38 and the concomitant Pictet-Spengler cyclization of the intermediate aldehyde afforded 3-epi-19,20-dehydro-β-yohimbine 44. Uneventful catalytic hydrogenation of the C(19)-C20) double bond afforded pseudo-β-yohimbine 45. Oxidation of 45 gave

C(17) ketone, which on stereoselective reduction with NaBH4 afforded pseudoyohimbine 4. The C(3) epimerization of 4 gave yohimbine 1 and a similar epimerization of 45 furnished β-yohimbine 3. The hydrogenation of 3-epi-19,20-dehydro-β-yohimbine 44 with Adams‟ catalyst also furnished β-yohimbine 3 in one step.

Scheme 2.7: Brown’s Synthesis

2.1.2. D-ring Core as a Precursor

2.1.2.1. Wenkert’s Approach via N-alkylpyridinium salt

Wenkert‟s general synthetic scheme involves a two-step reaction sequence, a carbon nucleophile addition to the γ-carbon of the electron-poor N-alkylpyridinium salt followed by acid-induced ring closure of the resultant substituted 1,4-dihydropyridine. The E ring of the yohimbine isomer 46 can be made from Dieckmann cyclization of the tetracyclic diester 47 (Scheme 2.8). The diester 47 was made from decarboxylation and hydrogenation of dienenic triester 48. The tetracyclic intermediate 48 is the result of Wenkert‟s strategic step, i.e., carbon nucleophile addition to the γ- carbon of pyridinium ion 49 followed by acid-induced cyclization. Two C-C bonds (C(2)-C(3) and C(15)-C(16)), two stereocenters, and one ring are formed from two synthetic steps. The key synthetic intermediate, N-pyridinium salt 49, was made from the condensation of nicotinaldehyde with malonic acid followed by esterfication and N- tryptophylation of the resultant 3-pyridineacrylic acid.

Using the same basic synthetic strategy, variants of Dieckmann cyclization were developed later on to improve the yield and regioselectivity of the reaction. Thus, Wenkert and coworkers made both normal and allo-type yohimbine alkaloids using this strategy.

Scheme 2.8: Wenkert’s Retrosynthesis I

A formal synthesis of yohimbine 1 and β-yohimbine 3 was communicated using the two-step reaction sequence involving the N-alkylpyridinium salt (Scheme 2.9). The required N-alkylpyridinium salt 49 was prepared by the condensation of nicotinaldehyde with malonic acid followed by esterification of the intermediate monounsaturated carboxylic acid and subsequent N-alkylation with tryptophyl bromide.110 Dimethyl malonate was then added to the electrophilic γ-carbon of the pyridinium ring of 49, and acid-induced cyclization gave the tetracyclic dienic triester 48. Hydrogenation of 48 produced saturated triesters 50 and 51 in 82% and 15% respectively. Selective demethylation-decarboxylation of the malonate substructure in 50 under Krapcho conditions yielded diester 52. The epimerization of C(3) in 52 using acid-induced hydrolysis‒ esterification afforded the diester 53 with normal yohimbine configuration at C(3), C(15), and C(20), Szántay had converted the latter to β-yohimbine 3 and yohimbine 1.111

Scheme 2.9: Wenkert’s Synthesis I

Wenkert and coworkers completed the formal total synthesis of alloyohimbine 8, and α-yohimbine 7 using the same general methodology.110 The reduction of the common intermediate, the tetracyclic dienic triester 48, with NaBH3CN afforded a mixture of triesters 54, 50, and 51 in 46%, 41%, and 11% yields respectively (Scheme 2.10). The triester 54 was in turn hydrogenated to improve the yield of the epiallo triester 51. Basic hydrolysis-decarboxylation-reesterification of 51 produced epiallo diester 55. The epimerization of the latter at C(3) with mercuric acetate led to the allodiester 56, which Szántay had previously converted to alloyohimbine 8, and α-yohimbine 7.112

Scheme 2.10: Wenkert’s Synthesis II

In continuing efforts to prepare the other isomers of yohimbine, Wenkert also applied this methodology to the synthesis of pseudoyohimbine 4 and pseudoyohimbone 59.110 Dieckmann cyclization of the diester 52 afforded two regioisomers 57 and 58 in 47% and 40% yields respectively (Scheme 2.11). The undesired isomer 58 was hydrolyzed and decarboxylated to afford pseudoyohimbone 59, and 57 was hydrogenated to afford pseudoyohimbine 4.

Scheme 2.11: Wenkert’s Synthesis III

To avoid the formation of undesired regioisomer 58 in the synthesis, Wenkert modified the approach to block the undesired Dieckmann cyclization path (Scheme 2.12). This approach provided not only a unidirectional path to pseudoyohimbine 4 but also provided access to more highly functionalized yohimbines (Figure 2.2) such as deserpidine 60 and raunescine 61.113-114

Figure 2.2. Deserpidine and raunescine

The condensation of nicotinaldehyde with methyl methoxyacetate followed by N- alkylation with tryptophyl bromide yielded pyridinium salt 62. Treatment of the latter with dimethyl sodiomalonate followed by acid-induced cyclization afforded tetracycle 63. The lithium iodide-induced decarbomethoxylation of 63 followed by

NaBH3CN reduction afforded the diesters 64 and 65 in ca. 2:1 ratio. Catalytic hydrogenation of pseudo diester 65 and the Dieckmann condensation of the hydrogenated products yielded methoxyketoesters 66 and 67. The keto-ester moiety of 66 and 67 was protected as its enolacetate, and the step was followed by the conversion of 18-methoxy group to the corresponding bromides and the subsequent reductive debromination to afford pseudoyohimbone 59 which was previously transformed to pseudoyohimbine 4 by Wenkert.110 The diester 64 was used to synthesize highly functionalized yohimbine alkaloids like deserpidine 60 and raunescine 61.

Scheme 2.12: Wenkert’s Synthesis IV

An alternative formal synthesis114 of pseudoyohimbine 4 was also reported (Scheme 2.13) using an intermediate, diester 65, from the above synthesis. Treatment of 65 with methanolic hydrogen chloride yielded ketal 68 which underwent regioselective Dieckmann cyclization to form pentacyclic ketal 69. Deoxygenation of pentacyclic ketal 69 at C(18) by Lewis acid promoted sulfurization followed by desulfurization with Raney nickel yielded pseudoyohimbone 59, which was previously converted to pseudoyohimbine 4.110

Scheme 2.13: Wenkert’s Synthesis V

2.1.2.2. Wenkert’s Alternative Approach via N-alkylpyridinium salt

In an effort to expedite the process of assembling the pentacyclic yohimbine skeleton, Wenkert made Kametani‟s intermediate115 70, in as little as five steps, in an alternative approach.116 Although the strategic two-step sequence (addition of carbon nucleophile followed by acid-induced cyclization) is still the same, Wenkert replaced the multistep modified Dieckmann reaction with an intramolecular aldol reaction just by changing the malonic acid carbon nucleophile to methyl acetoacetate. Kametani‟s intermediate 70 was made from the reduction and acid-induced cyclization of the methoxy immonium salt, which was made from the intermediate, 28

formed from the nucleophilic addition-intramolecular aldol condensation of the pyridinium ion 71 with sodium salt of methyl acetoacetate, and the former was obtained by tryptophylation of nicotinaldehyde (Scheme 2.14).

Scheme 2.14: Wenkert’s Retrosynthesis II

The reaction sequence (Scheme 2.15) involves the preparation of 71 by N- alkylation of nicotinaldehyde with tryptophyl bromide. The pyridinium salt 71, when subjected to the enolate anion of methyl acetoacetate, yielded the isoquinolone 72. The isoquinolone 72, when exposed to trimethyloxonium tetrafluoroborate, yielded O- methylated salt 73, which on NaBH4 reduction followed by cyclization in acidic medium furnished Kametani‟s intermediate 70. Thus, the formal total synthesis of (±)-yohimbine was completed, as 70 was previously converted to (±)-yohimbine 1 by Kametani in six steps.117-118

Scheme 2.15: Wenkert’s Synthesis VI

2.1.2.3. Kuehne’s Approach via Annulations of 1,2-dihydro-4-pyridones

The stereoisomers of yohimbine were made from the reduction of α,β-unsaturated keto-ester 74 (Scheme 2.16). The E ring of 74 was made from the condensation of methyl 3-oxo-4-pentenoate 75 with methoxy immonium salt of 76.104 The vinylogous amide 75 was made from amino-ketone 77 by Polonovsky oxidation‒ acid-induced cyclization‒ oxidation sequence. The amino-ketone 77 was made from the reaction of tryptamine and ammonium salt of 4-piperidone 78.

Scheme 2.16: Kuehne’s Retrosynthesis

The vinylogous amide 79 was obtained in good yield by the reaction of tryptamine with ammonium salt of 4-piperidone 78 followed by the Polonovsky oxidation of the intermediate tricyclic amino-ketone 77 (Scheme 2.17). Acid-catalyzed cyclization of the vinylogous amide 79 followed by the oxidation of the intermediate amino-ketone 80 yielded tetracyclic 1,2-dihydro-4-pyridone 81. The protection of indolic moiety in 81 followed by O-methylation of 76 gave methoxy immonium salt 82, and the latter on condensation with vinyl ketone 75 provided tetradehydroyohimbinone derivative 83. The pentacyclic dienone 84 was obtained quantitatively from the methanolysis of urethane 83. The reduction of dienone 84 with

borohydride reducing agents proved to be futile but reduction of either 83 or 84 with Zn/Cu under various conditions afforded 3,20-cis 85(87) and/or 3-20-trans 86(88) isomers. The hydrogenation of 3,20-trans isomer 87 with Pt/AcOH afforded yohimbine 1 and β-yohimbine 3. The hydrogenation of N-protected 3,20-cis 86 and 3,20-trans 83 isomers under acidic conditions afforded the derivative of 3-epi-alloyohimbinone 89 with the apparent epimerization of 3,20-cis to to 3,20-trans isomer under acidic conditions. The deprotection of 89 afforded 3-epi-alloyohimbinone 90 in 23% overall yield which on reduction with NaBH4 afforded 3-epi-alloyohimbine 91 and 3-epi-17-epi-alloyohimbine 92, as proved by Szántay.119 Hydrogenation from the convex face of 3,20-cis isomer 85 afforded alloyohimbinone 93 which had been converted to alloyohimbine 8, α- yohimbine 7, 17-epi-alloyohimbine 94, and 17-epi-α-yohimbine 95 by Szántay.104,119-120 Thus, Kuehne‟s approach provided access to normal, allo, and 3-epi-allo classes of yohimbine alkaloids.

Scheme 2.17: Kuehne’s Synthesis

2.1.3. DE-ring Core as a Precursor

2.1.3.1. Stork’s Approach via Derivatives of Hydroisoquinolone Carboxylic Acids

Stork accomplished the synthesis of normal and pseudo isomers of yohimbine by using hydroisoquinolone carboxylic acid derivatives as DE-ring core precursors.121 The last step of the synthesis is the formation of C(2)-C(3) bond of 96 via an oxidative cyclization-reduction sequence (Scheme 2.18). The 2,3-seco-yohimbine 96 was made from tryptophylation of 97, and the latter was made from the stereoselective reduction of the intermediate obtained from the condensation of N-methyl-4-piperidone and methyl 3- oxo-4-pentenoate 75.

Scheme 2.18: Stork’s Retrosynthesis

The isoquinolone 98 was obtained in good yield from the condensation of N- methyl-4-piperidone and methyl 3-oxo-4-pentenoate (Scheme 2.19). Dissolving metal

reduction of isoquinolone 98 afforded trans-hydroisoquinolone ester 99. The trans- hydroisoquinolone ester 99 was then reduced stereoselectively, in the presence of platinum and hydrogen in acetic acid, to a mixture of amino alcohols followed by their conversion to cyano alcohols 100 and 101 in the ratio of 1.4:1. The reductive decyanation of 100 followed by tryptophylation afforded 2,3-seco-yohimbine 96. The formation of the C(2)-C(3) bond in 96 and 102, with the concomitant formation of C ring and the C(3) stereocenter, was effected via a mercuric-ion mediated oxidative cyclization-reduction sequence. The control of the configuration at the C(3) stereocenter was found to be dependent on reaction conditions. The oxidative cyclization of compound 96 with Hg(OAc)2/EDTA followed by reduction with NaBH4 afforded yohimbine 1. Alternatively, treatment of 96 with Hg(OAc)2/5% CH3COOH followed by

NaBH4 reduction afforded pseudoyohimbine 4. The cyano alcohol 101, which can also be obtained as a major isomer by cyanation and reduction (NaBH4) of 99, was converted to epimeric 2,3-seco-yohimbine 102. The product 102 when cyclized (Hg(OAc)2/EDTA) and reduced yielded β-yohimbine 3.

Scheme 2.19: Stork’s Synthesis

2.1.3.2. Martin’s Approach via Intramolecular Diels-Alder Reaction

In this strategy, the D and E rings of the target alkaloid are formed simultaneously by an intramolecular Diels-Alder reaction, followed by the elaboration of D and E rings, before the introduction of the tryptophyl subunit and the formation of C ring. Martin took advantage of the structural resemblances between reserpine and α-yohimbine and utilized one of the early intermediates 108 from his reserpine synthesis122 to synthesize α- yohimbine 7.103,123 The last two steps in Martin‟s synthesis are the same as in Stork‟s synthesis (Scheme 2.20). The synthetic subgoal 104 was made from 105 by regio- and stereoselective oxidation of the C(17)-C(18) double bond and stereoselective reduction of the C(19)-C(20) double bond. The dienic amide 105 was made from an intramolecular Diels-Alder (IMDA) reaction of 106. The latter was made from homoallylic amine 107, which in turn was made from propargyl alcohol.

Scheme 2.20: Martin’s Retrosynthesis

The synthetic intermediate 106 for the key Diels-Alder reaction was prepared from combining 2-oxopyran-6-carbonyl chloride with the secondary amine 107, which in turn was prepared from propargyl alcohol (Scheme 2.21). Uneventful thermolysis of trienic amide 106 provided the Diels-Alder adduct 105 in 93% yield. The configurations

of C(15) and C(16) were set by the virtue of this IMDA reaction. The next step was to install the OH functional group at C(17). Regioselective epoxidation of the more nucleophilic C(17)-C(18) double bond in 105 was carried out with m-CPBA in a stereoselective fashion from less crowded α-face. Several futile attempts were made to open the epoxide 108 reductively by various hydride reagents, catalytic hydrogenation, and dissolving-metal reductions, but Martin finally resorted to the tried and tested epoxide cleavage with lithium ethylhexanoate as in reserpine synthesis. This step served the purpose but added an additional step in the synthesis, viz. the deoxygenation of C(18) at a later stage. The resultant hydroxyl group at C(17) was then protected as the benzyl ether 109. Acid-catalyzed deprotection of MOM ether followed by the conversion of primary alcohol to the methyl ester and chemoselective reduction of the lactam with alane gave tertiary amine 110. Hydrogenolysis of tertiary amine 110 effected the stereoselective reduction of C(19)-C(20) double bond, selective O-debenzylation and concomitant acetylation, and deoxygenation at C(18) to afford 111, which now has the requisite functionality and DE-ring stereochemistry as in 7. Hydrogenolysis of N- benzylamine 119 with Pearlman‟s catalyst in glacial acetic and subsequent N-alkylation with tryptophyl bromide afforded 2,3-seco-α-yohimbine 103. Oxidative cyclization of

103 with mercuric acetate followed by reduction with NaBH4 afforded α-yohimbine 7 and the isomer 112 in equal amounts.

Scheme 2.21: Martin’s Synthesis

2.1.3.3. Momose’s Approach via Asymmetric Intramolecular Michael Addition

In 1990, Momose reported the first formal asymmetric synthesis of yohimbine 1.124-125 The key step in Momose‟s strategy (Scheme 2.22) featured an asymmetric intramolecular Michael reaction to prepare the D ring of yohimbine alkaloids. The conversion of 2,3-seco-yohimbine 96 to yohimbine 1 was already known at the time. The target 96 was made from the bicyclic unsaturated ketone 113, which in turn

was made from cyclization of the monocyclic keto-ester 114. The intermediate 114 was made from the strategic asymmetric intramolecular Michael reaction of the unsaturated keto-ester 115.

Scheme 2.22: Momose’s Retrosynthesis

The intramolecular Michael reaction of the enamine formed from the condensation of (+)-α-phenylethylamine and the ketone 115, and the subsequent debenzylation and BOC-protection provided the urethane 114 in 80% yield (3 steps) and 98% ee (Scheme 2.23). It was proposed that the reaction goes through a transition state where it assumes a thermodynamically more stable conformation 116, a quasi-chair with the enamine in the E configuration. It was also proposed that a Re-Re approach of the enamine to the unsaturated ester occurs as depicted in the Newman projection 117. Kinetic deprotonation of 114 and cyclization yielded a bicyclic ketone 118, which on treatment with p-TsOH/MeOH afforded a 1:3.7 mixture of two vinylogous ethers 119 and 120. The minor isomer was equilibrated under the same conditions to form the desired major isomer 120. The compound 120 was subjected to DIBAL reduction to form the corresponding alcohol, which, on treating with p-TsOH, gave α,β-unsaturated ketone 113. The regioselective installation of carbomethoxy group in 113 by Mander‟s reagent followed by catalytic hydrogenation of the double bond gave the bicyclic keto-ester 121. The reduction of the ketone in 121 was carried out with L-selectride which gave the desired C(17)-α-OH stereochemistry. Thus, the synthesis of DE rings was accomplished with all the requisite functional groups and stereochemistry as in yohimbine. A couple of

protecting group manipulations and N-tryptophylation of 122 yielded 2,3-seco-yohimbine 96. The transformation of 2,3-seco-yohimbine 96 to yohimbine 1 was reported.121,126 Thus, Momose and coworkers completed the first formal asymmetric total synthesis of yohimbine.

Scheme 2.23: Momose’s Synthesis

2.1.3.4. Aubé’s Approach via Asymmetric Nitrogen-Insertion of Oxaziridine

Aubé imagined the formation of the C(2)-C(3) bond in yohimbine 1127 by Bischler-Napieralski cyclization of the intermediate 123, which in turn would be made from the selective dehydration of 124. The photochemical nitrogen insertion of the oxaziridine 125 would lead to the trans-fused bicyclic lactam 124, and the former would be made from the epoxidation of the intermediate imine formed from the reaction of tryptamine with the ketone 126. The ketone 126 could be made from the dicarboxylic acid 127, obtained from the homologation of the enantiopure Diels-Alder adduct formed between dimenthyl fumarate and 1,3-butadiene.

Scheme 2.24: Aubé’s Retrosynthesis

The synthesis began with a diastereoselective Diels-Alder reaction between dimenthyl fumarate with 1,3-butadiene in the presence of Lewis acid to afford the cycloadduct 128 as a single isomer (Scheme 2.25). Homologation of cycloadduct 128 led to cyclohexenedicarboxylic acid 127. Esterification of 127 followed by Dieckmann condensation and decarboxylation afforded trans-hydrindanone 126 in 33% overall yield.

In an attempt to functionalize the E ring efficiently, the C2 axis of symmetry in 126 was used to advantage to render a single diacetoxy ketone 129 by cis dihydroxylation and acetylation.

The diacetoxy ketone 129 was condensed with tryptamine, and the resultant imine was oxidized with m-CPBA to afford a mixture of oxaziridines 130a-d (95% yield) in the ratio of 71:4:13:13. The major product has the indolylethyl substituent on the nitrogen atom pointing away from the closest ring fused hydrogen (Hα). Photolysis of 130a-d allowed nitrogen insertion to form two inseparable trans-fused bicyclic lactams 131 and 132 (77% yield) in the ratio of 2.5:1 respectively. The removal of the acetyl groups in 131 and 132 and selective esterification of the equatorial hydroxyl by bulky pivaloyl chloride gave 124 and 133 respectively, which allowed the regiochemical differentiation between the hydroxyl groups. Although, in principle, both 124 and 133 could be converted to yohimbine (both are in the same enantiomeric series), only the major isomer (124) was used in the synthesis. Elimination of the C(19) hydroxyl group in 124 with Martin‟s sulfurane reagent provided 123. The compound 123 when subjected to Bischler-Napieralski cyclization-reduction followed by C(3) epimerization and C(17)-OH oxidation, resulted in the desired enone 134 with C(3)-C(15) syn stereochemistry. The final steps in the synthesis closely followed that of Momose.124-125 The presence of C(18)-C(19) double bond in 134 was used to advantage for the regioselective installation of the carbomethoxy group at C(16). Deprotonation and addition of Mander‟s reagent gave N,C-carbomethoxylated product 135 in 90% yield. The hydrogenation of C(18)-

C(19) double bond followed by N-deacylation with K2CO3 yielded yohimbinone 136. The L-selectride reduction of the latter afforded (+)-yohimbine 1 in 13 steps (7.8% overall yield) from trans-hydrindanone 126.

Scheme 2.25: Aubé’s Synthesis

2.2. Syntheses Using Strategy II

2.2.1. ABC-ring Core (β-carboline derivative) as a Precursor

2.2.1.1. Szántay’s Approach via Dieckmann Cyclization

Szántay and coworkers utilized a Dieckmann cyclization strategy to construct both the normal and allo series of yohimbine alkaloids. His approach utilized the reaction of subunits such as 140a or 140b with intact ABC ring system 139 to form the D ring, which can be elaborated further to form E ring. The E ring of the stereoisomers of yohimbine was made by Dieckmann cyclization of tetracyclic diester 137 (Scheme 2.26). The C(15)-C(16) bond in 137 was made from tetracyclic ketone 138 by Horner-Emmons olefination-reduction sequence. The D ring of 138 was made from the condensation of the β-carboline derivative 139 with 140a or 140b. By using the common intermediate 138, in their further work, variants of the Dieckmann cyclization reaction were reported to enhance the efficiency of the synthesis by improving the regioselectivity of the Dieckmann cyclization step.

Scheme 2.26: Szántay’s Retrosynthesis

The quaternary ammonium salt 140a or the keto-ester 140b was obtained by a series of reactions from 2-acetylglutaric ester. Condensation of the cyclization product of

N-formyltryptamine, the β-carboline 139, with 140a or 140b afforded a tetracyclic ketone 141 (Scheme 2.27). The latter when subjected to Horner-Emmons olefination- hydrogenation sequence afforded the diester 142 with the desired trans stereochemistry for the synthesis of normal yohimbine series. The Dieckmann cyclization of 142 in heterogeneous phase using sodium methoxide led to the formation of regioisomers 143 and 136 in 1:1 ratio. Borohydride reduction of the β-ketoester 136 afforded β- yohimbine 3 and yohimbine 1 in 3:1 ratio.111,128

Scheme 2.27: Szántay’s Synthesis I

The efficiency of the synthetic sequence was improved by using the nitrile 144 (Scheme 2.28). The nitrile 144 when subjected to Dieckmann conditions afforded α- cyano ketone 146, which on hydride reduction afforded epimeric β-cyano alcohols 147a-

c. The nitriles 147a and 147b were then converted to yohimbine 1 and β-yohimbine 3 respectively.111,128

Scheme 2.28: Szántay’s Synthesis II

Using the common intermediate 141, Szántay and coworkers synthesized α- and allo-type yohimbine alkaloids (Scheme 2.29).112 After many unfruitful attempts, the condensation of methyl cyanoacetate with tetracyclic ketone 141 was successful when triethylammonium acetate was used as a solvent in the presence of phosphorus pentoxide, to afford α,β-unsaturated cyanodiester 148 with concomitant epimerization at C(20). The requisite cis stereochemistry of the DE ring fusion in allo series was established by the reduction of α,β-unsaturated double bond in 148 by NaBH4 to afford the cyanodiester 149. The basic hydrolysis, decarboxylation, and reesterification of the cyanodiester 149 provided the diester 56. Compound 56 when subjected to strategic Dieckmann cyclization step afforded pentacyclic β-ketoester 150 in 30% yield, its subsequent

reduction with NaBH4 gave 7:3:2 ratio of unnatural and undesired base 95, alloyohimbine 8, and α-yohimbine 7 respectively.

Scheme 2.29: Szántay’s Synthesis III

In 1986, Szántay and coworkers reported the enantioselective total synthesis129 of yohimbine 1 and β-yohimbine 3, utilizing the tetracyclic ketone 141 prepared during their racemic synthesis (Scheme 2.30).111,128 The key step was to utilize a second-order asymmetric transformation to resolve 141 using the solubility differences of the diastereomeric salts formed between 141 and optically pure tartaric acid. The tetracyclic ketone (-)-141 was obtained in both enantiomerically as well as diastereomerically enriched forms from repetitive equilibration and isolation of (±)-tetracyclic ketone 141. Olefination of (-)-141 furnished α,β-unsaturated ester (+)-151, which underwent complete racemization during the palladium catalyzed hydrogenation of the double bond. To prevent this puzzling racemization step, reduction of the double bond was postponed, and the E ring was formed first using Dieckmann cyclization to give (-)-Δ15,16-

dehydroyohimbinone 87. Nickel boride reduction of 87 resulted in simultaneous reduction of α,β-unsaturated double bond and the ketone to afford (-)-β-yohimbine 3 and (+)-yohimbine 1 in 2:1 mixture. A similar synthetic sequence starting from (+)-141 was also carried out to afford the unnatural isomers (+)-β-yohimbine and (-)-yohimbine.

Scheme 2.30: Szántay’s Synthesis IV

2.2.1.2. Kametani’s Approach via Dieckmann Cyclization and Robinson-type

Annulation

The strategy featured the construction of D ring of yohimbine by Dieckmann cyclization and the E ring by Robinson-type annulation.115,130 Yohimbinone 136 was made from the tetracyclic ketone 80 by Robinson-type annulation, which resulted in two C-C bonds (C(15)-C(16) and C(19)-C(20)) with the concomitant formation of the E ring. The latter was formed from Dieckmann cyclization and decyanation of 152, which in turn is a derivative of 153 (Scheme 2.31).

Scheme 2.31: Kametani’s Retrosynthesis I

The tertiary amine 152 was obtained by condensation of the secondary amine 153 with acrylonitrile (Scheme 2.32). The former, when subjected to Dieckmann cyclization followed by decyanation, afforded a tetracyclic ketone 80. The pyrrolidine enamine 154 of ketone 80 underwent Robinson-type annulation with methyl-3-oxo-pentenoate to afford 15,16-dehydroyohimbine 87. The compound 87 upon catalytic hydrogenation afforded yohimbinone 136. Yohimbinone 136 had been converted to yohimbine 1 and β- yohimbine 3 by Szántay.120

Scheme 2.32: Kametani’s Synthesis I

2.2.1.3. Ninomiya’s Approach via Photocyclization of Enamide

The formal synthesis of yohimbine 1 and alloyohimbine 8 was accomplished by Ninomiya and coworkers by utilizing enamide photocyclization strategy.131-132 Their approach (Scheme 2.33) featured photocyclization of exocyclic enamide 156 to form the D ring with concomitant generation of the pentacyclic skeleton, which was further elaborated to form the normal and allo-type yohimbine isomers.

Scheme 2.33: Ninomiya’s Retrosynthesis

The synthesis began with N-acylation of harmalane 157 with 4-methoxybenzoyl chloride to provide exocyclic enamide 156 (Scheme 2.34). Reductive photocyclization in the presence of NaBH4 converted enamide 156 into a pentacyclic enol ether 155 in excellent yield. Reduction of the lactam followed by acid hydrolysis of 155 provided β,γ- unsaturated ketone 158. Heating 158 in tartaric acid, malic acid, or conc. hydrochloric acid lead to the formation of trans-fused conjugated enone 134, whereas treating 158 under basic conditions or with silica gel afforded cis-fused conjugated enone 159 in excellent yield. Moreover, cis-fused enone 158 when heated in conc. hydrochloric acid isomerized to trans-fused enone 134. Acylation of the lithium enolate of enone 134 with methyl cyanoformate afforded exclusively the C(16)-acylated product, which, on catalytic hydrogenation, provided yohimbinone 136. Alternatively, acylation of the magnesium enolate of 159 with methyl chloroformate and catalytic hydrogenation afforded alloyohimbinone 93, but acylation of the lithium enolate with methyl

cyanoformate and subsequent hydrogenation provided the C,N-acylated product 160.

Product 160 was converted to 93 with K2CO3/MeOH. Both yohimbinone 136 and alloyohimbinone 93 were intermediates in Szántay‟s yohimbine120,128 and alloyohimbine112 synthesis respectively.

Scheme 2.34: Ninomiya’s Synthesis

2.2.1.4. Jacobsen’s Approach via Catalytic Asymmetric Acyl-Pictet-Spengler and Intramolecular Diels-Alder Reactions In 2008, Jacobsen and coworkers published an enantioselective synthesis of (+)- yohimbine 1. Their approach (Scheme 2.35) involved the synthesis of the enantiopure tetrahydro-β-carboline ring system (ABC rings of yohimbine) via a thiourea-catalyzed asymmetric acyl-Pictet-Spengler reaction and a substrate-controlled intramolecular Diels- Alder reaction (IMDA).133 The ingenuity lies in imagining an enantioriched intramolecular Diels-Alder substrate such as 161 for an efficient and stereoselective synthesis of yohimbine. Two rings (D and E), two C-C bonds (C(15)-C(20) and C(16)-C(17)), and four contiguous stereocenters (C(20), C(15), C(16), and C(17)) were set by an IMDA reaction, whereas the remaining stereocenter was set by an asymmetric catalytic acyl-Pictet-Spengler reaction. Triene 161 would be made from the aldehyde 162, which would be made from by N-alkylation of 163. The enantioriched β-carboline derivative 163 would be made from imine 164, obtained by the condensation of tryptamine and the corresponding aldehyde.

Scheme 2.35: Jacobsen’s Retrosynthesis

The tryptamine was condensed with the corresponding aldehyde, and the resulting imine was acetylated and cyclized using a thiourea-catalyzed asymmetric acyl-Pictet- Spengler reaction to afford the enantioriched key intermediate, N-acetyltetrahydro-β- carboline 163 (Scheme 2.36). The intermediate 163 was then deacetylated, and the diene side chain was introduced via reductive amination, yielding a dienic tertiary amine 165. The protection of the indole nitrogen in 165 with Cbz-Cl afforded the corresponding N- Cbz indole in 92% yield. The deprotection of TBDPS in 165, followed by oxidation gave the aldehyde. The resultant aldehyde was then treated with an appropriate modified Wittig reagent to form the triene 161 which is all set for the key IMDA reaction. The

IMDA reaction in the presence of the Lewis acid (Sc(OTf)3) proceeded uneventfully with unexpectedly high selectivity leading to a single diastereomer 166. The unexpectedly high endo/exo selectivity was attributed to the presence of the N-Cbz group on the indole. Finally, removal of the N-Cbz and O-Bz protecting groups and hydrogenation of the C(17)-C(18) olefin afforded (+)-yohimbine 1 in quantitative yield. Thus, Jacobsen et. al. reported a concise, efficient, and stereoselective synthesis of (+)-yohimbine (11 steps, 14% overall yield), proving the utility of enantioenriched tetrahydro-β-carbolines.

Scheme 2.36: Jacobsen’s Synthesis

2.3. Synthesis Using an Alternative Strategy

2.3.1. Kametani’s Alternative Approach via Birch Reduction

The unsaturated keto-ester 87 would be made from the Birch reduction of the O- methylhexadehydroyohimbine 70.117-118 The intermediate 70 would be made from the photolysis of the spiro compound 167, which in turn was imagined making from the Pictet-Spengler reaction of the intermediate imine obtained from the condensation of 1,2- dione 168 with tryptamine. The 1,2-dione was made in eleven steps from m- methoxybenzaldehyde (Scheme 2.37).

