Synthèse de buténolides naturels et développement
d'une nouvelle réaction en cascade pour l'élaboration de
furo (2,3-b) chromones
Thèse
Ramesh Muddala
Doctorat en chimie
Philosophiæ doctor (Ph. D.)
Québec, Canada
Synthèse de buténolides naturels et
développement d’une nouvelle réaction en
cascade pour l’élaboration de
furo[2,3-b]chromones
Thèse
Ramesh Muddala
Sous la direction de :
Résumé
Cette thèse décrit le développement d’une nouvelle méthode de synthèse et l’établissement de plusieurs synthèses totales de produits naturels poly-oxygénés d’intérêt biologique et médicinal.
En particulier, nous décrirons la première synthèse de l’antibiotique antitumoral basidalin comportant une structure unique (chapitre 2). Originalement isolé d’une éponge terrestre en 1983, basidalin est le seul et unique produit naturel possédant un motif tétronamide. De plus, il a démontré des activités antitumorales in vitro et in vivo significatives. Ces attributs ont attiré l’attention des communautés de chimistes de synthèse et médicinale depuis environ trois décennies. Bien que plusieurs approches aient été rapportées dans la littérature, aucune d’entre-elles n’a permis de fournir la basidalin. Afin de surmonter ce défi, une méthode précédemment développée dans le groupe du professeur Boukouvalas a été judicieusement appliquée prouvant ainsi sa haute efficacité. Ainsi, nous avons complété la première synthèse de la basidalin avec un rendement global de 39% pour 5 étapes incluant seulement 3 purifications par chromatographie.
Le chapitre 3 concerne le développement d’un procédé de catalyse au fer pour l’installation de substituants carbonés à la position d’un buténolide, et son application pour la première synthèse d’un antibiotique marin, I’enhygrolide A. Plus spécifiquement, nous avons démontré que le groupement pivalate, jusqu’ici inexploré, est supérieur au triflate en tant que partenaire électrophile dans la réaction de couplage croisé avec des réactifs de Grignard catalysé au fer. Cette découverte aura permis la préparation efficace de I’enhygrolide A en 5 étapes (54%) à partir de produits commerciaux.
Dans le chapitre 4, nous décrirons l’élaboration d’une méthode pour la construction d’un composé antitumoral rare de la famille des acétogénines, caractérisé par un motif –(2-hydroxyalkyl)––hydroxybuténolide. La puissance de cette méthodologie a été démontrée par la première synthèse de la donnaienin A. Notre voie de synthèse est convergente (total de 24 étapes, séquence linéaire la plus longue de 15 étapes, rendement global de 6,5%) offrant une flexibilité synthétique considérable pour de futures applications.
Finalement, nous avons développé une séquence réactionnelle nouvelle et efficace pour la synthèse de furo[2,3-b]chromones. Ce procédé implique une réaction de cycloaddition/cyclo-inversion de Diels-Alder régiocontrôlée entre un oxazole et une ynone. Elle est suivie par une réaction in situ d’addition/élimination d’oxa-Michael fournissant les
furo[2,3-b]chromones avec, de manière générale, de haut rendements. Son utilité a été démontrée lors
Summary
This thesis describes the development of new synthetic methods and the establishment of streamlined total syntheses of densely functionalized oxacyclic natural products of biological and medicinal interest.
In particular, we describe the first synthesis of the structurally unique antitumor antibiotic basidalin (Chapter 2). Originally isolated from a terrestrial fungus in 1983, basidalin is the first and only natural product known thus far to possess a tetronamide motif. In addition, basidalin displays significant antitumor activity in vitro and in vivo. These attributes have captured the interests of the synthetic and medicinal chemistry communities for over three decades. Notwithstanding the several approaches reported in the literature, none of them were successful in delivering even traces of basidalin. To overcome this challenge, advantage of previously conveyed technology by the Boukouvalas group was taken to judiciously design a strategy that proved highly effective. Indeed, we were able to synthesize basidalin in 39% overall yield after 5 steps and only 3 purifications by chromatography.
Chapter 3 concerns the development of a new, iron-catalyzed process for installing carbon substituents onto the –position of the butenolide ring and its application to the first synthesis of the marine myxobacterial antibiotic enhygrolide A. Specifically, we have shown that the hitherto unexplored butenolide pivalates are superior to triflates as electrophilic partners in iron-catalyzed sp2-sp3 cross-coupling with Grignard reagents. This discovery, combined with
a tactically sound synthesis plan, enabled enhygrolide A to be prepared with high overall efficiency (54%) in 5 steps from commercial chemicals.
In Chapter 4 we describe a new methodology for constructing a rare type of antitumor annonaceous acetogenins, characterized by an –(2-hydroxyalkyl)––hydroxybutenolide motify. The power of this methodology was demonstrated by the first synthesis of such an acetogenin, namely donnaienin A. Our route is convergent (24 steps in total, longest linear route: 15 steps, 6.5% yield) offering considerable synthetic flexibility for future applications. Finally, we have developed a new and efficient tandem reaction sequence for the synthesis of furo[2,3-b]chromones. This process involves regiocontrolled oxazole−ynone Diels−Alder
cycloaddition/cycloreversion followed by in situ oxa-Michael addition/elimination to deliver furo[2,3-b]chromones in generally high yields. Its utility was demonstrated by the first synthesis of a furo[2,3-b]chromone natural product (bothriofuran A), accomplished in 5 steps (27% overall).
Table of contents
Résumé ... iii
Summary... v
Table of contents ... vii
List of tables ... xi
List of schemes ... xii
List of figures ... xv
List of abbreviations ... xvii
Dedication... xix
Acknowledgements ... xx
Chapter 1. General introduction ... 1
1.1 Natural products ... 2
1.2 Traditional medicines ... 2
1.3 Isolation and discovery of natural products ... 4
1.3.1 Natural products from microorganisms ... 4
1.3.2 Natural products from plants ... 5
1.3.3 Natural products from the marine organisms ... 7
1.4 The beginning of total synthesis ... 8
1.5 Discovery of new reactions ... 11
1.5.1 The Diels-Alder reaction ... 11
1.5.2 Cross-coupling reactions ... 13
1.5.3 Metathesis reactions ... 14
1.6 A platform for innovation ... 16
1.6.1 Structural determination and confirmation of structure ... 16
1.6.2 Ideal synthesis... 17
1.7 Different synthetic strategies ... 19
1.7.1 Divergent synthesis ... 19
1.7.2 Biomimetic synthesis... 21
1.9 Thesis objectives... 24
1.10 Description of the format of the thesis ... 25
1.11 References ... 26
Chapter 2. Total synthesis of the antitumor antibiotic basidalin ... 29
2.1 Introduction specific ... 30
2.1.1 Tetronamides ... 30
2.2 Previous synthetic approaches to basidalin ... 32
2.3 Preamble ... 37 2.4 Résumé ... 37 2.5 Abstract ... 37 2.6 Article ... 38 2.7 Supporting information... 42 2.8 References ... 46
Chapter 3. Synthesis of marine myxobacterial antibiotic enhygrolide A ... 49
3.1 Introduction specific ... 50
3.1.1 Enhygrolides ... 50
3.1.2 Nostoclides... 50
3.2 Previous synthetic approaches to nostoclides ... 51
3.2.1 Boukouvalas synthesis ... 51
3.2.2 Bellinas synthesis ... 52
3.2.3 Argades synthesis ... 53
3.2.4 Ngi & Thibonnets synthesis ... 54
