enantioselective synthesis of hydroxylated pyrans, pyrrolidine alkaloid and lactones using ...

298 Pages·2012·10.36 MB·English

ENANTIOSELECTIVE SYNTHESIS OF HYDROXYLATED
PYRANS, PYRROLIDINE ALKALOID AND LACTONES
USING ASYMMETRIC DIHYDROXYLATION,
HYDROLYTIC KINETIC RESOLUTION AND
ORGANOCATALYTIC ALDOL REACTION

A THESIS SUBMITTED TO THE
SAVITRIBAI PHULE PUNE UNIVERSITY
FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
IN
CHEMISTRY
BY
KRISHANU SHOW

(RESEARCH GUIDE)
Dr. PRADEEP KUMAR

DIVISION OF ORGANIC CHEMISTRY
CSIR-NATIONAL CHEMICAL LABORATORY
PUNE-411008, INDIA
NOVEMBER 2015
CSIR-NATIONAL CHEMICAL LABORATORY
Dr. Homi Bhabha Road, PUNE-411 008, INDIA

Dr. Pradeep Kumar, FNA Telephone: + 91-20-25902627
Chief Scientist & Head Fax: + 91-20-25902629
Division of Organic Chemistry E-mail: [email protected]
Website: http://www.ncl-india.org

CERTIFICATE

This is to certify that the work presented in the thesis entitled
“ENANTIOSELECTIVE SYNTHESIS OF HYDROXYLATED PYRANS,
PYRROLIDINE ALKALOID AND LACTONES USING ASYMMETRIC
DIHYDROXYLATION, HYDROLYTIC KINETIC RESOLUTION AND
ORGANOCATALYTIC ALDOL REACTION” submitted by Krishanu Show was
carried out by the candidate at CSIR-National Chemical Laboratory, Pune under my
supervision. Such materials as obtained from other sources have been duly
acknowledged in the thesis.

(Dr. Pradeep Kumar)
Research Guide
Division of Organic Chemistry
CSIR-National Chemical Laboratory
Pune 411008, INDIA November 2015
CANDIDATE’S DECLARATION

I hereby declare that the thesis entitled “ENANTIOSELECTIVE SYNTHESIS OF
HYDROXYLATED PYRANS, PYRROLIDINE ALKALOID AND LACTONES
USING ASYMMETRIC DIHYDROXYLATION, HYDROLYTIC KINETIC
RESOLUTION AND ORGANOCATALYTIC ALDOL REACTION” submitted
for the degree of Doctor of Philosophy in Chemistry to the Savitribai Phule Pune
University has not been submitted by me to any other University or Institution. This
work was carried out at CSIR-National Chemical Laboratory, Pune, India.

Krishanu Show
Senior Research Fellow
Division of Organic Chemistry
CSIR-National Chemical Laboratory
Pune-411008, INDIA November 2015
Dedicated to
My Beloved Family
&
well wishers
Acknowledgements