Scheme 2.37: Kametani’s Retrosynthesis II

The indanone 173, made from m-methoxybenzaldehyde in nine steps, on hydroxyimination and hydrolysis afforded the 1,2-dione 168 (Scheme 2.38). The condensation of the more electrophilic ketone of 168 with tryptamine hydrochloride formed the imine, which underwent in situ Pictet-Spengler reaction to provide the spiro compound 167. The photolysis of 167 gave two products, which were subsequently reduced to 70. The Birch reduction and reesterification of the carboxylic acid of O- methylhexadehydroyohimbine115 70 afforded the enol ether 176, which underwent acid- mediated demethylation and double bond isomerization to give 15,16-dehydroyohimbine 87. The compound 87 was a known precursor to yohimbine 1 and β-yohimbine 3.130

Scheme 2.38: Kametani’s Synthesis II

2.4. Grossman’s Approach via Double Annulation

We are interested in synthesizing some of the yohimbine alkaloids via double annulation, a methodology which was developed in our laboratory for the synthesis of highly functionalized trans-decalin and trans-perhydroisoquinoline ring systems. Our approach involves a double Michael reaction to construct the E ring, and an intramolecular cyclization to construct the D ring. Finally, the functionality on the D ring can be elaborated to form the C ring of the yohimbine alkaloids. More details of this approach can be seen in the third chapter.

Chapter 3 Our Double Annulation Approach to Yohimbine Alkaloids

The indole alkaloids, a class of natural products, have received much synthetic attention for years due to their diverse structures and interesting biological properties. We are particularly interested in synthesizing some of the yohimbine alkaloids (Figure 3.1) extracted from the bark of a tall evergreen African tree (Corynanthe 6 yohimbe, commonly known as fringe tree). Yohimbine, 1, is an α2-adrenoceptor selective antagonist, whereas corynanthine, 2, is an α1-adrenoceptor selective antagonist.86 These isomers feature a pentacyclic ring system with two heteroatoms and five stereogenic centers.

yohimbine (1) α-yohimbine (7) 16-epi: corynanthine (2) 16-epi: allo-yohimbine (8)

Figure 3.1. Isomers of yohimbine

3.1. Brief Introduction to Double Annulation Methodology

3.1.1. A General Double Michael Reaction

Over the years, much work has been done in our laboratory in developing the double annulation methodology. The double annulation methodology consists of two separate ring-forming synthetic transformations.134 The first step is a double Michael reaction, in which a “tethered diacid” is allowed to react with an alkynone to yield highly substituted carbocycles and heterocycles (Scheme 3.1). The resultant double Michael adduct contains two newly formed C-C bonds, a ring, two quaternary centers, and up to three new stereocenters.

Scheme 3.1: General representation of a double Michael reaction

3.1.2. “Tethered Diacids” in the Formation of Carbocycles and Heterocycles

Tethered diacids are compounds that contain two carbon acids joined by a tether of two to four carbon atoms. Many specific examples of “tethered diacids” used in a double Michael reaction to construct carbocycles (Scheme 3.2) and heterocycles (Scheme 3.3) can be seen below.

Scheme 3.2: Double Michael route to carbocycles

Scheme 3.3: Double Michael route to heterocycles

3.1.3. Double Annulation Products

In the second, intramolecular step, using the functionality on the double Michael adduct, a second carbocycle or azacycle can be formed (Scheme 3.4).135-138 Overall, by double annulation methodology, we are able to access cis- and trans- perhydroisoquinoline substructures, which are important subunits of many of the natural products.

Scheme 3.4: Selected examples of double annulation products

As discussed earlier, our access to cis- and trans-perhydroisoquinoline substructures through our double annulation methodology, and the presence of trans- perhydroisoquinoline substructure in the natural products yohimbine and corynanthine (Figure 3.2), led us to design a synthesis to validate the utility of our double annulation methodology.

yohimbine (1) 16-epi: corynanthine (2) Figure 3.2. Illustration of trans-perhydroisoquinoline substructure 61

3.2. Retrosynthetic Strategy

Our retrosynthetic plan (Scheme 3.5) was directed towards the synthesis of yohimbine 1 and corynanthine 2. Our approach involved a double Michael reaction to construct the E ring of the yohimbine alkaloids and a reductive amination reaction to construct the C and D rings. We envisioned that the C(3)-N(4) and N(4)-C(5) bonds of yohimbine could be made by a reductive amination reaction; disconnection of these bonds and the C(6)-C(7) bond led to compound 177. We planned to make the C(16)-C(14) and C(20)-C(14) bonds of 177 by a double Michael reaction of the tethered diacid 178 and an indole alkynone 179. The tethered diacid 178 and the indole alkynone 179 could be made from their corresponding aldehydes 180 and 181.

Scheme 3.5: Retrosynthetic strategy

3.2.1. Difference Between our Synthesis and all Other Syntheses

All of the syntheses involving strategy I (Scheme 2.1), and also Kametani‟s alternative approach (Scheme 2.37) depended on Pictet-Spengler or Bischler-Napieralski reactions or modified versions of either to construct the crucial C(2)-C(3) bond with the concomitant formation of the C ring and the C(3) stereocenter. Furthermore, all these syntheses utilized tryptamine or tryptophyl bromide to connect the indole portion of the molecule with the DE ring core.

The rest of the syntheses utilized strategy II (Scheme 2.1), where a β-carboline derivative was used as a starting material, which already has the C(2)-C(3) bond, and features intact ABC rings with pendant functionality for the annulation of D and E rings. Like strategy II, our strategy also has the C(2)-C(3) bond in the starting material, but we differ in not utilizing the β-carboline derivative (intact ABC rings) as a starting material. Our approach, like strategy I, features the formation of C ring, but not by employing tryptamine or tryptophyl bromide and not via formation of the C(2)-C(3) bond. Our approach thus features a potential novel solution to the synthesis of yohimbine alkaloids, and emerges as a “hybrid approach” of strategies I and II; a summary of basic differences in the strategies is presented in the Table 3.1. Table 3.1: Summary of basic differences in synthetic strategies C(2)-C(3) Utilized Utilized β-carboline bond present C ring Strategy tryptamine/tryptophyl derivative (ABC in the starting formed bromide rings) material Strategy I Yes No No Yes Strategy II No Yes Yes No Grossman‟s No Yes No Yes Strategy

3.3. Preparation of Tethered Diacid and Alkynone

In view of the fact that our approach presents a convergent synthetic plan, our synthesis began with the preparation of two starting materials, the “tethered diacid” and the indole alkynone.

3.3.1. Synthesis of Indole Alkynone

The indole alkynone 179 was prepared from the commercially available ethyl indole-2-carboxylate 182 as shown in Scheme 3.6. Also, five other indole alkynones were prepared as well by similar methods (Figure 3.3).

Scheme 3.6: Synthesis of indole alkynone

3.3.2. Synthesis of Tethered Diacid

The “tethered diacid” was prepared as shown in Scheme 3.7. The oxidative cleavage of alkene 185 to aldehyde 180, either by ozonolysis or by Johnson-Lemieux oxidation, worked well on a small scale but gave poor yields on scale-up. However, extractive work-up conditions (see experimental section) following the ozonolysis furnished a relatively clean sample of aldehyde 180, which without further purification was immediately carried on to the next step to afford tethered diacid 178 in reproducible yields (55% over two steps).

Scheme 3.7: Synthesis of tethered diacid

3.4. The Double Michael Reaction

3.4.1. The Double Michael Reaction with the Tethered Diacid 178

Our laboratory had not previously used, in a double Michael reaction, a “tethered diacid” of type 178 with a β-ketoester moiety containing two acidic protons on one side and a cyano sulfone moiety on the other side of the tether. The “tethered diacid” gave very poor yields in the double Michael reaction (Scheme 3.8) with any of the indole alkynones (Figure 3.3).

Scheme 3.8: Failed double Michael reaction with tethered diacid and various indole alkynones

Figure 3.3. Various indole alkynones

3.4.2. Hypothesis on the Failure of the Double Michael Reaction with 178

The Hx in phenylsulfonyl acetonitrile is slightly more acidic than the Hy in ethyl 139-140 acetoacetate (Figure 3.4). We surmised if the same is also true with Hx1 and Hy1 of

the “tethered diacid” 178, the initial deprotonation of the cyano sulfone, and its reaction with the alkynone 179 in a Michael reaction forms the mono Michael adduct 191, which in turn reacts in a intramolecular Michael reaction with the deprotonation of the β- ketoester moiety to give the double Michael adduct 192 (Scheme 3.9).

Figure 3.4. pKa’s of phenylsulfonyl acetonitrile and ethyl acetoacetate

Scheme 3.9: Anticipated double Michael reaction with the tethered diacid

The failure of the double Michael reaction, however, led us to believe that the impelling negative inductive effects, due to the proximal presence of cyano sulfone and the keto-ester moieties, may have caused the subtle variation in acidities rendering Hy1 slightly more acidic than the Hx1, or it could also be that at any given time the concentration of the cyano sulfone anion is more than the keto-ester anion, but the rate of addition of the cyano sulfone anion to ynone may be slower than the addition of the ketoester anion. Given these presumptions, the mono Michael adduct 193, now formed on the β-ketoester side, presents the remaining acidic proton (Hy1) with much lower pKa as it is now flanked between the three carbonyl groups (Scheme 3.10). This, in turn, implies that the reaction impedes at this stage; the more acidic Hy1 will be deprotonated in preference to the Hx1, and thwarts the Michael addition of the cyano sulfone to form the double Michael adduct 192.

Scheme 3.10: Presumed initial Michael reaction on the β-ketoester moiety and the failure of the double Michael reaction

If our hypothesis was true, blocking the protons of the β-ketoester moiety, and allowing the cyano sulfone moiety to react first in a Michael reaction should circumvent the problem of initial Michael addition on the β-ketoester side and the consequent cessation of the reaction. This logic led us to protect the β-ketoester.

3.5. The Double Michael Reaction with Silyl enol ether of Tethered Diacid 196

As a result, silyl enol ether 196 was made, to block the presumably more acidic β- ketoester moiety, as shown in Scheme 3.11, and the double Michael reaction was executed in two separate steps, as illustrated in Scheme 3.12 for the alkynone 179.

Scheme 3.11: Preparation of silyl enol ether

Validating our hypothesis, with the silyl enol ether 196, the double Michael reaction finally bore double Michael adducts 197, 198, and 199 (Figure 3.5), with the alkynones 179, 187, and 190 respectively. However, only double Michael adduct 197 was utilized in the synthesis. Of the compounds 198 and 199, the double Michael adduct 198 is of particular interest, because it presents an indolylethyl alcohol appendage, which has an inherent potential for the formation of the C ring of the alkaloid. However, the low yields of 187 and 198, and the reluctance of 199, in our initial attempts, to undergo the intramolecular cyclization reaction with the pendant ketone and also its future requirement of an additional synthetic step, viz. debenzylation, led us to move forward only with 197.

Figure 3.5. Double Michael adducts

3.5.1. The Double Michael Reaction of the Alkynone 179 with 196

The key double Michael reaction was executed in two separate steps (Scheme 3.12). First, the cyano sulfone moiety of 196 was allowed to react with the alkynone of 141 179 in a reaction catalyzed by Ph3P. Second, desilylation of the intermediate was promoted by KF, and a second Michael reaction occurred concomitantly to give the double Michael adduct 197 in 58% yield over two steps.

Scheme 3.12: The double Michael adduct

The structure and stereochemistry of 197 was confirmed by X-ray crystallographic analysis (Figure 3.6). The sulfonyl and CH2COAr groups were trans in 197, as expected from the thermodynamically preferred structure of nascent double Michael adduct 192, but the enolization of the -ketoester and the resultant 1,2-allylic strain caused both large groups to assume unexpected axial orientations.

Figure 3.6: X-ray crystal structure of 197

3.6. 1,2-Allylic Strain and the Double Michael Adduct

3.6.1. A1,2 Strain in 2,3-dimethyl-1-butene

First recognized in 1965 by Johnson and Malhotra,142 1,2-allylic strain (also known as 1,2-A strain or A1,2 strain) is defined as a steric interaction between the substituents at 1 and 2 positions of an allylic system as shown in the compound 201b. This type of steric interaction plays an important role in influencing the conformational preferences of alkenes. The unfavorable steric interaction between geminal dimethyl groups on C(2) and the methyl group on C(1) would make the compound preferentially exist in 201a or 201c rather than 201b (Scheme 3.13).

Scheme 3.13: 1,2-allylic strain in 2,3-dimethyl-1-butene

3.6.2. A1,2 Strain in 1,6-dimethyl-1-cyclohexene

1,2-allylic strain is also evidenced in substituted cyclohexenes143-144 such as compound 202. When C(2)-CH3 is equatorial, the dihedral angle between C(1)-CH3 and

C(2)-CH3, as in 202a, is approximately 35˚. As a result there is steric encumbrance in 202a. To avoid this unfavorable steric interaction, the ring flips, thereby increasing the dihedral angle to approximately 85˚, favoring 202b over 202a.

Scheme 3.14: 1,2-allylic strain in 1,6-dimethyl-1-cyclohexene

3.6.3. Effect of A1,2 Strain on the Double Michael Adduct

We hypothesized that the enolization of the β-ketoester of the thermodynamically preferred nascent double Michael adduct 192 formed nascent 192a, which suffered 1,2- allylic strain between CO2Et and CH2COAr groups (Scheme 3.15). As a result of this unfavorable steric interaction between the two large groups, the ring flipped placing the

CH2COAr group axial, and thereby increasing the dihedral angle and eliminating the 1,2- allylic strain.

Scheme 3.15: Effect of 1,2-allylic strain on the double Michael adduct

3.7. The First Approach to DE-Ring Core

3.7.1. Formation of Double Annulated Adduct 203

After many attempts, we found that the crucial reductive desulfonylation of 197, which sets the stereochemistry at C(20) earlier in the synthesis, led to intractable products. At that stage, desulfonylation was postponed; an acid-promoted cyclization, after tweaking the conditions, converted 197 to 203 rather uneventfully (Scheme 3.16), which was then carried out further in the synthesis without purification. The stereochemical assignment of 203 was made by 1H NMR: the olefinic H atom and the adjacent methine H atom participated in a coupling of 6.5 Hz, establishing the equatorial orientation (with respect to the piperidone ring) of the ring fusion methine H atom. Later, the structure was unambiguously assigned by single crystal X-ray analysis (Figure 3.7).

Scheme 3.16: The double annulated adduct

Figure 3.7: X-ray crystal structure of 203

3.7.2. Desulfonylation of Double Annulated Adduct

The desulfonylation was attempted again, but now on the double annulated adduct

203. On a tiny scale, the reaction of 203 with Mg/HgCl2/EtOH gave us a glimmer of hope by causing the disappearance of the phenyl group resonances in the 1H NMR spectrum, but the result was irreproducible. Finally, with samarium diiodide, the reductive desulfonylation of 203 occurred with retention of the cis ring fusion, providing entry into the - and alloyohimbine stereochemical framework (Scheme 3.17). Though a nontrivial transformation, given the dense functionality on 203, it was much to our dismay that the reaction was obscured by reproducibly low yields and unclean product.

Scheme 3.17: Desulfonylation of double annulated adduct

3.7.3. Hydrogenation of Enamine from the Convex Face and Subsequent Reactions

The bicyclic unsaturated lactam 204a,b underwent hydrogenation from the convex face, as desired (Scheme 3.18), but the yield of the product obtained from this and subsequent reactions were prohibitively low. Undaunted, en route to α-yohimbine, we took a detour, and that was to reduce the enamine of 203 prior to desulfonylation.

Scheme 3.18: Hydrogenation of enamine 204 from the convex face and subsequent reactions

3.8. The Second Approach to DE-Ring Core

3.8.1. Hydrogenation of the Double Annulated Adduct 203

Considering the first approach as a prelude to the second approach, we proceeded to reduce the double bond in bicyclic unsaturated lactam 203 (Scheme 3.19). Considerable effort was expended in screening silane-mediated reductions and catalytic hydrogenations under neutral and acidic conditions. Guided by the screening efforts, hydrogenation of 203 was attained in the presence of CF3COOH, which worked like a charm, albeit to give the unnatural epimer at C(3). The 1H NMR spectrum of 208 showed the methine H adjacent to the indole group as an approx. dd with one large and one small coupling constant (J = 7.7 Hz, J = 4.9 Hz), establishing its axial orientation. Eventually, the structure was unambiguously secured by single crystal X-ray analysis (Figure 3.8). The undesired C(3)-epimer 208 veered our focus toward the synthesis of 3-epi-

alloyohimbinone 210 (Scheme 3.20), which Szántay had previously converted to α- and alloyohimbine.145

Scheme 3.19: Hydrogenation of the double annulated adduct

3.8.2. Desulfonation After the Enamine Reduction

Gratifyingly, desulfonation of 208 occurred uneventfully with retention of the cis DE ring fusion, providing entry into the epi-α- and epi-alloyohimbine stereochemical framework (Scheme 3.20). The prior reduction of the sensitive enamine function may have improved the yield and reproducibility of the desulfonation by avoiding undesired side reactions. The 1H NMR spectrum of 209 at room temperature showed broad peaks attributable to fluxional behavior on the NMR timescale; it was difficult to assign the stereochemistry, and a low temperature 1H NMR was not taken at the time, but we obtained a single crystal X-ray analysis to establish the relative stereochemistry (Figure 3.9).

Scheme 3.20: Desulfonation after the enamine reduction

Figure 3.8: X-ray crystal structure of 208

Figure 3.9: X-ray crystal structure of 209

3.9. Hydrogenation from the Sterically Encumbered Concave Face of 203

The previous work in the Grossman lab evidenced a similar hydrogenation from the sterically encumbered concave face (Scheme 3.21). The hypothesis discerned by Grossman et al. can be adapted to explain the hydrogenation of compound 203.146

Scheme 3.21: Hydrogenation from the concave face – reported example

3.9.1. Steric and Stereoelectronic Factors Effecting Reduction from Convex Face of

203

The two major conformations of the compound 203, A and B, are shown in Scheme 3.22. As shown in 203c (Figure 3.10), the reduction from the convex face of the conformer B is facile because the approach of the catalyst is unhindered, and also the reduction places the nascent piperidone ring in a half-chair conformation with an equatorial indolyl group. Therefore, it is both sterically and stereoelectronically favored. Contrarily, the hydrogenation from the convex face of the conformer A is difficult because, the reduction (axial delivery from top) requires the nascent piperidone ring to assume a half-boat conformation where the phenylsulfone has a severe flagpole interaction with the Y group and a 1,3-diaxial interaction with the X group (203a), i.e., it is both sterically and stereoelectronically disfavored or the equatorial delivery from top requires that the indolyl group assume an axial orientation adding one another 1,3-diaxial interaction (203b) and is therefore sterically disfavored.

Scheme 3.22: The major conformations of the doubly annulated adduct 203

Figure 3.10: Reduction from the convex face of conformers A and B

3.9.2. Conformational Preference of 203

Compound 203 exists primarily in conformation A, as shown by a larger coupling constant (J = 6.5 Hz) between the olefinic H atom and the adjacent methine H atom, and it may be conformationally more rigid because of the presence of the bulky phenylsulfonyl group and the enolic double bond. Also, the destabilizing dipole-dipole and 1,3-diaxial interactions in 203-B may have caused the compound 203 to stay in conformation A (Scheme 3.23). The concentration of 203-B, therefore, may be too low for the hydrogenation to occur from the convex face, and, therefore, the hydrogenation of 203-A from the concave face becomes competitive. Scheme 3.23: Preference of conformer A over conformer B

3.9.3. Catalytic Hydrogenation: Traditional Insertion vs. Ionic Mechanism

As explained earlier, the insertion of Pd–H from the convex face of the C═C π bond of 203-A may be a high-energy process (Figure 3.10), and the insertion of Pd–H from the sterically encumbered concave face is not expected to be facile. Therefore, we hypothesize that the hydrogenation switches from traditional insertion mechanism to an ionic protonation–hydride-transfer mechanism (Scheme 3.24). Although strange to think H–Pd(II)–H as a proton donor, the acidity of the palladium(II) hydride intermediates in the last step of the Mizoroki-Heck reaction is a well established fact. Also, Spencer et al. reported the induction of polarization of the Pdδ–‒ Hδ+ bond by a strongly polarized alkene,147-148 and the alkene in our case, of course, is strongly polarized by the N and the indole groups.

3.9.4. Ionic Protonation–Hydride-Transfer Mechanism

The protonation of the enamine C═C π bond in 203 by H–Pd(II)–H gives [H– Pd(0)]‒ and a carbocation stabilized by NH and the indole groups. The less sterically demanding hydride-transfer step then proceeds with an axial attack, with concomitant regeneration of neutral catalyst Pd(0), placing the nascent piperidone ring in a half-chair conformation with an equatorial indole group (Scheme 3.24).

Scheme 3.24: Ionic hydrogenation mechanism

3.10. Unsuccessful End-Game

At this stage, all that remained to attain the known precursor 210, thereby completing the formal total synthesis of α-yohimbine and alloyohimbine, were amide reduction of 209, addition of C ring by linking D and B rings with a two-carbon chain, 83

and a transesterfication. Unfortunately, all our attempts to reduce the amide or to reduce the enol or to protect the enol of the bicyclic lactam 209 failed to proceed or gave intractable products.

3.11. A Serendipitous Discovery – To End on an Optimistic Note

We also explored another strategy (Scheme 3.24), which was to reduce the enol of 203 earlier in the synthesis. Although hydride reductions and catalytic hydrogenation of the enol resulted in multiple products, a rather surprising and elusive result but desired result was obtained when the enol reduced selectively in the presence of enamide double 1 bond with Et3SiH/MsOH to afford 214 in quantitative yield. The H NMR shows a coupling of 6.5 Hz between the olefinic H atom and the ring fusion H atom, suggesting that the dihedral angle between them is close to 0˚. The methine H atom adjacent to the carbonyl participates in two large couplings (J = 11.7 Hz, J = 10.3 Hz), suggesting that it is coupled to axial (with respect to carbocycle) ring fusion H atom and to axial methine H atom adjacent to OH group. The stereochemistry again is unambiguously established by single crystal X-ray analysis (Figure 3.11). The early enol reduction points the way forward; the desulfonation and enamide reduction of the intermediate 214 will be investigated to further improvise the synthesis.

Scheme 3.25: The enol reduction

Figure 3.11: X-ray crystal structure of 214

3.12. Experimental Section

3.12.1. Materials and Methods

Unless stated otherwise, all reactions were carried out at room temperature. Oven-dried glassware (~130 ˚C), anhydrous solvents, and a nitrogen atomosphere were used for reactions requiring inert conditions. Tetrahydrofuran (THF) was distilled from sodium/benzophenone ketyl, methylene chloride (CH2Cl2) and triethylamine (Et3N) were distilled from calcium hydride, and N,N-dimethylformamide (DMF) was stirred with

KOH and distilled from barium oxide (BaO). Borane-dimethyl sulfide complex (BH3-

DMS) (1.0 M solution in CH2Cl2), tert-butylchlorodiphenylsilane, ethynyl magnesium bromide (HCCMgBr) (0.5 M solution in THF), samarium iodide (SmI2) (0.1 M solution in THF), and triethylsilane purchased from Aldrich Chemical Company in Sure/Seal™ bottles and other commercially obtained reagents were used as received. Liquids and solutions were transferred via a syringe or a cannula. Ozone was generated using OREC ozone generator (model 850). Higher reaction temperatures were controlled using a silicone oil bath coupled to a VARIAC (Powerstat 3PN116C), and lower reaction temperatures (˂ 0 ˚C) were controlled using an immersion cooler (Julabo, FT901). Unless stated otherwise, all reactions were magnetically stirred and monitored by thin-layer chromatography (TLC). Thin-layer chromatography (TLC) was performed using Sorbent Technologies Silica Gel, w/UV254, aluminum backed (0.2 mm thick) TLC plates and visualized using a combination of UV, and potassium permanganate stain. Column or flash chromatography (silica) was performed with the indicated solvents using silica gel (particle size 0.032-0.063 mm) purchased from MP Biomedicals or Dynamic Adsorbents. In general, the chromatography guidelines reported by Still were followed.149 All melting points were obtained on an Electrothermal Manual Mel-Temp melting point apparatus (model: 1001D) and are uncorrected. Infrared spectra were recorded on a Thermo Nicolet Avatar 360 FTIR or a Thermo Scientific Smart iTR (Nicolet iS10) and are reported in terms of frequency of absorption (cm-1). The 400 MHz 1H NMR and 100 MHz 13C NMR data were collected on a Varian VXR-400S. The 50 MHz 13C NMR data were collected on a Varian Gemini 200. Data for 1H NMR spectra are reported as 86

follows: chemical shift (δ ppm), multiplicity, coupling constant (Hz), and integration. Data for 13C NMR spectra are reported in terms of chemical shift. Chemical shifts are 1 13 1 reported relative to internal Me4Si ( H and C, δ 0.00 ppm) or CDCl3 ( H, δ 7.27 ppm, 13C, δ 77.0 ppm). X-ray crystallographic structures were obtained by Dr. Sean Parkin of Department of Chemistry, University of Kentucky.

3.12.2. Preparative Procedures

1-(1H-indol-2-yl)prop-2-yn-1-ol (184). To a solution of 181150 (6.53 g, 45 mmol) in 20 mL THF, ethynyl magnesium bromide (0.5 N solution in THF, 400 mL, 200 mmol) was added and stirred at rt for 4 h. The reaction was quenched with saturated aq. NH4Cl, extracted with ether, dried over MgSO4, and evaporated to give the crude product. The crude was carried on to the next step 1 without further purification; H NMR (400 MHz, CDCl3): 8.39 (s, broad, 1H), 7.59 (dd, J = 7.9 Hz, 0.9 Hz, 1H), 7.36 (dd, J = 8.2 Hz, 0.9 Hz, 1H), 7.21 (ddd, J = 8.2 Hz, 7.1 Hz, 1.1 Hz, 1H), 7.11 (ddd, J = 7.8 Hz, 7.1 Hz, 1.1 Hz, 1H), 6.61 (ddd, J = 1.8 Hz, 0.7 Hz, 0.7 Hz, 1H) 5.67 (d, broad, J = 3.6 Hz, 1H), 2.71 (d, J = 2.2 Hz, 1H), 2.39 (broad, 1H); 13 C NMR (400 MHz, CDCl3): 136.5, 136.5, 128.1, 122.9, 121.2, 120.3, 111.3, 101.4, 81.8, 75.0, 59.1; IR (KBr): 3550, 3468, 3432, 3288, 3051, 3023, 2949, 2925, 2124, 1638, - 1 1617 cm ; Anal. Calcd for C15H17NO5S: C, 55.72; H, 5.30. Found: C, 55.64; H, 5.39.

1-(1H-indol-2-yl)prop-2-yn-1-one (179).

The crude obtained from the above reaction was dissolved in 200 mL CH2Cl2 and treated with MnO2 (44 g, ~505 mmol). After stirring at rt for 2.5 h, the reaction mixture was filtered through a pad of Celite®, and the organic layer was evaporated to give the crude.

Flash chromatography (30% EtOAc in petroleum ether) gave 179 (2.76 g, 16.31 mmol, 32% yield(over four steps)) as a yellow solid; mp 132-134 ˚C; 1H NMR (400 MHz,

CDCl3): 9.45 (s, broad, 1H), 7.72 (ddd, J = 8.0 Hz, 1.6 Hz, 0.7 Hz, 1H), 7.49 (dd, J = 2.2 Hz, 0.9 Hz, 1H), 7.45 (ddd, J = 2.0 Hz, 0.9 Hz, 1H), 7.38 (dd + d + s, J = 6.8 Hz, 1.1 Hz, + J = 1.1 Hz, 1H), 7.16 (ddd, J = 8.0 Hz, 6.8 Hz, 1.1 Hz, 1H), 3.37 (s, 1H); 13C NMR

(400 MHz, CDCl3): 168.7, 139.0, 136.7, 128.3, 128.0, 124.2, 122.0, 115.4, 113.1, 80.8, 80.0; IR (KBr): 3320, 3250, 3075, 2089, 1650, 1600, 1561, 1514 cm- 1; Anal. Calcd for

C11H7NO: C, 78.09; H, 4.17. Found: C, 77.72; H, 4.32.

2-(phenylsulfonyl)hex-5-enenitrile (185). A solution of phenylsulfonyl acetonitrile (30.0 g, 165.7 mmol) in THF (150 mL) was added slowly to a stirring suspension of 60% NaH (6.63 g, 165.7 mmols) in THF (50 mL) at rt under N2. The flask was heated for 1 h at 50 ˚C. Then 4-bromo-1-butene (16.83 mL, 165.7 mmol) was added all at once and the reaction mixture was allowed to stir for 5 h at 50 ˚C. The reaction was quenched with ice cold water and diluted with ether. The resulting mixture was extracted with ether, washed with water and brine, dried over

MgSO4, and evaporated to give the crude product. Flash chromatography (30% EtOAc in petroleum ether) gave 185 (30.75 g, 130.72 mmol, 79% yield) as a colorless oil; 1H

NMR (400 MHz, CDCl3): 8.01 (dd, J = 8.0 Hz, 1.2 Hz, 2H), 7.77 (dt, Jd = 7.3 Hz, Jt = 1.2 Hz, 1H), 7.62 (dd, J = 8.0 Hz, 7.3 Hz, 2H), 5.72 (dddd, J = 17.2 Hz, 8.2 Hz, 7.7 Hz, 5.6 Hz, 1H), 5.11-5.17 (m, 2H), 3.94 (dd, J = 11.1 Hz, 4.2 Hz, 1H), 2.41-2.50 (m, 1H), 13 2.17-2.35 (m, 2H), 1.96-2.07 (m, 1H); C NMR (100 MHz, CDCl3): 135.2, 135.1, 134.4, 129.4, 129.3, 117.7, 113.6, 56.4, 29.9, 25.6; IR (neat): 3070, 2980, 2246, 1642, - 1 1584 cm ; Anal. Calcd for C12H13NO2S: C, 61.25; H, 5.57. Found: C, 61.19; H, 5.63.

5-oxo-2-(phenylsulfonyl)pentanenitrile (180).

The solution of 185 (7.05 g, 30.00 mmol) in CH2Cl2 (90 mL) was subjected to ozonolysis (90 V, 1.2 L/min) at -78 ˚C. After 65 min, the solution turned blue indicating the end of the reaction. After sparging with oxygen until the blue color was gone, 15 mL of Me2S was added and slowly warmed to room temperature. The reaction mixture was then transferred into a 1000 mL R. B. flask and stirred overnight with ~800 mL of water. The organic layer (containing aldehyde 7 in ~90 mL CH2Cl2) was separated, dried over 1 MgSO4, and immediately carried on to the next step. H NMR (400 MHz, CDCl3): 9.79 (s, 1H), 8.03 (dd, J = 8.0 Hz, 1.2 Hz, 2H), 7.79 (tt, J = 7.2 Hz, 1.2 Hz, 1H), 7.66 (ddd, J = 8.0 Hz, 7.2 Hz, 1.2 Hz, 2H), 4.24 (dd, J = 9.6 Hz, 5.2 Hz, 1H), 2.97 (ddd, J = 19.2 Hz, 6.8 Hz, 5.6 Hz, 1H), 2.80 (ddd, J = 19.2 Hz, 7.6 Hz, 6.8 Hz, 1H), 2.55 (dddd, J = 14.4 Hz, 7.6 Hz, 6.8 Hz, 5.2 Hz, 1H), 2.20 (dddd, J = 14.4 Hz, 9.6 Hz, 6.8 Hz, 5.6 Hz, 13 1H); C NMR (50 MHz, CDCl3): 199.0, 135.5, 129.8, 129.6, 113.5, 55.9, 39.6, 19.7; - 1 IR (neat): 3060, 2928, 2248, 1722, 1580 cm ; Calcd for C11H11NO3S: C, 55.68; H, 4.67. Ethyl 6-cyano-3-oxo-6-(phenylsulfonyl)hexanoate (178). To the above solution of 180, ethyl diazoacetate (3.31 mL, 31.50 mmol) was added followed by SnCl2 (338 mg, 5 mol%). After stirring the reaction mixture overnight at rt,

40 mL saturated aq. NH4Cl and 100 mL water were added, and stirred for 30 min. The resulting mixture was extracted with CH2Cl2, dried over MgSO4, and evaporated to give the crude product. Flash chromatography (20% EtOAc in petroleum ether) gave 178 (5.39 g, 16.67 mmol, 55% yield (over two steps)) as a white waxy solid; mp 66 ˚C; 1H

NMR (400 MHz, CDCl3): 8.01-8.04 (m, 2H), 7.79 (tt, J = 7.2 Hz, 1.2 Hz, 1H), 7.64- 7.69 (m, 2H), 4.24 (dd, J = 9.7 Hz, 5.6 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.48 (s, 2H),

3.03 (dt, Jd = 18.8 Hz, Jt = 6.0 Hz, 1H), 2.87 (ddd, J = 18.8 Hz, 8.1 Hz, 6.4 Hz, 1H), 2.54 89

(dddd, J = 14.1 Hz, 8.1 Hz, 6.4 Hz, 5.7 Hz, 1H), 2.19 (dddd, J = 14.1 Hz, 9.7 Hz, 6.4 Hz, 13 6.0 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H); C NMR (100 MHz, CDCl3): 200.6, 166.6, 135.3, 129.6, 129.4, 113.5, 61.5, 55.7, 48.8, 38.3, 20.8, 13.9; IR (KBr): 3063, 2984, 2929, - 1 2252, 1736, 1686, 1448 cm . Anal. Calcd for C15H17NO5S: C, 55.72; H, 5.30. Found: C, 55.64; H, 5.39.

