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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, raghuchamala@yahoo.com
Recommended Citation
Chamala, Raghu Ram, "STUDIES TOWARD THE TOTAL SYNTHESIS OF (±)-α-YOHIMBINE BY DOUBLE ANNULATION"
(2010). University of Kentucky Doctoral Dissertations. Paper 78.
http://uknowledge.uky.edu/gradschool_diss/78
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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
By
Raghu Ram Chamala
Lexington, KY
Director: Dr. R. B. Grossman, Professor of Chemistry
Lexington, KY
2010
Copyright © Raghu Ram Chamala 2010
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
By
Raghu Ram Chamala
Lexington, KY
Director: Dr. R. B. Grossman, Professor of Chemistry
Lexington, KY
2010
Copyright © Raghu Ram Chamala 2010
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 everentertaining 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 fatherin-law, Smt. Saraswathi and Shri. Janardhan Reddy, for their unwavering support, and for
embellishing me with Jayashree, their most precious jewel.
iv
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.
v
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
viii
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
Figure 3.12: 1H NMR (400 MHz, CDCl3) of compound 186 .......................................... 91
Figure 3.13:
13
C NMR (400 MHz, CDCl3) of compound 186 ......................................... 92
Figure 3.14: Infrared spectrum (neat) of compound 186 ................................................. 93
Figure 3.15: 1H NMR (400 MHz, CDCl3) of compound 187 .......................................... 95
Figure 3.16: 1H NMR (400 MHz, CDCl3) of compound 188 .......................................... 97
Figure 3.17:
13
C NMR (400 MHz, CDCl3) of compound 188 ......................................... 98
Figure 3.18: Infrared spectrum (thin film/KBr) of compound 188 .................................. 99
Figure 3.19: 1H NMR (400 MHz, CDCl3) of compound 189 ........................................ 101
Figure 3.20:
13
C NMR (400 MHz, CDCl3) of compound 189 ....................................... 102
Figure 3.21: Infrared spectrum (neat) of compound 189 ............................................... 103
Figure 3.22: 1H NMR (400 MHz, CDCl3) of compound 190 ........................................ 105
Figure 3.23:
13
C NMR (400 MHz, CDCl3) of compound 190 ....................................... 106
Figure 3.24: Infrared spectrum (neat) of compound 190 ............................................... 107
Figure 3.25: 1H NMR (400 MHz, CDCl3) of compound 196 ........................................ 109
Figure 3.26:
13
C NMR (400 MHz, CDCl3) of compound 196 ....................................... 110
ix
Figure 3.27: Infrared spectrum (neat) of compound 196 ............................................... 111
Figure 3.28: 1H NMR (400 MHz, CDCl3) of compound 197 ........................................ 113
Figure 3.29:
13
C NMR (400 MHz, CDCl3) of compound 197 ....................................... 114
Figure 3.30: Infrared spectrum (neat) of compound 197 ............................................... 115
Figure 3.31: 1H NMR (400 MHz, CDCl3) of compound 198 ........................................ 117
Figure 3.32:
13
C NMR (400 MHz, CDCl3) of compound 198 ....................................... 118
Figure 3.33: 1H NMR (400 MHz, CDCl3) of compound 199 ........................................ 120
Figure 3.34:
13
C NMR (400 MHz, CDCl3) of compound 199 ....................................... 121
Figure 3.35: Infrared Spectrum (neat) of compound 199 .............................................. 122
Figure 3.36: 1H NMR (400 MHz, CDCl3) of compound 203 ........................................ 124
Figure 3.37:
13
C NMR (400 MHz, CDCl3) of compound 203 ....................................... 125
Figure 3.38: Infrared spectrum (neat) of compound 203 ............................................... 126
Figure 3.39: 1H NMR (400 MHz, CDCl3) of compound 204a,b ................................... 128
Figure 3.40: 1H NMR (400 MHz, CDCl3) of compound 205 ........................................ 130
Figure 3.41: 1H NMR (400 MHz, CDCl3) of compound 207 ........................................ 132
Figure 3.42:
13
C NMR (400 MHz, CDCl3) of compound 207 ....................................... 133
Figure 3.43: 1H NMR (400 MHz, CDCl3) of compound 208 ........................................ 135
Figure 3.44:
13
C NMR (400 MHz, CDCl3) of compound 208 ....................................... 136
Figure 3.45: Infrared spectrum (neat) of compound of 208........................................... 137
Figure 3.46: 1H NMR (400 MHz, CDCl3) of compound 209 ........................................ 139
Figure 3.47:
13
C NMR (400 MHz, CDCl3) of compound 209 ....................................... 140
Figure 3.48: Infrared spectrum (KBr) of compound 209 ............................................... 141
Figure 3.49: 1H NMR (400 MHz, DMSO-d6) of compound 214 .................................. 143
Figure 3.50:
13
C NMR (400 MHz, DMSO-d6) of compound 214 ................................. 144
Figure 3.51: Infrared spectrum (KBr) of compound 214 ............................................... 145
x
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
xi
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 (11971248) 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.