3.3 Preamble ... 55 3.4 Résumé ... 55 3.5 Abstract ... 56 3.6 Article ... 56 3.7 Experimental section ... 60 3.8 References ... 65
3.9 Sustainable access to substituted butenolides by iron-catalyzed cross-coupling reaction ... 68
3.9.1 Introduction specific ... 68
3.9.2 Results and discussion ... 69
3.9.3 Synthesis of butenolides ... 70
3.9.4 Synthesis of butenolide pivalates ... 71
3.9.5 Synthesis of substituted butenolides ... 72
3.9.6 Conclusion ... 73
3.9.7 Experimental section ... 73
3.9.8 References ... 82
Chapter 4. First synthesis of donnaienin A ... 83
4.1 Introduction to acetogenins ... 84
4.1.1 Discovery and properties... 84
4.2 -Hydroxybutenolide derived natural products ... 86
4.3 γ-Hydroxybutenolide-containing acetogenins ... 88
4.4 Previous synthetic approaches to -hydroxybutenolides ... 91
4.5 Previous synthetic route to α-substituted butenolides ... 94
4.6 Total synthesis of annomolon A ... 95
4.7 Access to -hydroxybutenolide... 97
4.8 Total synthesis of donnaienin A ... 97
4.8.1 Original retrosynthetic plan for donnaienin A ... 97
4.9 Synthesis of -hydroxybutenolide fragment ... 99
4.10 Synthesis of the chiral-THF fragment ... 102
4.11 Initial protecting-group-free studies ... 106
4.12 Completion of donnaienin A synthesis ... 107
4.13 Conclusion ... 109
4.14 Experimental section ... 109
4.15 References ... 117
Chapter 5. A new methodology for the synthesis of furo[2,3-b]chromones ... 120
5.1 Introduction to γ-pyrone-based heterocyclic scaffolds ... 121
5.1.1 Furo[2,3-g]chromones ... 122
5.1.2 Furo[2,3-b]quinolines ... 124
5.4 New methodology for constructing furo[2,3-b]chromones ... 129
5.5 Preparation of o-alkynoylphenols ... 131
5.6 Methodology expansion to thieno[2,3-b]chromones ... 139
5.6.1 Preparation of 4-methyl-5-ethoxythiazole ... 140
5.7 Conclusion ... 141
5.8 Experimental Section ... 142
5.9 References ... 162
Chapter 6. Conclusions and perspectives ... 164
6.1 Conclusions and perspectives ... 165
6.2 References ... 172
Appendix ... 173
List of tables
Table 3.1. Optimization of cross-coupling reaction ______________________________ 69 Table 3.2. Preparation of butenolide pivalates _________________________________ 71 Table 3.3.Substrate scope __________________________________________________ 72 Table 4.1. Optimization of epoxide-opening of 4.35 ____________________________ 100 Table 5.1. Preparation of o-alkynoylphenols 5.29d-n ___________________________ 132 Table 5.2. Optimization of Diels-Alder reaction between compound 5.29a with 5-ethoxy-4-methyloxazole 5.30 ______________________________________________________ 134 Table 5.3. Substrate scope of o-alkynoylphenols _______________________________ 136
List of schemes
Scheme 1.1. Diels-Alder reaction between quinone with cyclopentadiene ____________ 12 Scheme 1.2. Application of Diels-Alder reaction in the total synthesis of cortisone and cholesterol _____________________________________________________________ 13 Scheme 1.3. Different types of metathesis reactions _____________________________ 15 Scheme 1.4. Synthesis of antibiotic everninomicin 13,364-1 _______________________ 16 Scheme 1.5. Biosynthetic route to penicillins ___________________________________ 19 Scheme 1.6. Li’s divergent route to taiwaniaquinols and taiwaniaquinones ___________ 20 Scheme 1.7. Biomimetic synthesis of progesterone ______________________________ 21 Scheme 1.8. Production of the antimalarial drug (+)-artemisinin __________________ 22 Scheme 2.1. Synthesis of flupyradifurone ______________________________________ 31 Scheme 2.2. Hiyama’s synthetic route to basidalin ______________________________ 33 Scheme 2.3. Hiyama’s another synthetic route to basidalin _______________________ 34 Scheme 2.4. Eguchi’s synthetic route to (Z)-formylmethylenetetronate _______________ 35 Scheme 2.5. Eguchi’s synthetic route to E-basidalin _____________________________ 35 Scheme 2.6. Dechoux’s synthetic approach to basidalin __________________________ 36 Scheme 2.7. Attempted syntheses of 2.1 _______________________________________ 39 Scheme 2.8. Our retrosynthetic analysis ______________________________________ 40 Scheme 2.9. Total synthesis of basidalin ______________________________________ 41 Scheme 3.1. Synthesis of nostoclides I and II ___________________________________ 52 Scheme 3.2. Synthesis of nostoclides I and II ___________________________________ 53 Scheme 3.3. Synthesis of nostoclide I _________________________________________ 54 Scheme 3.4. Synthesis of nostoclide I and II____________________________________ 55 Scheme 3.5. Retrosynthesis _________________________________________________ 58 Scheme 3.6. Total synthesis of enhygrolide A (3.1) ______________________________ 58 Scheme 3.7. Fe-catalysed cross-coupling reaction of butenolide pivalate with i-BuMgBr 68 Scheme 3.8. Synthesis of compound 3.41a _____________________________________ 70 Scheme 3.9. Synthesis of compound 3.41b _____________________________________ 71 Scheme 4.1. Tautomerization of γ-hydroxybutenolide ____________________________ 91 Scheme 4.2. Synthesis of γ-hydroxybutenolides (1/2) _____________________________ 91 Scheme 4.3. Synthesis of γ-hydroxybutenolides (2/2) _____________________________ 93
Scheme 4.4. Boukouvalas method for γ-hydroxybutenolide (4.9) synthesis ____________ 94 Scheme 4.5. One-pot synthesis of α-substituted butenolides 4.12 ___________________ 94 Scheme 4.6. Boukouvalas total synthesis of anti-inflammatory gorgonian lipid ________ 95 Scheme 4.7. Boukouvalas total synthesis of annomolon A _________________________ 96 Scheme 4.8. Preparation of -hydroxybutenolide 4.24____________________________ 97 Scheme 4.9. Retrosynthetic analysis of donnaienin A ____________________________ 98 Scheme 4.10. Synthesis of silyloxyfuran 4.16 ___________________________________ 99 Scheme 4.11. Preparation of -hydroxybutenolide 4.30__________________________ 101 Scheme 4.12. Mechanistic pathways for DMDO mediated oxyfunctionalisation ______ 102 Scheme 4.13. Synthesis of ester 4.41 ________________________________________ 103 Scheme 4.14. Synthesis of α,β-unsaturated dienoate 4.44 ________________________ 103 Scheme 4.15. Synthesis of compound 4.46 ____________________________________ 104 Scheme 4.16. Synthesis of compound 4.47 ____________________________________ 104 Scheme 4.17. Preparation of iodonium dicollidine perchlorate (IDCP) _____________ 105 Scheme 4.18. Synthesis of chiral-THF fragments 4.3 & 4.19 _____________________ 105 Scheme 4.19. Cross-metathesis reaction between the compounds 4.27 and 4.30 ______ 106 Scheme 4.20. Synthesis of compound 4.50 ____________________________________ 106 Scheme 4.21. Synthesis of compound 4.51 ____________________________________ 107 Scheme 4.22. Synthesis of compound 4.52 ____________________________________ 107 Scheme 4.23. Synthesis of donnaienin A______________________________________ 108 Scheme 5.1. Synthesis of furo[2,3-b]chromone 5.1 _____________________________ 126 Scheme 5.2. CAN mediated oxidative cyclization of 4-hydroxycoumarin with
phenylacetylene ________________________________________________________ 126 Scheme 5.3. Rhodium(II)-catalyzed reaction of 3-diazo-2,4-chromenedione with TMS acetylene ______________________________________________________________ 127 Scheme 5.4. Coupling and heteroannulation of 5.18 with 5.19 ____________________ 127 Scheme 5.5. Access to furo[2,3-b]chromone 5.24 via iodocyclisation pathway _______ 128 Scheme 5.6. Proposed mechanism for the formation of angularly fused furochromone _ 128 Scheme 5.7. Copper-catalyzed intramolecular cycloetherification of 5.26a-d ________ 129 Scheme 5.8. Discovery of furo[2,3-b]chromone through Diels-Alder reaction ________ 130 Scheme 5.9. Synthesis of compound 5.29a ____________________________________ 131