Ethyl 2-(2-(3-(trimethylsilyl)propioloyl)-1H-indol-3-yl)acetate (186). The crude acid chloride151 (~1.33 g, ~5 mmol), made from 215152, was dissolved in

CH2Cl2 (10 mL) and to the solution was added 1,2-bis(trimethylsilyl)ethyne (1.02 g, 6.0 mmol) followed by quick addition of AlCl3 (800 mg, 6.0 mmol). After stirring for 20 min., 8 mL of saturated aq. NaHCO3 was added, and the reaction mixture was filtered through a cotton plug, and the filtrate was extracted with ether. The organic layer was dried over MgSO4, evaporated to give the crude product. The crude product was recrystallized from petroleum ether to afford 186 (690 mg, 2.1 mmol, 42% yield (over 1 two steps)) as yellow minuscule needles; mp 120-121 ˚C; H NMR (400 MHz, CDCl3): 9.01 (s, broad, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.38 (m, 2H), 7.17 (ddd, J = 7.8 Hz, 5.1 Hz, 2.7 Hz, 1H), 4.4 (s, 2H), 4.16 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1, 3H), 0.33 (s, 9H); 13C

NMR (400 MHz, CDCl3): 170.3, 167.6, 136.2, 132.7, 128.3, 127.6, 121.5, 121.1, 118.1, 112.1, 101.7, 101.3, 61.0, 30.6, 29.6, 14.1, -0.87; IR (neat): 3296, 3145, 3065, 2697, - 1 2954, 2927, 2896, 2162, 1717, 1677, 1614, 1579, 1227 cm . Calcd for C18H21NO3Si: C, 66.02; H, 6.46.

1 Figure 3.12: H NMR (400 MHz, CDCl3) of compound 186

13 Figure 3.13: C NMR (400 MHz, CDCl3) of compound 186

Figure 3.14: Infrared spectrum (neat) of compound 186

1-(3-(2-hydroxyethyl)-1H-indol-2-yl)prop-2-yn-1-one (187). The suspension of LAH (2.85 g, 75 mmol) in 60 mL THF was cooled to 0 ˚C and 216152 (6.90 g, 25 mmol) was added and stirred for 30 min. The granular salt formed, after quenching the reaction with the addition of water (3 mL) followed by 15% NaOH (3 mL) followed by water (15 mL), was vaccum filtered and the filtrate was evaporated to give the crude diol. The crude diol 217 was transformed into 187, by adapting the procedures 1 shown for compound 184 and 179. H NMR (400 MHz, CDCl3): 9.03 (s, broad, 1H), 7.69 (dd, J = 8.2 Hz, 0.73 Hz, 1H), 7.39 (m, 2H), 7.17 (m, 1H), 3.98 (t, broad, J = 6.9 Hz,

3H), 3.58 (t, J = 6.8 Hz, 2H), 3.52 (s, 1H); Calcd for C13H11NO2: C, 73.23; H, 5.20.

1 Figure 3.15: H NMR (400 MHz, CDCl3) of compound 187

1-(1H-indol-2-yl)-3-(trimethylsilyl)prop-2-yn-1-one (188). Using the preparative procedure for compound 186, compound 218 (800 mg, 5 mmol) was transformed to afford 188 (540 mg, 2.23 mmol, 44% yield) as a brown solid; mp 1 136-137 ˚C; H NMR (400 MHz, CDCl3): 9.25 (s, broad, 1H), 7.54 (approx. dd, J = 8.2 Hz, 0.9 Hz, 1H), 7.26 (dd, J = 1.8 Hz, 0.9 Hz, 1H), 7.24 (approx. dd, J = 2.9 Hz, 0.9 Hz, 1H), 7.18 (ddd, J = 7.8 Hz, 6.7 Hz, 1.1 Hz, 1H), 6.97 (ddd, J = 8.0 Hz, 6.9 Hz, 1.1 Hz, 13 1H), 0.15 (s, 9H); C NMR (400 MHz, CDCl3): 169.2, 138.9, 137.0, 128.0, 127.9, 124.0, 121.9, 114.7, 113.1, 101.3, 99.8, -0.008; IR (KBr): 3320, 3189, 3084, 3057, 3041, - 1 2969, 2898, 2865, 2158, 1600, 1567, 1517, 1242 cm ; Calcd for C14H15NOSi: C, 69.67; H, 6.26.

1 Figure 3.16: H NMR (400 MHz, CDCl3) of compound 188

13 Figure 3.17: C NMR (400 MHz, CDCl3) of compound 188

Figure 3.18: Infrared spectrum (thin film/KBr) of compound 188

1-(1-benzyl-1H-indol-2-yl)-3-(trimethylsilyl)prop-2-yn-1-one (189). Using the preparative procedure for compound 186, compound 219151,153 (1.10 g, 4.40 mmol) was transformed to afford 189 (1.02 g, 3.07 mmol, 70% yield) as a viscous pale 1 yellow oil; H NMR (400 MHz, CDCl3): 7.75 (dt, Jd = 8.1 Hz, 0.9 Hz, 1H), 7.65 (s,

1H), 7.35(approx. t + d, Jt = 1.1 Hz, Jd = 0.92 Hz, 2H), 7.20 (m, 4H), 7.06 (approx. d, J = 13 6.6 Hz, 2H), 5.83 (s, 2H), 0.32 (s, 9H); C NMR (400 MHz, CDCl3): 169.6, 141.5, 138.5, 136.0, 129.2, 127.9, 127.9, 127.2, 126.8, 124.1, 121.9, 118.4, 111.7, 102.5, 97.4, 48.8, 0.034; IR (neat): 3092, 3061, 3025, 2958, 2900, 2865, 2148, 1734, 1605, 1508, - 1 1245 cm ; Calcd for C21H21NOSi: C, 76.09; H, 6.39.

100

1 Figure 3.19: H NMR (400 MHz, CDCl3) of compound 189

101

13 Figure 3.20: C NMR (400 MHz, CDCl3) of compound 189

102

Figure 3.21: Infrared spectrum (neat) of compound 189

103

1-(1-benzyl-1H-indol-2-yl)prop-2-yn-1-one (190). By adapting the preparative procedure for compound 179, 210153(13.47 g, 48 mmol) was transformed to afford 190 (8.34 g, 32.16 mmol, 67% yield, 65% yield overall) as a yellow 1 solid; mp 92-94 ˚C; H NMR (400 MHz, CDCl3): 7.74 (dt, Jd = 8.0 Hz, Jt = 0.9 Hz, 1H), 7.70 (s, 1H), 7.36 (m, 2H), 7.20 (m, 4H), 7.06 (dm, J = 6.6 Hz, 2H), 5.82 (s, 2H), 13 3.26 (s, 1H); C NMR (400 MHz, CDCl3): 169.0, 141.7, 138.3, 135.7, 129.2, 128.2, 127.9, 127.2, 126.8, 124.3, 122.1, 119.0, 111.7, 81.9, 78.1, 48.8; IR (neat): 3214, 3135, - 1 3062, 3024, 2945, 2913, 2853, 2093, 1612, 1584, 1508, 1495 cm ; Calcd for C18H13NO: C, 83.37; H, 5.05.

104

1 Figure 3.22: H NMR (400 MHz, CDCl3) of compound 190

105

13 Figure 3.23: C NMR (400 MHz, CDCl3) of compound 190

106

Figure 3.24: Infrared spectrum (neat) of compound 190

107

ethyl 3-((tert-butyldiphenylsilyl)oxy)-6-cyano-6-(phenylsulfonyl)hex-2-enoate (196).

To the stirring solution of 178 (7.47 g, 23 mmol) in DMF (20 mL) at rt under N2, Et3N (3.8 mL, 27.6 mmol) was added followed by TBDPSCl (9 mL, 34.66 mmol). After the completion of the reaction (monitored by TLC), the reaction mixture was directly loaded on to the flash column. Flash chromatography (15% EtOAc in petroleum ether) gave 196 1 (10.80 g, 20.90 mmol, 90% yield) as a colorless gum; H NMR (400 MHz, CDCl3): 8.02 (approx. dd, J = 8.5 Hz, 1.2 Hz, 2H), 7.75 (tt, J = 6.9 Hz, 1.4 Hz, 1H), 7.59-7.67 (m, 6H), 7.39-7.51 (m, 6H), 4.90 (s, 1H), 4.02 (dd, J = 11.1 Hz, 4.1 Hz, 1H), 3.96 (q, J = 7.1 Hz, 2H), 3.17 (ddd, J = 13.5 Hz, 8.3 Hz, 7.3 Hz, 1H), 2.98 (ddd, J = 14.0 Hz, 8.5 Hz, 5.7 Hz, 1H), 2.57 (dddd, J = 17.6 Hz, 8.3 Hz, 7.3 Hz, 4.1 Hz, 1H), 2.22 (dddd, J = 19.2 Hz, 10.9 Hz, 8.3 Hz, 5.7 Hz, 1H), 1.10 (t, J = 7.1 Hz, 3H), 1.03 (s, 9H); 13C NMR (400 MHz,

CDCl3): 171.8, 168.0, 167.6, 136.1, 135.9, 131.4, 131.4, 131.1, 131.1, 130.3, 130.2, 128.8, 128.7, 114.5, 103.5, 61.0, 60.3, 57.7, 30.9, 27.0, 25.4, 21.7, 20.0, 14.8, 14.8; IR (neat): 3074, 2954, 2927, 2896, 2856, 2242, 1703, 1623, 1334, 1129 cm- 1; Calcd for

C31H35NO5SSi: C, 66.28; H, 6.28.

108

1 Figure 3.25: H NMR (400 MHz, CDCl3) of compound 196

109

13 Figure 3.26: C NMR (400 MHz, CDCl3) of compound 196

110

Figure 3.27: Infrared spectrum (neat) of compound 196

111

(5R,6R)-ethyl-6-(2-(1H-indol-2-yl)-2-oxoethyl)-5-cyano-2-hydroxy-5- (phenylsulfonyl)cyclohex-1-enecarboxylate (197).

The solution of 196 (10.8 g, 20.9 mmol) and 179 (3.5 g, 20.9 mmol) in CH3CN (300 mL) was treated with PPh3 (50 mg, 1 mol%). After the reaction was complete in ~5 min (monitored by TLC), the solvent was evaporated and crude product obtained was used in the next step without further purification.

The above obtained crude product was dissolved in EtOH (500 mL), and KF•2H2O (2.0 g, 21.94 mmol) was added and stirred at rt for 18 h. The precipitated product was filtered, washed with EtOH and dried in vacuo to afford 197 (5.97 g, 12.12 mmol, 58% yield) as a pale yellow solid. Suitable crystals for X-ray diffraction were grown from hot 1 EtOH; mp 170-172 ˚C; H NMR (400 MHz, CDCl3): 12.54 (s, 1H), 8.94 (s, broad, 1H), 8.06 (approx. dd, J = 8.5 Hz, 1.2 Hz, 2H), 7.8 (tt, J = 6.9 Hz, 1.2 Hz, 1H), 7.66

(approx. t + d + m, Jt = 8.1 Hz, Jd = 7.5 Hz, 3H), 7.38 (ddd, J = 8.5 Hz, 2.2 Hz, 0.9 Hz, 1H), 7.33 (ddd, J = 7.7 Hz, 6.5 Hz, 0.9 Hz, 1H), 7.14 (ddd, J = 8.1 Hz, 6.7 Hz, 1.4 Hz,

1H), 7.09 (dd, J = 2.2 Hz, 0.8 Hz, 1H), 4.29 (t, J = 4.9 Hz, 1H), 4.14 (dq, Jd = 10.9 Hz, Jq

= 7.1 Hz, 1H), 3.98 (dq, Jd = 10.9 Hz, Jq = 7.1 Hz, 1H), 3.57 (dd, J = 17.3 Hz, 5.7 Hz, 1H), 3.12 (dd, J = 17.3 Hz, 4.6 Hz, 1H), 2.78 (m, 1H), 2.60 (m, 2H), 2.38 (m, 1H), 1.03 13 (t, J = 7.1 Hz, 3H); C NMR (400 MHz, CDCl3): 188.6, 171.8, 171.3, 137.8, 136.1, 135.0, 134.7. 131.6, 130.0, 128.1, 127.1, 123.8, 121.7, 117.4, 112.7, 109.6, 98.4, 65.9, 61.8, 44.5, 31.4, 26.1, 25.8, 14.4; IR (neat): 3532, 3443, 3323, 3288, 3207, 3061, 2980, 2936, 2242, 2918, 1663, 1645, 1614, 1579, 1294, 1218, 1143 cm- 1; Calcd for

C26H24N2O6S: C, 63.40; H, 4.91.

112

1 Figure 3.28: H NMR (400 MHz, CDCl3) of compound 197

113

13 Figure 3.29: C NMR (400 MHz, CDCl3) of compound 197

114

Figure 3.30: Infrared spectrum (neat) of compound 197

115

Ethyl-5-cyano-2-hydroxy-6-(2-(3-(2-hydroxyethyl)-1H-indol-2-yl)-2-oxoethyl)-5- (phenylsulfonyl)cyclohex-1-enecarboxylate (198).

To the solution of 196 (280 mg, 0.5 mmol) in CH3CN (8 mL) was added Ru[H2(PPh3)4]

(17 mg, 3 mol%) and the solution of 187 (100 mg, 0.5 mmol) in CH3CN (2.5 mL). After ~2 min, the reaction mixture was passed through a pad of Celite®, the solvent was evaporated and the crude product obtained was used in the next step without further purification.

The above obtained crude product was dissolved in CH3CN (12 mL), and KF•2H2O (47 mg, 0.5 mmol) was added and stirred at rt for 18 h. The solvent was removed in vacuo and flash chromatography (40% EtOAc in petroleum ether) gave 198 (93 mg, 0.175 1 mmol, 35% yield (over two steps)) as a pale brown solid. H NMR (400 MHz, CDCl3): 12.25 (s, 1H), 8.96 (s, broad, 1H), 8.06 (approx. dd, J = 8.5 Hz, 1.2 Hz, 2H), 7.82 (tt, J = 7.5 Hz, 1.2 Hz, 1H), 7.67 (approx. d + dd + d, J = 8.3 Hz + 2.4 Hz, 1.8 Hz + 0.8 Hz, 3H), 7.34 (dd, J = 4.3 Hz, 0.79 Hz, 2H), 7.14 (dd + s, J = 8.1 Hz, 3.9 Hz, 1H), 4.45 (dd, J = 6.9

Hz, 3.2 Hz, 1H), 4.22 (dq, Jd = 10.9 Hz, Jq = 7.1 Hz, 1H), 4.07 (dq, Jd = 10.9 Hz, Jq = 7.1 Hz, 1H), 3.92 (m, 3H), 3.36 (m, 1H), 3.26 (m, 1H), 3.04 (dd, J = 17.6 Hz, 3.4 Hz, 1H), 2.82 (ddd, J = 17.2 Hz, 7.9 Hz, 5.9 Hz, 1H), 2.60 (m, 2H), 2.42 (ddd, J = 16.0 Hz, 10.1 13 Hz, 6.7 Hz, 1H), 1.03 (t, J = 7.1 Hz, 3H); C NMR (400 MHz, CDCl3): 189.4, 171.6, 171.3, 136.9, 136.0, 134.6, 132.8, 131.4, 130.0, 128.7, 127.1, 121.57, 121.0, 119.9, 117.9, 112.7, 98.3, 66.4, 65.6, 63.5, 61.7, 30.6, 30.3, 29.4, 25.9, 25.4, 15.8, 14.4; Calcd for

C28H28N2O7S: C, 62.67; H, 5.26.

116

1 Figure 3.31: H NMR (400 MHz, CDCl3) of compound 198

117

13 Figure 3.32: C NMR (400 MHz, CDCl3) of compound 198

118

Ethyl-6-(2-(1-benzyl-1H-indol-2-yl)-2-oxoethyl)-5-cyano-2-hydroxy-5- (phenylsulfonyl)cyclohex-1-enecarboxylate (199).

The solution of 196 (300 mg, 0.53 mmol) and 190 (137 mg, 0.53 mmol) in CH3CN

(12 mL) was treated with PPh3 (1.4 mg, 1 mol%). After the reaction was complete in ~5 min (monitored by TLC), the solvent was evaporated and crude product obtained was used in the next step without further purification. The above obtained crude product was dissolved in EtOH (6 mL), and KF•2H2O (52 mg, 0.55 mmol) was added and stirred at rt for 18 h. The precipitated product was filtered, washed with EtOH and dried in vacuo to afford 199 (173 mg, 0.29 mmol, 56% yield) as a pale yellow solid. 1H NMR (400 MHz,

CDCl3): 12.45 (s, 1H), 8.03 (d, J = 8.1 Hz, 2H), 7.73 (t, J = 7.5 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.59 (t, J = 7.5 Hz, 2H), 7.12-7.36 (m, 7H), 7.02 (d, J = 7.1 Hz, 2H), 5.76 (dd, J = 49.8 Hz, 16.0 Hz, 2H), 4.30 (t, J = 4.3 Hz, 1H), 3.98 (m, 2H), 3.57 (dd, J = 17.4 Hz, 6.1 Hz, 1H), 3.12 (dd, J = 17.4 Hz, 3.7 Hz, 1H), 2.74 (m, 1H), 2.54 (m, 2H), 2.35 (m, 13 1H), 0.98 (t, J = 7.1 Hz, 3H); C NMR (400 MHz, CDCl3): 188.9, 171.6, 171.4, 140.6, 138.8, 135.9, 134.7, 134.2, 131.5, 129.9, 129.0, 127.7, 127.3, 127.0, 126.6, 123.6, 121.7, 117.5, 112.4, 111.6, 98.5, 65.9, 61.6, 48.8, 45.7, 31.0, 26.0, 25.8, 14.5; IR (neat): 3087, 3025, 2985, 2949, 2927, 2242, 1659, 1610, 1579, 1298, 1227, 1147 cm-1; Calcd for

C33H30N2O6S: C, 68.02; H, 5.19.

119

1 Figure 3.33: H NMR (400 MHz, CDCl3) of compound 199

120

13 Figure 3.34: C NMR (400 MHz, CDCl3) of compound 199

121

Figure 3.35: Infrared Spectrum (neat) of compound 199

122

(4aR,8aR)-ethyl-6-hydroxy-3-(1H-indol-2-yl)-1-oxo-8a-(phenylsulfonyl)- 1,2,4a,7,8,8a-hexahydroisoquinoline-5-carboxylate (203). MsOH (8 mL) was added dropwise to a stirred solution of 197 (1.00 g, 2 mmol) in

EtOH/CH2Cl2 (7 mL/70 mL) at 0 ˚C. The reaction mixture was then allowed to warm to rt, and after 18 h, the reaction mixture was warmed to 50 ˚C for 3 h. The reaction mixture was then cooled in an ice-water bath, quenched with slow addition of saturated aq. NaHCO3, and extracted with CH2Cl2. The combined organic layers were dried over

MgSO4 and evaporated to give quantitative yield of the crude product 203 as a yellow solid, which without further purification was carried on to the next step. Suitable crystals for X-ray diffraction were grown from EtOAc/toluene by slow evaporation; 1H NMR

(400 MHz, CDCl3): 12.19 (s, 1H), 8.79 (s, broad, 1H), 8.49 (s, broad, 1H), 7.92 (m, 2H), 7.53 (d, J = 2.2 Hz, 1H),7.40 (m, 3H), 7.34 (dd, J = 8.1 Hz, 0.99 Hz, 1H), 7.21 (ddd, J = 8.1 Hz, 6.9 Hz, 1.2 Hz, 1H), 7.11 (ddd, J = 7.9 Hz, 6.9 Hz, 1.0 Hz, 1H), 6.43 (d, J = 1.4 Hz, 1H), 5.74 (dd, J = 6.5 Hz, 1.6 Hz, 1H), 4.40 (m, 2H), 2.74 (approx. ddd, J = 14.5 Hz, 4.7 Hz, 2.6 Hz, 1H), 2.34-2.56 (m, 2H), 2.04 (ddd, J = 13.3 Hz, 11.9 Hz, 5.7 Hz, 1H), 13 1.45 (t, J = 7.1 Hz, 3H); C NMR (400 MHz, CDCl3): 171.6, 171.2, 165.7, 137.2, 136.5, 135.1, 131.4, 130.8, 130.7, 129.5, 128.6, 128.3, 128.6, 128.3, 123.9, 121.4, 121.2, 111.9, 104.2, 101.2, 98.5, 70.7, 61.8, 33.1, 26.6, 24.8, 15.2; IR (neat): 3372, 3252, 3101, 3069, 2980, 2932, 1690, 1668, 1641, 1579, 1223, 1192, 1138 cm-1; Calcd for

C26H24N2O6S: C, 63.40; H, 4.91.

123

1 Figure 3.36: H NMR (400 MHz, CDCl3) of compound 203

124

13 Figure 3.37: C NMR (400 MHz, CDCl3) of compound 203

125

Figure 3.38: Infrared spectrum (neat) of compound 203

126

Ethyl-6-hydroxy-3-(1H-indol-2-yl)-1-oxo-1,2,4a,7,8,8a-hexahydroisoquinoline-5- carboxylate (204a,b). To the chilled (-78 ˚C) solution of 203 (580 mg, 1.17 mmol) in 4 mL THF was added

0.1 M solution of SmI2 in THF (70 mL, 7 mmol). After 10 min, 10% aq. K2CO3/ saturated aq. Rochelle salt solution was added. The aqueous layer was extracted with

EtOAc, dried over MgSO4 and evaporated to give the crude product. Flash chromatography (40% EtOAc in petroleum ether) gave 204a,b (120 mg, 0.34 mmol, 1 30% yield) as a pale brown solid. H NMR (400 MHz, CDCl3): 12.20 (s, 1H), 8.62 (s, broad, 1H), 8.32 (s, broad, 1H), 7.59 (approx. d, J = 7.7 Hz, 1H), 7.35 (approx. dd, J =

8.1 Hz, 0.79 Hz, 1H), 7.23 (approx. dt + d, Jd = 7.1 Hz, Jt = 1.2 Hz + 1.2 Hz, 1H), 7.12 (m, 1H), 6.65 (d, J = 2.0, 1H), 5.39 (t, J = 1.4, 1H), 4.34 (m, 2H), 3.91 (dd, J = 6.0 Hz, 2.6 Hz, 1H), 2.67 (m, 2H), 2.44 (dd + s, J = 6.9 Hz, 3.5 Hz, 2H), 2.10 (m, 1H), 1.95 (m, 1H), 1.38 (t, J = 7.1 Hz, 3H); selected peaks of the keto tautomer: 1H NMR (400 MHz,

CDCl3): 5.63 (dd, J = 6.1 Hz, 1.6 Hz, 1H), 3.52 (d, J = 11.7 Hz); Calcd for C20H20N2O4: C, 68.17; H, 5.72.

127

1 Figure 3.39: H NMR (400 MHz, CDCl3) of compound 204a,b

128

(3S,4aS,8aS)-ethyl-6-hydroxy-3-(1H-indol-2-yl)-1-oxo-1,2,3,4,4a,7,8,8a- octahydroisoquinoline-5-carboxylate (205).

A suspension of 20% Pd(OH)2/C (15 mg, 16.6 wt%) and 204a,b (90 mg, 0.25 mmol) in

MeOH (4 mL) was allowed to stir at rt under H2 atm (balloon) for 7.5 h. The reaction mixture was passed through a pad of Celite®, and the organic layer was evaporated to give the crude product. Flash chromatography (5% MeOH in CH2Cl2) gave 205 (15 mg, 1 0.042 mmol, 17% yield) as a brown solid; H NMR (400 MHz, DMSO-d6): 12.20 (s, 1H), 11.19 (s, 1H), 7.80 (s, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.10

(t, Jt = 7.1 Hz, 1H), 6.90 (t, Jt = 7.8 Hz, 1H), 6.38 (d, J = 1.6, 1H), 4.61 (dd, J = 11.5 Hz, 4.0 Hz, 1H), 4.20 (m, 2H), 2.99 (ddd, J = 12.1 Hz, 5.1 Hz, 2.4 Hz, 1H), 2.19-2.50 (m, 3H), 1.98 (m, 2H), 1.38 (t, J = 6.9 Hz, 3H).

129

1 Figure 3.40: H NMR (400 MHz, CDCl3) of compound 205

130

(3S,4aS,8aS)-ethyl-6-hydroxy-3-(1H-indol-2-yl)-2-(2-methoxy-2-oxoethyl)- 1,2,3,4,4a,7,8,8a-octahydroisoquinoline-5-carboxylate (207).

A suspension of PtO2 (50 mg, 29.3 wt%) and 204a,b (170 mg, 0.48 mmol) in EtOH

(10 mL) was allowed to stir at rt under H2 atm (balloon) for 14 h. The reaction mixture was passed through a pad of Celite®, and the organic layer was evaporated to give the crude product. Without further purification, the solution of the crude product in 5 mL

THF was treated with 1.0 M solution of BH3•DMS in CH2Cl2 (0.50 mL, 0.50 mmol). After 2 h, 1N HCl (6 mL) was added, stirred for 30 min, diluted with water, extracted with EtOAc, dried over MgSO4, and evaporated to give the crude product. To the solution of crude product in 4 mL CH2Cl2 was added methyl bromoacetate (45 µL, 0.48 mmol), K2CO3 (69 mg, 0.5 mmol) and catalytic amount of tetrabutylammonium iodide.

After 2 h, saturated aq. NH4Cl was added, extracted with EtOAc, dried over MgSO4, and evaporated to give the crude product. Flash chromatography (5% EtOAc in petroleum ether) gave 207 (4.9 mg, 0.012 mmol, 2.5% yield) as a white solid. 1H NMR (400 MHz,

CDCl3): 12.39 (s, 1H), 8.53 (s, broad, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.29 (dd, J = 8.1 Hz, 0.8 Hz, 1H), 7.11 (ddd, J = 8.1 Hz, 6.9 Hz, 1.2 Hz,1H), 7.04 (ddd, J = 8.1 Hz, 7.1 Hz, 0.9 Hz, 1H), 6.35 (dd, J = 1.9 Hz, 0.8 Hz, 1H), 4.15 (m, 2H), 3.74 (dd, J = 11.7 Hz, 2.9 Hz, 1H), 3.58 (s, 3H), 3.22 (d, J = 16.8 Hz, 1H), 2.94 (dd, J = 11.5 Hz, 1.9 Hz, 1H), 2.87

(d, 17 Hz, 1H), 2.77 (dd, J = 11.5 Hz, 3.4 Hz, 1H), 2.68 (dt, Jd = 12.1 Hz, Jt = 4.5 Hz,

1H), 2.35-2.45 (m, 3H), 2.07 (approx. dt, Jd = 13.7 Hz, Jt = 3.3 Hz, 1H), 1.67-1.86 (dd + 13 broad, J = 25.2 Hz, 11.9 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H); C NMR (400 MHz, CDCl3): 173.5, 172.9, 172.4, 140.6, 136.6, 128.7, 122.3, 120.8, 120.3, 111.6, 102.2, 101.6, 60.9,

60.6, 59.3, 56.7, 52.0, 38.0, 34.5, 33.3, 30.3, 30.0, 22.4, 14.9; Calcd for C23H28N2O5: C, 66.97; H, 6.84.

131

1 Figure 3.41: H NMR (400 MHz, CDCl3) of compound 207

132

13 Figure 3.42: C NMR (400 MHz, CDCl3) of compound 207

133

(3R,4aR,8aR)-ethyl-6-hydroxy-3-(1H-indol-2-yl)-1-oxo-8a-(phenylsulfonyl)- 1,2,3,4,4a,7,8,8a-octahydroisoquinoline-5-carboxylate (208). A suspension of 10% Pd/C (62.5 mg, 25 wt%) and 203 (250 mg, 0.50 mmol) in TFA

(5 mL) was allowed to stir at rt under H2 atm (balloon) for 6 h. The reaction mixture was diluted with water, neutralized with saturated aq. NaHCO3, and extracted with EtOAc.

The organic layer was dried over Na2SO4, and evaporated to give the crude product. Flash chromatography (40% EtOAc in petroleum ether) gave 208 (180 mg, 0.36 mmol, 72% yield) as a off-white solid. Suitable crystals for X-ray diffraction were grown from 1 CH2Cl2/petroleum ether by slow evaporation; 182-184 ˚C; H NMR (400 MHz, CDCl3): 12.40 (s, 1H), 9.0 (s, 1H), 7.93 (approx. d, J = 7.5 Hz, 2H), 7.68 (approx t, J = 7.5 Hz, 1H), 7.54 (m, 3H), 7.41 (d, J = 7.9 Hz, 1H), 7.20 (t, J = 6.9 Hz, 1H), 7.11 (t, J = 7.7 Hz, 1H), 6.38 (s, 1H), 6.35 (s, broad, 1H), 4.70 (approx. dd, J = 7.7 Hz, 4.9 Hz, 1H), 4.19 (m, 2H), 4.09 (m, 1H), 2.85 (ddd, J = 14.2 Hz, 9.1 Hz, 3.7 Hz, 1H), 2.25-2.52 (m, 3H), 1.97- 13 2.12 (m, 2H), 1.11 (t, J = 7.1 Hz, 3H); C NMR (400 MHz, CDCl3): 172.8, 171.8, 167.4, 137.7, 137.0, 136.5, 134.9, 131.2, 129.1, 128.4, 122.8, 120.9, 120.5, 112.0, 100.8, 98.0, 71.5, 61.6, 49.3, 33.0, 31.1, 26.5, 26.4, 14.8, 14.4; IR (neat): 3336, 3056, 3083, - 1 2954, 2927, 2851, 1663, 1645, 1614 cm ; Calcd for C26H26N2O6S: C, 63.14; H, 5.30.

134

1 Figure 3.43: H NMR (400 MHz, CDCl3) of compound 208

135

13 Figure 3.44: C NMR (400 MHz, CDCl3) of compound 208

136

Figure 3.45: Infrared spectrum (neat) of compound of 208

137

(3R,4aS,8aS)-ethyl-6-hydroxy-3-(1H-indol-2-yl)-1-oxo-1,2,3,4,4a,7,8,8a- octahydroisoquinoline-5-carboxylate (209).

