SYNTHESIS OF BIOLOGICALLY ACTIVE COMPOUNDS BY DUSHANT ANANDRAO KHOBRAGADE DIVISION OF ORGANIC CHEMISTRY: TECHNOLOGY NATIONAL CHEMICAL LABORATORY PUNE 411008, INDIA DECEMBER 2006 SYNTHESIS OF BIOLOGICALLY ACTIVE COMPOUNDS A THESIS SUBMITTED TO THE UNIVERSITY OF PUNE FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN CHEMISTRY BY DUSHANT ANANDRAO KHOBRAGADE Division of Organic Chemistry: Technology National Chemical Laboratory Pune 411008 INDIA DECEMBER 2006 CERTIFICATE This is to certify that the work incorporated in the thesis entitled “Synthesis of Biologically Active Compounds” submitted by Mr. Dushant A. Khobragade was carried out by him under my supervision at National Chemical Laboratory, Pune. Material that has been obtained from other sources is duly acknowledged in this thesis. Date: Subhash P. Chavan Research Supervisor DECLARATION I hereby declare that the thesis entitled “Synthesis of Biologically Active Compounds” submitted for Ph. D. degree to the University of Pune has been carried out at National Chemical Laboratory, under the supervision of Dr. Subhash P. Chavan. This work is original and has not been submitted in part or full by me for any degree or diploma to this or any other university. Date: Dushant A. Khobragade Division of Organic Chemistry: Technology National Chemical Laboratory Pune 411 008. Dedicated To My (late) Uncle and Grandmother Acknowledgements It gives me great pleasure to express my deep gratitude to my research guide, Dr. S. P. Chavan, for introducing me to the fascinating field of Organic Chemistry, for his inspiring guidance and never diminishing encouragement throughout my research programme. I am thankful to Dr. S. K. Kamat and Dr. U. R. Kalkote for their affection, suggestions and helping me to speed up work throughout my research programme. I am also thankful to Dr. T. Ravindranathan (former head, OCT), Dr. M. K. Gurjar (Head, OCT) and Dr. S. Sivaram (Director, NCL) for permitting me to work in NCL. Help rendered from all the senior scientists Mrs. Latha Sivadasan, Mrs. K. Balakrishnan, Dr. V. H. Deshpande, Dr. Kelkar, Dr. Bhide, Dr. Deshmukh, Dr. Pansare, Dr. Karthikeyan, Dr. Renu Vyas, Dr. Lahoti, Dr. Pradipkumar, Dr. K. V. Srinivasan, Dr. Mrs. Wakharkar, Dr. Mrs. Bhanu Chanda, Dr. H. B. Borate, Dr. R. A. Joshi, Mrs. R. R. Joshi, Mr. I. Shivakumar, Dr. Sawaikar, Dr. Gajbhiye, Dr. C. V. Ramana, Dr. Hotha Srinivas, Dr. Ramalingam, Dr. Muthukrishnan, Dr. Mrs. Chandawadkar of NCL is gratefully acknowledged. I am indebted to Mr. M. D. Uplenchwar, Prof. Mr. and Mrs. McKelvey, Mrs. Nilima Jail, Mr. Ramakant Tamboli, Mr. Bhandarkar, Mr. Tarale, FFE foundation for their invaluable assistance. I would also like to thank Prof. M. S. Wadia, Prof. R. S. Mali, Prof. Mrs. Kusurkar, Prof. D. D. Dhawale, Dr. M. G. Kulkarni, Dr. S. L. Kelkar, Dr. Dhananjay Lokhande for their useful guidence. My sincere thanks to Prof. Shinji Yamada for providing spectral data of some compounds and Alkali Metals Limited, Hydreabad for their help in the form of chemicals. Special thanks to Tanveer Wajid, Shashikant, Sanjay, Sachin, Bhalchandra, Mahesh Shinde, Ganesh, Nitin Patil, Kiran Kale, and Parminder Singh. I take this opportunity to thank my seniors and labmates Amar, Anil Sharma, R. Sivappa, K. Sivasankar, Rajendra, K. Pasupathy, Ramesh, Preeti, Sambhaji, G. Ramakrishna, Ch. Praveen, Pallavi, Mahesh, Ashok, Sanjay Chandke, Abasaheb, Ganesh, Lalit, Kishore, Swapna, Sudhir, Vikas, Manoj, Kiran, Shankar, Makrand for their help. I would like to thank Ruta, Swapnaja, Kiran, Archana, Sachin, Sachin