Synthetic chemists often define their achievements in terms of the number of natural
products they have synthesized or the number of novel reactions they have developed.
Yet, I realize that my greatest achievements have been the professional and personal
relationships I have developed that have got me to this stage in life. So, it is with
tremendous gratitude that I write these acknowledgements to show my appreciation to
some of the people who have helped me throughout the years. I am grateful to my guide,
Dr. Pradeep Kumar (Head, Division of Organic Chemistry) not only for the unwavering
support and freedom in the choice of my research and the execution of my own ideas, but
also for his competent guidance and advice when my ideas failed. I will never forget his
encouraging words and patience when my motivation was at a low. I preserve an
everlasting gratitude for him. Thank you Sir, thanks for everything you have done for me.
No thanks can be enough to acknowledge the endless encouragement, care and
support which I have had from Dr. Avalokiteswar Sen and his family (Madam and sister,
Shruti) and Swami Sarvapremananda (Saibal Maharaj, Ramakrishna Mission
Vidyamandira, Belur Math) and Bamapada Das Sir (ex-Head, Salkia Hindu High School,
Unit-2). Their constant encouragement helped me in pursuing the Ph. D and made me
achieve the goal. Once again, my very special thanks to them from the bottom of my
heart.
My sincere thanks goes to Dr. Ganesh Pandey (former Head, OCD), Dr. N. N.
Joshi, Dr. D. S. Reddy, Dr. M. Sashidhar, Dr. S.P. Chavan, Dr. Santosh Mhaske, Dr. M.
Muthukrishnan, Dr. Ashish Bhattacharya, Dr. Monisha Fernandes, Dr. A. T. Biju, Dr.
Pradip Maity, Dr. Amitava Das, Dr. Utpal Das, Dr. R. Kontham, Dr. Nitin Patil, Dr.
Dhiman Sarkar, Dr. Sayam Sengupta, Dr. Rahul Banerjee, Dr.Sakya S. Sen, Dr. Sayan
Bagchi, Dr. Arup Rath, Dr. Neelanjana Sengupta, Dr. (Mrs.) P. Pawar and Mrs. Mary
Joseph for their help during the course of this work. I extend my thanks to the technical
and official staff of NCL for their assistance.
Help from the spectroscopy and mass groups is gratefully acknowledged. I
sincerely thank Dr. Rajmohanan, Dinesh, Rohini, Kavya, Pramod, Sreedevi, Dr. Shanta
Kumari and Mr. Swapnil for their kind co-operation. Support from OCD office staff,
Catherine Madam, Thangaraji, Rannowde and Fernandes is also acknowledged.
I would like to thank my school teachers, Mr. Debiprasad Mitra, Mr. Tapan Roy,
Mrs. Bithika Debnath and college teachers, Dr. Atanu Bhattacharaya, Dr. Amitava
Bagchi, Dr. Pinaki Chowdhuri and Dr. Prafulla Mahapatra. They have played an
important role in making me who I am, and will be guiding lights in all my future
endeavors.
Thanks to all my senior colleagues, Dr. Priti Gupta, Dr. Pushpesh Upadhyay,
Dr. Abhishek Dubey, Dr. Nagendra B. Kondekar, Dr. Divya Tripathi, Dr. Shijo K
Cherian, Dr. Vishwajeet Jha, Dr. Menaka Pandey, Dr. Partha S. Chowdhury, Dr. Anand
Harbindu, Dr. Ankush Bhise, Dr. Namrata Dwivedi, Dr. Ruchi Jain, Dr. Eshwara Begari
and Dr. Sandeep Shindhe from whom I have learnt a great deal of chemistry and together
with their achievements, are a source of inspiration to me. I would also like to thank my
labmates, Brijesh, Nookaraju, Ravi, Arjun, Shruti, Jayant, Chandani, Kiran, Poonam,
Sunil, Madhukar, Trupti, Nilesh, Jignesh and Shrikant and Summer fellows, Amit,
Jagajeet and Dheeraj for maintaining a warm and cheerful atmosphere in the lab.
My stay in NCL has been memorable because of my friends - Ravi Jangir,
Tamboli, Sumantada, Roopa Di, Nirmal, Debabrata da, Arijitda, Chini, Anupam, Tamas,
Manik, Anup, late Agnimitra, Kanak, Patida, Analda, Saikat, Arpan, Chandan, Kakada,
Prtithvi, Soumen De, Soumen Das, Prasenjit, Sankha, Laxmiprasad, Kaushik dey,
Santigopal, Anirban, Basudav, Saibal Bera, Saibal Bhowmik, Manjoor, Arunava,
Hridesh, Suman, Bittu, Somsuvra, Arjun, Indra, Sandeepan, Sanjukta, Pranay, Jaga,
Ramkrishna, subhrashish, Tamal, Tapas, Debu, Prnav, Arya, Abhijit, Shiba, Sutanu,
Subha, Anagh, Chakadola, Raju, Bahusaheb, Atul, T.Rajesh, Sachin ……. the list goes
on.
I extend my deep sense of gratitude to my core group of friends like Mantosh
(Shyam), Saina, Animesh, Arijit, Bikash, Dos, Joyashish, Munmun, Tanaya, Debasis da,
Sujitda, Sanjeev, Pravat, Sarang, Mohitosh, Suvendu, Himadri Sasmal, Jeetu, Santigopal,
Barreto & Mohunbagan which has stood the test of time and I am grateful to them for
always encouraging me in whatever I chose to do.
I would like to thank all my childhood friends, Victor, Anup, Raju, Niloy and
Bapan. Over the years, they have always been there to support me and they have taught
me the true meaning of friendship.
It is impossible to express my sense of gratitude for my family, father (Baba),
Mother (Maa), Brother (Bhai), grand parents (Dadubhai, Dida, Thakuma), uncle
(Sanokaku, Chotokaku, Mama, Meso), and aunts (Chotomasi, Sejomasi, Sanomasi), in
mere words. Whatever I am and whatever I will be in future is because of their enormous
blessings, hard work, commitments to my ambitions and their selfless sacrifices. It was
their single minded pursuit for the cause of my education that gave me the strength and
will continue to guide my future. Although this appreciation is insufficient, I preserve an
everlasting gratitude to them. Words fall short to thank my brothers Santanu, Mahim and
my sister, Bubu, Megha, Beauty for their never ending encouragement and support. I am
indeed indebted to other close family members, Borda, Chotda, Late Jethu and Jethima
and my special and best friend, Dr. Mousumi for their love and support at tough times.
They brought a great deal of happiness to my life. They deserve this Ph.D as much as I
do.
This page would be incomplete without the mention of one of the best persons I
have ever met in my life - Dr. V. Paralikar, for holding my hand during the toughest
times of my Ph.D career. Thank you Sir, thanks for everything you have done for me.
I thank Director, CSIR-National Chemical Laboratory, Pune for providing
infrastructural facilities to complete my work successfully. I am also thankful to CSIR,
New Delhi for the financial assistance in the form of fellowship.
At last but not the least, I thank whole heartedly, the omnipotent God, the
illimitable superior spirit, who reveals himself in the slight details I am able to perceive
with my frail and feeble mind.