A solution of 0.1 M SmI2 in THF (40 mL, 4 mmol) was added to 208 (1.08 g, 2.2 mmol) at rt under N2. The reaction mixture was stirred for 30 min and quenched with 0.1 M HCl. The resulting mixture was saturated with brine, extracted with EtOAc, dried over

Na2SO4, and evaporated to give the crude product. Flash chromatography (60% EtOAc in petroleum ether) gave 209 (506 mg, 1.43 mmol, 65% yield) as a brown solid. Suitable crystals for X-ray diffraction were grown from CH2Cl2/petroleum ether by slow 1 evaporation; mp 174-176 ˚C; H NMR (400 MHz, CDCl3): 12.50 (s, 1H), 9.18 (s, broad, 1H), 7.62 (s, broad, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.14 (t, J = 7.1 Hz, 1H), 7.07 (t, J = 7.1 Hz, 1H), 6.47 (s, 1H), 4.81 (s, broad, 1H), 4.16 (m, 2H), 3.10 (d, broad, J = 9.52, 1H), 2.34-2.54 (m, broad, 3H), 1.86-2.24 (m, broad, 4H), 1.13 (t, 13 J = 7.1 Hz, 3H); C NMR (400 MHz, CDCl3): 176.2, 173.9, 172.7, 139.4, 137.0, 128.7, 122.6, 120.9, 120.6, 111.6, 100.1, 99.4, 61.4, 59.2, 50.2, 31.0, 29.3, 27.8, 23.0, 14.6; IR (KBr): 3440, 3249, 3200, 3057, 3024, 2986, 2931, 1715, 1649, 1616 cm- 1; Calcd for C20H22N2O4: C, 67.78; H, 6.26.

138

1 Figure 3.46: H NMR (400 MHz, CDCl3) of compound 209

139

13 Figure 3.47: C NMR (400 MHz, CDCl3) of compound 209

140

Figure 3.48: Infrared spectrum (KBr) of compound 209

141

(4aR,5R,6R,8aR)-ethyl-6-hydroxy-3-(1H-indol-2-yl)-1-oxo-8a-(phenylsulfonyl)- 1,2,4a,5,6,7,8,8a-octahydroisoquinoline-5-carboxylate (214).

To the solution of compound 203 (100 mg, 0.20 mmol) in 1.5 mL CH2Cl2, Et3SiH (0.5 mL) and MsOH (0.2 mL) were added and stirred at rt for 2h. The reaction was quenched with saturated aq. NaHCO3, extracted with CH2Cl2, dried over Na2SO4, and evaporated to give the crude product. Recrystallization from CH2Cl2/Petroleum ether gave 214 (98mg, ~0.20 mmol) in quantitative yield as a light brown solid. Suitable crystals for X-ray diffraction were grown from CH2Cl2/petroleum ether by slow evaporation; mp 189-191 1 ˚C; H NMR (400 MHz, DMSO-d6): 11.08 (s, 1H), 10.28 (s, 1H), 7.71 (approx. dm, J = 6.9 Hz, 2H), 7.48 (m, 4H), 7.31 (dd, J = 8.1 Hz, 0.8 Hz, 1H), 7.11 (ddd, J = 8.1 Hz, 7.1 Hz, 1.2 Hz,1H), 6.97 (ddd, J = 7.9 Hz, 7.9 Hz, 0.9 Hz, 1H), 6.77 (d, 1.6 Hz, 1H), 5.63 (dd, J = 6.5 Hz, 1.4 Hz, 1H), 5.05 (d, J = 6.9 Hz, 1H), 4.13 (m, 2H), 3.5 (m, 1H), 3.28 (dd, J = 11.7 Hz, 6.5 Hz, 1H), 2.23 (dm, J = 13.3 Hz, 1H), 2.15 (dd, J = 11.7 Hz, 10.3 Hz, 1H), 1.83 (m, 1H), 1.70 (m, 1H), 1.26 (m, 1H), 1.16 (t, J = 7.1 Hz, 3H); 13C NMR (400

MHz, DMSO-d6): 172.3, 164.0, 136.8, 136.6, 134.0, 131.1, 131.0, 129.6, 128.7, 127.3, 122.4, 120.4, 119.2, 110.9, 100.2, 99.5, 69.7, 69.3, 60.3, 55.1, 36.4, 30.9, 28.4, 27.0, 26.4, 14.1; IR (KBr): 3501, 3452, 3419, 3380, 3090, 3068, 3058, 2986, 2953, 2931, 1720, - 1 1676, 1659, 1309, 1150 cm ; Calcd for C26H26N2O6S: C, 63.14; H, 5.30.

142

1 Figure 3.49: H NMR (400 MHz, DMSO-d6) of compound 214

143

13 Figure 3.50: C NMR (400 MHz, DMSO-d6) of compound 214

144

Figure 3.51: Infrared spectrum (KBr) of compound 214

145

Chapter 4 Conclusion

The goal of my research project was to synthesize (±)-α-yohimbine. We developed an efficient route to an advanced intermediate, which contained the A, B, D, and E rings of α-yohimbine. In our first approach, the reductive desulfonation of the doubly annulated adduct formed the cis-C(15),C(20) ring fusion, and also the hydrogenation of the enamine C═C π bond occurred from the convex face as desired. However, unfortunately, the desulfonation and the ensuing reactions resulted in very low yields and unclean products. Following the undesired results from the first approach, in the second approach, hydrogenation of the enamine C═C π bond was done prior to the desulfonation. Although desulfonation resulted in the desired cis-C(15),C(20) ring fusion, the hydrogenation occurred from the concave face resulting in the unnatural, undesired epimer at C(3). Though the conversion of unnatural to the natural C(3)-epimer is well precedented, our efforts to complete the synthesis were restrained by insurmountably difficult amide and enol reductions. However, as a blessing in disguise, we serendipitously found the reaction conditions that could selectively reduce the enol of the doubly annulated adduct. The early enol reduction opens several new avenues and points the way forward. Our future plan, alongside investigating the second approach, is to investigate the desulfonation and enamide reduction of the doubly annulated adduct with a reduced enol, and of course to complete the synthesis of (±)-α-yohimbine.

Appendix

Table A.1: Crystal data and structure refinement for 197.

Empirical formula C28H30N2O7S

Formula weight 538.60

Temperature 90.0(2) K

Wavelength (Å) 1.54178

Crystal system Triclinic

Space group P –1

Unit cell dimensions a (Å) 8.2428(4) α (˚) 82.856(2) b (Å) 11.5405(5) β (˚) 78.515(2) c (Å) 14.6555(6) γ (˚) 71.762(2)

Volume (Å3) 1294.69(10)

Z 2

Calculated density (Mg/m3) 1.382

Absorption coefficient (mm-1) 1.542

147

F(000) 568

Crystal size (mm) 0.13 x 0.08 x 0.01

Θ range for data collection 3.08 to 68.00 (˚)

Limiting indices -9≤h≤9 -13≤k≤13 -17≤l≤17

Reflections collected / unique 16613 / 4577 [R(int) = 0.0453]

Completeness to Θ = 68.00 96.9 %

Absorption correction Semi-empirical from equivalents

Max. transmission 0.9847

Min. transmission 0.8103

Refinement method Full-matrix least-squares on F2

Data / restraints / parameters 4577 / 0 / 348

Goodness-of-fit on F2 1.036

148

Final R indices [I>2σ(I)] R1 = 0.0414, ωR2 = 0.1002

R indices (all data) R1 = 0.0502, ωR2 = 0.1056

Extinction coefficient 0.0006(2)

Largest diff. peak .277 and -.365 and hole (e.Å-3)

149

Table A.2: Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2 x 103) for 197. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

x y z U(eq)

S(1) 1557(1) 5018(1) 7686(1) 20(1) O(1) 6698(2) 2426(1) 7212(1) 28(1) O(2) 6248(2) 6436(1) 9163(1) 26(1) O(3) 6924(2) 4482(1) 8826(1) 21(1) O(4) 4095(2) 8032(1) 8304(1) 26(1) O(5) 1258(2) 5694(1) 8490(1) 23(1) O(6) 236(2) 5286(1) 7119(1) 26(1) N(1) 9718(2) 1334(2) 6052(1) 21(1) N(2) 4004(3) 3874(2) 5533(1) 29(1) C(2) 8957(3) 2579(2) 6011(1) 20(1) C(3) 7408(3) 3094(2) 6690(1) 20(1) C(7) 9883(3) 3117(2) 5295(2) 22(1) C(8) 11273(3) 2165(2) 4864(1) 21(1) C(9) 12630(3) 2116(2) 4105(2) 27(1) C(10) 13763(3) 996(2) 3867(2) 28(1) C(11) 13583(3) -96(2) 4363(2) 26(1) C(12) 12264(3) -79(2) 5105(2) 23(1) C(13) 11124(3) 1058(2) 5356(1) 21(1) C(14) 6794(3) 4469(2) 6743(1) 20(1) C(15) 5074(3) 4914(2) 7419(1) 19(1) C(16) 5070(3) 5951(2) 7957(1) 18(1) C(17) 4082(3) 7116(2) 7832(1) 20(1)

150

C(18) 2791(3) 7509(2) 7195(2) 24(1) C(19) 3053(3) 6590(2) 6484(1) 22(1) C(20) 3494(3) 5258(2) 6907(1) 19(1) C(21) 3798(3) 4461(2) 6144(1) 22(1) C(22) 6130(3) 5668(2) 8687(1) 20(1) C(23) 7848(3) 4141(2) 9617(1) 23(1) C(24) 8504(3) 2771(2) 9693(2) 28(1) C(25) 2153(3) 3449(2) 8030(1) 20(1) C(26) 1999(3) 2623(2) 7463(2) 24(1) C(27) 2492(3) 1388(2) 7743(2) 28(1) C(28) 3120(3) 998(2) 8570(2) 29(1) C(29) 3264(3) 1829(2) 9129(2) 26(1) C(30) 2780(3) 3065(2) 8864(2) 23(1) O(1E) -972(2) 9280(1) 7186(1) 28(1) C(1E) -1857(3) 9256(2) 8127(2) 38(1) C(2E) -1188(4) 9949(2) 8675(2) 43(1)

151

Table A.3: Bond lengths [Å] and angles [˚] for 197. S(1)-O(5) 1.4317(15) S(1)-O(6) 1.4340(15) S(1)-C(25) 1.758(2) S(1)-C(20) 1.845(2) O(1)-C(3) 1.217(3) O(2)-C(22) 1.232(2) O(3)-C(22) 1.329(2) O(3)-C(23) 1.459(2) O(4)-C(17) 1.338(2) O(4)-H(4) 0.8400 N(1)-C(13) 1.366(3) N(1)-C(2) 1.375(3) N(1)-H(1) 0.8800 N(2)-C(21) 1.144(3) C(2)-C(7) 1.373(3) C(2)-C(3) 1.462(3) C(3)-C(14) 1.513(3) C(7)-C(8) 1.420(3) C(7)-H(7) 0.9500 C(8)-C(9) 1.404(3) C(8)-C(13) 1.414(3) C(9)-C(10) 1.375(3) C(9)-H(9) 0.9500 C(10)-C(11) 1.409(3) C(10)-H(10) 0.9500 C(11)-C(12) 1.373(3) C(11)-H(11) 0.9500 C(12)-C(13) 1.396(3) C(12)-H(12) 0.9500 C(14)-C(15) 1.539(3) C(14)-H(14A) 0.9900 C(14)-H(14B) 0.9900 C(15)-C(16) 1.512(3) C(15)-C(20) 1.551(3) C(15)-H(15) 1.0000 C(16)-C(17) 1.348(3) C(16)-C(22) 1.457(3) C(17)-C(18) 1.481(3) C(18)-C(19) 1.517(3) C(18)-H(18A) 0.9900 C(18)-H(18B) 0.9900 C(19)-C(20) 1.543(3) C(19)-H(19A) 0.9900 C(19)-H(19B) 0.9900 C(20)-C(21) 1.469(3) C(23)-C(24) 1.500(3) 152

C(23)-H(23A) 0.9900 C(23)-H(23B) 0.9900 C(24)-H(24A) 0.9800 C(24)-H(24B) 0.9800 C(24)-H(24C) 0.9800 C(25)-C(30) 1.389(3) C(25)-C(26) 1.391(3) C(26)-C(27) 1.387(3) C(26)-H(26) 0.9500 C(27)-C(28) 1.381(3) C(27)-H(27) 0.9500 C(28)-C(29) 1.382(3) C(28)-H(28) 0.9500 C(29)-C(30) 1.383(3) C(29)-H(29) 0.9500 C(30)-H(30) 0.9500 O(1E)-C(1E) 1.428(3) O(1E)-H(1E) 0.8400 C(1E)-C(2E) 1.483(4) C(1E)-H(1E1) 0.9900 C(1E)-H(1E2) 0.9900 C(2E)-H(2E1) 0.9800 C(2E)-H(2E2) 0.9800 C(2E)-H(2E3) 0.9800

O(5)-S(1)-O(6) 119.44(9) O(5)-S(1)-C(25) 108.65(9) O(6)-S(1)-C(25) 109.34(10) O(5)-S(1)-C(20) 107.48(9) O(6)-S(1)-C(20) 106.08(9) C(25)-S(1)-C(20) 104.87(9) C(22)-O(3)-C(23) 115.70(16) C(17)-O(4)-H(4) 109.5 C(13)-N(1)-C(2) 108.87(17) C(13)-N(1)-H(1) 125.6 C(2)-N(1)-H(1) 125.6 C(7)-C(2)-N(1) 109.40(18) C(7)-C(2)-C(3) 131.77(19) N(1)-C(2)-C(3) 118.84(18) O(1)-C(3)-C(2) 120.33(19) O(1)-C(3)-C(14) 122.11(18) C(2)-C(3)-C(14) 117.50(18) C(2)-C(7)-C(8) 107.13(18) C(2)-C(7)-H(7) 126.4 C(8)-C(7)-H(7) 126.4 C(9)-C(8)-C(13) 118.69(19) C(9)-C(8)-C(7) 134.7(2)

153

C(13)-C(8)-C(7) 106.62(18) C(10)-C(9)-C(8) 118.9(2) C(10)-C(9)-H(9) 120.6 C(8)-C(9)-H(9) 120.6 C(9)-C(10)-C(11) 121.5(2) C(9)-C(10)-H(10) 119.3 C(11)-C(10)-H(10) 119.3 C(12)-C(11)-C(10) 121.0(2) C(12)-C(11)-H(11) 119.5 C(10)-C(11)-H(11) 119.5 C(11)-C(12)-C(13) 117.7(2) C(11)-C(12)-H(12) 121.2 C(13)-C(12)-H(12) 121.2 N(1)-C(13)-C(12) 129.7(2) N(1)-C(13)-C(8) 107.98(18) C(12)-C(13)-C(8) 122.28(19) C(3)-C(14)-C(15) 112.82(17) C(3)-C(14)-H(14A) 109.0 C(15)-C(14)-H(14A) 109.0 C(3)-C(14)-H(14B) 109.0 C(15)-C(14)-H(14B) 109.0 H(14A)-C(14)-H(14B) 107.8 C(16)-C(15)-C(14) 111.26(17) C(16)-C(15)-C(20) 111.94(16) C(14)-C(15)-C(20) 111.55(16) C(16)-C(15)-H(15) 107.3 C(14)-C(15)-H(15) 107.3 C(20)-C(15)-H(15) 107.3 C(17)-C(16)-C(22) 117.75(18) C(17)-C(16)-C(15) 123.94(18) C(22)-C(16)-C(15) 118.23(17) O(4)-C(17)-C(16) 123.64(19) O(4)-C(17)-C(18) 112.60(17) C(16)-C(17)-C(18) 123.68(19) C(17)-C(18)-C(19) 113.34(17) C(17)-C(18)-H(18A) 108.9 C(19)-C(18)-H(18A) 108.9 C(17)-C(18)-H(18B) 108.9 C(19)-C(18)-H(18B) 108.9 H(18A)-C(18)-H(18B) 107.7 C(18)-C(19)-C(20) 112.80(16) C(18)-C(19)-H(19A) 109.0 C(20)-C(19)-H(19A) 109.0 C(18)-C(19)-H(19B) 109.0 C(20)-C(19)-H(19B) 109.0 H(19A)-C(19)-H(19B) 107.8 C(21)-C(20)-C(19) 107.48(16)

154

C(21)-C(20)-C(15) 111.51(16) C(19)-C(20)-C(15) 112.58(16) C(21)-C(20)-S(1) 104.14(14) C(19)-C(20)-S(1) 109.17(14) C(15)-C(20)-S(1) 111.54(13) N(2)-C(21)-C(20) 177.6(2) O(2)-C(22)-O(3) 122.08(18) O(2)-C(22)-C(16) 124.13(18) O(3)-C(22)-C(16) 113.74(17) O(3)-C(23)-C(24) 106.71(17) O(3)-C(23)-H(23A) 110.4 C(24)-C(23)-H(23A) 110.4 O(3)-C(23)-H(23B) 110.4 C(24)-C(23)-H(23B) 110.4 H(23A)-C(23)-H(23B) 108.6 C(23)-C(24)-H(24A) 109.5 C(23)-C(24)-H(24B) 109.5 H(24A)-C(24)-H(24B) 109.5 C(23)-C(24)-H(24C) 109.5 H(24A)-C(24)-H(24C) 109.5 H(24B)-C(24)-H(24C) 109.5 C(30)-C(25)-C(26) 121.6(2) C(30)-C(25)-S(1) 118.93(16) C(26)-C(25)-S(1) 119.48(16) C(27)-C(26)-C(25) 118.5(2) C(27)-C(26)-H(26) 120.7 C(25)-C(26)-H(26) 120.7 C(28)-C(27)-C(26) 120.2(2) C(28)-C(27)-H(27) 119.9 C(26)-C(27)-H(27) 119.9 C(27)-C(28)-C(29) 120.7(2) C(27)-C(28)-H(28) 119.7 C(29)-C(28)-H(28) 119.7 C(28)-C(29)-C(30) 120.2(2) C(28)-C(29)-H(29) 119.9 C(30)-C(29)-H(29) 119.9 C(29)-C(30)-C(25) 118.8(2) C(29)-C(30)-H(30) 120.6 C(25)-C(30)-H(30) 120.6 C(1E)-O(1E)-H(1E) 109.5 O(1E)-C(1E)-C(2E) 108.3(2) O(1E)-C(1E)-H(1E1) 110.0 C(2E)-C(1E)-H(1E1) 110.0 O(1E)-C(1E)-H(1E2) 110.0 C(2E)-C(1E)-H(1E2) 110.0 H(1E1)-C(1E)-H(1E2) 108.4 C(1E)-C(2E)-H(2E1) 109.5

155

C(1E)-C(2E)-H(2E2) 109.5 H(2E1)-C(2E)-H(2E2) 109.5 C(1E)-C(2E)-H(2E3) 109.5 H(2E1)-C(2E)-H(2E3) 109.5 H(2E2)-C(2E)-H(2E3) 109.5

Symmetry transformations used to generate equivalent atoms:

156

Table A.4: Anisotropic displacement parameters (Å2 x 103) for 197. The anisotropic displacement factor exponent takes the form: -2 Π2 [ h2 a*2 U11 + ... + 2 h k a* b* U12 ]

U11 U22 U33 U23 U13 U12

S(1) 16(1) 21(1) 24(1) -1(1) -5(1) -7(1) O(1) 28(1) 21(1) 33(1) 0(1) 2(1) -9(1) O(2) 28(1) 24(1) 28(1) -6(1) -9(1) -7(1) O(3) 21(1) 21(1) 22(1) -1(1) -8(1) -4(1) O(4) 30(1) 18(1) 30(1) -4(1) -8(1) -5(1) O(5) 22(1) 23(1) 24(1) -4(1) -3(1) -7(1) O(6) 19(1) 31(1) 32(1) 2(1) -11(1) -9(1) N(1) 21(1) 18(1) 22(1) 0(1) -3(1) -5(1) N(2) 31(1) 36(1) 26(1) -4(1) -3(1) -19(1) C(2) 17(1) 18(1) 25(1) -3(1) -6(1) -4(1) C(3) 18(1) 21(1) 24(1) -2(1) -6(1) -7(1) C(7) 22(1) 19(1) 27(1) -3(1) -6(1) -8(1) C(8) 21(1) 21(1) 24(1) -2(1) -6(1) -10(1) C(9) 24(1) 28(1) 31(1) -3(1) -3(1) -12(1) C(10) 21(1) 34(1) 30(1) -7(1) -1(1) -11(1) C(11) 21(1) 27(1) 30(1) -6(1) -7(1) -3(1) C(12) 24(1) 21(1) 26(1) -1(1) -8(1) -5(1) C(13) 18(1) 25(1) 22(1) -3(1) -6(1) -8(1) C(14) 19(1) 19(1) 21(1) -3(1) -3(1) -7(1) C(15) 19(1) 20(1) 20(1) -1(1) -6(1) -6(1) C(16) 16(1) 18(1) 21(1) -2(1) -3(1) -6(1) C(17) 20(1) 19(1) 21(1) -1(1) -2(1) -8(1) C(18) 23(1) 17(1) 31(1) 3(1) -8(1) -5(1) C(19) 21(1) 23(1) 25(1) 5(1) -9(1) -9(1)

157

C(20) 19(1) 21(1) 20(1) 0(1) -6(1) -8(1) C(21) 20(1) 26(1) 22(1) 2(1) -5(1) -11(1) C(22) 17(1) 21(1) 21(1) -3(1) -2(1) -6(1) C(23) 21(1) 29(1) 20(1) 0(1) -8(1) -7(1) C(24) 26(1) 28(1) 27(1) 1(1) -7(1) -4(1) C(25) 16(1) 22(1) 25(1) -1(1) -2(1) -8(1) C(26) 22(1) 27(1) 27(1) -4(1) -3(1) -11(1) C(27) 28(1) 25(1) 34(1) -9(1) 1(1) -12(1) C(28) 24(1) 19(1) 42(1) -4(1) -2(1) -5(1) C(29) 24(1) 24(1) 31(1) 2(1) -6(1) -8(1) C(30) 22(1) 23(1) 26(1) -3(1) -3(1) -11(1) O(1E) 26(1) 27(1) 33(1) 0(1) -9(1) -8(1) C(1E) 35(1) 41(1) 40(1) 0(1) 0(1) -16(1) C(2E) 62(2) 34(1) 34(1) -1(1) -4(1) -20(1)

158

Table A.5: Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2 x 103) for 197.

x y z U(eq)

H(4) 4789 7760 8684 39 H(1) 9357 803 6460 25 H(7) 9639 3967 5120 26 H(9) 12762 2845 3762 32 H(10) 14688 958 3357 33 H(11) 14386 -856 4182 32 H(12) 12133 -815 5436 28 H(14A) 6645 4861 6112 23 H(14B) 7693 4729 6947 23 H(15) 4974 4216 7883 23 H(18A) 2858 8298 6862 29 H(18B) 1616 7646 7571 29 H(19A) 4003 6672 5972 27 H(19B) 1983 6779 6213 27 H(23A) 7058 4447 10196 27 H(23B) 8826 4494 9512 27 H(24A) 7525 2435 9780 42 H(24B) 9111 2500 10228 42 H(24C) 9304 2483 9121 42 H(26) 1565 2898 6895 29 H(27) 2397 808 7366 34 H(28) 3457 151 8757 35 H(29) 3696 1551 9697 32 H(30) 2875 3641 9245 27 H(1E) -1471 9021 6845 43

159

H(1E1) -1652 8400 8392 46 H(1E2) -3119 9631 8149 46 H(2E1) 60 9567 8653 65 H(2E2) -1782 9942 9325 65 H(2E3) -1401 10794 8410 65

160

Table A.6: Torsion angles [˚] for 197. C(13)-N(1)-C(2)-C(7) -0.8(2) C(13)-N(1)-C(2)-C(3) 179.64(18) C(7)-C(2)-C(3)-O(1) 172.5(2) N(1)-C(2)-C(3)-O(1) -8.1(3) C(7)-C(2)-C(3)-C(14) -10.3(3) N(1)-C(2)-C(3)-C(14) 169.07(17) N(1)-C(2)-C(7)-C(8) 0.6(2) C(3)-C(2)-C(7)-C(8) -180.0(2) C(2)-C(7)-C(8)-C(9) 178.9(2) C(2)-C(7)-C(8)-C(13) -0.1(2) C(13)-C(8)-C(9)-C(10) 0.0(3) C(7)-C(8)-C(9)-C(10) -179.0(2) C(8)-C(9)-C(10)-C(11) 0.4(3) C(9)-C(10)-C(11)-C(12) -0.1(3) C(10)-C(11)-C(12)-C(13) -0.7(3) C(2)-N(1)-C(13)-C(12) -178.0(2) C(2)-N(1)-C(13)-C(8) 0.7(2) C(11)-C(12)-C(13)-N(1) 179.7(2) C(11)-C(12)-C(13)-C(8) 1.1(3) C(9)-C(8)-C(13)-N(1) -179.59(19) C(7)-C(8)-C(13)-N(1) -0.4(2) C(9)-C(8)-C(13)-C(12) -0.8(3) C(7)-C(8)-C(13)-C(12) 178.43(19) O(1)-C(3)-C(14)-C(15) -7.8(3) C(2)-C(3)-C(14)-C(15) 175.10(17) C(3)-C(14)-C(15)-C(16) 141.40(17) C(3)-C(14)-C(15)-C(20) -92.8(2) C(14)-C(15)-C(16)-C(17) 110.5(2) C(20)-C(15)-C(16)-C(17) -15.1(3) C(14)-C(15)-C(16)-C(22) -72.7(2)

161

C(20)-C(15)-C(16)-C(22) 161.74(17) C(22)-C(16)-C(17)-O(4) 3.8(3) C(15)-C(16)-C(17)-O(4) -179.41(18) C(22)-C(16)-C(17)-C(18) -172.63(19) C(15)-C(16)-C(17)-C(18) 4.2(3) O(4)-C(17)-C(18)-C(19) 165.51(18) C(16)-C(17)-C(18)-C(19) -17.7(3) C(17)-C(18)-C(19)-C(20) 42.1(2) C(18)-C(19)-C(20)-C(21) -177.27(17) C(18)-C(19)-C(20)-C(15) -54.1(2) C(18)-C(19)-C(20)-S(1) 70.35(19) C(16)-C(15)-C(20)-C(21) 159.97(17) C(14)-C(15)-C(20)-C(21) 34.6(2) C(16)-C(15)-C(20)-C(19) 39.1(2) C(14)-C(15)-C(20)-C(19) -86.3(2) C(16)-C(15)-C(20)-S(1) -84.06(18) C(14)-C(15)-C(20)-S(1) 150.54(14) O(5)-S(1)-C(20)-C(21) 175.40(13) O(6)-S(1)-C(20)-C(21) -55.77(15) C(25)-S(1)-C(20)-C(21) 59.90(15) O(5)-S(1)-C(20)-C(19) -70.05(15) O(6)-S(1)-C(20)-C(19) 58.78(15) C(25)-S(1)-C(20)-C(19) 174.45(14) O(5)-S(1)-C(20)-C(15) 55.01(15) O(6)-S(1)-C(20)-C(15) -176.16(13) C(25)-S(1)-C(20)-C(15) -60.49(16) C(19)-C(20)-C(21)-N(2) -20(5) C(15)-C(20)-C(21)-N(2) -144(5) S(1)-C(20)-C(21)-N(2) 96(5) C(23)-O(3)-C(22)-O(2) 3.9(3) C(23)-O(3)-C(22)-C(16) -173.57(17)

162

C(17)-C(16)-C(22)-O(2) -3.9(3) C(15)-C(16)-C(22)-O(2) 179.10(19) C(17)-C(16)-C(22)-O(3) 173.54(18) C(15)-C(16)-C(22)-O(3) -3.5(3) C(22)-O(3)-C(23)-C(24) 175.15(17) O(5)-S(1)-C(25)-C(30) -20.05(19) O(6)-S(1)-C(25)-C(30) -151.99(16) C(20)-S(1)-C(25)-C(30) 94.63(18) O(5)-S(1)-C(25)-C(26) 160.35(16) O(6)-S(1)-C(25)-C(26) 28.4(2) C(20)-S(1)-C(25)-C(26) -84.97(18) C(30)-C(25)-C(26)-C(27) -0.2(3) S(1)-C(25)-C(26)-C(27) 179.42(16) C(25)-C(26)-C(27)-C(28) 0.0(3) C(26)-C(27)-C(28)-C(29) 0.1(3) C(27)-C(28)-C(29)-C(30) -0.1(3) C(28)-C(29)-C(30)-C(25) 0.0(3) C(26)-C(25)-C(30)-C(29) 0.2(3) S(1)-C(25)-C(30)-C(29) -179.42(16)

Symmetry transformations used to generate equivalent atoms:

163

Table A.7: Hydrogen bonds for 197 [Å and ˚].

D-H...A d(D-H) d(H...A) d(D...A) <(DHA)

O(4)-H(4)...O(2) 0.84 1.79 2.528(2) 146.1

N(1)-H(1)...O(1E)#1 0.88 2.00 2.862(2) 165.1

Symmetry transformations used to generate equivalent atoms: #1 x+1,y-1,z

164

Table A.8: Crystal data and structure refinement for 203.

Empirical formula C26H24N2O6S

Formula weight 492.53

Temperature (K) 100.0(2)

Wavelength (Å) 1.54178

Crystal system Triclinic

Space group P -1

Unit cell dimensions a (Å) 8.6189(7)

α (˚) 105.666(4) b (Å) 12.6857(11)

β (˚) 98.831(3) c (Å) 12.8383(10)

γ (˚) 105.624(4)

Volume (Å3) 1262.28(18)

Z 2

165

Calculated density (Mg/m3) 1.296

Absorption coefficient (mm-1) 1.504

F(000) 516

Crystal size (mm) 0.22 x 0.18 x 0.15

Θ range for data collection (˚) 3.69 to 68.13

Limiting indices -10≤h≤10 -15≤k≤13 -15≤l≤15

Reflections collected / unique 14677 / 4431 [R(int) = 0.0295]

Completeness to Θ = 68.13 96.0 %

Absorption correction Semi-empirical from equivalents

Max. transmission 0.806

Min. transmission 0.709

Refinement method Full-matrix least- squares on F2

Data / restraints / parameters 4431 / 1058 / 494

166

Goodness-of-fit on F2 1.155

Final R indices [I>2σ(I)] R1 = 0.0664

ωR2 = 0.1945

R indices (all data) R1 = 0.0690

ωR2 = 0.2032

Extinction coefficient 0.0150(17)

Largest diff. peak and hole .670 and -.481 (e.Å-3)

167

Table A.9: Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2 x 103) for 203. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. x y z U(eq)

C(3) 6508(3) 5299(2) 2946(2) 27(1) N(4) 6079(2) 5429(2) 3973(2) 26(1) N(1) 5305(14) 4203(8) 839(8) 35(1) C(2) 5338(15) 4367(10) 1950(11) 29(1) C(7) 4024(10) 3536(7) 2092(7) 30(1) C(8) 3111(10) 2812(6) 1050(6) 38(1) C(9) 1709(10) 1855(6) 722(5) 45(1) C(10) 1053(11) 1294(7) -408(5) 48(1) C(11) 1769(11) 1685(8) -1194(7) 43(1) C(12) 3193(16) 2615(11) -873(11) 40(1) C(13) 3879(16) 3208(12) 271(10) 36(1) N(1A) 5263(17) 4312(11) 1059(10) 37(1) C(2A) 5405(16) 4403(12) 2102(11) 30(1) C(7A) 4377(12) 3395(9) 2126(9) 28(1) C(8A) 3600(13) 2620(8) 1086(8) 37(1) C(9A) 2423(13) 1552(8) 790(7) 44(1) C(10A) 1753(14) 993(9) -354(7) 48(1) C(11A) 2261(14) 1467(9) -1134(9) 45(1) C(12A) 3425(19) 2564(14) -816(14) 40(1) C(13A) 4086(19) 3203(14) 327(12) 37(1) N(1B) 5210(20) 3966(12) 798(15) 34(1) C(2B) 5260(20) 4352(14) 1908(19) 30(1) C(7B) 3699(15) 3764(10) 2006(10) 31(1) C(8B) 2755(15) 3060(10) 953(10) 38(1) C(9B) 1164(15) 2302(11) 655(9) 46(2)

168

C(10B) 516(17) 1685(12) -476(9) 46(2) C(11B) 1406(18) 1790(14) -1230(13) 44(1) C(12B) 3010(20) 2480(17) -952(15) 40(1) C(13B) 3720(20) 3147(17) 172(13) 37(1) C(14) 7904(3) 6027(2) 2892(2) 30(1) C(15) 9062(3) 6963(2) 3909(2) 30(1) C(16) 10417(3) 6554(2) 4427(3) 38(1) O(17) 11924(3) 6286(2) 5983(2) 63(1) C(17) 10825(3) 6696(2) 5519(3) 44(1) C(18) 10112(3) 7334(2) 6351(2) 41(1) C(19) 9268(3) 8086(2) 5909(2) 32(1) C(20) 8103(3) 7378(2) 4766(2) 26(1) O(21) 6245(2) 6488(1) 5719(1) 29(1) C(21) 6730(3) 6392(2) 4857(2) 25(1) O(22) 12246(3) 5495(2) 4003(3) 69(1) C(22) 11336(3) 6023(2) 3709(3) 47(1) O(23) 11168(2) 6185(2) 2739(2) 51(1) C(24) 11981(4) 5621(3) 1948(4) 69(1) C(25) 10944(12) 4465(8) 1251(8) 87(2) C(24A) 11981(4) 5621(3) 1948(4) 69(1) C(25A) 11880(11) 6136(8) 1061(7) 84(2) S(1) 7057(1) 8295(1) 4248(1) 25(1) O(1) 5568(2) 7552(1) 3428(1) 32(1) O(2) 8292(2) 9088(1) 3946(1) 30(1) C(26) 6507(3) 9100(2) 5390(2) 28(1) C(27) 7616(3) 10165(2) 6058(2) 36(1) C(28) 7154(4) 10810(2) 6932(2) 41(1) C(29) 5626(4) 10387(2) 7135(2) 40(1) C(30) 4541(3) 9322(3) 6465(2) 42(1) C(31) 4972(3) 8664(2) 5583(2) 36(1)

169

Table A.10: Bond lengths [Å] and angles [˚] for 203.