Scheme 5.10. Synthesis of compounds 5.29b,c _________________________________ 131 Scheme 5.11. Synthesis of o-alkynoylphenols 5.29o,p ___________________________ 133 Scheme 5.12. Plausible mechanism for the construction of furo[2,3-b]chromones _____ 137 Scheme 5.13. Synthesis of aldehyde 5.35c ____________________________________ 138 Scheme 5.14. Sythesis of bothriofuran A _____________________________________ 138 Scheme 5.15. Synthesis of thieno[2,3-b]chromone 5.27c _________________________ 139 Scheme 5.16. Synthesis of 4-Methyl-5-ethoxythiazole ___________________________ 140 Scheme 5.17. Attempted synthesis of thieno[2,3-b]chromones ____________________ 140 Scheme 5.18. Alternative route to thieno[2,3-b]chromone _______________________ 141 Scheme 6.1. Synthesis of basidalin __________________________________________ 165 Scheme 6.2. Synthesis of enhygrolide A ______________________________________ 166 Scheme 6.3. Synthesis of substituted butenolide uisng iron catalyst ________________ 167 Scheme 6.4. Synthesis of -hydroxylbutenolide 4.50 ____________________________ 167 Scheme 6.5. Synthesis of chiral-THF fragment 4.51 ____________________________ 169 Scheme 6.6. Synthesis of donnaienin A_______________________________________ 170 Scheme 6.7. General route to furo[2,3-b]chromones ____________________________ 171 Scheme 6.8. Synthesis of bothriofuran A _____________________________________ 171
List of figures
Figure 1.1. Traditionally important natural products _____________________________ 3 Figure 1.2. Reported structure of penicillin G ___________________________________ 4 Figure 1.3. Structures of vancomycin and erythromycin ___________________________ 5 Figure 1.4. Structures of Taxol® and baccatin III ________________________________ 6 Figure 1.5. Reported stuctures of artemisinin and avermectins______________________ 7 Figure 1.6. Marine-derived antitumor agent ____________________________________ 7 Figure 1.7. Some medicinally important marine natural products ___________________ 8 Figure 1.8. Structure of mauveine A, camphor, and glucose. _______________________ 9 Figure 1.9. Natural products synthesized by Woodward’s group ___________________ 10 Figure 1.10. Natural products synthesized by Corey’s group ______________________ 11 Figure 1.11. Commonly used catalysts for metathesis reactions ____________________ 14 Figure 1.12. Examples of the most complex natural compounds synthesized __________ 17 Figure 1.13. The quantitative measure for an “ideal’’ total synthesis _______________ 18 Figure 1.14. Different synthetic strategies _____________________________________ 20 Figure 1.15. Structure of kinase inhibitor sorafenib approved by FDA ______________ 23 Figure 1.16. Structures of substituted butenolides and general synthetic route to furo[2,3-b]chromones ____________________________________________________________ 24 Figure 2.1. Structures of basidalin and thiobasidalin ____________________________ 30 Figure 2.2. Structures of podophyllotoxin and 4-aza-podophyllotoxin derivatives ______ 32 Figure 2.3. Some examples of antibacterial active tetronamides____________________ 32 Figure 2.4. Reported structures of basidalin and relatives ________________________ 38 Figure 3.1. Representative structure of enhygrolides ____________________________ 50 Figure 3.2. Structure of nostoclides I and II ___________________________________ 50 Figure 4.1. General structure representation of acetogenins ______________________ 84 Figure 4.2. Classification of acetogenins ______________________________________ 85 Figure 4.3. Acetogenins with -methylbutenolide unit ____________________________ 85 Figure 4.4. Biologically active -hydroxybutenolides ____________________________ 87 Figure 4.5. Anti-inflammatory active luffariellolide and antitumor active dysidiolide ___ 88 Figure 4.6. -hydroxybutenolide-containing acetogenins _________________________ 89 Figure 4.7. Epimeric mixtures of -hydroxybutenolide-containing acetogenins ________ 90
Figure 5.1. Structural representation of -pyrone, chromone, xanthone and
furo[2,3-b]chromone ____________________________________________________________ 121 Figure 5.2. Furo[2,3-b]chromone based natural products _______________________ 122 Figure 5.3. Representative examples for biologically potent pyridyl-chromones ______ 122 Figure 5.4. Furo[2,3-g]chromone based natural products _______________________ 123 Figure 5.5. Structures of sodium cromoglycate (antiasthmatic agent) and amiodarone (antiarrhythmic) ________________________________________________________ 123 Figure 5.6. Some natural products that are derived from furo[2,3-b]quinolines ______ 124 Figure 5.7. Furo[2,3-b]chromone-2-carboxylate analogues ______________________ 124 Figure 5.8. Neo-tanshinlactone antitumor agent (breast cancer) __________________ 129 Figure 5.9. X-ray crystallographic structure of compound 5.34a __________________ 137
List of abbreviations
Ac: acetyl
acac: acetylacetonate
AIBN: azobisisobutyronitrile AMP: adenosine monophosphate aq: aqueous Ar: aryl AP: aminopeptidase ATP: adenosine-5'-triphosphate Bu: butyl Bn: benzyl
CAN: cerium ammonium nitrate cat: catalytic quantity
CBS (reagent): Corey-Bakshi-Shibata oxazaborolidine reagent CDI: carbonyldiimidazole
CSA: camphorsulfonic acid
DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCE: 1,2-dichloroethene
DIBAL-H: diisobutylaluminium hydride DIPEA: diisopropylethylamine (Hünig’s base) DMAP: 4-(N,N-dimethylamino)pyridine DMDO: dimethyldioxirane
DMF: N,N-dimethylformamide DMP: 2,2-dimethoxypropane DMSO: dimethylsulfoxide
E1cB: elimination via a carbanionic intermediate E: electrophile
Et: ethyl
ED50: half maximal (50%) effective dose
ESI: electronspray ionization ETS: electron transport system
FDA: Food and Drug Administration (USA) FTIR: Fourier transform infrared spectroscopy HRMS: high resolution mass spectroscopy HMPA: hexamethylphosphoramide
HPLC: high performance liquid chromatography IC50: half maximal (50%) inhibitory concentration
IDC-Hex: iodonium bis(sym-collidine) hexafluorophosphate IDCP: iodonium bis(sym-collidine) perchlorate
LDA: lithium diisopropylamide Lit: literature
Me: methyl Mp: melting point
Mes: mesityl (1,3,5-trimethylbenzene) MIC: Minimum inhibitory concentration
MTPA: α-methoxy-α-trifluoromethylphenylacetate
NADH: nicotinamide adenine dinucleotide (reduced form) NBS: N-bromosuccinimide
NMP: N-Methyl-2-pyrrolidone PG: protecting group
Ph: phenyl
Piv: pivalyl (trimethylacetyl) PLA2: Phospholipase A2
PMB: para-methoxybenzyl PPA: polyphosphoric acid
PPE: polyphosphoric acid ethyl ester Pr: propyl
PPTS: pyridinium p-toluenesulfonate py: pyridine
RCM: ring-closing metathesis Ref: reference
NCE’s: new chemical entities
NMR: nuclear magnetic spectroscopy rt: room temperature sym-collidine: 2,4,5-trimethylpyridine TBS/TBDMS: tert-butyldimethylsilyl Tf: trifluoromethylsulfonyl THF: tetrahydrofuran TIPS: triisopropylsilyl
TLC: thin layer chromatography TMS: trimethylsilyl
Ts: para-toluenesulfonyl
TPPMS: monosulfonated triphenylphosphine UV: ultra-violet
Dedication
Acknowledgements
I thank all who in one way or another contributed in the completion of this thesis. First, I give thanks to God for protection and ability to do work.