Krishanu Show
CONTENTS

ABBREVIATION i
GENERAL REMARKS iii
ABSTRACT iv

CHAPTER 1
Introduction to Asymmetric Dihydroxylation, Hydrolytic Kinetic Resolution and
Organocatalytic Aldol Reaction

1.1 Asymmetric Dihydroxylation

1.1.1 Introduction 1
1.1.2 Empirical rules for predicting the face Selectivity 3
1.1.3 Reaction conditions 3
1.1.4 The substrate preferences of Cinchona alkaloids 4

1.2 Hydrolytic Kinetic Resolution (HKR)

1.2.1 Introduction 5
1.2.2 Preparation of Catalyst and General Experimental Consideration 7

1.3 Organocatalytic Aldol Reaction

1.3.1 Introduction to Organocatalysis 9
1.3.2 Proline a “Universal catalyst” 9
1.3.3 Proline-catalyzed Aldol reaction 10
1.3.4 Mechanism of Aldol reaction 11
1.3.5 Scope of the proline-catalyzed Aldol reaction 12
1.4 References 15
CHAPTER 2
Enantioselective synthesis of hydroxylated pyrans and pyrrolidine alkaloid

2.1 Section A: An Asymmetric Dihydroxylation route to (-) Bulgecinine

2.1.1 Introduction 20
2.1.2 Review of Literature 21
2.1.3 Present Work 27
2.1.4 Results and Discussion 27
2.1.5 Conclusion 29
2.1.6 Experimental Section 31
2.1.7 Spectra 41
2.1.8 References 51

2.2 Section B: Stereoselective Synthesis of Ophiocerins A and C

2.2.1 Introduction 53
2.2.2 Review of Literature 53
2.2.3 Present Work 59
2.2.4 Results and Discussion 59
2.2.5 Conclusion 63
2.2.6 Experimental Section 64
2.2.7 Spectra 74
2.2.8 References 89
CHAPTER 3

Studies towards the total synthesis of Pandangolide via Organocatalytic and Chiral
Pool Approach

3.1 Section A: Attempted synthesis of Pandangolide using Organocatalytic Aldol
Reaction
3.1.1 Introduction 91
3.1.2 Present Work 94
3.1.3 Results and Discussion 95
3.1.4 Experimental Section 99
3.1.5 Spectra 107
3.1.6 References 116

3.2 Section B: Studies toward the total synthesis of Pandangolide via Chiral Pool
Approach
3.2.1 Introduction 118
3.2.2 Present Work 118
3.2.3 Results and Discussion 118
3.2.4 Experimental Section 122
3.2.5 Spectra 131
3.2.6 References 140