C(3)-C(14) 1.329(3) C(3)-C(2A) 1.343(14) C(3)-N(4) 1.403(3) C(3)-C(2) 1.481(13) C(3)-C(2B) 1.54(2) N(4)-C(21) 1.335(3) N(4)-H(4) 0.8800 N(1)-C(2) 1.379(11) N(1)-C(13) 1.424(11) N(1)-H(1) 0.8800 C(2)-C(7) 1.397(12) C(7)-C(8) 1.370(9) C(7)-H(7) 0.9500 C(8)-C(9) 1.374(8) C(8)-C(13) 1.410(12) C(9)-C(10) 1.380(8) C(9)-H(9) 0.9500 C(10)-C(11) 1.393(10) C(10)-H(10) 0.9500 C(11)-C(12) 1.368(12) C(11)-H(11) 0.9500 C(12)-C(13) 1.403(11) C(12)-H(12) 0.9500 N(1A)-C(2A) 1.296(13) N(1A)-C(13A) 1.455(14) N(1A)-H(1) 0.8800 C(2A)-C(7A) 1.357(15) C(7A)-C(8A) 1.363(12) C(7A)-H(7A) 0.9500

170

C(8A)-C(9A) 1.368(12) C(8A)-C(13A) 1.421(15) C(9A)-C(10A) 1.397(12) C(9A)-H(9A) 0.9500 C(10A)-C(11A) 1.369(13) C(10A)-H(10A) 0.9500 C(11A)-C(12A) 1.388(15) C(11A)-H(11A) 0.9500 C(12A)-C(13A) 1.410(15) C(12A)-H(12A) 0.9500 N(1B)-C(2B) 1.366(18) N(1B)-C(13B) 1.378(15) N(1B)-H(1B) 0.8800 C(2B)-C(7B) 1.394(18) C(7B)-C(8B) 1.381(14) C(7B)-H(7B) 0.9500 C(8B)-C(9B) 1.372(14) C(8B)-C(13B) 1.402(16) C(9B)-C(10B) 1.391(14) C(9B)-H(9B) 0.9500 C(10B)-C(11B) 1.337(16) C(10B)-H(10B) 0.9500 C(11B)-C(12B) 1.355(17) C(11B)-H(11B) 0.9500 C(12B)-C(13B) 1.401(16) C(12B)-H(12B) 0.9500 C(14)-C(15) 1.496(3) C(14)-H(14) 0.9500 C(15)-C(16) 1.532(3) C(15)-C(20) 1.540(3) C(15)-H(15) 1.0000

171

C(16)-C(17) 1.342(4) C(16)-C(22) 1.451(4) O(17)-C(17) 1.335(3) O(17)-H(17) 0.8400 C(17)-C(18) 1.476(4) C(18)-C(19) 1.516(3) C(18)-H(18B) 0.9900 C(18)-H(18B) 0.9900 C(19)-C(20) 1.523(3) C(19)-H(19B) 0.9900 C(19)-H(19B) 0.9900 C(20)-C(21) 1.518(3) C(20)-S(1) 1.846(2) O(21)-C(21) 1.229(3) O(22)-C(22) 1.239(4) C(22)-O(23) 1.309(4) O(23)-C(24) 1.460(3) C(24)-C(25) 1.445(9) C(24)-H(24B) 0.9900 C(24)-H(24B) 0.9900 C(25)-H(25B) 0.9800 C(25)-H(25B) 0.9800 C(25)-H(25C) 0.9800 C(25A)-H(25D) 0.9800 C(25A)-H(25E) 0.9800 C(25A)-H(25F) 0.9800 S(1)-O(1) 1.4294(17) S(1)-O(2) 1.4338(16) S(1)-C(26) 1.756(2) C(26)-C(31) 1.378(3) C(26)-C(27) 1.378(3)

172

C(27)-C(28) 1.380(4) C(27)-H(27) 0.9500 C(28)-C(29) 1.374(4) C(28)-H(28) 0.9500 C(29)-C(30) 1.373(4) C(29)-H(29) 0.9500 C(30)-C(31) 1.379(4) C(30)-H(30) 0.9500 C(31)-H(31) 0.9500

C(14)-C(3)-C(2A) 127.0(6) C(14)-C(3)-N(4) 119.5(2) C(2A)-C(3)-N(4) 113.5(6) C(14)-C(3)-C(2) 122.6(6) C(2A)-C(3)-C(2) 5.0(11) N(4)-C(3)-C(2) 117.9(5) C(14)-C(3)-C(2B) 122.8(8) C(2A)-C(3)-C(2B) 5.7(9) N(4)-C(3)-C(2B) 117.6(8) C(2)-C(3)-C(2B) 1.7(7) C(21)-N(4)-C(3) 124.22(19) C(21)-N(4)-H(4) 117.9 C(3)-N(4)-H(4) 117.9 C(2)-N(1)-C(13) 103.6(9) C(2)-N(1)-H(1) 128.2 C(13)-N(1)-H(1) 128.2 N(1)-C(2)-C(7) 112.0(10) N(1)-C(2)-C(3) 128.8(10) C(7)-C(2)-C(3) 119.2(10) C(8)-C(7)-C(2) 107.2(8) C(8)-C(7)-H(7) 126.4

173

C(2)-C(7)-H(7) 126.4 C(7)-C(8)-C(9) 130.8(7) C(7)-C(8)-C(13) 107.3(7) C(9)-C(8)-C(13) 121.9(7) C(8)-C(9)-C(10) 117.6(6) C(8)-C(9)-H(9) 121.2 C(10)-C(9)-H(9) 121.2 C(9)-C(10)-C(11) 121.5(6) C(9)-C(10)-H(10) 119.2 C(11)-C(10)-H(10) 119.2 C(12)-C(11)-C(10) 121.1(9) C(12)-C(11)-H(11) 119.5 C(10)-C(11)-H(11) 119.5 C(11)-C(12)-C(13) 118.5(12) C(11)-C(12)-H(12) 120.7 C(13)-C(12)-H(12) 120.7 C(12)-C(13)-C(8) 119.3(10) C(12)-C(13)-N(1) 130.8(11) C(8)-C(13)-N(1) 109.9(8) C(2A)-N(1A)-C(13A) 111.9(12) C(2A)-N(1A)-H(1) 124.1 C(13A)-N(1A)-H(1) 124.1 N(1A)-C(2A)-C(3) 123.9(13) N(1A)-C(2A)-C(7A) 106.4(11) C(3)-C(2A)-C(7A) 129.4(12) C(2A)-C(7A)-C(8A) 112.7(10) C(2A)-C(7A)-H(7A) 123.7 C(8A)-C(7A)-H(7A) 123.7 C(7A)-C(8A)-C(9A) 128.8(9) C(7A)-C(8A)-C(13A) 105.9(9) C(9A)-C(8A)-C(13A) 124.8(9)

174

C(8A)-C(9A)-C(10A) 115.7(9) C(8A)-C(9A)-H(9A) 122.2 C(10A)-C(9A)-H(9A) 122.2 C(11A)-C(10A)-C(9A) 122.4(9) C(11A)-C(10A)-H(10A) 118.8 C(9A)-C(10A)-H(10A) 118.8 C(10A)-C(11A)-C(12A) 121.0(11) C(10A)-C(11A)-H(11A) 119.5 C(12A)-C(11A)-H(11A) 119.5 C(11A)-C(12A)-C(13A) 119.5(14) C(11A)-C(12A)-H(12A) 120.3 C(13A)-C(12A)-H(12A) 120.3 C(12A)-C(13A)-C(8A) 116.3(12) C(12A)-C(13A)-N(1A) 140.6(13) C(8A)-C(13A)-N(1A) 103.0(10) C(2B)-N(1B)-C(13B) 112.8(14) C(2B)-N(1B)-H(1B) 123.6 C(13B)-N(1B)-H(1B) 123.6 N(1B)-C(2B)-C(7B) 105.6(15) N(1B)-C(2B)-C(3) 135.1(15) C(7B)-C(2B)-C(3) 119.0(15) C(8B)-C(7B)-C(2B) 108.1(12) C(8B)-C(7B)-H(7B) 126.0 C(2B)-C(7B)-H(7B) 126.0 C(9B)-C(8B)-C(7B) 128.4(11) C(9B)-C(8B)-C(13B) 121.8(11) C(7B)-C(8B)-C(13B) 109.6(11) C(8B)-C(9B)-C(10B) 116.3(11) C(8B)-C(9B)-H(9B) 121.9 C(10B)-C(9B)-H(9B) 121.9 C(11B)-C(10B)-C(9B) 122.2(12)

175

C(11B)-C(10B)-H(10B) 118.9 C(9B)-C(10B)-H(10B) 118.9 C(10B)-C(11B)-C(12B) 122.8(15) C(10B)-C(11B)-H(11B) 118.6 C(12B)-C(11B)-H(11B) 118.6 C(11B)-C(12B)-C(13B) 117.5(16) C(11B)-C(12B)-H(12B) 121.2 C(13B)-C(12B)-H(12B) 121.2 N(1B)-C(13B)-C(12B) 136.9(15) N(1B)-C(13B)-C(8B) 103.8(12) C(12B)-C(13B)-C(8B) 119.3(14) C(3)-C(14)-C(15) 121.5(2) C(3)-C(14)-H(14) 119.2 C(15)-C(14)-H(14) 119.2 C(14)-C(15)-C(16) 110.9(2) C(14)-C(15)-C(20) 110.83(18) C(16)-C(15)-C(20) 110.9(2) C(14)-C(15)-H(15) 108.0 C(16)-C(15)-H(15) 108.0 C(20)-C(15)-H(15) 108.0 C(17)-C(16)-C(22) 118.6(2) C(17)-C(16)-C(15) 123.0(2) C(22)-C(16)-C(15) 118.4(3) C(17)-O(17)-H(17) 109.5 O(17)-C(17)-C(16) 124.4(3) O(17)-C(17)-C(18) 112.0(3) C(16)-C(17)-C(18) 123.6(2) C(17)-C(18)-C(19) 112.2(2) C(17)-C(18)-H(18B) 109.2 C(19)-C(18)-H(18B) 109.2 C(17)-C(18)-H(18B) 109.2

176

C(19)-C(18)-H(18B) 109.2 H(18B)-C(18)-H(18B) 107.9 C(18)-C(19)-C(20) 109.6(2) C(18)-C(19)-H(19B) 109.7 C(20)-C(19)-H(19B) 109.7 C(18)-C(19)-H(19B) 109.7 C(20)-C(19)-H(19B) 109.7 H(19B)-C(19)-H(19B) 108.2 C(21)-C(20)-C(19) 110.25(18) C(21)-C(20)-C(15) 112.86(18) C(19)-C(20)-C(15) 111.42(19) C(21)-C(20)-S(1) 105.84(14) C(19)-C(20)-S(1) 109.23(16) C(15)-C(20)-S(1) 106.99(14) O(21)-C(21)-N(4) 121.8(2) O(21)-C(21)-C(20) 120.6(2) N(4)-C(21)-C(20) 117.62(19) O(22)-C(22)-O(23) 122.8(3) O(22)-C(22)-C(16) 122.9(3) O(23)-C(22)-C(16) 114.3(2) C(22)-O(23)-C(24) 117.3(3) C(25)-C(24)-O(23) 112.8(4) C(25)-C(24)-H(24B) 109.0 O(23)-C(24)-H(24B) 109.0 C(25)-C(24)-H(24B) 109.0 O(23)-C(24)-H(24B) 109.0 H(24B)-C(24)-H(24B) 107.8 H(25D)-C(25A)-H(25E) 109.5 H(25D)-C(25A)-H(25F) 109.5 H(25E)-C(25A)-H(25F) 109.5 O(1)-S(1)-O(2) 119.34(10)

177

O(1)-S(1)-C(26) 108.33(10) O(2)-S(1)-C(26) 107.81(10) O(1)-S(1)-C(20) 108.12(10) O(2)-S(1)-C(20) 106.15(10) C(26)-S(1)-C(20) 106.39(10) C(31)-C(26)-C(27) 121.8(2) C(31)-C(26)-S(1) 119.32(19) C(27)-C(26)-S(1) 118.87(18) C(26)-C(27)-C(28) 118.6(2) C(26)-C(27)-H(27) 120.7 C(28)-C(27)-H(27) 120.7 C(29)-C(28)-C(27) 120.3(2) C(29)-C(28)-H(28) 119.8 C(27)-C(28)-H(28) 119.8 C(30)-C(29)-C(28) 120.3(2) C(30)-C(29)-H(29) 119.8 C(28)-C(29)-H(29) 119.8 C(29)-C(30)-C(31) 120.4(2) C(29)-C(30)-H(30) 119.8 C(31)-C(30)-H(30) 119.8 C(26)-C(31)-C(30) 118.6(2) C(26)-C(31)-H(31) 120.7 C(30)-C(31)-H(31) 120.7

Symmetry transformations used to generate equivalent atoms:

178

Table A.11: Anisotropic displacement parameters (Å2 x 103) for 203. The anisotropic displacement factor exponent takes the form: -2 Π2 [ h2 a*2 U11 + ... + 2 h k a* b* U12 ] U11 U22 U33 U23 U13 U12

C(3) 28(1) 22(1) 36(1) 12(1) 11(1) 10(1) N(4) 26(1) 21(1) 32(1) 11(1) 9(1) 4(1) N(1) 43(2) 31(2) 28(2) 7(2) 13(2) 7(2) C(2) 36(2) 26(2) 25(2) 8(1) 12(2) 6(1) C(7) 38(2) 26(2) 23(1) 8(2) 11(2) 0(2) C(8) 42(2) 33(2) 30(1) 8(1) 8(2) 3(1) C(9) 47(2) 39(2) 36(2) 9(2) 9(2) -3(2) C(10) 48(2) 43(2) 38(2) 6(2) 5(2) 1(2) C(11) 45(2) 42(2) 32(2) 6(2) 4(2) 7(2) C(12) 45(2) 39(2) 30(2) 10(2) 6(2) 6(2) C(13) 42(2) 34(2) 28(1) 10(1) 9(1) 5(1) N(1A) 43(2) 32(2) 30(2) 9(2) 11(2) 4(2) C(2A) 36(2) 27(2) 26(2) 9(2) 12(2) 6(2) C(7A) 35(2) 26(2) 23(2) 9(2) 12(2) 4(2) C(8A) 41(2) 34(2) 29(2) 8(1) 10(2) 3(2) C(9A) 46(2) 39(2) 36(2) 9(2) 9(2) -1(2) C(10A) 49(2) 43(2) 38(2) 6(2) 7(2) 1(2) C(11A) 47(2) 42(2) 33(2) 5(2) 7(2) 5(2) C(12A) 44(2) 39(2) 30(2) 9(2) 7(2) 6(2) C(13A) 43(2) 34(2) 28(2) 9(1) 9(2) 5(2) N(1B) 42(2) 31(2) 28(2) 8(2) 12(2) 7(2) C(2B) 37(2) 27(2) 26(2) 8(2) 12(2) 5(2) C(7B) 35(2) 28(2) 25(2) 7(2) 12(2) 2(2) C(8B) 42(2) 35(2) 30(2) 6(2) 8(2) 3(2) C(9B) 44(2) 43(2) 36(2) 6(2) 9(2) -2(2)

179

C(10B) 45(2) 43(2) 37(2) 5(2) 6(2) 2(2) C(11B) 46(2) 41(2) 33(2) 7(2) 5(2) 5(2) C(12B) 45(2) 38(2) 29(2) 9(2) 7(2) 7(2) C(13B) 42(2) 34(2) 29(2) 9(2) 9(2) 6(2) C(14) 29(1) 29(1) 38(1) 15(1) 14(1) 14(1) C(15) 24(1) 27(1) 43(1) 17(1) 11(1) 9(1) C(16) 24(1) 28(1) 66(2) 22(1) 9(1) 9(1) O(17) 42(1) 52(1) 99(2) 42(1) -5(1) 18(1) C(17) 29(1) 34(1) 70(2) 30(1) 0(1) 7(1) C(18) 31(1) 42(2) 49(2) 31(1) -1(1) 1(1) C(19) 26(1) 27(1) 38(1) 17(1) 3(1) -1(1) C(20) 22(1) 24(1) 35(1) 15(1) 7(1) 6(1) O(21) 29(1) 25(1) 32(1) 12(1) 9(1) 4(1) C(21) 22(1) 21(1) 34(1) 13(1) 7(1) 7(1) O(22) 38(1) 41(1) 132(2) 29(1) 18(1) 22(1) C(22) 25(1) 27(1) 86(2) 16(1) 11(1) 8(1) O(23) 31(1) 41(1) 73(1) 2(1) 19(1) 13(1) C(24) 41(1) 61(2) 88(2) -10(1) 27(1) 18(1) C(25) 73(4) 74(4) 92(4) -5(3) 25(3) 22(3) C(24A) 41(1) 61(2) 88(2) -10(1) 27(1) 18(1) C(25A) 67(4) 90(4) 75(3) -14(3) 40(3) 22(3) S(1) 25(1) 21(1) 29(1) 11(1) 7(1) 7(1) O(1) 29(1) 29(1) 34(1) 8(1) 3(1) 11(1) O(2) 33(1) 25(1) 37(1) 17(1) 15(1) 10(1) C(26) 29(1) 24(1) 32(1) 11(1) 8(1) 8(1) C(27) 36(1) 25(1) 42(1) 10(1) 15(1) 2(1) C(28) 44(2) 30(1) 41(1) 6(1) 14(1) 4(1) C(29) 47(2) 42(2) 38(1) 11(1) 17(1) 22(1) C(30) 31(1) 46(2) 52(2) 16(1) 18(1) 14(1) C(31) 26(1) 32(1) 45(1) 10(1) 9(1) 6(1)

180

Table A.12: Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2 x 103) for 203.

x y z U(eq) H(4) 5334 4837 4039 31 H(1) 6000 4615 550 42 H(7) 3805 3482 2782 36 H(9) 1209 1590 1254 54 H(10) 92 625 -655 58 H(11) 1259 1299 -1965 52 H(12) 3706 2855 -1412 48 H(1) 5814 4855 822 44 H(7A) 4216 3245 2794 34 H(9A) 2084 1213 1328 53 H(10A) 915 256 -600 58 H(11A) 1809 1038 -1904 54 H(12A) 3774 2882 -1365 48 H(1B) 6052 4213 514 41 H(7B) 3347 3836 2680 37 H(9B) 540 2204 1191 55 H(10B) -596 1172 -720 55 H(11B) 891 1362 -1994 52 H(12B) 3636 2510 -1498 48 H(14) 8172 5951 2190 36 H(15) 9614 7634 3679 35 H(17) 12329 5950 5491 95 H(18B) 11007 7829 7026 49 H(18B) 9293 6774 6569 49 H(19B) 10116 8757 5851 38 H(19B) 8631 8383 6431 38

181

H(24B) 12288 6097 1467 83 H(24B) 13018 5581 2365 83 H(25B) 10855 3944 1696 130 H(25B) 11439 4192 636 130 H(25C) 9836 4477 948 130 H(24C) 11402 4775 1647 83 H(24D) 13154 5768 2310 83 H(25D) 10738 6123 817 126 H(25E) 12205 5693 429 126 H(25F) 12630 6939 1341 126 H(27) 8675 10449 5918 43 H(28) 7896 11550 7397 49 H(29) 5320 10833 7741 48 H(30) 3487 9036 6610 50 H(31) 4225 7926 5117 43

182

Table A.13: Torsion angles [˚] for 203.

C(14)-C(3)-N(4)-C(21) 17.7(3) C(2A)-C(3)-N(4)-C(21) -162.8(6) C(2)-C(3)-N(4)-C(21) -160.3(4) C(2B)-C(3)-N(4)-C(21) -158.4(6) C(13)-N(1)-C(2)-C(7) 0.0(7) C(13)-N(1)-C(2)-C(3) -177.5(9) C(14)-C(3)-C(2)-N(1) -11.7(7) C(2A)-C(3)-C(2)-N(1) -165(9) N(4)-C(3)-C(2)-N(1) 166.2(4) C(2B)-C(3)-C(2)-N(1) 87(41) C(14)-C(3)-C(2)-C(7) 170.9(4) C(2A)-C(3)-C(2)-C(7) 17(8) N(4)-C(3)-C(2)-C(7) -11.2(7) C(2B)-C(3)-C(2)-C(7) -91(42) N(1)-C(2)-C(7)-C(8) 0.0(4) C(3)-C(2)-C(7)-C(8) 177.8(7) C(2)-C(7)-C(8)-C(9) 179.5(9) C(2)-C(7)-C(8)-C(13) 0.0(9) C(7)-C(8)-C(9)-C(10) 179.8(8) C(13)-C(8)-C(9)-C(10) -0.7(14) C(8)-C(9)-C(10)-C(11) -0.7(13) C(9)-C(10)-C(11)-C(12) 2.8(15) C(10)-C(11)-C(12)-C(13) -3.2(17) C(11)-C(12)-C(13)-C(8) 1.7(19) C(11)-C(12)-C(13)-N(1) -178.5(13) C(7)-C(8)-C(13)-C(12) 179.9(11) C(9)-C(8)-C(13)-C(12) 0.3(18) C(7)-C(8)-C(13)-N(1) 0.0(12) C(9)-C(8)-C(13)-N(1) -179.6(9)

183

C(2)-N(1)-C(13)-C(12) -179.9(14) C(2)-N(1)-C(13)-C(8) 0.0(11) C(13A)-N(1A)-C(2A)-C(3) 174.3(12) C(13A)-N(1A)-C(2A)-C(7A) 0.4(8) C(14)-C(3)-C(2A)-N(1A) -21.6(9) N(4)-C(3)-C(2A)-N(1A) 159.0(5) C(2)-C(3)-C(2A)-N(1A) 6(8) C(2B)-C(3)-C(2A)-N(1A) 23(8) C(14)-C(3)-C(2A)-C(7A) 150.8(7) N(4)-C(3)-C(2A)-C(7A) -28.6(11) C(2)-C(3)-C(2A)-C(7A) 179(9) C(2B)-C(3)-C(2A)-C(7A) -165(9) N(1A)-C(2A)-C(7A)-C(8A) 2.2(6) C(3)-C(2A)-C(7A)-C(8A) -171.2(11) C(2A)-C(7A)-C(8A)-C(9A) -176.0(10) C(2A)-C(7A)-C(8A)-C(13A) -3.9(11) C(7A)-C(8A)-C(9A)-C(10A) 174.9(11) C(13A)-C(8A)-C(9A)-C(10A) 4.1(18) C(8A)-C(9A)-C(10A)-C(11A) 1.3(17) C(9A)-C(10A)-C(11A)-C(12A) -3.1(19) C(10A)-C(11A)-C(12A)-C(13A) 0(2) C(11A)-C(12A)-C(13A)-C(8A) 5(2) C(11A)-C(12A)-C(13A)-N(1A) 179.6(18) C(7A)-C(8A)-C(13A)-C(12A) -179.9(12) C(9A)-C(8A)-C(13A)-C(12A) -7(2) C(7A)-C(8A)-C(13A)-N(1A) 3.7(13) C(9A)-C(8A)-C(13A)-N(1A) 176.3(11) C(2A)-N(1A)-C(13A)-C(12A) -177.5(19) C(2A)-N(1A)-C(13A)-C(8A) -2.7(13) C(13B)-N(1B)-C(2B)-C(7B) -0.8(10) C(13B)-N(1B)-C(2B)-C(3) -174.2(14)

184

C(14)-C(3)-C(2B)-N(1B) 4.1(10) C(2A)-C(3)-C(2B)-N(1B) -135(9) N(4)-C(3)-C(2B)-N(1B) -180.0(7) C(2)-C(3)-C(2B)-N(1B) -79(42) C(14)-C(3)-C(2B)-C(7B) -168.7(6) C(2A)-C(3)-C(2B)-C(7B) 53(8) N(4)-C(3)-C(2B)-C(7B) 7.3(10) C(2)-C(3)-C(2B)-C(7B) 109(42) N(1B)-C(2B)-C(7B)-C(8B) -1.1(6) C(3)-C(2B)-C(7B)-C(8B) 173.6(11) C(2B)-C(7B)-C(8B)-C(9B) 177.9(13) C(2B)-C(7B)-C(8B)-C(13B) 2.6(14) C(7B)-C(8B)-C(9B)-C(10B) -179.2(12) C(13B)-C(8B)-C(9B)-C(10B) -4(2) C(8B)-C(9B)-C(10B)-C(11B) 2(2) C(9B)-C(10B)-C(11B)-C(12B) 2(3) C(10B)-C(11B)-C(12B)-C(13B) -3(3) C(2B)-N(1B)-C(13B)-C(12B) -180(2) C(2B)-N(1B)-C(13B)-C(8B) 2.3(16) C(11B)-C(12B)-C(13B)-N(1B) -177(2) C(11B)-C(12B)-C(13B)-C(8B) 1(3) C(9B)-C(8B)-C(13B)-N(1B) -178.6(13) C(7B)-C(8B)-C(13B)-N(1B) -2.9(17) C(9B)-C(8B)-C(13B)-C(12B) 3(3) C(7B)-C(8B)-C(13B)-C(12B) 178.5(16) C(2A)-C(3)-C(14)-C(15) -177.5(7) N(4)-C(3)-C(14)-C(15) 1.9(3) C(2)-C(3)-C(14)-C(15) 179.8(5) C(2B)-C(3)-C(14)-C(15) 177.8(6) C(3)-C(14)-C(15)-C(16) 93.2(3) C(3)-C(14)-C(15)-C(20) -30.4(3)

185

C(14)-C(15)-C(16)-C(17) -131.8(3) C(20)-C(15)-C(16)-C(17) -8.2(3) C(14)-C(15)-C(16)-C(22) 50.3(3) C(20)-C(15)-C(16)-C(22) 173.9(2) C(22)-C(16)-C(17)-O(17) -6.4(4) C(15)-C(16)-C(17)-O(17) 175.6(2) C(22)-C(16)-C(17)-C(18) 173.2(2) C(15)-C(16)-C(17)-C(18) -4.8(4) O(17)-C(17)-C(18)-C(19) 163.4(2) C(16)-C(17)-C(18)-C(19) -16.2(4) C(17)-C(18)-C(19)-C(20) 48.9(3) C(18)-C(19)-C(20)-C(21) 63.1(2) C(18)-C(19)-C(20)-C(15) -63.0(2) C(18)-C(19)-C(20)-S(1) 179.04(16) C(14)-C(15)-C(20)-C(21) 40.4(2) C(16)-C(15)-C(20)-C(21) -83.3(2) C(14)-C(15)-C(20)-C(19) 165.05(19) C(16)-C(15)-C(20)-C(19) 41.4(2) C(14)-C(15)-C(20)-S(1) -75.62(19) C(16)-C(15)-C(20)-S(1) 160.73(16) C(3)-N(4)-C(21)-O(21) 175.7(2) C(3)-N(4)-C(21)-C(20) -4.3(3) C(19)-C(20)-C(21)-O(21) 29.3(3) C(15)-C(20)-C(21)-O(21) 154.6(2) S(1)-C(20)-C(21)-O(21) -88.7(2) C(19)-C(20)-C(21)-N(4) -150.7(2) C(15)-C(20)-C(21)-N(4) -25.4(3) S(1)-C(20)-C(21)-N(4) 91.3(2) C(17)-C(16)-C(22)-O(22) 14.4(4) C(15)-C(16)-C(22)-O(22) -167.5(3) C(17)-C(16)-C(22)-O(23) -163.2(2)

186

C(15)-C(16)-C(22)-O(23) 14.8(3) O(22)-C(22)-O(23)-C(24) 5.7(4) C(16)-C(22)-O(23)-C(24) -176.6(2) C(22)-O(23)-C(24)-C(25) 88.7(6) C(21)-C(20)-S(1)-O(1) -39.46(17) C(19)-C(20)-S(1)-O(1) -158.14(15) C(15)-C(20)-S(1)-O(1) 81.13(16) C(21)-C(20)-S(1)-O(2) -168.62(14) C(19)-C(20)-S(1)-O(2) 72.70(17) C(15)-C(20)-S(1)-O(2) -48.03(17) C(21)-C(20)-S(1)-C(26) 76.72(17) C(19)-C(20)-S(1)-C(26) -41.96(18) C(15)-C(20)-S(1)-C(26) -162.69(15) O(1)-S(1)-C(26)-C(31) 25.0(2) O(2)-S(1)-C(26)-C(31) 155.47(19) C(20)-S(1)-C(26)-C(31) -91.0(2) O(1)-S(1)-C(26)-C(27) -153.6(2) O(2)-S(1)-C(26)-C(27) -23.2(2) C(20)-S(1)-C(26)-C(27) 90.3(2) C(31)-C(26)-C(27)-C(28) -0.7(4) S(1)-C(26)-C(27)-C(28) 177.9(2) C(26)-C(27)-C(28)-C(29) 0.7(4) C(27)-C(28)-C(29)-C(30) -0.4(4) C(28)-C(29)-C(30)-C(31) 0.1(4) C(27)-C(26)-C(31)-C(30) 0.4(4) S(1)-C(26)-C(31)-C(30) -178.2(2) C(29)-C(30)-C(31)-C(26) -0.1(4)

Symmetry transformations used to generate equivalent atoms:

187

Table A.14: Hydrogen bonds for 203 [Å and ˚].

D-H...A d(D-H) d(H...A) d(D...A) <(DHA)

N(4)-H(4)...O(21)#1 0.88 1.99 2.867(2) 176.1

O(17)-H(17)...O(22) 0.84 1.82 2.557(4) 144.7

O(17)-H(17)...N(4)#2 0.84 2.66 3.122(3) 116.3

Symmetry transformations used to generate equivalent atoms: #1 -x+1,-y+1,-z+1 #2 -x+2,-y+1,-z+1

188

Table A.15: Crystal data and structure refinement for 208.