1
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
Type
Alkaloid
MP ( oC)
Synonyms
[α]D
(pyridine)
Occurrencea
Quebrachine
Yohimbine
Aphrodine
235-236
Corynine
+106
1-12
-85
5,13
Hydroaergotocin
Normal
Pseudo
Corynanthine
Rauhimbine
β-Yohimbine
Amsonine
225-226
236-237
Pseudo-
268
yohimbine
2
-54
+27
1,3,5,7,8,14,
15
1,5
Table 1.1: Sources of yohimbine and stereoisomers, continued
epi-3-
252-256
-13
203-204
-83
Synthetic
135-140
-84
1,5
Corynanthine
epi-3-βYohimbine
Alloyohimbine
Synthetic
Corynantheidine
Allo
α-Yohimbine
Rauwolscine
Isoyohimbine
235-236
-18
1,5,6,13,
16
Mesoyohimbine
epi-3-
224
+151
Synthetic
Alloyohimbine
Epiallo
epi-3-αYohimbine
a
epi-3Rawolscine
225
-104
Isorauhimbine
Numbers 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.
3
5
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
Yohimbine
Witkop,32 Cookson,33
Chatterjee,
34
Van
Tamelen
Year of Publication
1949, 1953, 1954, 1956
35
Corynanthine
Janot36
1952
β-Yohimbine
Le Hir,37-38 Godtfredsen,39
1953, 1957,1958, 1961, 1965
Janot,40 Albright41-42
Pseudoyohimbine
Janot,36 Wenkert43
4
1952, 1958
Table 1.2: Determination of relative configuration of yohimbine and stereoisomers,
continued
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
Alloyohimbine
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
5
Figure 1.2. General structure of yohimbine and stereoisomers
Table 1.3: Classification and relative configuration of yohimbine and stereoisomers
Series
Normal
Pseudo
C(3)-H C(20)-H C(16)-H C(17)-H
α
β
β
β
Allo
α
α
Epiallo
β
α
Alkaloid
β
β
Yohimbine (1)
α
β
Corynanthine (2)
β
α
β-Yohimbine (3)
β
β
Pseudoyohimbine (4)
α
β
3-epi-Corynanthine (5)
β
α
3-epi-β-Yohimbine (6)
α
β
α-Yohimbine (7)
β
β
Alloyohimbine (8)
α
β
3-epi-α-Yohimbine (9)
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 αadrenergic 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
6
radiolabeled yohimbine and α-yohimbine.60-64
Yohimbine has high affinity for α2-
adrenergic receptor, moderate affinity for the α1-adrenergic, 5-HT1A, 5-HT1B, 5-HT1D, 5HT1F, 5-HT2B, and D2 receptors, and weak affinity for the 5-HT1E, 5-HT2A, 5-HT5A, 5HT7, and D3 receptors.65 It acts as an antagonist at α1-adrenergic, α2-adrenergic, 5-HT1B,
5-HT1D, 5-HT2A, 5-HT2B, and D2, and as a partial agonist at 5-HT1A.65-68 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 α2adrenergic 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.7980
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 posttraumatic 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 norepinephrineinduced contraction in corpus cavernosum.86 Corynanthine acts as an antagonist at both
7
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-(5phospho-β-D-ribosyl)-anthranilate 11. The intermediate 12, formed after the ribose ringopening, 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
9
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-Derythritol 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.