In my journey towards this degree, I have found a teacher, a friend, an inspiration, a role model and a pillar of support in my advisor, Prof. John Boukouvalas. He has been there providing his heartfelt support and guidance at all times and has given me invaluable guidance, inspiration and suggestions in my quest for knowledge. He has given me all the freedom to pursue my research, while silently and non-obtrusively ensuring that I stay on course and do not deviate from the core of my research. Thank you Professor, for giving me an opportunity to do this doctoral research. Without You my doctoral research would not have seen the light of the day.
Besides my advisor, I would like to thank the rest of my doctoral jury memebers: Dr. Guillaume Bélanger, Dr. Denis Giguère, Dr. Claudio Sturino for taking some of their precious time for reading my thesis.
It has been a real pleasure, privilege, and honor to work with the present and past members of the Boukouvalas research team. I would like to thank Marc, Charles, Vincent, Raphaël, Jaime, Thais, Richard, Lolo, Clémence, Tushar, for being great colleagues and fantastic friends. They have been invaluable for discussing chemistry, proof readings, and keeping me sane over the past years. I wish you all the best and hope to stay connected for a long time. I would like to thank all the members of chemistry department, especially Mélanie Tremblay, Denyse Michaud, Pierre Audet for their help during my research. And also, my special thanks to the students from all other research teams in the department of chemistry.
I wish to express my warm and sincere thanks to my former team leaders: Dr. Anish Bandyopadhyay, Dr. Yogesh Munot, Dr. Nadim Shaik for your support and valuable suggestions during my stay at TATA Advinus Therapeutic Ltd, Pune. I am also highly grateful to my colleagues of TATA Advinus Therapeutics Ltd. My special thanks to Shailesh Shinde for his guidance and support during my stay at Advinus.
I would like to thank my former supervisors Dr. J. S. Yadav (Former Director, CSIR-IICT), Dr. G. Sabitha, who provided me an opportunity to join their team as intern student during my master studies at IICT, Hyderabad.
I also wish to thank my all teachers, especially Anjaneyaswamy master, Kalaga Shankar, Chalapathi, T. S. N Murthy for everything that they have done for me.
No words are sufficient to acknowledge my prized friends who have helped me at various stages during my studies. I express my thanks to school, college, UG and PG friends. Special thanks to Swamy, Nag, Ramesh babu, Vasu, Chandu, Ravi, kranthi, Satyaramakrishna, Suresh, Nookaraju, Lakshman. I also wish to thank all of my friends I have made in Quebec City, Prenitha, Chandu (Fasak), Praveena, Surya, Minty, Vamsi, Kallol, Siddarth, Manasa, Rama, Di Meng, Madhavi, Kishan, Somaiah, Ravindor, Paresh, Henry, Jeff, Vincent, and the many others whose names I missed out here. I am very thankful to Sai Sampath, Srikanth, Prakash, Chon, AJ. The road trips, game nights, dinners and general help and friendship were all greatly appreciated. I have met so many nice and friendly people here that neither I can write all their names here but nor can I ignore them. I am really glad that I chose Quebec City in Canada to do my Doctoral studies. It’s a wonderful city!
My family is always source of inspiration and great moral support for me in perceiving my education, I thank god of almighty for providing me such a beautiful family. I take this opportunity to my sense of gratitude to my parents for their tons of love, sacrifice, blessings, unconditional support, always believing in me and encouraging me to follow my dreams and supporting me spiritually throughout my life. I am grateful to my brothers, Dr. Nagendra Prasad, V.D.L Varaprasad, who have provided me through moral and emotional support in my life. Without you, I would have never make it. You are simply the best persons in the world. I would like to express my deepest gratitude goes to my sister in laws Dr. Satya Laxmi, Tejaswi for their love, encouragement, endless support. My gratitude towards my niece Shree Jyotsna for bringing lots of joy!
Thanks a million for all your encouragement!!!
āpūryamāṇam achala-pratiṣhṭhaṁ samudram āpaḥ pravivśhanti yadvat
tadvat kāmā yaṁ praviśhanti sarve sa śhāntim āpnoti na kāma-kāmī
(Just as the ocean remains undisturbed by the incessant flow of waters from rivers merging into it, likewise the sage who is unmoved despite the flow of desirable objects all around
him attains peace, and not the person who strives to satisfy desires)
-Bhagavad Gita
1.1 Natural products
Natural products are part of our day-to-day life in a multitude of aspects. Apart from their dietary significance, natural products have been the most successful inspiration for potential drug lead candidates.1,2,3,4 Since less than 10% of the world’s biodiversity has been evaluated
for potential biological activity, many more useful natural lead compounds could be possibly awaiting discovery with the challenge being how to accessthis natural chemical diversity. The earliest records of natural products were depicted on clay tablets from Mesopotamia (2600 B.C) which documented oils from Cupressus sempervirens (Cypress) and
Commiphora species (myrrh) which are still used today to treat cough, cold and
inflammation. The Egyptian Ebers Papyrus (2900 B.C) documented over 700 plant-based drugs.3 The Chinese traditional medicine has been extensively documented over the centuries
with the first record dating from 1100 B.C. (Wu Shi Er Bing Fang, containing 52 prescriptions) and the Shennong Herbal (100 B.C., 365 drugs). The Indian traditional medical system called Ayurveda was developed dates from about 1000 B.C., and it is generally accepted that the defining text from Susruta and Charaka.3 The Greek physician, Dioscorides,
(100 C.E), recorded the collection, storage and the uses of medicinal herbs, while the Greek philosopher and natural scientist, Theophrastus (~300 B.C) dealt with medicinal herbs. The Arabs were the first to privately own pharmacies (8th century) with Avicenna, a Persian pharmacist, physician, philosopher and poet, contributing much to the sciences of pharmacy and medicine through works such as the Canon Medicinae.3
1.2 Traditional medicines
Traditional medical practices are the basis for most of the new therapeutics which were later on followed by chemical, pharmacological and clinical studies. Traditional medicine is still essential in developing countries where 65-70% of the world's population does not have access to modern medicines.5 Since its inception, the modern pharmaceutical industry has
Figure 1.1. Traditionally important natural products
A well-known example would be the synthesis of the anti-inflammatory agent, acetylsalicylic acid (aspirin) (Figure 1.1) derived from the natural product, salicin isolated from the bark of the willow tree Salix alba L.6 In 1803, morphine (Figure 1.1) was successfully isolated from
Papaver somniferum L. (opium poppy), which was then reported to be an important
analgesic. Historically, it is documented that the Sumerians and Ancient Greeks used poppy extracts medicinally, while the Arabian texts described opium to be addictive.6 Digitalis
purpurea L. (foxglove) had been traced back to Europe in the 10th century and in 1875 its
active constituent digitoxin (Figure 1.1), a cardiotonic glycoside, was isolated. It was found to enhance cardiac conduction, thereby improving the strength of cardiac contractibility. The antimalarial drug quinine (Figure 1.1) was isolated from the bark of Cinchona succirubra Pav. Ex Klotsch. It has been used for centuries for the treatment of malaria, fever, indigestion, mouth and throat diseases and cancer. Formal use of the bark to treat malaria was established in the mid-1800s when the British began the worldwide cultivation of the plant.6 Thus from
O H HO HO N H morphine O HO HO OH HO O HO AcO HO O aspirin salicin N N MeO HO H quinine O O O O O O O O OH H H OH H HO HO H HO H digitoxin
these examples, one could make a case that these discoveries have had a significant impact on society and have revolutionized pharmaceutical research.