Empirical formula C26H26N2O6S

Formula weight 494.55

Temperature (K) 90.0(2)

Wavelength (Å) 0.71073

Crystal system Triclinic

Space group P -1

Unit cell dimensions a (Å) 8.7283(3)

α (˚) 112.816(2) b (Å) 13.1200(5)

β (˚) 107.153(2) c (Å) 13.1392(5)

γ (˚) 92.621(2)

Volume (Å3) 1303.14(9)

Z 2

189

Calculated density (Mg/m3) 1.260

Absorption coefficient (mm-1) 0.166

F(000) 520

Crystal size (mm) 0.45 x 0.15 x 0.04

Θ range for data collection (˚) 1.71 to 27.40

Limiting indices -11≤h≤11 -16≤k≤16 -16≤l≤16

Reflections collected / unique 25765 / 5896 [R(int) = 0.0508]

Completeness to Θ = 27.40 99.4 %

Absorption correction Semi-empirical from equivalents

Max. transmission 0.993

Min. transmission 0.929

Refinement method Full-matrix least- squares on F2

Data / restraints / parameters 5896 / 69 / 330

190

Goodness-of-fit on F2 1.060

Final R indices [I>2σ(I)] R1 = 0.0603

ωR2 = 0.1537

R indices (all data) R1 = 0.0941

ωR2 = 0.1678

Extinction coefficient 0.007(2)

Largest diff. peak and hole 0.353 and -0.387 (e.Å-3)

191

Table A.16: Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2 x 103) for 208. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

x y z U(eq)

S(1) 2071(1) 9328(1) 3280(1) 32(1) O(1) 622(2) 8521(1) 2470(1) 38(1) N(1) -698(3) 7052(2) -1722(2) 44(1) O(2) 3329(2) 8997(1) 4017(1) 36(1) C(2) 588(3) 7006(2) -833(2) 32(1) C(3) 1917(3) 7997(2) -20(2) 33(1) N(4) 1235(2) 9031(1) 359(2) 33(1) C(7) 446(3) 5932(2) -921(2) 34(1) C(8) -977(3) 5275(2) -1892(2) 36(1) C(9) -1747(3) 4145(2) -2421(2) 40(1) C(10) -3165(4) 3795(2) -3354(2) 55(1) C(11) -3862(4) 4544(2) -3789(3) 76(1) C(12) -3122(4) 5659(2) -3311(3) 75(1) C(13) -1675(3) 6014(2) -2367(2) 46(1) C(14) 2976(3) 7838(2) 1027(2) 32(1) C(15) 4109(3) 8932(2) 1970(2) 33(1) C(16) 5309(3) 9421(2) 1553(2) 40(1) O(17) 6630(3) 10964(2) 1434(2) 62(1) C(17) 5598(3) 10520(2) 1798(2) 45(1) C(18) 4847(3) 11389(2) 2509(2) 42(1) C(19) 4092(3) 10966(2) 3213(2) 35(1) C(20) 3054(3) 9802(2) 2424(2) 31(1) O(21) 989(2) 10700(1) 1624(1) 35(1)

192

C(21) 1670(3) 9867(2) 1424(2) 31(1) O(22) 7117(2) 9003(2) 456(2) 68(1) C(22) 6292(3) 8721(3) 942(2) 50(1) O(23) 6250(30) 7723(17) 1014(19) 59(2) C(24) 7157(7) 7066(4) 224(5) 49(1) C(25) 6695(9) 5900(5) 108(6) 80(2) O(23') 6300(50) 7710(30) 880(30) 59(2) C(24') 7145(12) 6703(9) 491(8) 49(1) C(25') 5828(13) 6020(9) -720(9) 86(3) C(26) 1485(3) 10507(2) 4204(2) 34(1) C(27) -90(3) 10704(2) 3837(2) 44(1) C(28) -559(4) 11595(2) 4603(3) 54(1) C(29) 527(4) 12273(2) 5692(3) 53(1) C(30) 2100(4) 12080(2) 6056(2) 53(1) C(31) 2584(3) 11186(2) 5304(2) 43(1)

193

Table A.17: Bond lengths [Å] and angles [˚] for 208.

S(1)-O(1) 1.4363(17) S(1)-O(2) 1.4414(15) S(1)-C(26) 1.764(2) S(1)-C(20) 1.857(2) N(1)-C(13) 1.368(3) N(1)-C(2) 1.383(3) N(1)-H(1) 0.8800 C(2)-C(7) 1.365(3) C(2)-C(3) 1.494(3) C(3)-N(4) 1.472(3) C(3)-C(14) 1.511(3) C(3)-H(3) 1.0000 N(4)-C(21) 1.328(3) N(4)-H(4) 0.8800 C(7)-C(8) 1.424(3) C(7)-H(7) 0.9500 C(8)-C(9) 1.403(3) C(8)-C(13) 1.414(3) C(9)-C(10) 1.364(4) C(9)-H(9) 0.9500 C(10)-C(11) 1.395(4) C(10)-H(10) 0.9500 C(11)-C(12) 1.383(4) C(11)-H(11) 0.9500 C(12)-C(13) 1.387(4) C(12)-H(12) 0.9500 C(14)-C(15) 1.531(3) C(14)-H(14A) 0.9900 C(14)-H(14B) 0.9900

194

C(15)-C(16) 1.535(3) C(15)-C(20) 1.549(3) C(15)-H(15) 1.0000 C(16)-C(17) 1.344(3) C(16)-C(22) 1.459(4) O(17)-C(17) 1.343(3) O(17)-H(17) 0.8400 C(17)-C(18) 1.485(4) C(18)-C(19) 1.523(3) C(18)-H(18A) 0.9900 C(18)-H(18B) 0.9900 C(19)-C(20) 1.523(3) C(19)-H(19A) 0.9900 C(19)-H(19B) 0.9900 C(20)-C(21) 1.534(3) O(21)-C(21) 1.242(2) O(22)-C(22) 1.223(3) C(22)-O(23') 1.30(4) C(22)-O(23) 1.35(3) O(23)-C(24) 1.519(14) C(24)-C(25) 1.501(7) C(24)-H(24A) 0.9900 C(24)-H(24B) 0.9900 C(25)-H(25A) 0.9800 C(25)-H(25B) 0.9800 C(25)-H(25C) 0.9800 O(23')-C(24') 1.526(17) C(24')-C(25') 1.542(12) C(24')-H(24C) 0.9900 C(24')-H(24D) 0.9900 C(25')-H(25D) 0.9800

195

C(25')-H(25E) 0.9800 C(25')-H(25F) 0.9800 C(26)-C(31) 1.382(3) C(26)-C(27) 1.388(3) C(27)-C(28) 1.387(4) C(27)-H(27) 0.9500 C(28)-C(29) 1.368(4) C(28)-H(28) 0.9500 C(29)-C(30) 1.384(4) C(29)-H(29) 0.9500 C(30)-C(31) 1.387(3) C(30)-H(30) 0.9500 C(31)-H(31) 0.9500

O(1)-S(1)-O(2) 119.09(9) O(1)-S(1)-C(26) 108.16(11) O(2)-S(1)-C(26) 107.63(10) O(1)-S(1)-C(20) 107.98(10) O(2)-S(1)-C(20) 105.97(9) C(26)-S(1)-C(20) 107.51(10) C(13)-N(1)-C(2) 109.37(18) C(13)-N(1)-H(1) 125.3 C(2)-N(1)-H(1) 125.3 C(7)-C(2)-N(1) 108.5(2) C(7)-C(2)-C(3) 129.5(2) N(1)-C(2)-C(3) 121.87(18) N(4)-C(3)-C(2) 110.56(18) N(4)-C(3)-C(14) 110.76(17) C(2)-C(3)-C(14) 112.30(17) N(4)-C(3)-H(3) 107.7 C(2)-C(3)-H(3) 107.7

196

C(14)-C(3)-H(3) 107.7 C(21)-N(4)-C(3) 128.20(19) C(21)-N(4)-H(4) 115.9 C(3)-N(4)-H(4) 115.9 C(2)-C(7)-C(8) 108.2(2) C(2)-C(7)-H(7) 125.9 C(8)-C(7)-H(7) 125.9 C(9)-C(8)-C(13) 118.7(2) C(9)-C(8)-C(7) 135.1(2) C(13)-C(8)-C(7) 106.18(19) C(10)-C(9)-C(8) 119.4(2) C(10)-C(9)-H(9) 120.3 C(8)-C(9)-H(9) 120.3 C(9)-C(10)-C(11) 121.0(3) C(9)-C(10)-H(10) 119.5 C(11)-C(10)-H(10) 119.5 C(12)-C(11)-C(10) 121.4(3) C(12)-C(11)-H(11) 119.3 C(10)-C(11)-H(11) 119.3 C(11)-C(12)-C(13) 117.6(3) C(11)-C(12)-H(12) 121.2 C(13)-C(12)-H(12) 121.2 N(1)-C(13)-C(12) 130.4(2) N(1)-C(13)-C(8) 107.8(2) C(12)-C(13)-C(8) 121.8(2) C(3)-C(14)-C(15) 111.92(17) C(3)-C(14)-H(14A) 109.2 C(15)-C(14)-H(14A) 109.2 C(3)-C(14)-H(14B) 109.2 C(15)-C(14)-H(14B) 109.2 H(14A)-C(14)-H(14B) 107.9

197

C(14)-C(15)-C(16) 113.93(18) C(14)-C(15)-C(20) 108.62(18) C(16)-C(15)-C(20) 110.33(17) C(14)-C(15)-H(15) 107.9 C(16)-C(15)-H(15) 107.9 C(20)-C(15)-H(15) 107.9 C(17)-C(16)-C(22) 116.4(2) C(17)-C(16)-C(15) 122.3(2) C(22)-C(16)-C(15) 121.1(2) C(17)-O(17)-H(17) 109.5 O(17)-C(17)-C(16) 123.4(3) O(17)-C(17)-C(18) 111.9(2) C(16)-C(17)-C(18) 124.8(2) C(17)-C(18)-C(19) 111.63(19) C(17)-C(18)-H(18A) 109.3 C(19)-C(18)-H(18A) 109.3 C(17)-C(18)-H(18B) 109.3 C(19)-C(18)-H(18B) 109.3 H(18A)-C(18)-H(18B) 108.0 C(18)-C(19)-C(20) 109.85(18) C(18)-C(19)-H(19A) 109.7 C(20)-C(19)-H(19A) 109.7 C(18)-C(19)-H(19B) 109.7 C(20)-C(19)-H(19B) 109.7 H(19A)-C(19)-H(19B) 108.2 C(19)-C(20)-C(21) 109.49(16) C(19)-C(20)-C(15) 111.21(19) C(21)-C(20)-C(15) 112.58(17) C(19)-C(20)-S(1) 109.16(14) C(21)-C(20)-S(1) 106.54(14) C(15)-C(20)-S(1) 107.67(13)

198

O(21)-C(21)-N(4) 121.5(2) O(21)-C(21)-C(20) 119.59(19) N(4)-C(21)-C(20) 118.89(19) O(22)-C(22)-O(23') 115.8(18) O(22)-C(22)-O(23) 122.9(9) O(22)-C(22)-C(16) 125.1(3) O(23')-C(22)-C(16) 119.1(18) O(23)-C(22)-C(16) 112.0(9) C(22)-O(23)-C(24) 105(2) C(25)-C(24)-O(23) 101.2(12) C(25)-C(24)-H(24A) 111.5 O(23)-C(24)-H(24A) 111.5 C(25)-C(24)-H(24B) 111.5 O(23)-C(24)-H(24B) 111.5 H(24A)-C(24)-H(24B) 109.4 C(22)-O(23')-C(24') 142(4) O(23')-C(24')-C(25') 97.1(15) O(23')-C(24')-H(24C) 112.3 C(25')-C(24')-H(24C) 112.3 O(23')-C(24')-H(24D) 112.3 C(25')-C(24')-H(24D) 112.3 H(24C)-C(24')-H(24D) 109.9 C(24')-C(25')-H(25D) 109.5 C(24')-C(25')-H(25E) 109.5 H(25D)-C(25')-H(25E) 109.5 C(24')-C(25')-H(25F) 109.5 H(25D)-C(25')-H(25F) 109.5 H(25E)-C(25')-H(25F) 109.5 C(31)-C(26)-C(27) 121.3(2) C(31)-C(26)-S(1) 119.06(18) C(27)-C(26)-S(1) 119.55(19)

199

C(28)-C(27)-C(26) 118.7(3) C(28)-C(27)-H(27) 120.6 C(26)-C(27)-H(27) 120.6 C(29)-C(28)-C(27) 120.2(3) C(29)-C(28)-H(28) 119.9 C(27)-C(28)-H(28) 119.9 C(28)-C(29)-C(30) 121.1(2) C(28)-C(29)-H(29) 119.4 C(30)-C(29)-H(29) 119.4 C(29)-C(30)-C(31) 119.5(3) C(29)-C(30)-H(30) 120.3 C(31)-C(30)-H(30) 120.3 C(26)-C(31)-C(30) 119.2(2) C(26)-C(31)-H(31) 120.4 C(30)-C(31)-H(31) 120.4

Symmetry transformations used to generate equivalent atoms:

200

Table A.18: Anisotropic displacement parameters (Å2 x 103) for 208. The anisotropic displacement factor exponent takes the form: -2 Π2 [ h2 a*2 U11 + ... + 2 h k a* b* U12 ]

U11 U22 U33 U23 U13 U12

S(1) 36(1) 35(1) 34(1) 20(1) 17(1) 11(1) O(1) 38(1) 38(1) 42(1) 19(1) 16(1) 1(1) N(1) 61(2) 25(1) 37(1) 13(1) 6(1) 6(1) O(2) 42(1) 42(1) 39(1) 27(1) 21(1) 18(1) C(2) 40(1) 31(1) 30(1) 15(1) 16(1) 7(1) C(3) 39(1) 29(1) 38(1) 15(1) 21(1) 8(1) N(4) 38(1) 30(1) 30(1) 14(1) 9(1) 7(1) C(7) 39(1) 33(1) 37(1) 17(1) 20(1) 12(1) C(8) 45(2) 28(1) 38(1) 14(1) 20(1) 8(1) C(9) 54(2) 31(1) 43(1) 16(1) 25(1) 11(1) C(10) 68(2) 30(1) 54(2) 9(1) 13(2) 4(1) C(11) 82(2) 36(2) 65(2) 11(1) -20(2) -1(2) C(12) 93(3) 36(2) 60(2) 16(1) -19(2) 9(2) C(13) 63(2) 24(1) 42(1) 9(1) 10(1) 7(1) C(14) 32(1) 31(1) 39(1) 18(1) 18(1) 9(1) C(15) 30(1) 40(1) 35(1) 18(1) 15(1) 7(1) C(16) 37(1) 49(2) 33(1) 14(1) 15(1) -1(1) O(17) 59(1) 78(1) 61(1) 39(1) 27(1) -7(1) C(17) 46(2) 58(2) 38(1) 30(1) 12(1) -4(1) C(18) 46(2) 43(1) 40(1) 24(1) 10(1) -1(1) C(19) 41(1) 35(1) 32(1) 18(1) 10(1) 4(1) C(20) 37(1) 32(1) 31(1) 18(1) 15(1) 7(1) O(21) 45(1) 30(1) 31(1) 15(1) 11(1) 9(1) C(21) 38(1) 30(1) 31(1) 16(1) 14(1) 3(1)

201

O(22) 46(1) 110(2) 50(1) 30(1) 28(1) 2(1) C(22) 36(2) 64(2) 36(1) 6(1) 14(1) -6(1) O(23) 40(2) 61(1) 65(4) 5(2) 33(2) 9(1) C(24) 48(2) 57(3) 54(2) 23(2) 33(2) 25(2) C(25) 124(5) 61(3) 99(4) 45(3) 76(4) 53(3) O(23') 40(2) 61(1) 65(4) 5(2) 33(2) 9(1) C(24') 48(2) 57(3) 54(2) 23(2) 33(2) 25(2) C(26) 36(1) 42(1) 38(1) 25(1) 19(1) 17(1) C(27) 39(2) 53(2) 50(2) 28(1) 20(1) 19(1) C(28) 48(2) 70(2) 68(2) 40(2) 33(2) 34(2) C(29) 66(2) 58(2) 56(2) 28(2) 40(2) 34(2) C(30) 68(2) 57(2) 38(1) 17(1) 25(1) 27(2) C(31) 46(2) 52(2) 37(1) 22(1) 18(1) 23(1)

202

Table A.19: Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2 x 103) for 208.

x y z U(eq)

H(1) -862 7654 -1851 53 H(3) 2626 8086 -467 40 H(4) 439 9104 -188 39 H(7) 1171 5669 -421 41 H(9) -1286 3628 -2132 49 H(10) -3686 3030 -3714 66 H(11) -4865 4283 -4426 91 H(12) -3588 6164 -3618 90 H(14A) 3639 7261 765 38 H(14B) 2272 7560 1368 38 H(15) 4760 8773 2640 40 H(17) 7061 10457 1059 93 H(18A) 3995 11605 1983 51 H(18B) 5690 12067 3054 51 H(19A) 3407 11492 3541 42 H(19B) 4964 10931 3874 42 H(24A) 6783 7104 -547 58 H(24B) 8349 7338 595 58 H(25A) 7056 5895 886 120 H(25B) 7220 5381 -390 120 H(25C) 5509 5661 -249 120 H(24C) 7294 6305 1009 58 H(24D) 8205 6916 428 58 H(25D) 6194 5337 -1145 129 H(25E) 5641 6476 -1170 129

203

H(25F) 4811 5813 -614 129 H(27) -833 10236 3075 52 H(28) -1637 11736 4371 65 H(29) 195 12885 6207 64 H(30) 2842 12557 6814 64 H(31) 3659 11042 5543 51

204

Table A.20: Torsion angles [˚] for 208.

C(13)-N(1)-C(2)-C(7) 0.9(3) C(13)-N(1)-C(2)-C(3) 176.5(2) C(7)-C(2)-C(3)-N(4) -142.1(2) N(1)-C(2)-C(3)-N(4) 43.3(3) C(7)-C(2)-C(3)-C(14) -17.8(3) N(1)-C(2)-C(3)-C(14) 167.61(19) C(2)-C(3)-N(4)-C(21) 138.4(2) C(14)-C(3)-N(4)-C(21) 13.2(3) N(1)-C(2)-C(7)-C(8) -0.3(3) C(3)-C(2)-C(7)-C(8) -175.4(2) C(2)-C(7)-C(8)-C(9) 179.4(3) C(2)-C(7)-C(8)-C(13) -0.4(3) C(13)-C(8)-C(9)-C(10) -1.8(4) C(7)-C(8)-C(9)-C(10) 178.4(3) C(8)-C(9)-C(10)-C(11) -0.1(4) C(9)-C(10)-C(11)-C(12) 1.7(5) C(10)-C(11)-C(12)-C(13) -1.2(6) C(2)-N(1)-C(13)-C(12) 177.5(3) C(2)-N(1)-C(13)-C(8) -1.2(3) C(11)-C(12)-C(13)-N(1) -179.3(3) C(11)-C(12)-C(13)-C(8) -0.7(5) C(9)-C(8)-C(13)-N(1) -178.9(2) C(7)-C(8)-C(13)-N(1) 1.0(3) C(9)-C(8)-C(13)-C(12) 2.2(4) C(7)-C(8)-C(13)-C(12) -177.9(3) N(4)-C(3)-C(14)-C(15) -44.5(2) C(2)-C(3)-C(14)-C(15) -168.62(18) C(3)-C(14)-C(15)-C(16) -61.1(2) C(3)-C(14)-C(15)-C(20) 62.3(2)

205

C(14)-C(15)-C(16)-C(17) 135.5(2) C(20)-C(15)-C(16)-C(17) 13.0(3) C(14)-C(15)-C(16)-C(22) -49.3(3) C(20)-C(15)-C(16)-C(22) -171.8(2) C(22)-C(16)-C(17)-O(17) 5.2(4) C(15)-C(16)-C(17)-O(17) -179.4(2) C(22)-C(16)-C(17)-C(18) -173.9(2) C(15)-C(16)-C(17)-C(18) 1.5(4) O(17)-C(17)-C(18)-C(19) -163.2(2) C(16)-C(17)-C(18)-C(19) 16.0(3) C(17)-C(18)-C(19)-C(20) -47.5(3) C(18)-C(19)-C(20)-C(21) -61.2(2) C(18)-C(19)-C(20)-C(15) 63.8(2) C(18)-C(19)-C(20)-S(1) -177.51(15) C(14)-C(15)-C(20)-C(19) -170.47(17) C(16)-C(15)-C(20)-C(19) -44.9(2) C(14)-C(15)-C(20)-C(21) -47.2(2) C(16)-C(15)-C(20)-C(21) 78.4(2) C(14)-C(15)-C(20)-S(1) 69.98(18) C(16)-C(15)-C(20)-S(1) -164.48(15) O(1)-S(1)-C(20)-C(19) 155.30(15) O(2)-S(1)-C(20)-C(19) -76.06(16) C(26)-S(1)-C(20)-C(19) 38.81(18) O(1)-S(1)-C(20)-C(21) 37.15(16) O(2)-S(1)-C(20)-C(21) 165.79(13) C(26)-S(1)-C(20)-C(21) -79.33(16) O(1)-S(1)-C(20)-C(15) -83.85(16) O(2)-S(1)-C(20)-C(15) 44.79(16) C(26)-S(1)-C(20)-C(15) 159.66(15) C(3)-N(4)-C(21)-O(21) 179.75(19) C(3)-N(4)-C(21)-C(20) 0.2(3)

206

C(19)-C(20)-C(21)-O(21) -37.7(3) C(15)-C(20)-C(21)-O(21) -161.98(19) S(1)-C(20)-C(21)-O(21) 80.2(2) C(19)-C(20)-C(21)-N(4) 141.8(2) C(15)-C(20)-C(21)-N(4) 17.6(3) S(1)-C(20)-C(21)-N(4) -100.24(19) C(17)-C(16)-C(22)-O(22) -14.1(4) C(15)-C(16)-C(22)-O(22) 170.4(2) C(17)-C(16)-C(22)-O(23') 166.9(19) C(15)-C(16)-C(22)-O(23') -8.6(19) C(17)-C(16)-C(22)-O(23) 163.3(10) C(15)-C(16)-C(22)-O(23) -12.2(10) O(22)-C(22)-O(23)-C(24) -8.9(17) O(23')-C(22)-O(23)-C(24) 17(18) C(16)-C(22)-O(23)-C(24) 173.7(8) C(22)-O(23)-C(24)-C(25) -166.3(11) O(22)-C(22)-O(23')-C(24') 8(5) O(23)-C(22)-O(23')-C(24') -147(22) C(16)-C(22)-O(23')-C(24') -173(4) C(22)-O(23')-C(24')-C(25') -98(5) O(1)-S(1)-C(26)-C(31) 155.11(18) O(2)-S(1)-C(26)-C(31) 25.2(2) C(20)-S(1)-C(26)-C(31) -88.5(2) O(1)-S(1)-C(26)-C(27) -21.8(2) O(2)-S(1)-C(26)-C(27) -151.66(18) C(20)-S(1)-C(26)-C(27) 94.6(2) C(31)-C(26)-C(27)-C(28) -0.7(4) S(1)-C(26)-C(27)-C(28) 176.17(18) C(26)-C(27)-C(28)-C(29) 0.9(4) C(27)-C(28)-C(29)-C(30) -0.6(4) C(28)-C(29)-C(30)-C(31) 0.0(4)

207

C(27)-C(26)-C(31)-C(30) 0.1(4) S(1)-C(26)-C(31)-C(30) -176.74(19) C(29)-C(30)-C(31)-C(26) 0.2(4)

Symmetry transformations used to generate equivalent atoms:

208

Table A.21: Hydrogen bonds for 208 [Å and ˚].

D-H...A d(D-H) d(H...A) d(D...A) <(DHA)

N(1)-H(1)...O(21)#1 0.88 2.08 2.929(2) 163.2

N(4)-H(4)...O(21)#1 0.88 2.05 2.912(2) 166.4

O(17)-H(17)...O(22) 0.84 1.77 2.512(3) 146.5

Symmetry transformations used to generate equivalent atoms: #1 -x,-y+2,-z

209

Table A.22: Crystal data and structure refinement for 209.

Empirical formula C20H22N2O4

Formula weight 354.40

Temperature (K) 90.0(2)

Wavelength (Å) 0.71073

Crystal system Triclinic

Space group P -1

Unit cell dimensions a (Å) 5.7055(1)

α (˚) 110.4139(11) b (Å) 13.0751(3)

β (˚) 96.0096(11) c (Å) 13.0935(3)

γ (˚) 98.2689(11)

Volume (Å3) 893.20(3)

Z 2

210

Calculated density (Mg/m3) 1.318

Absorption coefficient (mm-1) 0.092

F(000) 376

Crystal size (mm) 0.30 x 0.15 x 0.07

Θ range for data collection (˚) 1.68 to 27.47

Limiting indices -7≤h≤7 -16≤k≤16 -16≤l≤16

Reflections collected / unique 19919 / 4086 [R(int) = 0.0311]

Completeness to Θ = 27.47 99.7 %

Semi-empirical from Absorption correction equivalents

Max. transmission 0.9936

Min. transmission 0.9728

Full-matrix least- Refinement method squares on F2

211

Data / restraints / parameters 4086 / 0 / 238

Goodness-of-fit on F2 1.053

Final R indices [I>2σ(I)] R1 = 0.0453

ωR2 = 0.1209

R indices (all data) R1 = 0.0643

ωR2 = 0.1335

Extinction coefficient 0.022(5)

Largest diff. peak and hole 0.310 and -0.266 (e.Å-3)

212

Table A.23: Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2 x 103) for 209. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

x y z U(eq)

N(1) 3554(2) 2386(1) 3258(1) 20(1) C(2) 1407(3) 2430(1) 2694(1) 19(1) C(3) 832(3) 3486(1) 2607(1) 18(1) N(4) 1080(2) 4348(1) 3716(1) 19(1) C(7) -43(3) 1406(1) 2298(1) 26(1) C(8) 1223(3) 677(1) 2638(1) 25(1) C(9) 673(3) -449(1) 2522(2) 33(1) C(10) 2345(3) -881(1) 3000(1) 32(1) C(11) 4572(3) -228(1) 3586(1) 29(1) C(12) 5168(3) 881(1) 3715(1) 26(1) C(13) 3458(3) 1319(1) 3243(1) 21(1) C(14) 2216(3) 3970(1) 1889(1) 19(1) C(15) 4790(2) 4552(1) 2460(1) 17(1) C(16) 6230(2) 4957(1) 1712(1) 18(1) O(17) 8373(2) 6437(1) 1303(1) 28(1) C(17) 7054(3) 6051(1) 1930(1) 21(1) C(18) 6619(3) 6967(1) 2913(1) 26(1) C(19) 4446(3) 6585(1) 3363(1) 23(1) C(20) 4735(3) 5511(1) 3548(1) 18(1) O(21) 2832(2) 5904(1) 5150(1) 21(1) C(21) 2808(2) 5247(1) 4182(1) 18(1) O(22) 7718(2) 4385(1) 6(1) 24(1) C(22) 6733(2) 4144(1) 703(1) 19(1)

213

O(23) 6032(2) 3087(1) 605(1) 22(1) C(23) 6398(3) 2242(1) -413(1) 29(1) C(24) 5316(4) 1136(1) -405(2) 41(1)

214

Table A.24: Bond lengths [Å] and angles [˚] for 209.