10
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
11
Scheme 1.6: Probable biosynthetic pathway for the formation of yohimbine
alkaloids
Copyright © Raghu Ram Chamala 2010
12
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 secoderivative 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.
14
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
15
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
16
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
17
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
18
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
19
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
20
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
21
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 γcarbon 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 Ntryptophylation of the resultant 3-pyridineacrylic acid.
22
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
23
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
24
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.
25
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
26
The condensation of nicotinaldehyde with methyl methoxyacetate followed by Nalkylation with tryptophyl bromide yielded pyridinium salt 62. Treatment of the latter
with
dimethyl
tetracycle 63.
sodiomalonate
followed
by
acid-induced
cyclization
afforded
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
27
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 Nalkylation 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 Omethylated 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
29
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
30
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, αyohimbine 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
31
32
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 3oxo-4-pentenoate 75.
Scheme 2.18: Stork’s Retrosynthesis
The isoquinolone 98 was obtained in good yield from the condensation of Nmethyl-4-piperidone and methyl 3-oxo-4-pentenoate (Scheme 2.19). Dissolving metal
33
reduction of isoquinolone 98 afforded trans-hydroisoquinolone ester 99. The transhydroisoquinolone 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.
34
Scheme 2.19: Stork’s Synthesis
35
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 αyohimbine 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
36
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
37
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
38
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
39
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
40
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.
41
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
42
43
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
44
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 αcyano ketone 146, which on hydride reduction afforded epimeric β-cyano alcohols 147a-
45
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
46
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 synthesis 129 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 (-)-Δ15,1647
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
48
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 βyohimbine 3 by Szántay.120
Scheme 2.32: Kametani’s Synthesis I
49
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
50
cyanoformate and subsequent hydrogenation provided the C,N-acylated product 160.
Product 160 was converted to 93 with K2CO3/MeOH.
alloyohimbinone
alloyohimbine
112
93
were
intermediates
synthesis respectively.
Scheme 2.34: Ninomiya’s Synthesis
51
in
Both yohimbinone 136 and
Szántay‟s
yohimbine120,128
and
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 DielsAlder 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.
52
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-PictetSpengler reaction to afford the enantioriched key intermediate, N-acetyltetrahydro-βcarboline 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 NCbz 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.
53
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 Omethylhexadehydroyohimbine 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 1,2dione 168 with tryptamine.
The 1,2-dione was made in eleven steps from m-
methoxybenzaldehyde (Scheme 2.37).
54
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 Omethylhexadehydroyohimbine115 70 afforded the enol ether 176, which underwent acidmediated 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
55
Scheme 2.38: Kametani’s Synthesis II
56
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.
Copyright © Raghu Ram Chamala 2010
57
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
yohimbe, commonly known as fringe tree).6
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.
α-yohimbine (7)
16-epi: allo-yohimbine (8)
yohimbine (1)
16-epi: corynanthine (2)
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.
58
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
59
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.
60
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 transperhydroisoquinoline 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.
62
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
Utilized
Strategy
tryptamine/tryptophyl
bromide
C(2)-C(3)
bond present
in the starting
Utilized β-carboline
derivative (ABC
rings)
material
C ring
formed
Strategy I
Yes
No
No
Yes
Strategy II
No
Yes
Yes
No
No
Yes
No
Yes
Grossman‟s
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).
63
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
64
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
acetoacetate (Figure 3.4).139-140 We surmised if the same is also true with Hx1 and Hy1 of
65
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 βketoester 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 H y1
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.
66
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 βketoester 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
67
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
179 in a reaction catalyzed by Ph3P.141 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.
68
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.
69
Figure 3.6: X-ray crystal structure of 197
70
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.
71
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 1,2allylic 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 1,2allylic strain.
Scheme 3.15: Effect of 1,2-allylic strain on the double Michael adduct
72
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
73
Figure 3.7: X-ray crystal structure of 203
74
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.
75
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-
76
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).
77
Scheme 3.20: Desulfonation after the enamine reduction
78
Figure 3.8: X-ray crystal structure of 208
79
Figure 3.9: X-ray crystal structure of 209
80
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.