1.3 Isolation and discovery of natural products
1.3.1 Natural products from microorganisms
Fungi are a class of eukaryotic organisms. Macro and micro fungi have been part of human life for thousands of years. Fungi serve as food (mushrooms), help in preparation of fermented beverages (yeasts), and synthesize compounds with immense medicinal or chemical significance. With the advances in biotechnology, their uses have extended to the extraction of enzymes, antibiotics and other pharmacologically active products.7
Figure 1.2. Reported structure of penicillin G
One of the most famous natural product discoveries derived from a fungus is penicillin G (Figure 1.2), isolated by Alexander Fleming in 1929 from the fungus Penicillium notatum.8
A countercurrent extractive separation technique which produced penicillin in high yields was required for the in vivo experimentation that revolutionized drug discovery, ultimately saved countless lives and won Ernst B. Chain and Howard Florey (along with Alexander Fleming) the 1945 Nobel prize in Physiology and Medicine.9
In 1953, Edmund Kornfeld isolated vancomycin (Figure 1.3) a glycopeptide antibiotic produced in cultures of Amycolatopsis orientalis. Vancomycin is active against a wide range of positive organisms such as Staphylococci and Streptococci and against gram-negative bacteria, mycobacteria and fungi and gained FDA approval for human usage in 1958. It is used for the treatment of severe infection and against susceptible organisms in patients hypersensitive to penicillin.4
N S H CO2H O H N O penicillin G
Figure 1.3. Structures of vancomycin and erythromycin
The macrolide erythromycin (Figure 1.3) from Saccharopolyspora erythraea is another antibiotic, which contains a 14-membered macrocycle composed entirely of propionate units. Erythromycin has a wide range of activities against gram-positive cocci and bacilli and is used for mild to moderate, upper and lower respiratory tract infections.4,10 At present there
are three semisynthetic ketolide derivatives of erythromycin, cethromycin (ABT-773, Restanza™), EP-420 (by Enanta Pharmaceuticals) and BAL-19403 (by Basilea) which are in clinical development.1
1.3.2 Natural products from plants
Plants have been well documented for their medicnal uses and they evolved and adapted over millions of years to withstand bacteria, insects, fungi and weather to produce unique microbial infections and tolerate weather changes to produce unique, structurally diverse secondary metabolites. Their ethnopharmacological properties have been used for centuries as essential sources of medicines for the earlier drug discovery.11 Even today, an
overwhelming number of the global population rely on traditional plant-based drugs for primary health care.12 A study in 2001 on 122 plant-derived drugs revealed that nearly 80%
of them were related to their ethnopharmacological purpose.13 Thus, the knowledge
assembled over centuries in traditional medicine (complementary or alternative herbal products) promoted further investigations of medicinal plants as potential medicines and led
N H H N O H N O N H OH O NHCH3 NH2 O O O O Cl O OH OH OH O O NH2 HO O O N H Cl HO NH O HOOC HO OH OH vancomycin O O O OH HO OH O O O O N HO OMe OH erythromycin
to the isolation of many natural products that have become well-known pharmaceuticals. A complete descriptive analysis of all such drugs is beyond the scope of this thesis, and thus only one specific example is highlighted here to give a general idea regarding the use of plant-derived medicine. Paclitaxel (Taxol®), (Figure 1.4) isolated from the bark of Taxus
brevifolia (Pacific Yew) is a common anticancer drug used to treat ovarian, breast, lung,
cervical, and pancreatic cancers as well as Kaposi sarcoma. In 1962 the United States Department of Agriculture (USDA) first collected the bark as part of their exploratory plant screening program at the National Cancer Institute (NCI).14
Figure 1.4. Structures of Taxol® and baccatin III
The bark from about three mature 100-year-old trees is required to provide 1 gram of Taxol® which is inefficient given that a course of treatment may need 2 grams of the drug. Current demand for Taxol® is in the region of 100–200 kg per annum (i.e., 50,000 treatments/year) and is now produced synthetically.10 Baccatin III (Figure 1.4) present in much higher
quantities and readily available from the needles of Taxus brevifolia and associated derivatives is an example of a structural analogue that can be efficiently transformed into Taxol®.10 O AcO OH O OH HO AcO O O H baccatin III O AcO OH O OH O AcO O O H O NH OH O paclitaxel (Taxol®)
Figure 1.5. Reported stuctures of artemisinin and avermectins
In 2015, the Noble Prize in Physiology and Medicine has been awarded to William C. Campbell, Santoshi Omura, for the discovery of avermectins, the derivatives of which, ivermectin (Figure 1.5), have radically lowered the incidence of onchocerciasis and lymphatic filariasis. In the same year, Youyou Tu was also honored with Noble Prize for the discovery of the plant natural product artemisinin (Figure 1.5), a drug that has significantly reduced the mortality rates for patients suffering from malaria. 15
1.3.3 Natural products from the marine organisms
Though plants have proven to be a good source for bioactive natural products, the marine environment also has also proven to offer several unique structural entities. Over the past decades a large number of marine natural products have been screened with broad range of biological activities, such as antitumor, antiviral, antibacterial antidiabetic and anti-inflammatory have been reported.16
Figure 1.6. Marine-derived antitumor agent
O O H H O O O artemisinin O O O O HO O O O O HO H O O H OH O Y X R H avermectin B1 R = Et or Me X-Y = CH=CH ivermectin R = Et (>80%) or Me (<20%) X-Y = CH2CH2 O N N O NH2 OH HO OH cytarabine (Ara-C)
Todate, seven marine-derived drugs have been approved by the Food and Drug Administration (FDA) so far, four of them are antitumor agents.17 Cytarabine (Ara-C) is one
of the marine-derived drug with antitumor activity (Figure 1.6).18
Despite the large number of NCEs isolated from marine organisms, most of them have not reached clinical trials, and only very few have been marketed as pharmaceutical products. Apart from the usual difficulties associated with any drug discovery process, the development of many promising marine natural products were hampered by lack of the sustainable source of raw material and issues related to structural complexity and scale up. The Food and Drug Administration (FDA) or European Medicines Agency (EMEA) have approved Yondelis® and Prialt® (Figure 1.7) as a drugs, without any modification from the original natural molecule. Overall it took 20-30 years to enter into the market from lead discovery stage.19
Figure 1.7. Some medicinally important marine natural products
1.4 The beginning of total synthesis
Following the discovery of naturally occurring substances such as urea, quinine, morphine and strychnine in the late eighteenth and early nineteenth centuries, considerable efforts were made for their chemical synthesis.20 The first natural product to be synthesized in the
laboratory was urea. This meant that for the first time, the person was able to synthesize an organic compounds, the molecules of living nature, in the laboratory and without the aid of living creatures or their organs. The synthesis of urea by Wöhler marked the birth of total synthesis, a sub-discipline of organic synthesis dealing with the construction of nature’s
H-Cys-Lys-Gly-Lys Cys-Ser-Arg-Leu-Met Cys Lys H2N-Cys Asp-Tyr Thr Gly-Ser Gly-Ser-Arg-Cys Lys Ala-Gly N N HO OMe OH O O OAc S O O NH MeO HO Yondelis® Prialt®
organic molecules.21 A true landmark came in 1890 with Fischer is synthesis of glucose
(Figure 1.8). Other notable total syntheses of the pre-war era include those of camphor (Komppa, 1903; Perkin, 1904, Figure 1.8), α-terpineol (Perkin, 1904), tropinone (Robinson, 1917), hemin (H. Fischer, 1929), and equilenin (Bachmann, 1939).22 The advent of organic
synthesis can also be credited with the birth of dye industry and then to pharmaceutical industries with the synthesis and commercialization of mauve (or mauveine by William Henry Perkin, Figure 1.8) which in turn served as triggers for the industrial revolution.23
Figure 1.8. Structure of mauveine A, camphor, and glucose.