N(1)-C(13) 1.3812(18) N(1)-C(2) 1.3820(18) N(1)-H(1) 0.8800 C(2)-C(7) 1.361(2) C(2)-C(3) 1.5039(19) C(3)-N(4) 1.4722(17) C(3)-C(14) 1.5288(19) C(3)-H(3) 1.0000 N(4)-C(21) 1.3288(18) N(4)-H(4) 0.8800 C(7)-C(8) 1.433(2) C(7)-H(7) 0.9500 C(8)-C(13) 1.405(2) C(8)-C(9) 1.411(2) C(9)-C(10) 1.377(2) C(9)-H(9) 0.9500 C(10)-C(11) 1.399(2) C(10)-H(10) 0.9500 C(11)-C(12) 1.387(2) C(11)-H(11) 0.9500 C(12)-C(13) 1.394(2) C(12)-H(12) 0.9500 C(14)-C(15) 1.5323(19) C(14)-H(14A) 0.9900 C(14)-H(14B) 0.9900 C(15)-C(16) 1.5233(19) C(15)-C(20) 1.5417(18) C(15)-H(15) 1.0000 C(16)-C(17) 1.358(2)

215

C(16)-C(22) 1.464(2) O(17)-C(17) 1.3427(17) O(17)-H(17) 0.8400 C(17)-C(18) 1.494(2) C(18)-C(19) 1.521(2) C(18)-H(18A) 0.9900 C(18)-H(18B) 0.9900 C(19)-C(20) 1.5338(19) C(19)-H(19A) 0.9900 C(19)-H(19B) 0.9900 C(20)-C(21) 1.5159(19) C(20)-H(20) 1.0000 O(21)-C(21) 1.2559(16) O(22)-C(22) 1.2265(17) C(22)-O(23) 1.3398(17) O(23)-C(23) 1.4623(17) C(23)-C(24) 1.493(2) C(23)-H(23A) 0.9900 C(23)-H(23B) 0.9900 C(24)-H(24A) 0.9800 C(24)-H(24B) 0.9800 C(24)-H(24C) 0.9800

C(13)-N(1)-C(2) 108.61(12) C(13)-N(1)-H(1) 125.7 C(2)-N(1)-H(1) 125.7 C(7)-C(2)-N(1) 109.43(13) C(7)-C(2)-C(3) 127.59(13) N(1)-C(2)-C(3) 122.93(12) N(4)-C(3)-C(2) 110.24(11) N(4)-C(3)-C(14) 109.18(11)

216

C(2)-C(3)-C(14) 117.20(12) N(4)-C(3)-H(3) 106.5 C(2)-C(3)-H(3) 106.5 C(14)-C(3)-H(3) 106.5 C(21)-N(4)-C(3) 126.78(12) C(21)-N(4)-H(4) 116.6 C(3)-N(4)-H(4) 116.6 C(2)-C(7)-C(8) 107.49(13) C(2)-C(7)-H(7) 126.3 C(8)-C(7)-H(7) 126.3 C(13)-C(8)-C(9) 118.65(15) C(13)-C(8)-C(7) 106.59(13) C(9)-C(8)-C(7) 134.73(15) C(10)-C(9)-C(8) 118.95(16) C(10)-C(9)-H(9) 120.5 C(8)-C(9)-H(9) 120.5 C(9)-C(10)-C(11) 121.31(15) C(9)-C(10)-H(10) 119.3 C(11)-C(10)-H(10) 119.3 C(12)-C(11)-C(10) 121.16(15) C(12)-C(11)-H(11) 119.4 C(10)-C(11)-H(11) 119.4 C(11)-C(12)-C(13) 117.34(15) C(11)-C(12)-H(12) 121.3 C(13)-C(12)-H(12) 121.3 N(1)-C(13)-C(12) 129.56(14) N(1)-C(13)-C(8) 107.86(13) C(12)-C(13)-C(8) 122.58(14) C(3)-C(14)-C(15) 112.18(11) C(3)-C(14)-H(14A) 109.2 C(15)-C(14)-H(14A) 109.2

217

C(3)-C(14)-H(14B) 109.2 C(15)-C(14)-H(14B) 109.2 H(14A)-C(14)-H(14B) 107.9 C(16)-C(15)-C(14) 112.20(11) C(16)-C(15)-C(20) 111.61(11) C(14)-C(15)-C(20) 109.55(11) C(16)-C(15)-H(15) 107.8 C(14)-C(15)-H(15) 107.8 C(20)-C(15)-H(15) 107.8 C(17)-C(16)-C(22) 117.83(13) C(17)-C(16)-C(15) 122.74(12) C(22)-C(16)-C(15) 119.43(12) C(17)-O(17)-H(17) 109.5 O(17)-C(17)-C(16) 124.39(13) O(17)-C(17)-C(18) 112.19(12) C(16)-C(17)-C(18) 123.42(13) C(17)-C(18)-C(19) 111.26(12) C(17)-C(18)-H(18A) 109.4 C(19)-C(18)-H(18A) 109.4 C(17)-C(18)-H(18B) 109.4 C(19)-C(18)-H(18B) 109.4 H(18A)-C(18)-H(18B) 108.0 C(18)-C(19)-C(20) 108.86(12) C(18)-C(19)-H(19A) 109.9 C(20)-C(19)-H(19A) 109.9 C(18)-C(19)-H(19B) 109.9 C(20)-C(19)-H(19B) 109.9 H(19A)-C(19)-H(19B) 108.3 C(21)-C(20)-C(19) 108.57(11) C(21)-C(20)-C(15) 114.13(11) C(19)-C(20)-C(15) 112.07(11)

218

C(21)-C(20)-H(20) 107.2 C(19)-C(20)-H(20) 107.2 C(15)-C(20)-H(20) 107.2 O(21)-C(21)-N(4) 120.11(12) O(21)-C(21)-C(20) 119.06(12) N(4)-C(21)-C(20) 120.81(12) O(22)-C(22)-O(23) 121.93(13) O(22)-C(22)-C(16) 124.51(13) O(23)-C(22)-C(16) 113.56(12) C(22)-O(23)-C(23) 115.65(11) O(23)-C(23)-C(24) 107.21(13) O(23)-C(23)-H(23A) 110.3 C(24)-C(23)-H(23A) 110.3 O(23)-C(23)-H(23B) 110.3 C(24)-C(23)-H(23B) 110.3 H(23A)-C(23)-H(23B) 108.5 C(23)-C(24)-H(24A) 109.5 C(23)-C(24)-H(24B) 109.5 H(24A)-C(24)-H(24B) 109.5 C(23)-C(24)-H(24C) 109.5 H(24A)-C(24)-H(24C) 109.5 H(24B)-C(24)-H(24C) 109.5

Symmetry transformations used to generate equivalent atoms:

219

Table A.25: Anisotropic displacement parameters (Å2 x 103) for 209. The anisotropic displacement factor exponent takes the form: -2 Π2 [ h2 a*2 U11 + ... + 2 h k a* b* U12 ]

U11 U22 U33 U23 U13 U12

N(1) 19(1) 17(1) 23(1) 8(1) 2(1) 2(1) C(2) 19(1) 21(1) 19(1) 6(1) 6(1) 4(1) C(3) 16(1) 18(1) 18(1) 5(1) 3(1) 2(1) N(4) 19(1) 18(1) 19(1) 6(1) 7(1) 3(1) C(7) 21(1) 20(1) 31(1) 6(1) 2(1) 1(1) C(8) 26(1) 19(1) 29(1) 7(1) 8(1) 3(1) C(9) 32(1) 20(1) 45(1) 11(1) 10(1) 2(1) C(10) 42(1) 19(1) 41(1) 13(1) 18(1) 8(1) C(11) 45(1) 25(1) 25(1) 12(1) 14(1) 16(1) C(12) 34(1) 23(1) 21(1) 7(1) 6(1) 9(1) C(13) 26(1) 18(1) 19(1) 6(1) 10(1) 6(1) C(14) 19(1) 21(1) 18(1) 7(1) 3(1) 4(1) C(15) 18(1) 18(1) 18(1) 8(1) 4(1) 4(1) C(16) 18(1) 20(1) 19(1) 9(1) 6(1) 6(1) O(17) 36(1) 22(1) 32(1) 13(1) 19(1) 5(1) C(17) 21(1) 22(1) 24(1) 13(1) 7(1) 5(1) C(18) 33(1) 17(1) 30(1) 10(1) 14(1) 4(1) C(19) 29(1) 18(1) 26(1) 9(1) 11(1) 6(1) C(20) 18(1) 18(1) 18(1) 7(1) 5(1) 3(1) O(21) 22(1) 20(1) 18(1) 5(1) 5(1) 2(1) C(21) 18(1) 18(1) 19(1) 8(1) 4(1) 5(1) O(22) 25(1) 26(1) 23(1) 11(1) 9(1) 3(1) C(22) 16(1) 21(1) 21(1) 9(1) 2(1) 3(1)

220

O(23) 27(1) 18(1) 21(1) 6(1) 7(1) 5(1) C(23) 34(1) 23(1) 26(1) 3(1) 10(1) 4(1) C(24) 65(1) 24(1) 28(1) 6(1) 8(1) 2(1)

221

Table A.26: Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2 x 103) for 209.

x y z U(eq)

H(1) 4779 2944 3574 24 H(3) -905 3316 2274 22 H(4) -31 4258 4112 22 H(7) -1607 1210 1874 31 H(9) -826 -902 2120 40 H(10) 1979 -1636 2931 39 H(11) 5695 -550 3902 35 H(12) 6681 1325 4110 31 H(14A) 1360 4510 1712 23 H(14B) 2263 3364 1185 23 H(15) 5603 3999 2652 21 H(17) 8554 5901 752 43 H(18A) 6354 7605 2703 31 H(18B) 8055 7222 3497 31 H(19A) 2962 6449 2832 28 H(19B) 4320 7168 4070 28 H(20) 6321 5667 4033 22 H(23A) 8135 2288 -444 35 H(23B) 5611 2355 -1065 35 H(24A) 6174 1015 219 61 H(24B) 5443 549 -1098 61 H(24C) 3621 1116 -330 61

222

Table A.27: Torsion angles [˚] for 209.

C(13)-N(1)-C(2)-C(7) -1.29(16) C(13)-N(1)-C(2)-C(3) 176.20(12) C(7)-C(2)-C(3)-N(4) 121.53(15) N(1)-C(2)-C(3)-N(4) -55.47(17) C(7)-C(2)-C(3)-C(14) -112.79(17) N(1)-C(2)-C(3)-C(14) 70.20(17) C(2)-C(3)-N(4)-C(21) 107.93(15) C(14)-C(3)-N(4)-C(21) -22.17(18) N(1)-C(2)-C(7)-C(8) 0.86(17) C(3)-C(2)-C(7)-C(8) -176.47(13) C(2)-C(7)-C(8)-C(13) -0.13(17) C(2)-C(7)-C(8)-C(9) 177.67(17) C(13)-C(8)-C(9)-C(10) -0.2(2) C(7)-C(8)-C(9)-C(10) -177.80(17) C(8)-C(9)-C(10)-C(11) -0.6(2) C(9)-C(10)-C(11)-C(12) 0.6(2) C(10)-C(11)-C(12)-C(13) 0.3(2) C(2)-N(1)-C(13)-C(12) -178.83(14) C(2)-N(1)-C(13)-C(8) 1.18(15) C(11)-C(12)-C(13)-N(1) 178.82(14) C(11)-C(12)-C(13)-C(8) -1.2(2) C(9)-C(8)-C(13)-N(1) -178.86(13) C(7)-C(8)-C(13)-N(1) -0.64(16) C(9)-C(8)-C(13)-C(12) 1.1(2) C(7)-C(8)-C(13)-C(12) 179.37(14) N(4)-C(3)-C(14)-C(15) 50.12(15) C(2)-C(3)-C(14)-C(15) -76.08(15) C(3)-C(14)-C(15)-C(16) 175.61(11) C(3)-C(14)-C(15)-C(20) -59.84(15)

223

C(14)-C(15)-C(16)-C(17) 114.96(15) C(20)-C(15)-C(16)-C(17) -8.44(19) C(14)-C(15)-C(16)-C(22) -64.06(16) C(20)-C(15)-C(16)-C(22) 172.53(12) C(22)-C(16)-C(17)-O(17) -2.5(2) C(15)-C(16)-C(17)-O(17) 178.43(13) C(22)-C(16)-C(17)-C(18) 178.47(13) C(15)-C(16)-C(17)-C(18) -0.6(2) O(17)-C(17)-C(18)-C(19) 158.91(13) C(16)-C(17)-C(18)-C(19) -22.0(2) C(17)-C(18)-C(19)-C(20) 51.99(17) C(18)-C(19)-C(20)-C(21) 170.07(12) C(18)-C(19)-C(20)-C(15) -62.94(16) C(16)-C(15)-C(20)-C(21) 163.89(11) C(14)-C(15)-C(20)-C(21) 38.99(16) C(16)-C(15)-C(20)-C(19) 39.95(16) C(14)-C(15)-C(20)-C(19) -84.94(14) C(3)-N(4)-C(21)-O(21) -178.33(12) C(3)-N(4)-C(21)-C(20) 3.2(2) C(19)-C(20)-C(21)-O(21) -64.52(16) C(15)-C(20)-C(21)-O(21) 169.69(12) C(19)-C(20)-C(21)-N(4) 113.93(14) C(15)-C(20)-C(21)-N(4) -11.87(18) C(17)-C(16)-C(22)-O(22) -4.7(2) C(15)-C(16)-C(22)-O(22) 174.42(13) C(17)-C(16)-C(22)-O(23) 174.64(12) C(15)-C(16)-C(22)-O(23) -6.29(18) O(22)-C(22)-O(23)-C(23) -3.3(2) C(16)-C(22)-O(23)-C(23) 177.40(12) C(22)-O(23)-C(23)-C(24) -175.13(14) Symmetry transformations used to generate equivalent atoms:

224

Table A.28: Hydrogen bonds for 209 [Å and ˚].

D-H...A d(D-H) d(H...A) d(D...A) <(DHA)

N(1)-H(1)...O(21)#1 0.88 2.02 2.8497(15) 155.8

N(4)-H(4)...O(21)#2 0.88 1.98 2.8492(15) 172.1

O(17)-H(17)...O(22) 0.84 1.84 2.5733(15) 144.8

O(17)-H(17)...O(22)#3 0.84 2.46 3.0449(15) 127.2

Symmetry transformations used to generate equivalent atoms: #1 -x+1,-y+1,-z+1 #2 -x,-y+1,-z+1 #3 -x+2,-y+1,-z

225

Table A.29: Crystal data and structure refinement for 215.

Empirical formula C23.74H24.36Cl1.25N1.78O5.65S0.89

Formula weight 497.63

Temperature (K) 90.0(2)

Wavelength (Å) 1.54178

Crystal system Tetragonal

Space group I 41/a

Unit cell dimensions a (Å) 43.9413(10) α (˚) 90 b (Å) 43.9413(10) β (˚) 90 c (Å) 11.8367(7) γ (˚) 90

Volume (Å3) 22854.8(15)

Z 36

Calculated density (Mg/m3) 1.302

Absorption coefficient (mm-1) 2.581

226

F(000) 9354

Crystal size (mm) 0.15 x 0.04 x 0.04

Θ range for data collection 2.84 to 68.48 (˚)

Limiting indices -50≤h≤53 -52≤k≤53 -14≤l≤14

Reflections collected / 163587 / 10513 unique [R(int) = 0.0658]

Completeness to Θ = 68.48 100.0 %

Absorption correction Semi-empirical from equivalents

Max. transmission 0.904

Min. transmission 0.642

Refinement method Full-matrix least-squares on F2

Data / restraints / 10513 / 69 / 750 parameters

227

Goodness-of-fit on F2 1.070

Final R indices [I>2σ(I)] R1 = 0.0591, ωR2 = 0.1712

R indices (all data) R1 = 0.0689, ωR2 = 0.1835

Extinction coefficient 0.000050(9)

Largest diff. peak and hole 0.966 and -0.562 (e.Å-3)

228

Table A.30: Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2 x 103) for 215. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

x y z U(eq)

S(1B) 7379(1) 2795(1) 5286(1) 20(1) N(1B) 6727(1) 2497(1) 8979(2) 20(1) O(1B) 7623(1) 2634(1) 5838(2) 25(1) C(2B) 6599(1) 2579(1) 7961(2) 18(1) O(2B) 7445(1) 2966(1) 4281(2) 29(1) C(3B) 6749(1) 2499(1) 6901(2) 18(1) N(4B) 6639(1) 2645(1) 5928(2) 18(1) C(7B) 6326(1) 2720(1) 8154(2) 21(1) C(8B) 6281(1) 2725(1) 9349(2) 20(1) C(9B) 6048(1) 2834(1) 10053(2) 25(1) C(10B) 6082(1) 2809(1) 11206(2) 26(1) C(11B) 6344(1) 2675(1) 11678(2) 26(1) C(12B) 6574(1) 2564(1) 11008(2) 24(1) C(13B) 6539(1) 2590(1) 9838(2) 19(1) C(14B) 6981(1) 2304(1) 6822(2) 18(1) C(15B) 7110(1) 2223(1) 5686(2) 18(1) C(16B) 6930(1) 1953(1) 5176(2) 22(1) O(17B) 6945(1) 1588(1) 3639(2) 36(1) C(17B) 7071(1) 1862(1) 4031(2) 28(1) C(18B) 7032(1) 2128(1) 3228(2) 28(1) C(19B) 7191(1) 2412(1) 3667(2) 23(1) C(20B) 7096(1) 2498(1) 4875(2) 18(1) O(21B) 6680(1) 2782(1) 4094(2) 22(1)

229

C(21B) 6784(1) 2652(1) 4926(2) 17(1) O(22B) 6698(1) 1528(1) 6110(2) 26(1) C(22B) 6921(1) 1682(1) 5963(2) 24(1) O(23B) 7185(1) 1633(1) 6474(3) 52(1) C(24B) 7181(1) 1407(1) 7451(6) 31(1) C(25B) 7277(1) 1114(1) 6961(5) 41(1) C(24D) 7224(2) 1311(2) 6870(8) 31(1) C(25D) 7133(3) 1360(3) 8085(10) 54(3) C(26B) 7216(1) 3050(1) 6267(2) 23(1) C(27B) 7075(1) 3312(1) 5861(3) 29(1) C(28B) 6956(1) 3517(1) 6635(3) 38(1) C(29B) 6978(1) 3459(1) 7783(3) 37(1) C(30B) 7117(1) 3199(1) 8173(3) 32(1) C(31B) 7239(1) 2990(1) 7418(2) 25(1) S(1A) 5963(1) 3787(1) 5936(1) 22(1) O(1A) 6278(1) 3805(1) 5617(2) 29(1) N(1A) 6453(1) 3772(1) 1913(2) 26(1) O(2A) 5763(1) 4037(1) 5667(2) 29(1) C(2A) 6456(1) 3544(1) 2709(2) 22(1) C(3A) 6186(1) 3480(1) 3375(2) 23(1) N(4A) 6218(1) 3241(1) 4178(2) 20(1) C(7A) 6740(1) 3416(1) 2754(3) 28(1) C(8A) 6926(1) 3576(1) 1959(3) 31(1) C(9A) 7238(1) 3566(1) 1694(3) 41(1) C(10A) 7348(1) 3768(1) 897(4) 53(1) C(11A) 7154(1) 3981(1) 376(4) 49(1) C(12A) 6850(1) 4003(1) 648(3) 39(1) C(13A) 6738(1) 3797(1) 1449(3) 28(1) C(14A) 5924(1) 3636(1) 3335(2) 19(1) C(15A) 5667(1) 3545(1) 4101(2) 19(1) C(16A) 5486(1) 3280(1) 3564(2) 18(1)

230

O(17A) 5062(1) 2933(1) 3804(2) 22(1) C(17A) 5226(1) 3172(1) 4334(2) 19(1) C(18A) 5353(1) 3075(1) 5469(2) 21(1) C(19A) 5536(1) 3328(1) 6035(2) 20(1) C(20A) 5790(1) 3447(1) 5265(2) 19(1) O(21A) 6093(1) 3016(1) 5828(2) 23(1) C(21A) 6048(1) 3215(1) 5120(2) 19(1) O(22A) 5257(1) 3636(1) 2274(2) 34(1) C(22A) 5354(1) 3384(1) 2451(2) 22(1) O(23A) 5348(1) 3158(1) 1693(2) 26(1) C(24A) 5183(1) 3224(1) 656(3) 35(1) C(25A) 5142(1) 2929(1) 43(3) 46(1) C(26A) 5946(1) 3729(1) 7409(2) 22(1) C(27A) 5710(1) 3857(1) 8024(3) 28(1) C(28A) 5705(1) 3816(1) 9181(3) 32(1) C(29A) 5934(1) 3650(1) 9706(3) 30(1) C(30A) 6170(1) 3526(1) 9086(3) 28(1) C(31A) 6178(1) 3564(1) 7923(3) 25(1) C(1S) 7009(2) 1026(2) 10957(6) 62(2) Cl(1S) 7192(1) 1372(1) 10686(2) 62(1) Cl(2S) 6816(1) 879(1) 9734(2) 80(1) O(1W) 6951(4) 760(3) 10396(14) 98(3) C(2S) 8323(4) 4366(5) 1511(16) 90(4) Cl(3S) 8234(1) 4705(1) 2521(4) 79(2) Cl(4S) 8129(1) 4171(1) 1090(3) 67(1) C(2S') 8283(4) 4545(4) 1185(16) 80(4) Cl(5S) 8356(3) 4678(2) 2170(11) 142(3) Cl(6S) 7965(2) 4305(3) 868(7) 144(4) O(3W) 7382(2) 493(2) 7160(10) 80(3)

231

Table A.31: Bond lengths [Å] and angles [˚] for 215.

S(1B)-O(2B) 1.437(2) S(1B)-O(1B) 1.442(2) S(1B)-C(26B) 1.764(3) S(1B)-C(20B) 1.866(3) N(1B)-C(13B) 1.373(3) N(1B)-C(2B) 1.377(3) N(1B)-H(1B) 0.8800 C(2B)-C(7B) 1.370(4) C(2B)-C(3B) 1.460(4) C(3B)-C(14B) 1.337(4) C(3B)-N(4B) 1.402(3) N(4B)-C(21B) 1.346(3) N(4B)-H(4B) 0.8800 C(7B)-C(8B) 1.429(4) C(7B)-H(7B) 0.9500 C(8B)-C(13B) 1.403(4) C(8B)-C(9B) 1.404(4) C(9B)-C(10B) 1.378(4) C(9B)-H(9B) 0.9500 C(10B)-C(11B) 1.412(4) C(10B)-H(10B) 0.9500 C(11B)-C(12B) 1.371(4) C(11B)-H(11B) 0.9500 C(12B)-C(13B) 1.398(4) C(12B)-H(12B) 0.9500 C(14B)-C(15B) 1.501(4) C(14B)-H(14B) 0.9500 C(15B)-C(20B) 1.545(3) C(15B)-C(16B) 1.549(4)

232

C(15B)-H(15B) 1.0000 C(16B)-C(22B) 1.512(4) C(16B)-C(17B) 1.542(4) C(16B)-H(16B) 1.0000 O(17B)-C(17B) 1.405(4) O(17B)-H(17D) 0.8400 C(17B)-C(18B) 1.515(4) C(17B)-H(17B) 1.0000 C(18B)-C(19B) 1.524(4) C(18B)-H(18A) 0.9900 C(18B)-H(18B) 0.9900 C(19B)-C(20B) 1.537(4) C(19B)-H(19A) 0.9900 C(19B)-H(19B) 0.9900 C(20B)-C(21B) 1.530(3) O(21B)-C(21B) 1.227(3) O(22B)-C(22B) 1.202(3) C(22B)-O(23B) 1.327(4) O(23B)-C(24D) 1.500(9) O(23B)-C(24B) 1.525(6) C(24B)-C(25B) 1.473(8) C(24B)-H(24A) 0.9900 C(24B)-H(24B) 0.9900 C(25B)-H(25A) 0.9800 C(25B)-H(25B) 0.9800 C(25B)-H(25C) 0.9800 C(24D)-C(25D) 1.508(13) C(24D)-H(24C) 0.9900 C(24D)-H(24D) 0.9900 C(25D)-H(25D) 0.9800 C(25D)-H(25E) 0.9800

233

C(25D)-H(25F) 0.9800 C(26B)-C(31B) 1.390(4) C(26B)-C(27B) 1.396(4) C(27B)-C(28B) 1.385(5) C(27B)-H(27B) 0.9500 C(28B)-C(29B) 1.386(5) C(28B)-H(28B) 0.9500 C(29B)-C(30B) 1.377(5) C(29B)-H(29B) 0.9500 C(30B)-C(31B) 1.386(4) C(30B)-H(30B) 0.9500 C(31B)-H(31B) 0.9500 S(1A)-O(1A) 1.439(2) S(1A)-O(2A) 1.442(2) S(1A)-C(26A) 1.764(3) S(1A)-C(20A) 1.856(3) N(1A)-C(13A) 1.372(4) N(1A)-C(2A) 1.375(4) N(1A)-H(1A) 0.8800 C(2A)-C(7A) 1.372(4) C(2A)-C(3A) 1.454(4) C(3A)-C(14A) 1.342(4) C(3A)-N(4A) 1.422(3) N(4A)-C(21A) 1.348(3) N(4A)-H(4A) 0.8800 C(7A)-C(8A) 1.432(4) C(7A)-H(7A) 0.9500 C(8A)-C(9A) 1.406(4) C(8A)-C(13A) 1.411(4) C(9A)-C(10A) 1.384(5) C(9A)-H(9A) 0.9500

234

C(10A)-C(11A) 1.407(6) C(10A)-H(10A) 0.9500 C(11A)-C(12A) 1.379(5) C(11A)-H(11A) 0.9500 C(12A)-C(13A) 1.400(4) C(12A)-H(12A) 0.9500 C(14A)-C(15A) 1.501(4) C(14A)-H(14A) 0.9500 C(15A)-C(20A) 1.542(4) C(15A)-C(16A) 1.546(4) C(15A)-H(15A) 1.0000 C(16A)-C(22A) 1.509(4) C(16A)-C(17A) 1.534(4) C(16A)-H(16A) 1.0000 O(17A)-C(17A) 1.421(3) O(17A)-H(17C) 0.8400 C(17A)-C(18A) 1.516(4) C(17A)-H(17A) 1.0000 C(18A)-C(19A) 1.527(4) C(18A)-H(18C) 0.9900 C(18A)-H(18D) 0.9900 C(19A)-C(20A) 1.532(4) C(19A)-H(19C) 0.9900 C(19A)-H(19D) 0.9900 C(20A)-C(21A) 1.531(4) O(21A)-C(21A) 1.227(3) O(22A)-C(22A) 1.205(3) C(22A)-O(23A) 1.336(3) O(23A)-C(24A) 1.456(3) C(24A)-C(25A) 1.500(5) C(24A)-H(24E) 0.9900

235

C(24A)-H(24F) 0.9900 C(25A)-H(25G) 0.9800 C(25A)-H(25H) 0.9800 C(25A)-H(25I) 0.9800 C(26A)-C(27A) 1.386(4) C(26A)-C(31A) 1.391(4) C(27A)-C(28A) 1.381(4) C(27A)-H(27A) 0.9500 C(28A)-C(29A) 1.389(5) C(28A)-H(28A) 0.9500 C(29A)-C(30A) 1.381(4) C(29A)-H(29A) 0.9500 C(30A)-C(31A) 1.387(4) C(30A)-H(30A) 0.9500 C(31A)-H(31A) 0.9500 C(1S)-Cl(1S) 1.751(7) C(1S)-Cl(2S) 1.798(8) C(1S)-H(1S1) 0.9900 C(1S)-H(1S2) 0.9900 C(2S)-Cl(4S) 1.31(2) C(2S)-Cl(3S) 1.948(17) C(2S)-H(2S1) 0.9900 C(2S)-H(2S2) 0.9900 C(2S')-Cl(5S) 1.34(2) C(2S')-Cl(6S) 1.794(15) C(2S')-H(2S3) 0.9900 C(2S')-H(2S4) 0.9900

O(2B)-S(1B)-O(1B) 118.75(12) O(2B)-S(1B)-C(26B) 107.14(13) O(1B)-S(1B)-C(26B) 108.37(13)

236

O(2B)-S(1B)-C(20B) 106.50(12) O(1B)-S(1B)-C(20B) 105.76(12) C(26B)-S(1B)-C(20B) 110.18(12) C(13B)-N(1B)-C(2B) 108.9(2) C(13B)-N(1B)-H(1B) 125.5 C(2B)-N(1B)-H(1B) 125.5 C(7B)-C(2B)-N(1B) 109.3(2) C(7B)-C(2B)-C(3B) 130.3(2) N(1B)-C(2B)-C(3B) 120.3(2) C(14B)-C(3B)-N(4B) 119.8(2) C(14B)-C(3B)-C(2B) 124.0(2) N(4B)-C(3B)-C(2B) 116.2(2) C(21B)-N(4B)-C(3B) 124.8(2) C(21B)-N(4B)-H(4B) 117.6 C(3B)-N(4B)-H(4B) 117.6 C(2B)-C(7B)-C(8B) 107.1(2) C(2B)-C(7B)-H(7B) 126.5 C(8B)-C(7B)-H(7B) 126.5 C(13B)-C(8B)-C(9B) 119.2(2) C(13B)-C(8B)-C(7B) 106.8(2) C(9B)-C(8B)-C(7B) 133.9(3) C(10B)-C(9B)-C(8B) 118.8(3) C(10B)-C(9B)-H(9B) 120.6 C(8B)-C(9B)-H(9B) 120.6 C(9B)-C(10B)-C(11B) 120.9(3) C(9B)-C(10B)-H(10B) 119.5 C(11B)-C(10B)-H(10B) 119.5 C(12B)-C(11B)-C(10B) 121.3(3) C(12B)-C(11B)-H(11B) 119.3 C(10B)-C(11B)-H(11B) 119.3 C(11B)-C(12B)-C(13B) 117.6(3)

237

C(11B)-C(12B)-H(12B) 121.2 C(13B)-C(12B)-H(12B) 121.2 N(1B)-C(13B)-C(12B) 130.0(3) N(1B)-C(13B)-C(8B) 107.9(2) C(12B)-C(13B)-C(8B) 122.1(3) C(3B)-C(14B)-C(15B) 120.2(2) C(3B)-C(14B)-H(14B) 119.9 C(15B)-C(14B)-H(14B) 119.9 C(14B)-C(15B)-C(20B) 110.9(2) C(14B)-C(15B)-C(16B) 109.8(2) C(20B)-C(15B)-C(16B) 109.7(2) C(14B)-C(15B)-H(15B) 108.8 C(20B)-C(15B)-H(15B) 108.8 C(16B)-C(15B)-H(15B) 108.8 C(22B)-C(16B)-C(17B) 110.3(2) C(22B)-C(16B)-C(15B) 112.1(2) C(17B)-C(16B)-C(15B) 109.7(2) C(22B)-C(16B)-H(16B) 108.2 C(17B)-C(16B)-H(16B) 108.2 C(15B)-C(16B)-H(16B) 108.2 C(17B)-O(17B)-H(17D) 109.5 O(17B)-C(17B)-C(18B) 114.3(2) O(17B)-C(17B)-C(16B) 110.8(2) C(18B)-C(17B)-C(16B) 107.8(2) O(17B)-C(17B)-H(17B) 107.9 C(18B)-C(17B)-H(17B) 107.9 C(16B)-C(17B)-H(17B) 107.9 C(17B)-C(18B)-C(19B) 111.6(2) C(17B)-C(18B)-H(18A) 109.3 C(19B)-C(18B)-H(18A) 109.3 C(17B)-C(18B)-H(18B) 109.3

238

C(19B)-C(18B)-H(18B) 109.3 H(18A)-C(18B)-H(18B) 108.0 C(18B)-C(19B)-C(20B) 113.2(2) C(18B)-C(19B)-H(19A) 108.9 C(20B)-C(19B)-H(19A) 108.9 C(18B)-C(19B)-H(19B) 108.9 C(20B)-C(19B)-H(19B) 108.9 H(19A)-C(19B)-H(19B) 107.8 C(21B)-C(20B)-C(19B) 112.9(2) C(21B)-C(20B)-C(15B) 110.8(2) C(19B)-C(20B)-C(15B) 112.1(2) C(21B)-C(20B)-S(1B) 106.21(17) C(19B)-C(20B)-S(1B) 103.51(17) C(15B)-C(20B)-S(1B) 111.03(17) O(21B)-C(21B)-N(4B) 122.8(2) O(21B)-C(21B)-C(20B) 120.4(2) N(4B)-C(21B)-C(20B) 116.7(2) O(22B)-C(22B)-O(23B) 123.6(3) O(22B)-C(22B)-C(16B) 123.6(2) O(23B)-C(22B)-C(16B) 112.8(2) C(22B)-O(23B)-C(24D) 113.4(4) C(22B)-O(23B)-C(24B) 116.3(3) C(25B)-C(24B)-O(23B) 105.6(5) C(25B)-C(24B)-H(24A) 110.6 O(23B)-C(24B)-H(24A) 110.6 C(25B)-C(24B)-H(24B) 110.6 O(23B)-C(24B)-H(24B) 110.6 H(24A)-C(24B)-H(24B) 108.8 C(24B)-C(25B)-H(25A) 109.5 C(24B)-C(25B)-H(25B) 109.5 H(25A)-C(25B)-H(25B) 109.5

239

C(24B)-C(25B)-H(25C) 109.5 H(25A)-C(25B)-H(25C) 109.5 H(25B)-C(25B)-H(25C) 109.5 O(23B)-C(24D)-C(25D) 97.6(7) O(23B)-C(24D)-H(24C) 112.2 C(25D)-C(24D)-H(24C) 112.2 O(23B)-C(24D)-H(24D) 112.2 C(25D)-C(24D)-H(24D) 112.2 H(24C)-C(24D)-H(24D) 109.8 C(24D)-C(25D)-H(25D) 109.5 C(24D)-C(25D)-H(25E) 109.5 H(25D)-C(25D)-H(25E) 109.5 C(24D)-C(25D)-H(25F) 109.5 H(25D)-C(25D)-H(25F) 109.5 H(25E)-C(25D)-H(25F) 109.5 C(31B)-C(26B)-C(27B) 121.6(3) C(31B)-C(26B)-S(1B) 119.8(2) C(27B)-C(26B)-S(1B) 118.5(2) C(28B)-C(27B)-C(26B) 118.4(3) C(28B)-C(27B)-H(27B) 120.8 C(26B)-C(27B)-H(27B) 120.8 C(27B)-C(28B)-C(29B) 120.3(3) C(27B)-C(28B)-H(28B) 119.9 C(29B)-C(28B)-H(28B) 119.9 C(30B)-C(29B)-C(28B) 120.7(3) C(30B)-C(29B)-H(29B) 119.6 C(28B)-C(29B)-H(29B) 119.6 C(29B)-C(30B)-C(31B) 120.3(3) C(29B)-C(30B)-H(30B) 119.9 C(31B)-C(30B)-H(30B) 119.9 C(30B)-C(31B)-C(26B) 118.7(3)

240

C(30B)-C(31B)-H(31B) 120.7 C(26B)-C(31B)-H(31B) 120.7 O(1A)-S(1A)-O(2A) 119.26(13) O(1A)-S(1A)-C(26A) 107.90(13) O(2A)-S(1A)-C(26A) 107.67(13) O(1A)-S(1A)-C(20A) 108.87(12) O(2A)-S(1A)-C(20A) 105.76(12) C(26A)-S(1A)-C(20A) 106.75(12) C(13A)-N(1A)-C(2A) 108.9(2) C(13A)-N(1A)-H(1A) 125.6 C(2A)-N(1A)-H(1A) 125.6 C(7A)-C(2A)-N(1A) 109.6(2) C(7A)-C(2A)-C(3A) 130.0(3) N(1A)-C(2A)-C(3A) 120.4(2) C(14A)-C(3A)-N(4A) 119.0(2) C(14A)-C(3A)-C(2A) 125.6(3) N(4A)-C(3A)-C(2A) 115.2(2) C(21A)-N(4A)-C(3A) 124.1(2) C(21A)-N(4A)-H(4A) 118.0 C(3A)-N(4A)-H(4A) 118.0 C(2A)-C(7A)-C(8A) 106.9(3) C(2A)-C(7A)-H(7A) 126.6 C(8A)-C(7A)-H(7A) 126.6 C(9A)-C(8A)-C(13A) 119.9(3) C(9A)-C(8A)-C(7A) 133.3(3) C(13A)-C(8A)-C(7A) 106.6(3) C(10A)-C(9A)-C(8A) 118.0(3) C(10A)-C(9A)-H(9A) 121.0 C(8A)-C(9A)-H(9A) 121.0 C(9A)-C(10A)-C(11A) 121.1(3) C(9A)-C(10A)-H(10A) 119.5