81
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
82
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
bond with Et3SiH/MsOH to afford 214 in quantitative yield. The 1H 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
84
Figure 3.11: X-ray crystal structure of 214
85
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 (BH3DMS) (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
13
C NMR spectra are reported in terms of chemical shift. Chemical shifts are
reported relative to internal Me4Si (1H and 13C, δ 0.00 ppm) or CDCl3 (1H, δ 7.27 ppm,
13
C, 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
without further purification; 1H 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,
1617 cm- 1; 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.
87
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),
2.17-2.35 (m, 2H), 1.96-2.07 (m, 1H);
13
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,
1584 cm- 1; Anal. Calcd for C12H13NO2S: C, 61.25; H, 5.57. Found: C, 61.19; H, 5.63.
88
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
MgSO4, and immediately carried on to the next step.
1
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,
1H);
13
C NMR (50 MHz, CDCl3):
199.0, 135.5, 129.8, 129.6, 113.5, 55.9, 39.6, 19.7;
IR (neat): 3060, 2928, 2248, 1722, 1580 cm- 1; 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,
6.0 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H);
13
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,
2252, 1736, 1686, 1448 cm- 1. 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
two steps)) as yellow minuscule needles; mp 120-121 ˚C; 1H 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,
2954, 2927, 2896, 2162, 1717, 1677, 1614, 1579, 1227 cm- 1. Calcd for C18H21NO3Si: C,
66.02; H, 6.46.
90
Figure 3.12: 1H NMR (400 MHz, CDCl3) of compound 186
91
Figure 3.13:
13
C NMR (400 MHz, CDCl3) of compound 186
92
Figure 3.14: Infrared spectrum (neat) of compound 186
93
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
shown for compound 184 and 179. 1H 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.
94
Figure 3.15: 1H NMR (400 MHz, CDCl3) of compound 187
95
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
136-137 ˚C; 1H 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,
1H), 0.15 (s, 9H);
13
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,
2969, 2898, 2865, 2158, 1600, 1567, 1517, 1242 cm- 1; Calcd for C14H15NOSi: C, 69.67;
H, 6.26.
96
Figure 3.16: 1H NMR (400 MHz, CDCl3) of compound 188
97
Figure 3.17:
13
C NMR (400 MHz, CDCl3) of compound 188
98
Figure 3.18: Infrared spectrum (thin film/KBr) of compound 188
99
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
yellow oil; 1H 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 =
6.6 Hz, 2H), 5.83 (s, 2H), 0.32 (s, 9H);
13
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,
1245 cm- 1; Calcd for C21H21NOSi: C, 76.09; H, 6.39.
100
Figure 3.19: 1H NMR (400 MHz, CDCl3) of compound 189
101
Figure 3.20:
13
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
solid; mp 92-94 ˚C; 1H 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),
3.26 (s, 1H);
13
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,
3062, 3024, 2945, 2913, 2853, 2093, 1612, 1584, 1508, 1495 cm- 1; Calcd for C18H13NO:
C, 83.37; H, 5.05.
104
Figure 3.22: 1H NMR (400 MHz, CDCl3) of compound 190
105
Figure 3.23:
13
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
(10.80 g, 20.90 mmol, 90% yield) as a colorless gum;
1
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
Figure 3.25: 1H NMR (400 MHz, CDCl3) of compound 196
109
Figure 3.26:
13
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
EtOH; mp 170-172 ˚C; 1H 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
(t, J = 7.1 Hz, 3H);
13
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
Figure 3.28: 1H NMR (400 MHz, CDCl3) of compound 197
113
Figure 3.29:
13
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
mmol, 35% yield (over two steps)) as a pale brown solid. 1H 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
Hz, 6.7 Hz, 1H), 1.03 (t, J = 7.1 Hz, 3H); 13C 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
Figure 3.31: 1H NMR (400 MHz, CDCl3) of compound 198
117
Figure 3.32:
13
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,
1H), 0.98 (t, J = 7.1 Hz, 3H); 13C 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
Figure 3.33: 1H NMR (400 MHz, CDCl3) of compound 199
120
Figure 3.34:
13
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;
(400 MHz, CDCl3):
1
H NMR
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),
1.45 (t, J = 7.1 Hz, 3H);
13
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
Figure 3.36: 1H NMR (400 MHz, CDCl3) of compound 203
124
Figure 3.37:
13
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-5carboxylate (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,
30% yield) as a pale brown solid. 1H 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
Figure 3.39: 1H 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,7,8,8aoctahydroisoquinoline-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,
0.042 mmol, 17% yield) as a brown solid; 1H 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
Figure 3.40: 1H 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 +
broad, J = 25.2 Hz, 11.9 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H); 13C 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
Figure 3.41: 1H NMR (400 MHz, CDCl3) of compound 207
132
Figure 3.42:
13
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
CH2Cl2/petroleum ether by slow evaporation; 182-184 ˚C; 1H 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), 1.972.12 (m, 2H), 1.11 (t, J = 7.1 Hz, 3H);
13
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,
2954, 2927, 2851, 1663, 1645, 1614 cm- 1; Calcd for C26H26N2O6S: C, 63.14; H, 5.30.