The significance of these early achievements in organic synthesis and total synthesis could also be appreciated by the fact that within first 5 years of the existence Nobel prize in Chemistry, two were awarded to the German chemists Emil Fischer (1902) and Adolf von Baeyer (1905) were recognized for their contributions to organic synthesis.24
The total synthesis of strychnine (Figure 1.9) was accomplished by the prominent American organic chemist Robert Burns Woodward, a major actor in the area of total synthesis, who revolutionized the field in the 1950s and 60s.23 In addition to strychnine, he successfully
accomplished the total synthesis of some important molecules as shown in the Figure 1.9. In collaboration with the Swiss chemist Albert Eschenmoser, he also orchestrated the total
N N N H H2N mauveine A (Perkin 1865) O OH HO HO glucose (Fisher 1890) camphor (Komppa 1908, Perkin 1904) OH OH O
Figure 1.9. Natural products synthesized by Woodward’s group
synthesis of vitamin B12, the most complex natural product to be replicated in a laboratory at that time and it took over a decade to complete.25 His numerous contributions to this field
of chemistry were recognized with the 1965 Nobel Prize ‘for his achievements in the art of organic synthesis’.24 Woodward’s contributions also included the adoption of modern
instrumentation for purification and structural elucidation purposes, as well as theoretical aspects of organic chemistry, for example, the Woodward–Hoffmann rules.26 The American
chemist, Elias J. Corey, is one of the most eminent chemistry whose numerous contributions helped shape organic synthesis during the second half of the twentieth century. His achievements included the introduction of the theory of retrosynthetic analysis, the development of several new synthetic methods, reagents and catalysts, and the total synthesis of numerous bioactive naturally occurring substances, some of which are shown in the Figure
1.10.27,28 He was particularly active in the area of asymmetric synthesis, and the development
of boron-based asymmetric catalysis, such as the Corey-Bakshi-Shibata oxazaborolidine reagent.29 Corey was awarded the Nobel Prize in Chemistry in 1990 ‘for his development of
the theory and methodology of organic synthesis’.30
N H N H MeO2C O O OMe OMe OMe OMe H H reserpine (1958) O OH H O O H H cortisone (1951) NMe HN CO2H H lysergic acid (1954) N O O H H H H N strychnine (1954) MeO OH
Figure 1.10. Natural products synthesized by Corey’s group
The latter part of the twentieth century witnessed impressive advances in the area of new synthetic methodology, which propelled the art of organic synthesis to higher levels of elegance, practicality and efficiency. These new methods facilitated discovery research, product development and manufacturing of pharmaceuticals and other fine chemicals that benefited society. Besides those of Corey and Woodward, the field of total synthesis has benefited from the groundbreaking contributions of many innovative and resourceful chemists, such as Brown, Stork, Eschenmoser, Djerassi, Bartlett, Nicolaou, Danishefsky and Ley to name but a few.31,32,33
1.5 Discovery of new reactions
1.5.1 The Diels-Alder reaction
In the early part of the 20th century, amidst continuing efforts to develop the [4+2]
cycloaddition reaction by multiple groups in the field of organic chemistry Professor Otto Diels and his student, Kurt Alder, were successful in properly identifying the products arising from the reaction of quinone (1.1) cyclopentadiene (1.2, Scheme 1.1).34
CO2H OH HO HO prostagladin F2a (1969) O O OH OH O OH OH erythronolide B (1975) O O OH OAc H OH forskolin (1988) H CO2H O O HO antheridic acid (1985) OH OH H
Scheme 1.1. Diels-Alder reaction between quinone with cyclopentadiene
This represented a historic event in the field of chemistry, and Diels and Alder espoused the virtues of this eponymous reaction in their landmark 1928 paper. They particularly envisioned its application in the field of natural product synthesis, by remarking “Thus it appears to us that the possibility of synthesis of complex compounds related to or identical with natural products such as terpenes, sesquiterpenes, perhaps even alkaloids, has been moved to the near prospect’’.34 The truly visionary application of the Diels-Alder reaction to
total synthesis had to await imaginative and creative aptitudes of next generation of chemists such as R. B. Woodward, who used it in some highly elegant and instructive syntheses. In 1952, Woodward et al. described their pioneering method of a quinone-based Diels-Alder reaction for the biosynthesis of the steroids cortisone (1.12, Scheme 1.2) and cholesterol (1.13, Scheme 1.2).34 O O O O H H O O O O H H endo (1.5) endo (1.3) O O H H H H Diels-Alder diadduct (1.6) monoadduct (1.4) Diels-Alder + 1.1 1.2
Scheme 1.2. Application of Diels-Alder reaction in the total synthesis of cortisone and cholesterol
1.5.2 Cross-coupling reactions
Ever since the birth of organic synthesis, carbon-carbon bond forming reactions for the formation of a carbon framework have been the definitions of progress in this field. Palladium-catalyzed cross-coupling reactions and metathesis reactions two more such reactions emerged as rivals in the last quarter of the previous century.35 In the evolution of
organic chemistry, no other type of reaction has played a larger role than carbon-carbon bond-forming reactions. Among them, the palladium-catalyzed cross-coupling reactions are the most prominent.35 Recently, iron complexes have found increasing application in organic
synthesis, especially as catalysts. As a fact, metal-catalyzed reactions are essential tools of synthetic chemistry. It is postulated that the catalysts which possess a combination of efficiency, selectivity and reliability with cost-effectiveness and low toxicity, will be ideal for optimal usage in the future.36. In this context, iron offers a unique advantage over other
transition metals: it is inexpensive, most of its salts exhibit low toxicity and are with low environment poisoning or CMR classification (carcinogenic, mutagenic or toxic for reproduction). Therefore, even when used in stoichiometric amounts, iron salts remain cheaper and safer that many other catalytic metal complexes (e.g. palladium salts), that are used in cross-coupling reactions. These advantages make iron complexes the promoters of
O O endo TS (1.9) MeO O O MeO [Diels-Alder] O O MeO H O O O H OH H H H H H H HO and cholesterol (1.13) cortisone (1.12) [epimerisation] 1.7 1.10 O O MeO H + 1.8 1.11 OH
choice (under catalytic or even stoichiometric amounts) for C-C bond formation, as required to build the carbon backbone of poly-functionalized molecules in the total synthesis of natural products and bioactive ingredients.36
1.5.3 Metathesis reactions
Except for palladium-catalyzed cross-couplings, no other group of reactions has had such a profound impact on in the field of total synthesis than the metathesis reactions of olefins, enynes, and alkynes (Scheme 1.3).37 The alkene-metathesis reaction is the most commonly
employed of the metathesis based carbon-carbon bond forming reactions. In the context of total synthesis, the alkene ring-closing metathesis reaction and, more recently, the alkene cross-metathesis reaction are the ones that have been used mostly. The success of the alkene-metathesis reaction is largely due to the ready availability of catalytic systems that display high activity and excellent functional group tolerance. Three of the most commonly used catalysts (all of which are commercially available) are shown in the Figure 1.11.37
Figure 1.11. Commonly used catalysts for metathesis reactions
N Mo O O F3C F3C Ph F3C CF3 Ru Ph (Cy)3P (Cy)3P Cl Cl Ru (Cy)3P Cl Cl N N
Schrock catalyst First-generation Grubbs catalyst Second-generation Grubbs catalyst
Scheme 1.3. Different types of metathesis reactions
In 1990, Schrock and his co-workers first used the molybdenum-based catalyst (Figure
1.11).38 A case in point is the early studies toward the synthesis of the ornate oligosaccharide
antibiotic everninomicin13,384-1 (1.17, Scheme 1.4) reported by the Nicolaou group.39
These are impressive examples featuring multiple uses of RCM reactions including the formation of several medium-sized rings. Lately, however, alkyne metathesis has gained prominence in the field of total synthesis in its own right.40 There are still some unresolved
issues with the existing metathesis catalysts such as availability of cheaper and stable catalysts, efficient removal of metal impurities, and high dilutions for macrocyclizations. Thus the next important development in this field would be catalysts with more control on the stereochemistry of the newly formed double bond. There have been recent reports regarding such progress, and further developments are expected.37
R1 R2 R 3 R4 R 1 R3 R 2 R4 alkene cross-metathesis ring closng metathesis ring-opening metathesis
ring-closing enyne metathesis
R3
R4
enyne cross-metathesis
ring-closing alkyne metathesis
alkyne cross-metathesis R1 R2 R3 R4 R1 R3 R2 R4 R1 R2 R 1 R2 R4 R3 (1) (2) (3) (4) (5) (6) + + + + +
Scheme 1.4. Synthesis of antibiotic everninomicin 13,364-1
1.6 A platform for innovation
1.6.1 Structural determination and confirmation of structure
Since the discovery of modern analytical techniques such as X-ray diffraction and nuclear magnetic resonance spectroscopy, determining structures have become much more precise.41,42 However, despite these revolutionary techniques the result can still be
incomplete or misinterpreted leading to structural errors that are still reported to date. It has been reported that over a period of five years, 369 natural products are poorly assigned and represented.43 Common structural errors include link connectivity errors, stereochemistry of
alkenes, the number of carbon on long aliphatic chains (or molecular weight), absolute configuration and relative configuration of compounds bearing stereogenic centers.44
As mentioned earlier, the development of newer methods of synthesis drives forward the research on new structures. Since the days of pioneers of organic synthesis such as Woodward and Corey, the total synthesis of natural products has led to a detailed understanding of organic chemistry and accelerated the discovery of reactions to fuel an array of synthetic methodologies.45 With the availability of these synthetic methods, it is now
possible to construct enormous structures of impressive complexity, excellent regio-chemical and stereochemical control. Synthetic chemistry is said to have been pushed to its limits with
Cl HO Cl OMe O O O O O O OMe NO2 O HO O O O O O OMe O O O O O O O HO OH O O OH OH OMe OH O O MeO OH Cl HO Cl OMe O O O O O O OMe NO2 O HO OMe O O TBSO O O TBSO ring-closing metathesis everninomicin 13,364-1 (1.17) 1.16 1.14 1.15 Grubbs' catalyst
the synthesis of molecules such as ciguatoxin (Figure 1.12),46,47 or palytoxin (Figure
1.12).48,49 Now the question is no longer whether we are capable of synthesizing a targeted
molecule, but how to synthesize it.
