Enantioselective Synthesis of Bioactive Molecules and Development of Synthetic Methodologies ...

251 Pages·2015·3.87 MB·English

by  3 Idiots

Enantioselective Synthesis of Bioactive Molecules
and Development of Synthetic Methodologies
Involving N-Heterocyclic Carbene and Iodine
Catalysis of Alkenes and Aldehydes

Thesis Submitted to the AcSIR for the Award of
The Degree of
DOCTOR OF PHILOSOPHY
In Chemical Sciences

By
Rambabu Reddi
AcSIR Roll: 10CC11J26002

UNDER THE GUIDANCE OF
Dr. A. Sudalai

Chemical Engineering and Process Development Division
CSIR-National Chemical Laboratory
Pune-411008, INDIA

June 2015
(cid:1)

Dedicated To
Amma – Nanna
and Tammudu
(cid:1)
Dr. A. Sudalai [phone]
Senior Principal Scientist
[email protected]
Chemical Engineering &
Process Development Division

CERTIFICATE

This is to certify that the work incorporated in the thesis entitled
“Enantioselective Synthesis of Bioactive molecules and Development of
Synthetic Methodologies Involving N-Heterocyclic Carbene and Iodine
catalysis of Alkenes and Aldehydes” which is being submitted to the AcSIR for
the award of Doctor of Philosophy in Chemical Sciences by Mr. Rambabu
Reddi was carried out by him under my supervision at the CSIR-National
Chemical Laboratory, Pune. Such material as has been obtained from other
sources has been duly acknowledged in the thesis.

June 2015 Dr. A. Sudalai
Pune (Research Guide)
CCSIR-NATIONAL CCHEMICAAL LABOORATORYY

DECCLARATIION
I hereby decllare that the thesis entitled “Enanttioselective Synthesis of Bioactivve
mmolecules aand Devellopment ooff Synthetiic Methoddologies Innvolving NN-
HHeterocyclicc Carbenee and Iodiine catalyssis of Alkkenes and Aldehydess”
suubmitted to AcSIR for the award oof degree off Doctor off Philosophyy in Chemical
Sciences, hass not been ssubmitted byy me to anyy other univeersity or insstitution. Thhis
wwork was carrried out at thhe CSIR-Naational Chemmical Laborattory, Pune, IIndia.

Juune 2015 Rambabu RReddi
PPune CE & PD DDivision
CSIR-Natioonal Chemical Laboratorry
Pune-411 008, INDIA.
CONTENTS
Page No.
Acknowledgement i
Abbreviations iv
General Remarks vi
Abstract vii

Chapter I N-Heterocyclic Carbene Catalyzed Oxidative Coupling of
Aromatic Aldehydes with nBu SnCl and allylic C-H Bonds
3
Section I N-Heterocyclic Carbene-Catalyzed Oxidative Stannylation of
Aromatic Aldehydes: A Facile Entry to Organotin(IV)
Carboxylates
1.1.1 N-Heterocyclic Carbene Catalysis: Literature 1
1.1.2 Organotin(IV) Carboxylates: Introduction 5
1.1.3 Review of Literature 7
1.1.4 Present Work 9
1.1.4.1 Objective 9
1.1.4.2 Results and Discussion 9
1.1.5 Conclusion 16
1.1.6 Experimental Section 19
Section II N-Heterocyclic Carbene Catalyzed Oxidative Cross
Dehydrogenative Coupling of Aldehydes with Allylic sp3 C-H
Bonds
1.2.1 Cross Dehydrogenative Coupling 22
1.2.2 Review of Literature 23
1.2.3 Present Work 29
1.2.3.1 Objective 29
1.2.3.2 Results and Discussion 30
1.2.4 Conclusion 36
1.2.5 Experimental Section 36
1.2.6 References 39
Chapter II N-Heterocyclic Catalyzed Oxidative Coupling of Aldehydes with
Alkenes, Epoxides and α-Bromoacetophenones
Section I N-Heterocyclic Carbene Catalyzed Regioselective Oxo-
acyloxylation of Alkenes/Epoxides with Aromatic Aldehydes: A
High Yield Synthesis of α-Acyloxy Carbonyl Compounds
2.1.1 Introduction 43
2.1.2 Review of Literature 44
2.1.3 Present Work 49
2.1.3.1 Objective 49
2.1.3.3 Results and Discussion 49
2.1.4 Conclusion 58
2.1.5 Experimental Section 59
Section II N-Heterocyclic Carbene Catalyzed Oxidative Coupling of
Styrenes/α-Bromo Acetophenones with Aldehydes for the
Synthesis of α,β-Epoxy Ketones
2.2.1 Introduction 66
2.2.2 Review of Literature 67
2.2.3 Present Work 72
2.2.3.1 Objective 72
2.2.3.2 Results and Discussion 72
2.2.4 Conclusion 83
2.2.5 Experimental Section 83
2.2.6 References 87
Chapter III I Catalyzed Oxo- and Hydroxy-acyloxylation of Alkenes with
2
Carboxylic acids and Formal Synthesis of (S,S)- Reboxetine
Section I I -Catalyzed Regioselective Oxo- and Hydroxy-Acyloxylation of
2
Alkenes and Enol ethers: A Facile Access to α-Acyloxyketones
and Diol Derivatives