134
Figure 3.43: 1H NMR (400 MHz, CDCl3) of compound 208
135
Figure 3.44:
13
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,7,8,8aoctahydroisoquinoline-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
evaporation; mp 174-176 ˚C; 1H 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,
J = 7.1 Hz, 3H);
13
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
Figure 3.46: 1H NMR (400 MHz, CDCl3) of compound 209
139
Figure 3.47:
13
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
˚C; 1H 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,
1676, 1659, 1309, 1150 cm- 1; Calcd for C26H26N2O6S: C, 63.14; H, 5.30.
142
Figure 3.49: 1H NMR (400 MHz, DMSO-d6) of compound 214
143
Figure 3.50:
13
C NMR (400 MHz, DMSO-d6) of compound 214
144
Figure 3.51: Infrared spectrum (KBr) of compound 214
Copyright © Raghu Ram Chamala 2010
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.
Copyright © Raghu Ram Chamala 2010
146
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
-3
and hole (e.Å )
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)
S(1)-O(6)
S(1)-C(25)
S(1)-C(20)
O(1)-C(3)
O(2)-C(22)
O(3)-C(22)
O(3)-C(23)
O(4)-C(17)
O(4)-H(4)
N(1)-C(13)
N(1)-C(2)
N(1)-H(1)
N(2)-C(21)
C(2)-C(7)
C(2)-C(3)
C(3)-C(14)
C(7)-C(8)
C(7)-H(7)
C(8)-C(9)
C(8)-C(13)
C(9)-C(10)
C(9)-H(9)
C(10)-C(11)
C(10)-H(10)
C(11)-C(12)
C(11)-H(11)
C(12)-C(13)
C(12)-H(12)
C(14)-C(15)
C(14)-H(14A)
C(14)-H(14B)
C(15)-C(16)
C(15)-C(20)
C(15)-H(15)
C(16)-C(17)
C(16)-C(22)
C(17)-C(18)
C(18)-C(19)
C(18)-H(18A)
C(18)-H(18B)
C(19)-C(20)
C(19)-H(19A)
C(19)-H(19B)
C(20)-C(21)
C(23)-C(24)
1.4317(15)
1.4340(15)
1.758(2)
1.845(2)
1.217(3)
1.232(2)
1.329(2)
1.459(2)
1.338(2)
0.8400
1.366(3)
1.375(3)
0.8800
1.144(3)
1.373(3)
1.462(3)
1.513(3)
1.420(3)
0.9500
1.404(3)
1.414(3)
1.375(3)
0.9500
1.409(3)
0.9500
1.373(3)
0.9500
1.396(3)
0.9500
1.539(3)
0.9900
0.9900
1.512(3)
1.551(3)
1.0000
1.348(3)
1.457(3)
1.481(3)
1.517(3)
0.9900
0.9900
1.543(3)
0.9900
0.9900
1.469(3)
1.500(3)
152
C(23)-H(23A)
C(23)-H(23B)
C(24)-H(24A)
C(24)-H(24B)
C(24)-H(24C)
C(25)-C(30)
C(25)-C(26)
C(26)-C(27)
C(26)-H(26)
C(27)-C(28)
C(27)-H(27)
C(28)-C(29)
C(28)-H(28)
C(29)-C(30)
C(29)-H(29)
C(30)-H(30)
O(1E)-C(1E)
O(1E)-H(1E)
C(1E)-C(2E)
C(1E)-H(1E1)
C(1E)-H(1E2)
C(2E)-H(2E1)
C(2E)-H(2E2)
C(2E)-H(2E3)
0.9900
0.9900
0.9800
0.9800
0.9800
1.389(3)
1.391(3)
1.387(3)
0.9500
1.381(3)
0.9500
1.382(3)
0.9500
1.383(3)
0.9500
0.9500
1.428(3)
0.8400
1.483(4)
0.9900
0.9900