241

C(11A)-C(10A)-H(10A) 119.5 C(12A)-C(11A)-C(10A) 122.1(3) C(12A)-C(11A)-H(11A) 119.0 C(10A)-C(11A)-H(11A) 119.0 C(11A)-C(12A)-C(13A) 116.9(3) C(11A)-C(12A)-H(12A) 121.6 C(13A)-C(12A)-H(12A) 121.6 N(1A)-C(13A)-C(12A) 130.0(3) N(1A)-C(13A)-C(8A) 108.0(3) C(12A)-C(13A)-C(8A) 122.0(3) C(3A)-C(14A)-C(15A) 119.2(2) C(3A)-C(14A)-H(14A) 120.4 C(15A)-C(14A)-H(14A) 120.4 C(14A)-C(15A)-C(20A) 110.5(2) C(14A)-C(15A)-C(16A) 109.9(2) C(20A)-C(15A)-C(16A) 109.8(2) C(14A)-C(15A)-H(15A) 108.9 C(20A)-C(15A)-H(15A) 108.9 C(16A)-C(15A)-H(15A) 108.9 C(22A)-C(16A)-C(17A) 109.1(2) C(22A)-C(16A)-C(15A) 109.3(2) C(17A)-C(16A)-C(15A) 111.9(2) C(22A)-C(16A)-H(16A) 108.8 C(17A)-C(16A)-H(16A) 108.8 C(15A)-C(16A)-H(16A) 108.8 C(17A)-O(17A)-H(17C) 109.5 O(17A)-C(17A)-C(18A) 111.6(2) O(17A)-C(17A)-C(16A) 110.2(2) C(18A)-C(17A)-C(16A) 109.9(2) O(17A)-C(17A)-H(17A) 108.3 C(18A)-C(17A)-H(17A) 108.3

242

C(16A)-C(17A)-H(17A) 108.3 C(17A)-C(18A)-C(19A) 112.1(2) C(17A)-C(18A)-H(18C) 109.2 C(19A)-C(18A)-H(18C) 109.2 C(17A)-C(18A)-H(18D) 109.2 C(19A)-C(18A)-H(18D) 109.2 H(18C)-C(18A)-H(18D) 107.9 C(18A)-C(19A)-C(20A) 111.8(2) C(18A)-C(19A)-H(19C) 109.3 C(20A)-C(19A)-H(19C) 109.3 C(18A)-C(19A)-H(19D) 109.3 C(20A)-C(19A)-H(19D) 109.3 H(19C)-C(19A)-H(19D) 107.9 C(21A)-C(20A)-C(19A) 112.2(2) C(21A)-C(20A)-C(15A) 110.1(2) C(19A)-C(20A)-C(15A) 111.8(2) C(21A)-C(20A)-S(1A) 106.45(17) C(19A)-C(20A)-S(1A) 108.54(18) C(15A)-C(20A)-S(1A) 107.47(17) O(21A)-C(21A)-N(4A) 122.4(2) O(21A)-C(21A)-C(20A) 121.1(2) N(4A)-C(21A)-C(20A) 116.5(2) O(22A)-C(22A)-O(23A) 123.9(3) O(22A)-C(22A)-C(16A) 124.3(3) O(23A)-C(22A)-C(16A) 111.8(2) C(22A)-O(23A)-C(24A) 115.3(2) O(23A)-C(24A)-C(25A) 107.1(3) O(23A)-C(24A)-H(24E) 110.3 C(25A)-C(24A)-H(24E) 110.3 O(23A)-C(24A)-H(24F) 110.3 C(25A)-C(24A)-H(24F) 110.3

243

H(24E)-C(24A)-H(24F) 108.5 C(24A)-C(25A)-H(25G) 109.5 C(24A)-C(25A)-H(25H) 109.5 H(25G)-C(25A)-H(25H) 109.5 C(24A)-C(25A)-H(25I) 109.5 H(25G)-C(25A)-H(25I) 109.5 H(25H)-C(25A)-H(25I) 109.5 C(27A)-C(26A)-C(31A) 122.0(3) C(27A)-C(26A)-S(1A) 119.5(2) C(31A)-C(26A)-S(1A) 118.5(2) C(28A)-C(27A)-C(26A) 118.6(3) C(28A)-C(27A)-H(27A) 120.7 C(26A)-C(27A)-H(27A) 120.7 C(27A)-C(28A)-C(29A) 120.1(3) C(27A)-C(28A)-H(28A) 119.9 C(29A)-C(28A)-H(28A) 119.9 C(30A)-C(29A)-C(28A) 120.7(3) C(30A)-C(29A)-H(29A) 119.7 C(28A)-C(29A)-H(29A) 119.7 C(29A)-C(30A)-C(31A) 120.0(3) C(29A)-C(30A)-H(30A) 120.0 C(31A)-C(30A)-H(30A) 120.0 C(30A)-C(31A)-C(26A) 118.5(3) C(30A)-C(31A)-H(31A) 120.7 C(26A)-C(31A)-H(31A) 120.7 Cl(1S)-C(1S)-Cl(2S) 112.4(4) Cl(1S)-C(1S)-H(1S1) 109.1 Cl(2S)-C(1S)-H(1S1) 109.1 Cl(1S)-C(1S)-H(1S2) 109.1 Cl(2S)-C(1S)-H(1S2) 109.1 H(1S1)-C(1S)-H(1S2) 107.9

244

Cl(4S)-C(2S)-Cl(3S) 127.3(11) Cl(4S)-C(2S)-H(2S1) 105.5 Cl(3S)-C(2S)-H(2S1) 105.5 Cl(4S)-C(2S)-H(2S2) 105.5 Cl(3S)-C(2S)-H(2S2) 105.5 H(2S1)-C(2S)-H(2S2) 106.1 Cl(5S)-C(2S')-Cl(6S) 128.5(10) Cl(5S)-C(2S')-H(2S3) 105.2 Cl(6S)-C(2S')-H(2S3) 105.2 Cl(5S)-C(2S')-H(2S4) 105.2 Cl(6S)-C(2S')-H(2S4) 105.2 H(2S3)-C(2S')-H(2S4) 105.9

Symmetry transformations used to generate equivalent atoms:

245

Table A.32: Anisotropic displacement parameters (Å2 x 103) for 215. The anisotropic displacement factor exponent takes the form: -2 Π2 [ h2 a*2 U11 + ... + 2 h k a* b* U12 ]

U11 U22 U33 U23 U13 U12

S(1B) 16(1) 24(1) 21(1) 2(1) -1(1) -2(1) N(1B) 16(1) 27(1) 16(1) 3(1) -1(1) 2(1) O(1B) 16(1) 30(1) 30(1) -1(1) -4(1) 1(1) C(2B) 17(1) 22(1) 15(1) 2(1) -1(1) -1(1) O(2B) 30(1) 32(1) 25(1) 6(1) 2(1) -7(1) C(3B) 16(1) 23(1) 16(1) 3(1) -2(1) -4(1) N(4B) 14(1) 23(1) 16(1) 3(1) -2(1) 2(1) C(7B) 20(1) 25(1) 17(1) 3(1) -2(1) 2(1) C(8B) 19(1) 21(1) 18(1) 2(1) 0(1) 0(1) C(9B) 24(1) 28(1) 24(1) 2(1) 3(1) 4(1) C(10B) 28(1) 29(1) 22(1) -1(1) 6(1) 2(1) C(11B) 31(2) 30(2) 16(1) -1(1) 1(1) -5(1) C(12B) 23(1) 33(2) 18(1) 3(1) -4(1) -3(1) C(13B) 18(1) 23(1) 17(1) 1(1) 0(1) -4(1) C(14B) 16(1) 22(1) 15(1) 3(1) -2(1) -1(1) C(15B) 16(1) 21(1) 17(1) 1(1) -3(1) 1(1) C(16B) 20(1) 23(1) 23(1) 1(1) -6(1) 2(1) O(17B) 43(1) 32(1) 34(1) -9(1) -10(1) 0(1) C(17B) 34(2) 28(2) 23(1) -6(1) -2(1) 0(1) C(18B) 33(2) 32(2) 20(1) -4(1) -4(1) 3(1) C(19B) 22(1) 29(1) 16(1) 2(1) 0(1) 3(1) C(20B) 16(1) 23(1) 15(1) 1(1) -1(1) 0(1) O(21B) 23(1) 26(1) 16(1) 5(1) -2(1) 5(1) C(21B) 16(1) 18(1) 18(1) 0(1) -2(1) -2(1)

246

O(22B) 22(1) 30(1) 28(1) 1(1) -4(1) -5(1) C(22B) 20(1) 23(1) 29(2) -2(1) -6(1) 0(1) O(23B) 27(1) 41(1) 88(2) 40(1) -26(1) -11(1) C(24B) 29(2) 29(3) 35(4) 11(2) -11(3) -4(2) C(25B) 39(3) 31(3) 52(3) 16(3) 3(3) 3(2) C(24D) 29(2) 29(3) 35(4) 11(2) -11(3) -4(2) C(25D) 61(7) 61(7) 41(6) 26(5) -21(5) -23(5) C(26B) 17(1) 25(1) 29(1) -1(1) -4(1) -4(1) C(27B) 23(1) 27(2) 36(2) -1(1) -7(1) -2(1) C(28B) 27(2) 30(2) 55(2) -8(2) -7(1) 3(1) C(29B) 22(1) 40(2) 48(2) -18(2) 1(1) -1(1) C(30B) 22(1) 45(2) 30(2) -10(1) 0(1) -6(1) C(31B) 17(1) 32(2) 26(1) -2(1) -4(1) -6(1) S(1A) 22(1) 22(1) 22(1) 1(1) -3(1) -2(1) O(1A) 25(1) 36(1) 27(1) -1(1) -2(1) -8(1) N(1A) 22(1) 28(1) 27(1) 9(1) 4(1) 4(1) O(2A) 36(1) 21(1) 30(1) 1(1) -7(1) 1(1) C(2A) 23(1) 22(1) 22(1) 2(1) 3(1) 0(1) C(3A) 24(1) 24(1) 22(1) 4(1) 1(1) 0(1) N(4A) 18(1) 21(1) 22(1) 4(1) 2(1) 4(1) C(7A) 27(1) 27(1) 31(2) 7(1) 8(1) 7(1) C(8A) 30(2) 28(2) 36(2) 4(1) 11(1) 5(1) C(9A) 32(2) 41(2) 50(2) 8(2) 16(2) 9(1) C(10A) 38(2) 45(2) 76(3) 14(2) 30(2) 9(2) C(11A) 49(2) 39(2) 59(2) 15(2) 31(2) 5(2) C(12A) 40(2) 33(2) 42(2) 10(1) 15(2) 5(1) C(13A) 30(2) 28(2) 26(2) 2(1) 10(1) 2(1) C(14A) 20(1) 20(1) 18(1) 4(1) -1(1) 0(1) C(15A) 18(1) 20(1) 19(1) 2(1) -2(1) 2(1) C(16A) 17(1) 17(1) 21(1) 2(1) -1(1) 3(1) O(17A) 20(1) 20(1) 26(1) -3(1) -2(1) -2(1)

247

C(17A) 16(1) 19(1) 21(1) 0(1) 0(1) 0(1) C(18A) 21(1) 21(1) 21(1) 2(1) 2(1) 1(1) C(19A) 19(1) 22(1) 18(1) 1(1) 0(1) 2(1) C(20A) 17(1) 20(1) 18(1) 1(1) -1(1) 1(1) O(21A) 22(1) 28(1) 20(1) 7(1) -1(1) 5(1) C(21A) 16(1) 21(1) 19(1) 2(1) -2(1) -1(1) O(22A) 41(1) 23(1) 39(1) 6(1) -18(1) 4(1) C(22A) 19(1) 22(1) 24(1) 2(1) -3(1) 0(1) O(23A) 28(1) 31(1) 18(1) 0(1) -4(1) 3(1) C(24A) 35(2) 50(2) 19(1) 5(1) -8(1) -6(1) C(25A) 34(2) 71(3) 34(2) -18(2) -4(1) 1(2) C(26A) 24(1) 22(1) 23(1) -1(1) -4(1) -2(1) C(27A) 27(1) 27(1) 30(2) -5(1) -4(1) 5(1) C(28A) 32(2) 36(2) 28(2) -11(1) 3(1) 4(1) C(29A) 40(2) 30(2) 21(1) -4(1) -2(1) -1(1) C(30A) 32(2) 26(1) 27(2) -2(1) -8(1) 2(1) C(31A) 23(1) 25(1) 27(2) -2(1) -2(1) 1(1) C(1S) 50(3) 65(4) 71(4) 9(3) 20(3) 11(3) Cl(1S) 54(1) 71(1) 62(1) -3(1) 14(1) -2(1) Cl(2S) 66(1) 101(2) 72(1) -9(1) 14(1) -14(1) O(1W) 105(7) 88(6) 102(7) 35(6) 31(6) 10(6) C(2S) 81(7) 105(8) 84(8) -38(7) 45(6) -12(7) Cl(3S) 96(3) 61(2) 79(3) -27(2) 36(2) -19(2) Cl(4S) 70(3) 71(2) 60(2) -8(2) 17(2) -12(2) C(2S') 82(7) 60(7) 99(8) -29(7) 74(6) -44(6) Cl(5S) 147(7) 130(5) 147(7) -1(5) -51(5) 0(5) Cl(6S) 106(6) 165(8) 162(6) -13(5) -21(4) -80(6) O(3W) 64(5) 67(5) 109(7) 36(5) 2(5) 17(4)

248

Table A.33: Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2 x 103) for 215.

x y z U(eq)

H(1B) 6901 2401 9065 23 H(4B) 6462 2738 5975 21 H(7B) 6191 2799 7598 25 H(9B) 5870 2923 9739 30 H(10B) 5926 2883 11691 32 H(11B) 6363 2661 12476 31 H(12B) 6750 2474 11327 29 H(14B) 7065 2216 7486 22 H(15B) 7327 2161 5783 22 H(16B) 6716 2022 5039 27 H(17D) 6835 1622 3073 55 H(17B) 7294 1829 4149 34 H(18A) 6812 2171 3129 34 H(18B) 7117 2073 2481 34 H(19A) 7145 2585 3156 27 H(19B) 7414 2379 3649 27 H(24A) 7324 1471 8052 37 H(24B) 6975 1390 7777 37 H(25A) 7281 958 7554 61 H(25B) 7481 1135 6634 61 H(25C) 7133 1053 6370 61 H(24C) 7437 1240 6798 37 H(24D) 7086 1168 6474 37 H(25D) 7149 1167 8498 81 H(25E) 6922 1433 8115 81

249

H(25F) 7268 1511 8430 81 H(27B) 7060 3350 5072 35 H(28B) 6859 3697 6377 45 H(29B) 6895 3600 8307 44 H(30B) 7131 3162 8962 39 H(31B) 7336 2811 7682 30 H(1A) 6294 3884 1730 31 H(4A) 6358 3102 4051 24 H(7A) 6802 3251 3222 34 H(9A) 7369 3423 2051 49 H(10A) 7557 3763 699 64 H(11A) 7236 4114 -181 59 H(12A) 6722 4151 307 46 H(14A) 5901 3802 2829 23 H(15A) 5528 3723 4204 23 H(16A) 5627 3106 3424 22 H(17C) 5184 2796 3599 33 H(17A) 5084 3346 4459 23 H(18C) 5486 2895 5363 25 H(18D) 5183 3015 5971 25 H(19C) 5627 3250 6744 24 H(19D) 5398 3498 6233 24 H(24E) 5299 3370 183 42 H(24F) 4982 3316 832 42 H(25G) 5342 2841 -129 69 H(25H) 5031 2964 -662 69 H(25I) 5027 2787 520 69 H(27A) 5554 3970 7657 34 H(28A) 5545 3901 9618 38 H(29A) 5928 3621 10501 36 H(30A) 6326 3415 9456 34

250

H(31A) 6339 3480 7488 30 H(1S1) 6860 1055 11575 74 H(1S2) 7162 875 11214 74 H(2S1) 8427 4458 851 108 H(2S2) 8478 4243 1906 108 H(2S3) 8465 4424 973 96 H(2S4) 8272 4713 631 96

251

Table A.34: Torsion angles [˚] for 215.

C(13B)-N(1B)-C(2B)-C(7B) -1.2(3) C(13B)-N(1B)-C(2B)-C(3B) -178.2(2) C(7B)-C(2B)-C(3B)-C(14B) -164.4(3) N(1B)-C(2B)-C(3B)-C(14B) 11.8(4) C(7B)-C(2B)-C(3B)-N(4B) 16.6(4) N(1B)-C(2B)-C(3B)-N(4B) -167.2(2) C(14B)-C(3B)-N(4B)-C(21B) -13.7(4) C(2B)-C(3B)-N(4B)-C(21B) 165.4(2) N(1B)-C(2B)-C(7B)-C(8B) 0.0(3) C(3B)-C(2B)-C(7B)-C(8B) 176.5(3) C(2B)-C(7B)-C(8B)-C(13B) 1.2(3) C(2B)-C(7B)-C(8B)-C(9B) -179.3(3) C(13B)-C(8B)-C(9B)-C(10B) 1.1(4) C(7B)-C(8B)-C(9B)-C(10B) -178.3(3) C(8B)-C(9B)-C(10B)-C(11B) -0.4(4) C(9B)-C(10B)-C(11B)-C(12B) -0.3(5) C(10B)-C(11B)-C(12B)-C(13B) 0.3(4) C(2B)-N(1B)-C(13B)-C(12B) -178.4(3) C(2B)-N(1B)-C(13B)-C(8B) 2.0(3) C(11B)-C(12B)-C(13B)-N(1B) -179.1(3) C(11B)-C(12B)-C(13B)-C(8B) 0.4(4) C(9B)-C(8B)-C(13B)-N(1B) 178.5(2) C(7B)-C(8B)-C(13B)-N(1B) -2.0(3) C(9B)-C(8B)-C(13B)-C(12B) -1.1(4) C(7B)-C(8B)-C(13B)-C(12B) 178.4(3) N(4B)-C(3B)-C(14B)-C(15B) -4.3(4) C(2B)-C(3B)-C(14B)-C(15B) 176.7(2) C(3B)-C(14B)-C(15B)-C(20B) 34.2(3) C(3B)-C(14B)-C(15B)-C(16B) -87.1(3)

252

C(14B)-C(15B)-C(16B)-C(22B) -54.8(3) C(20B)-C(15B)-C(16B)-C(22B) -176.9(2) C(14B)-C(15B)-C(16B)-C(17B) -177.7(2) C(20B)-C(15B)-C(16B)-C(17B) 60.2(3) C(22B)-C(16B)-C(17B)-O(17B) 46.3(3) C(15B)-C(16B)-C(17B)-O(17B) 170.2(2) C(22B)-C(16B)-C(17B)-C(18B) 172.0(2) C(15B)-C(16B)-C(17B)-C(18B) -64.1(3) O(17B)-C(17B)-C(18B)-C(19B) -176.2(2) C(16B)-C(17B)-C(18B)-C(19B) 60.1(3) C(17B)-C(18B)-C(19B)-C(20B) -53.5(3) C(18B)-C(19B)-C(20B)-C(21B) -77.0(3) C(18B)-C(19B)-C(20B)-C(15B) 48.9(3) C(18B)-C(19B)-C(20B)-S(1B) 168.58(19) C(14B)-C(15B)-C(20B)-C(21B) -46.2(3) C(16B)-C(15B)-C(20B)-C(21B) 75.2(3) C(14B)-C(15B)-C(20B)-C(19B) -173.3(2) C(16B)-C(15B)-C(20B)-C(19B) -51.9(3) C(14B)-C(15B)-C(20B)-S(1B) 71.5(2) C(16B)-C(15B)-C(20B)-S(1B) -167.08(17) O(2B)-S(1B)-C(20B)-C(21B) -84.00(19) O(1B)-S(1B)-C(20B)-C(21B) 148.78(17) C(26B)-S(1B)-C(20B)-C(21B) 31.9(2) O(2B)-S(1B)-C(20B)-C(19B) 35.1(2) O(1B)-S(1B)-C(20B)-C(19B) -92.14(18) C(26B)-S(1B)-C(20B)-C(19B) 150.95(17) O(2B)-S(1B)-C(20B)-C(15B) 155.51(18) O(1B)-S(1B)-C(20B)-C(15B) 28.3(2) C(26B)-S(1B)-C(20B)-C(15B) -88.6(2) C(3B)-N(4B)-C(21B)-O(21B) -179.8(2) C(3B)-N(4B)-C(21B)-C(20B) -2.3(4)

253

C(19B)-C(20B)-C(21B)-O(21B) -23.5(3) C(15B)-C(20B)-C(21B)-O(21B) -150.1(2) S(1B)-C(20B)-C(21B)-O(21B) 89.3(3) C(19B)-C(20B)-C(21B)-N(4B) 158.9(2) C(15B)-C(20B)-C(21B)-N(4B) 32.3(3) S(1B)-C(20B)-C(21B)-N(4B) -88.4(2) C(17B)-C(16B)-C(22B)-O(22B) -98.5(3) C(15B)-C(16B)-C(22B)-O(22B) 139.0(3) C(17B)-C(16B)-C(22B)-O(23B) 81.5(3) C(15B)-C(16B)-C(22B)-O(23B) -41.0(3) O(22B)-C(22B)-O(23B)-C(24D) 23.2(6) C(16B)-C(22B)-O(23B)-C(24D) -156.9(5) O(22B)-C(22B)-O(23B)-C(24B) -11.8(5) C(16B)-C(22B)-O(23B)-C(24B) 168.2(4) C(22B)-O(23B)-C(24B)-C(25B) 96.3(5) C(24D)-O(23B)-C(24B)-C(25B) 3.8(7) C(22B)-O(23B)-C(24D)-C(25D) -98.0(7) C(24B)-O(23B)-C(24D)-C(25D) 4.7(6) O(2B)-S(1B)-C(26B)-C(31B) -154.4(2) O(1B)-S(1B)-C(26B)-C(31B) -25.2(3) C(20B)-S(1B)-C(26B)-C(31B) 90.1(2) O(2B)-S(1B)-C(26B)-C(27B) 23.6(3) O(1B)-S(1B)-C(26B)-C(27B) 152.8(2) C(20B)-S(1B)-C(26B)-C(27B) -91.9(2) C(31B)-C(26B)-C(27B)-C(28B) 0.1(4) S(1B)-C(26B)-C(27B)-C(28B) -177.9(2) C(26B)-C(27B)-C(28B)-C(29B) -0.1(5) C(27B)-C(28B)-C(29B)-C(30B) 0.1(5) C(28B)-C(29B)-C(30B)-C(31B) -0.1(5) C(29B)-C(30B)-C(31B)-C(26B) 0.0(4) C(27B)-C(26B)-C(31B)-C(30B) 0.0(4)

254

S(1B)-C(26B)-C(31B)-C(30B) 177.9(2) C(13A)-N(1A)-C(2A)-C(7A) -1.2(3) C(13A)-N(1A)-C(2A)-C(3A) 176.9(3) C(7A)-C(2A)-C(3A)-C(14A) 174.0(3) N(1A)-C(2A)-C(3A)-C(14A) -3.6(5) C(7A)-C(2A)-C(3A)-N(4A) -1.8(5) N(1A)-C(2A)-C(3A)-N(4A) -179.4(2) C(14A)-C(3A)-N(4A)-C(21A) -20.9(4) C(2A)-C(3A)-N(4A)-C(21A) 155.2(3) N(1A)-C(2A)-C(7A)-C(8A) 1.3(4) C(3A)-C(2A)-C(7A)-C(8A) -176.6(3) C(2A)-C(7A)-C(8A)-C(9A) 174.1(4) C(2A)-C(7A)-C(8A)-C(13A) -0.8(4) C(13A)-C(8A)-C(9A)-C(10A) -2.4(6) C(7A)-C(8A)-C(9A)-C(10A) -176.8(4) C(8A)-C(9A)-C(10A)-C(11A) 0.7(7) C(9A)-C(10A)-C(11A)-C(12A) 1.5(7) C(10A)-C(11A)-C(12A)-C(13A) -1.8(6) C(2A)-N(1A)-C(13A)-C(12A) -176.9(3) C(2A)-N(1A)-C(13A)-C(8A) 0.6(4) C(11A)-C(12A)-C(13A)-N(1A) 177.2(4) C(11A)-C(12A)-C(13A)-C(8A) -0.1(5) C(9A)-C(8A)-C(13A)-N(1A) -175.6(3) C(7A)-C(8A)-C(13A)-N(1A) 0.1(4) C(9A)-C(8A)-C(13A)-C(12A) 2.2(5) C(7A)-C(8A)-C(13A)-C(12A) 177.9(3) N(4A)-C(3A)-C(14A)-C(15A) -2.8(4) C(2A)-C(3A)-C(14A)-C(15A) -178.5(3) C(3A)-C(14A)-C(15A)-C(20A) 37.8(3) C(3A)-C(14A)-C(15A)-C(16A) -83.5(3) C(14A)-C(15A)-C(16A)-C(22A) -60.9(3)

255

C(20A)-C(15A)-C(16A)-C(22A) 177.4(2) C(14A)-C(15A)-C(16A)-C(17A) 178.2(2) C(20A)-C(15A)-C(16A)-C(17A) 56.4(3) C(22A)-C(16A)-C(17A)-O(17A) 58.0(3) C(15A)-C(16A)-C(17A)-O(17A) 179.0(2) C(22A)-C(16A)-C(17A)-C(18A) -178.6(2) C(15A)-C(16A)-C(17A)-C(18A) -57.5(3) O(17A)-C(17A)-C(18A)-C(19A) 178.7(2) C(16A)-C(17A)-C(18A)-C(19A) 56.2(3) C(17A)-C(18A)-C(19A)-C(20A) -54.9(3) C(18A)-C(19A)-C(20A)-C(21A) -70.6(3) C(18A)-C(19A)-C(20A)-C(15A) 53.7(3) C(18A)-C(19A)-C(20A)-S(1A) 172.01(17) C(14A)-C(15A)-C(20A)-C(21A) -50.0(3) C(16A)-C(15A)-C(20A)-C(21A) 71.4(3) C(14A)-C(15A)-C(20A)-C(19A) -175.4(2) C(16A)-C(15A)-C(20A)-C(19A) -54.0(3) C(14A)-C(15A)-C(20A)-S(1A) 65.6(2) C(16A)-C(15A)-C(20A)-S(1A) -173.01(17) O(1A)-S(1A)-C(20A)-C(21A) 28.5(2) O(2A)-S(1A)-C(20A)-C(21A) 157.79(17) C(26A)-S(1A)-C(20A)-C(21A) -87.73(19) O(1A)-S(1A)-C(20A)-C(19A) 149.46(18) O(2A)-S(1A)-C(20A)-C(19A) -81.26(19) C(26A)-S(1A)-C(20A)-C(19A) 33.2(2) O(1A)-S(1A)-C(20A)-C(15A) -89.48(19) O(2A)-S(1A)-C(20A)-C(15A) 39.8(2) C(26A)-S(1A)-C(20A)-C(15A) 154.28(17) C(3A)-N(4A)-C(21A)-O(21A) -175.7(3) C(3A)-N(4A)-C(21A)-C(20A) 4.7(4) C(19A)-C(20A)-C(21A)-O(21A) -23.7(3)

256

C(15A)-C(20A)-C(21A)-O(21A) -148.9(2) S(1A)-C(20A)-C(21A)-O(21A) 94.9(3) C(19A)-C(20A)-C(21A)-N(4A) 155.9(2) C(15A)-C(20A)-C(21A)-N(4A) 30.7(3) S(1A)-C(20A)-C(21A)-N(4A) -85.5(2) C(17A)-C(16A)-C(22A)-O(22A) 85.6(3) C(15A)-C(16A)-C(22A)-O(22A) -37.0(4) C(17A)-C(16A)-C(22A)-O(23A) -92.2(3) C(15A)-C(16A)-C(22A)-O(23A) 145.2(2) O(22A)-C(22A)-O(23A)-C(24A) -6.8(4) C(16A)-C(22A)-O(23A)-C(24A) 171.0(2) C(22A)-O(23A)-C(24A)-C(25A) -167.5(3) O(1A)-S(1A)-C(26A)-C(27A) 145.9(2) O(2A)-S(1A)-C(26A)-C(27A) 16.0(3) C(20A)-S(1A)-C(26A)-C(27A) -97.2(2) O(1A)-S(1A)-C(26A)-C(31A) -31.7(3) O(2A)-S(1A)-C(26A)-C(31A) -161.6(2) C(20A)-S(1A)-C(26A)-C(31A) 85.2(2) C(31A)-C(26A)-C(27A)-C(28A) -0.7(4) S(1A)-C(26A)-C(27A)-C(28A) -178.2(2) C(26A)-C(27A)-C(28A)-C(29A) 0.1(5) C(27A)-C(28A)-C(29A)-C(30A) 0.7(5) C(28A)-C(29A)-C(30A)-C(31A) -0.8(5) C(29A)-C(30A)-C(31A)-C(26A) 0.2(4) C(27A)-C(26A)-C(31A)-C(30A) 0.5(4) S(1A)-C(26A)-C(31A)-C(30A) 178.1(2)

Symmetry transformations used to generate equivalent atoms:

257

Table A.35: Hydrogen bonds for 215 [Å and ˚].

D-H...A d(D-H) d(H...A) d(D...A) <(DHA)

O(17B)-H(17D)...O(2A)#1 0.84 2.03 2.865(3) 173.0

O(17A)-H(17C)...O(17A)#1 0.84 1.92 2.720(3) 158.6

Symmetry transformations used to generate equivalent atoms: #1 y+1/4,-x+3/4,-z+3/4

258

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Vita

The author, Raghu Ram Chamala, was born on May 14, 1975 in Hyderabad, Andhra Pradesh, India. Raghu was raised in Hyderabad, where he attended Mani Jeremiah High School in S. R. Nagar, and Raja Jitender Public School in Begumpet. He graduated with Secondary School Certificate in 1991. He completed his Intermediate education in 1993 from Andhra Vidyalaya College of Arts, Science, and Commerce (popularly known as A. V. College), an affiliated college to Osmania University, located in Gagan Mahal. The author continued his education in A. V. College, and in 1996, he earned a Bachelor‟s degree (B.Sc.) in Botany, Zoology, and Chemistry. After obtaining his Bachelor‟s degree, he was trained, and also employed as a healthcare technician at Hariprasad Memorial Hospital, Pathergatti, Hyderabad. In 1998, after passing the national entrance examination conducted by University of Pune and National Chemical Laboratory, he went to University of Pune in Maharashtra, India, to pursue Master of Science (M.Sc.) in organic chemistry, where he worked with Professors Dilip D. Dhavale and Shriniwas L. Kelkar on “Monobromination of Phenols” as a part of M.Sc. degree. During this time he was the recipient of Krishna Iyer Doraiswami Scholarship. In 2001, Raghu moved to University of Kentucky, United States, and joined Professor Robert B. Grossman‟s research group in 2002 to pursue his doctoral studies. In 2010, he earned his Ph.D. in chemistry for investigations involving the total synthesis of the yohimbine alkaloids. During his time at the University of Kentucky he was the recipient of the Research Challenge Trust Fund Fellowship for three consecutive academic years (2004- 2007).

PUBLICATIONS

Raghu Ram Chamala, Roxana Ciochina, Raphael A. Finkel, Robert B. Grossman, Saravana Kannan, and Prasanth Ramachandran. "EPOCH: An Organic Chemistry Homework Program that Offers Response-Specific Feedback." J. Chem. Ed. 2006, 83(1), 164-169.

Raghu Ram Chamala, Vijaya N. Desai, Jos P. Varghese, Robert B. Grossman “Towards the Total Synthesis of α-Yohimbine by Double Annulation”, manuscript in preparation.

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