3.1.1 Introduction 89
3.1.2 Review of Literature 90
3.1.3 Present Work 101
3.1.3.1 Objective 101
3.1.3.2 Results and Discussion 101
3.1.4 Conclusion 109
3.1.5 Experimental Section 109
Section II Enantioselective Formal Synthesis of (S,S)-Reboxetine using I -
2
Catalyzed Oxoacyloxylation-CBS reduction Reaction
3.2.1 Introduction 116
3.2.2 Reboxetine and pharmacology 117
3.2.3 Review of Literature 118
3.2.4 Present Work 126
3.2.4.1 Objective 126
3.2.4.2 Results and Discussion 127
3.2.5 Conclusion 132
3.2.6 Experimental Section 133
3.2.7 References 137
Chapter IV Studies towards the Synthesis of (+)-Neopeltolide and Total
synthesis of DAB-1 and Zoledronic acid
Section I Studies Towards the Total Synthesis of (+)-Neopeltolide using
NHC Catalysed Oxo-acyloxylation/Reductive Oxa-Michel
Addition Strategy
4.1.1 Isolation, Structure and Pharmacology 140
4.1.2 Review of Literature 141
4.1.3 Present Work 157
4.1.4.1 Objective 157
4.1.4.2 Results and Discussion 158
4.1.5 Conclusion 172
4.1.6 Experimental Section 172
Section II Enantioselective Synthesis of 1,4-Dideoxy-1,4-imino-D-Arabinitol
using Co (III)(salen)-catalyzed HKR of Two-Stereocentered anti-
Azidoepoxide
4.2.1 Introduction and pharmacology 184
4.2.2 Review of Literature 185
4.2.3 Present Work 191
4.2.4 Objective 191
4.2.4.1 Results and Discussion 192
4.2.4.2 Conclusion 203
4.2.5 Experimental Section 204
Section III Process for the Synthesis of Zoledronic acid
4.2.1 Pharmacology of bisphosphonic acids: Zoledronic acid 211
4.2.2 Review of Literature 212
4.2.3 Present Work 214
4.2.3.1 Objective 214
4.2.3.2 Results and Discussion 214
4.2.4 Conclusion 218
4.2.5 Experimental Section 219
4.2.6 References 221
4.2.7 List of Publications 223
ACKNOWLEDGEMENT
I would like to sincerely thank everybody who has, in one way or the other,
contributed in the successful completion of my thesis. I wouldn’t be doing justice by
merely naming everybody who helped me but at the same time it will be too difficult
for me to express my sincere thanks in the form of words, I will nonetheless try to
make a sincere effort …
I wish to express my heartfelt gratitude towards my research supervisor Dr. A.
Sudalai, for his care and providing me an opportunity to work in his laboratory
where he estabilished the platform for advancing the knowledge through sharing of
his experience at every stage of my tenure which helped me to achieve this target. His
suggestions, criticisms and constant encouragement helped me immensely to grow as
a chemist. His constant effort to instill us with several most essential habits, like
weekly seminars, group meetings and daily planning, made me confident to start an
independent scientific career and hence I preserve an everlasting gratitude for him.
My sincere regards and reverence are for him, forever.(cid:1)I believe the better way of
thanking him would be through my future contribution to the scientific community.
I thank Dr. B. D. Kulkarni and Dr. V. V. Ranade, Deputy Director and Head,
CE-PD division, for their help and support. My special thanks to Dr. S. Gurunath for
his constant encouragement and moral support. I also thank the DAC members Dr.
Pradeep Kumar Tripathi, Dr. Akkattu T. Biju, and Dr. S. A. R. Mulla for scrutinizing
and evaluating my work at every stage of my progress. It’s my privilege to thank the