0.9800
0.9800
0.9800
O(5)-S(1)-O(6)
O(5)-S(1)-C(25)
O(6)-S(1)-C(25)
O(5)-S(1)-C(20)
O(6)-S(1)-C(20)
C(25)-S(1)-C(20)
C(22)-O(3)-C(23)
C(17)-O(4)-H(4)
C(13)-N(1)-C(2)
C(13)-N(1)-H(1)
C(2)-N(1)-H(1)
C(7)-C(2)-N(1)
C(7)-C(2)-C(3)
N(1)-C(2)-C(3)
O(1)-C(3)-C(2)
O(1)-C(3)-C(14)
C(2)-C(3)-C(14)
C(2)-C(7)-C(8)
C(2)-C(7)-H(7)
C(8)-C(7)-H(7)
C(9)-C(8)-C(13)
C(9)-C(8)-C(7)
119.44(9)
108.65(9)
109.34(10)
107.48(9)
106.08(9)
104.87(9)
115.70(16)
109.5
108.87(17)
125.6
125.6
109.40(18)
131.77(19)
118.84(18)
120.33(19)
122.11(18)
117.50(18)
107.13(18)
126.4
126.4
118.69(19)
134.7(2)
153
C(13)-C(8)-C(7)
C(10)-C(9)-C(8)
C(10)-C(9)-H(9)
C(8)-C(9)-H(9)
C(9)-C(10)-C(11)
C(9)-C(10)-H(10)
C(11)-C(10)-H(10)
C(12)-C(11)-C(10)
C(12)-C(11)-H(11)
C(10)-C(11)-H(11)
C(11)-C(12)-C(13)
C(11)-C(12)-H(12)
C(13)-C(12)-H(12)
N(1)-C(13)-C(12)
N(1)-C(13)-C(8)
C(12)-C(13)-C(8)
C(3)-C(14)-C(15)
C(3)-C(14)-H(14A)
C(15)-C(14)-H(14A)
C(3)-C(14)-H(14B)
C(15)-C(14)-H(14B)
H(14A)-C(14)-H(14B)
C(16)-C(15)-C(14)
C(16)-C(15)-C(20)
C(14)-C(15)-C(20)
C(16)-C(15)-H(15)
C(14)-C(15)-H(15)
C(20)-C(15)-H(15)
C(17)-C(16)-C(22)
C(17)-C(16)-C(15)
C(22)-C(16)-C(15)
O(4)-C(17)-C(16)
O(4)-C(17)-C(18)
C(16)-C(17)-C(18)
C(17)-C(18)-C(19)
C(17)-C(18)-H(18A)
C(19)-C(18)-H(18A)
C(17)-C(18)-H(18B)
C(19)-C(18)-H(18B)
H(18A)-C(18)-H(18B)
C(18)-C(19)-C(20)
C(18)-C(19)-H(19A)
C(20)-C(19)-H(19A)
C(18)-C(19)-H(19B)
C(20)-C(19)-H(19B)
H(19A)-C(19)-H(19B)
C(21)-C(20)-C(19)
154
106.62(18)
118.9(2)
120.6
120.6
121.5(2)
119.3
119.3
121.0(2)
119.5
119.5
117.7(2)
121.2
121.2
129.7(2)
107.98(18)
122.28(19)
112.82(17)
109.0
109.0
109.0
109.0
107.8
111.26(17)
111.94(16)
111.55(16)
107.3
107.3
107.3
117.75(18)
123.94(18)
118.23(17)
123.64(19)
112.60(17)
123.68(19)
113.34(17)
108.9
108.9
108.9
108.9
107.7
112.80(16)
109.0
109.0
109.0
109.0
107.8
107.48(16)
C(21)-C(20)-C(15)
C(19)-C(20)-C(15)
C(21)-C(20)-S(1)
C(19)-C(20)-S(1)
C(15)-C(20)-S(1)
N(2)-C(21)-C(20)
O(2)-C(22)-O(3)
O(2)-C(22)-C(16)
O(3)-C(22)-C(16)
O(3)-C(23)-C(24)
O(3)-C(23)-H(23A)
C(24)-C(23)-H(23A)
O(3)-C(23)-H(23B)
C(24)-C(23)-H(23B)
H(23A)-C(23)-H(23B)
C(23)-C(24)-H(24A)
C(23)-C(24)-H(24B)
H(24A)-C(24)-H(24B)
C(23)-C(24)-H(24C)
H(24A)-C(24)-H(24C)
H(24B)-C(24)-H(24C)
C(30)-C(25)-C(26)
C(30)-C(25)-S(1)
C(26)-C(25)-S(1)
C(27)-C(26)-C(25)
C(27)-C(26)-H(26)
C(25)-C(26)-H(26)
C(28)-C(27)-C(26)
C(28)-C(27)-H(27)
C(26)-C(27)-H(27)
C(27)-C(28)-C(29)
C(27)-C(28)-H(28)
C(29)-C(28)-H(28)
C(28)-C(29)-C(30)
C(28)-C(29)-H(29)