Figure 1.12. Examples of the most complex natural compounds synthesized
1.6.2 Ideal synthesis
In this new era of synthetic chemistry, simply synthesizing a natural compound is not enough.
O O O O O O O O O O O O O OH HO OH H H OH H H H H H H H H H H H H H H H H HO H OH H H ciguatoxin (2001) O N H N H HO O O OH OH OH HO OH OH H OH HO OH OH O O OH OH O OH HO OH OH OH O O OH HO OH HO OH OH OH OH OH OH H OH OH OH OH OH O O O O OH OH HO OH OH HO OH OH H2N OH palytoxin (1994)
time respect the environment. The usage of toxic reagents such as heavy metals that could contaminate a synthesized product is undesirable. Also, these syntheses need to be carried out on a large scale to facilitate evaluation and future commercialization.50 Thus the
construction of a complex molecule is not only challenging but also intellectually motivating. The concept of "ideal synthesis" brought about by Hendrickson in 1975 has now become a reality that affects the practice of synthetic chemistry.49,51 The concepts of atom economy,52
step economy53 and redox economy54 are the aphorisms of organic synthesis in the 21st
century.55
A tangible, quantitative expression to measure the ideality of a synthetic route was provided by Baran and co-workers by dividing the number of useful, constructive steps that contribute to the elaboration of the target structure, by the number of total reactions in the sequence (Figure 1.13).56 By this yardstick, many total syntheses were previously considered
proficient, such as synthesis of brevenal by Rainier, tend to fall by the wayside (38 steps, 0.99% overall yield).57
Figure 1.13. The quantitative measure for an “ideal’’ total synthesis
In comparison, Baran points to the 100% ideality of typical biosynthetic routes by an illustration of the natural synthesis of penicillins (1.20, Scheme 1.5). Starting from completely unprotected amino acids cysteine, valine, and amino adipate, a construction step led to tripeptide 1.18. After that, a strategic redox reaction follows in which isopenicillin-N-synthase builds up the bicyclic penam scaffold of isopencillin N 1.19. Another construction steps provided the structure 1.20, which is common to all pencillins. The similar analysis could also be used for other famous natural product classes (such as erythronolide, paclitaxel, and vancomycin).56
% IDEALITY =
Construction Reactions + Strategic Redox Reactions Total Steps
Scheme 1.5. Biosynthetic route to penicillins
1.7 Different synthetic strategies
1.7.1 Divergent synthesis
A typical approach taken in the development of a synthetic route of a compound is called target-oriented synthesis (TOS). Linear or convergent sequences are centered in obtaining a single product of interest (Figure. 1.14). A current aspect of total synthesis is the development of a single synthetic sequence to account for the synthesis of several targeted compounds. This approach differs substantially from linear syntheses or convergent syntheses because the synthesis of a common intermediate will be used to make different analogues by different synthetic routes.58 HOOC COOH NH2 3 (L)-2-aminoadipate HOOC SH NH2 HOOC NH2 (L)-valine (L)-cysteine 3 ATP 3 AMP H2O + 3 PPi enzyme HOOC H N O SH NH O HOOC 3 NH2 HOOC HN O 3 NH2 N O S COOH enzyme CoA + (L)- amino adipate RCOSCoA +H2O N S COOH O H N O R 1.18 1.19 pencillins (1.20) O2 2H2O enzyme
Figure 1.14. Different synthetic strategies
Scheme 1.6. Li’s divergent route to taiwaniaquinols and taiwaniaquinones
MeO OMe OMe H common intermediate (1.21) HO OMe OH taiwaniaquinol D HO OMe OH taiwaniaquinol B O O OH O H taiwaniaquinone A O OMe O H taiwaniaquinone F H MeO OMe OMe O H O H O H O H O H
As an example, Li’s reported on the synthesis of taiwaniaquinols and taiwaniaquinone by a divergent synthesis pathway. In their approach, synthesis of the common intermediate 1.21 was used to make different analogues by different synthetic routes (Scheme 1.6).59
1.7.2 Biomimetic synthesis
Cascade reactions and biomimetic sequences have been recognized as an attractive feature for the total synthesis of natural products and other complex molecules. Biomimetic reactions aim to replicate key reactions to achieve a good level of complexity with minimal steps. The cationic cyclization of isoprenoids to form steroidal structures is an excellent example of a natural reaction that can be replicated in the laboratory. The total synthesis of progesterone (1.25, Scheme 1.7) by biomimetic route reported by Johnson et al. is a good example.60 They
have demonstrated that 1.22 could be cyclized in one step to provide the structure 1.24 that was transformed into progesterone (1.25).