Director, NCL for giving me this opportunity and providing all necessary
infrastructure and facilities. I specially thank CSIR, New Delhi for the JRF and SRF
fellowship.
I thank NMR group, elemental analysis group and Dr. Santhakumari Madam
for their help in obtaining the analytical data. I thank the library staff, chemical
stores & purchase staff and glass blowing section staff of NCL for their cooperation. I
also thank Dr. C. G. Suresh and Student academic section at NCL for their help in
verifying all my documents. I thank PD office staff Mr. Bhosale, Mr. Kakade and Mr.
Suresh for their cooperation.
I am immensely thankful to my seniors Dr. Pandu, Dr. Tanveer, Dr.
Santhosh, Dr. Varun, Dr. Dayanand, Dr. Chaithanya, Dr. Senthil, Dr. Pratibha and
Dr. Dattatray for their useful training in the initial phase of my career. It’s my
i
pleasure to thank all my lab mates cum friends Dr. Venkat, Brij, Soumen, Sunita,
Pragati, Ravindra, Anil, Komal, Rohit, Arjun, Shubhangi, Rupali, Madhura, Ashwini,
Prabagar for providing me a cheerful atmosphere in the lab and in every aspect
throughout this research.
Especially, I take this opportunity to thank these four people, who helped me a lot in
completion of my thesis work. Firstly, Dr. Chaithanya Kiran, who tought me all the
lab techniques in the initial period to improve my working style and knowledge. I also
want to acknowledge Pushpa and Arjun, who worked with me during this period and
became a part of my work. My special and heartiest thanks to PKP, who helped me
through healthy discussions, ideas and analysis of research work which improvised
me a lot and made me achievement oriented.
I am privileged to be an inmate of Golden Jubilee Hostel where I experienced
company of Dr. Chandrababu Naidu, Dr. Manoj Kumar Warada, Dr. Suneel, Dr.
Rajendar-Yogita, Dr. Sridhar, Dr. Swaroop, Dr. Vilas-Sunita, Dr. E. V. V. Ramesh,
Dr. Srinivas vidadala, Dr. Venu, Dr. Narasimha, Dr. Bhogesh, Dr. Ravi, Balanagulu
who have given valuable suggestions and encouragement. My heartful thanks to all
my friends Janakiram, Rami Reddy, Suresh, Nagendra, Narendra, Venkateswara rao,
Devadatta, Kashi, Innaiah, Shantivardhan Reddy, Chaithanya Krishna, Sreekanth
Dama, Satish Chandra, Sateesh Battu, Seetharam, Trinadh, Hanuman Prasad and
Srikanth Tulusani, Venkatesh, Ravi Kiran Reddy for their fun, criticism with affection,
and wonderful help. They have always been there for me, whenever I needed their
help. I thank and appreciate their brilliant minds, courage to live on the cutting edge
and generous spirit. My special thanks to my roommates Dr. Chandrababu and
Manoj for their valuable presence with me at Room No: 102 in GJ Hostel. I could see
some of the most emerging young scientists with inspiring great human beings at
NCL, for all of them my thanks and wishes. With much appreciation, I would like to
admire all of my friends in NCL for their kind support.
I would like to thank all my teachers Dr. B. Jaganmohan Reddy, Ramakrishna
Sir who helped me a lot for their inspirational teaching useful advices and I also
thank Dr. Jadeja for igniting the spark of research in me. I wish to thank all my UG
and PG classmates for their motivation and support.
I would also like to extend my gratitude towards my Intermediate friend Nalla
Karteek for his encouragement and support, My B. Sc. Friends Nagaraju nekkala,
ii