C(30)-C(29)-H(29)
C(29)-C(30)-C(25)
C(29)-C(30)-H(30)
C(25)-C(30)-H(30)
C(1E)-O(1E)-H(1E)
O(1E)-C(1E)-C(2E)
O(1E)-C(1E)-H(1E1)
C(2E)-C(1E)-H(1E1)
O(1E)-C(1E)-H(1E2)
C(2E)-C(1E)-H(1E2)
H(1E1)-C(1E)-H(1E2)
C(1E)-C(2E)-H(2E1)
155
111.51(16)
112.58(16)
104.14(14)
109.17(14)
111.54(13)
177.6(2)
122.08(18)
124.13(18)
113.74(17)
106.71(17)
110.4
110.4
110.4
110.4
108.6
109.5
109.5
109.5
109.5
109.5
109.5
121.6(2)
118.93(16)
119.48(16)
118.5(2)
120.7
120.7
120.2(2)
119.9
119.9
120.7(2)
119.7
119.7
120.2(2)
119.9
119.9
118.8(2)
120.6
120.6
109.5
108.3(2)
110.0
110.0
110.0
110.0
108.4
109.5
C(1E)-C(2E)-H(2E2)
H(2E1)-C(2E)-H(2E2)
C(1E)-C(2E)-H(2E3)
H(2E1)-C(2E)-H(2E3)
H(2E2)-C(2E)-H(2E3)
109.5
109.5
109.5
109.5
109.5
Symmetry transformations used to generate equivalent atoms:
156
Table A.4:
Anisotropic displacement parameters (Å2 x 103)
for
The
197.
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
166
4431 / 1058 / 494
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:
for
203.
Anisotropic displacement parameters (Å2 x 103)
The
takes the form:
anisotropic
displacement
factor
exponent
-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
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
U(eq)
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
squares on F2
Data / restraints / parameters
190
5896 / 69 / 330
least-
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
Absorption correction
equivalents
Max. transmission
0.9936
Min. transmission
0.9728
Full-matrix
squares on F2
Refinement method
211
from
least-
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
-3
(e.Å )
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
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
U(eq)
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
225
#3 -x+2,-y+1,-z
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
S(1B)
16(1)
24(1)
21(1)
N(1B)
16(1)
27(1)
O(1B)
16(1)
C(2B)
U13
U12
2(1)
-1(1)
-2(1)
16(1)
3(1)
-1(1)
2(1)
30(1)
30(1)
-1(1)
-4(1)
1(1)
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
U23
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
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
z
U(eq)
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
Copyright © Raghu Ram Chamala 2010
258
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264
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 (20042007).
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.
265