Scheme 1.7. Biomimetic synthesis of progesterone
1.7.3 Semisynthesis
The semisynthesis of bioactive compounds and natural products are the most reliable approaches to meet the material needs of these design and production of medicines.61 The
OH O O O O H H H H O H H H H O progesterone (1.25) K2CO3 1.22 1.23 1.24 TFA
implementation of such a strategy and won the Nobel Prize in medicine in 2015.62 This
natural compound present in the plant Artemisia annua has been used in traditional Chinese medicine for ages. The typical yields of artemisinin based on dried plant material are reported to be in the range of 0.8% and the produced quantities have not always met the demand.61,63
However the development of total synthesis of artemisinin was not a viable large-scale and also cost-effective process.64 A biosynthetic pathway heterologous was first developed for
the production of artemisinic acid 1.26 from the yeast Saccharomyces cerevisiae.63,64
Synthetic efforts subsequently led to the transformation of 1.26 to artemisinin 1.28 by a 3-step process with 55% yield.62 Today, artemisinin is produced on a scale of more than 35
tons per year and has become a new-generation drug approved by the WHO to treat malaria.61
Scheme 1.8. Production of the antimalarial drug (+)-artemisinin
1.8 Natural products and drug discovery
Natural products and their derivatives have historically been invaluable as a source of therapeutic agents. Following the ‘Golden Age of Antibiotics’, there was a worldwide incentive in the pharmaceutical industries to discover additional novel antibiotics, which led to the initiation of natural product discovery (NPD) programs that focused not only on antibacterial and antifungal targets but also on infectious diseases. The outcome of some of these programs led to the development of compounds for the treatment of cancer, microbial infections, hypercholesteremia and immune-suppressive for controlling graft rejection during
O HO H H H RuCl2[(R)-dtbm-Segphos](DMF)2 H2, 22 bar Et3N, MeOH artemisinic acid (1.26) O O H H H EtO O O O H H O O O (+)-artemisinin (1.28) Hg vapor lamp tetraphenylporphyrin air, TFA 1.27 EtOC(O)Cl, K2CO3
(55% yield over all steps
organ transplantations.65,66 However, the NPD program was decommissioned by many of the
larger pharmaceutical companies during the 1990s and early 2000s with the advent of automated high throughput screenings (HTS). Because of supply problems, the time required to develop a natural product from an extract hit to a pharmaceutical was deemed to be too long. On the other hand, HTS technologies relied on combinatorial chemistry to generate large compound libraries. As a result, in the past two decades “classical natural product chemistry” has largely been replaced by molecular target-based drug discovery, utilizing large combinatorial libraries to obtain efficient “hits”.66 Nevertheless advances in technology
and sensitive instrumentation for the rapid identification of novel bioactive natural products and structure elucidation continue to improve the natural product discovery process. From the 1980s onwards it was thought that combinatorial chemistry would be the future source of numerous novel carbon skeletons and drug leads or new chemical entities (NCEs). However, during the late 1990s, synthetic chemists realized that these libraries lacked the complexity of the intricate natural products synthesized by nature.67
Figure 1.15. Structure of kinase inhibitor sorafenib approved by FDA
As a result, there has only been only one combinatorial NCE approved by the U.S Food and Drug Administration (FDA) in that period, the kinase inhibitor sorafenib (Figure 1.15) for renal carcinoma.67 Next, the concept of diversity-oriented synthesis (DOS) was adopted in
which synthetic chemist would synthesize compounds that resembled natural product (mimtics) or based on the natural product topologies. These compounds are currently being tested in a large number of variety of biological screens to determine their role (s) as leads to novel drug entities. An analysis of new drugs approved by the FDA (and similar organizations) between 1981 and 2014 revealed that half of these drugs were directly related to NPs.68 N H NH O F3C Cl O N N H O sorafenib
1.9 Thesis objectives
The preceding sections of this chapter serve as a brief introduction to the history of total synthesis and its central role in the development of organic chemistry and many other fields, particularly medicine and agriculture. The focus of research in the Boukouvalas group is the total synthesis of structurally unusual, biologically important natural products and the development of new synthetic methods. My doctoral research is mainly focused on estabilishing new synthetic methodologies for butenolide syntheses and their applications towards natural product synthesis (Figure 1.16).
Figure 1.16. Structures of substituted butenolides and general synthetic route to
furo[2,3-b]chromones O O H2N O basidalin O O enhygrolide A O O O R2 O N EtO O R2 R1 R1 O O O bothriofuran A O O OH OH OH O OH 10 donnaienin A O O OPG OPG OPG O OH 10 + O O R1 PivO O O R1 R2 FeCl2 R2MgX OH substituted butenolides furo[2,3-b]chromones OH 150 °C
The objectives of my doctoral studies are therefore:
1. To carry out the first total synthesis of antitumor antibiotic basidalin, the only natural product known thus far to possess a tetronamide motif (Chapter 2),
2. To develop a new, iron-catalyzed process for installing carbon substituents onto the -position of the butenolide ring and shown the utility of this method in the first synthesis of the marine myxobacterial antibiotic enhygrolide A (Chapter 3),
3. To establish a new methodology for the synthesis of -hydroxybutenolide residue and its application towards constructing a rare type of annonaceous acetogenin, namely donnaienin A (Chapter 4),
4. To discover an efficient method for the synthesis of furo[2,3-b]chromones using Diels−Alder chemistry with oxa-Michael addition/elimination, followed by exploring the scope of this new method and also its application in the first synthesis of a furo[2,3-b]chromone natural product (bothriofuran A) (Chapter 5).
1.10 Description of the format of the thesis
The content of Chapter 2 and Chapter 3 is identical to the published papers but have been reformatted to ensure the coherence of the thesis. Each chapter will begin with a specific introduction in order to give brief idea to the reader about the projects. Then, a preamble will clarify my contribution for each of the research projects will be discussed. After that a short summary in French and also in English, followed by complete article along with the experimental part will be presented. Chapter 3 (Section 3.9) and Chapter 4 and also Chapter 5 are corresponding to projects that have not been published, so they will be presented in the form of classic chapters and these will begin with general introduction followed by results and discussion and conclusions.
1.11 References
1 Mishra, B. B.; Tiwari, V. K. Eur. J. Med. Chem. 2011, 46, 4769.
2 Rey-Ladino, J.; Ross, A. G.; Cripps, A.W.; McManus, D. P.; Quinn, R. Vaccine 2011, 29,
6464.
3 Cragg, G. M.; Newman, D. J. Pure Appl. Chem. 2005, 77, 7. 4 Butler, M. S. J. Nat. Prod. 2004, 67, 2141.
5 Cragg, G. M.; Newman, D. J. Biochim. Biophys. Acta. 2013, 1830, 3670.
6 Der Marderosian, A.; Beutler, J. A. The Review of Natural Products, 2nd ed.; Facts and
Comparisons: Seattle, WA, USA, 2002; pp. 13.
7 Lorenzen, K.; Anke, T. Curr. Org. Chem. 1996, 2, 329.
8 Mann, J. Murder, Magic, and Medicine; Oxford University Press, Inc.: New York; 1994;
pp. 164.
9 Abraham, E. P.; Chain, E.; Fletcher, C. M. Lancet 1941, 16, 177.
10 Dewick, P. M. Medicinal Natural Products: A Biosynthentic Approach, 2nd ed.; John Wiley
and son: West Sussex, UK, 2002; pp. 520.
11 McRae, J.; Yang, Q.; Crawford, R.; Palombo, W. Environmentalist 2007, 27, 165.
12 Farnsworth, N. R.; Akerele, R. O.; Bingel, A. S.; Soejarto, D. D.; Guo, Z. Bull WHO 1985,
63, 965.
13 Fabricant, D. S.; Farnsworth, N. R. Environ. Health Perspect. 2001, 109, 69. 14 Cragg, G. M. Med. Res. Rev. 1998, 18, 315.
15 Shen, B. Cell 2015, 163, 1297.
16 Mayer, A. M. S.; Rodríguez, A. D.; Taglialatela-Scafati, O.; Fusetani, N. Mar. Drugs 2017,
15, 273.
17 Gomes, N.; Lefranc, F.; Kijjoa, A.; Kiss, R. Mar. Drugs 2015, 13, 3950. 18 Hunnisett-Dritz, D. Am. J. Health Syst. Pharm. 2012, 69, 1416.
19 Martins, A.; Vieira, H.; Gaspar, H.; Santos, S. Mar. Drugs 2014, 12, 1066. 20 Nicolaou, K. C. Angew. Chem. Int. Ed. 2013, 52, 131.
21 Wöhler, F. Ann. Phys. Chem. 1828, 12, 253.
22 Nicolaou, K. C.; Sorensen, E. J. J. Chem. Educ. 1998, 75, 1225. 23 Nicolaou, K. C. Proc. R. Soc. 2014, 470, 20130690.
24 http://www.nobelprize.org/nobel_prizes/ chemistry/laureates/ 25 Eschenmoser, A. Angew. Chem. Int. Ed. 2011, 50, 12412.
26 (a) Woodward, R. B. Spec. Publ. Chem. Soc. 1967, 21, 217. (b) Woodward, R. B.;
Hoffmann, R. Angew. Chem. Int. Ed. 1969, 8, 781.
27 Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; Wiley, New York, 1995. 28 (a) Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc. 1969,
91, 5675. (b) Corey, E. J.; Kim, S.; Yoo, S.; Nicolaou, K. C.; Melvin Jr., L. S. D.; Brunelle,
J.; Falck, J. R.; Trybulski, E. J.; Lett, R.; Sheldrake, P. W. J. Am. Chem. Soc. 1978, 100,