Shirke, Atul, Tejas, Abhijit, Mushtaq, Tushar, Maruthi, Ramana, Rupali, Pallavi Dhole, Sharan and Vikas Bansode. I would also like to thank Dhananjay Thorat, Mandar, Manjeet, Mandar Bodas, Shrinivas Dumbre, Sudhir Joshi, Sachin Patil, Kishor, Anis, DPS Reddy, Krishnakanth, Ravi, Nagaprasad, Ekambaram, Sahoo, Kiran, Siddarth, K. Mahesh, C. Ramesh, Sandeep Shinde, Pravin Shinde, Gajanan, Abhimanyu, Pandurang, Sankar, Sarita, Santosh Bhor, Prashant Waske, Sudhir Landge, Vivek Bulbule, Preeti Koranne, Mahesh Patil, Vivek Bhagwat, Smritilekha, Dhananjoy Mondal, Chinmoy, Rita, Rehman, Bhargav, Anuj, Raghupati, Ramdas, Gorakh, Abhijeet Purude, Anil Chopade, Ganesh Salunkhe, Sulakhe, Sonali, Varsha, Manjusha, Poorva, Sharad, Dhanajay Magar, Ashfaq, Shafi, Tanveer, Ismail, Tatya Potewar, Palimkar, Atul Gholap, Vaibhav Gholap, Vinod, Sandip Gholap, Vishal, P. D. Shinde, Amit, Sachin Nehete, Umesh Nehete, Santosh Kadam, Suleman, Amit Patwa, Umashankar, Aniruddha Doke, Jayprakash Nadgeri, Mahesh Sonar, Ulhas, Vasu, Subbarao, Nagendra Sharma, Nagendra Kondekar, Dr. Someshwar Sahare, Mr. Sanjay Dhabarde, Pratap, Adinath, Mayur, Kailash, Pushpesh, Mahesh Bhure, Dnyaneshwar, Manish, Pramod, Rahul, Sandip, Mahesh, Shivaji, Satish Chavre, Dilip, Ravi Deshmukh, Anil Bhise, Prashant Karandikar, Pankaj, Milind, Manmath, Anil Kumar Pande and many others who made my tenure at NCL cheerful. I wish to thank office staff (Mr. Balan, Mrs. Kulkarni, Mrs. Catherine, Mr. Fernandes, Mr. Tikhe, Mr. Ranwade, Mr. Varadrajan, Mr. Kakade, Mr. Bhise, Mr. Sambhu, Mr, Bhosale, Mr. Dhumal, Mr. Khopade) for the help whenever required. I would also like to acknowledge all the staff members of NMR, Microanalysis, Special Instruments Lab and Library for their assistance during the course of my work. Words fall short to thank my parents, family members and teachers, who have contributed a lot for me to reach this stage and will always remain a sole source of inspiration in my life. The thesis is a form of pay to respect their attributes. Finally I thank CSIR, New Delhi for financial support. NCL, Pune Dushant Khobragade Contents Page No. General Remarks i Abbreviations ii Abstract v Chapter I Total Synthesis of Antidepressants Section 1: Total Synthesis of (±)-Venlafaxine 1.1.1. Introduction 1 1.1.2. Antidepressants 3 1.1.3. Venlafaxine 11 1.1.4. Literature Review 14 1.1.5. Present Work 21 1.1.6. Experimental 34 1.1.7. Spectra 42 1.1.8. References 43 Section 2: Formal Total Synthesis of (±)-Paroxetine 1.2.1. Introduction 46 1.2.2. Polymorphism 46 1.2.3. Clinical Profile 46 1.2.4. Literature Review 47 1.2.5. Present work 68 1.2.6. Experimental 74 1.2.7. Spectra 82 1.2.8. References 83 Chapter II: Synthetic Studies Towards Other Biologically Active Molecules Section 1: Total Synthesis of (±)-Mesembrine 2.1.1. Introduction 86 2.1.2. Biosynthesis 87 2.1.3. Literature Review 93 2.1.4. Present Work 126 2.1.5. Experimental 135 2.1.6. Spectra 145 2.1.7. References 146 Section 2: Synthetic Studies Towards Zafirlukast 2.2.1. Introduction 149 2.2.2. Zafirlukast 153 2.2.3. Literature Review 155 2.2.4. Present Work 157 2.2.5. Experimental 163 2.2.6. Spectra 171 2.2.7. References 172 List of Publications 174 General Remarks 1. All the melting points are uncorrected and the temperatures are in the centigrade scale. 2. The compound numbers, scheme numbers and reference numbers given in each section refer to that section only. 3. All the solvents were distilled before use. Petroleum ether refers to the fraction boiling in the range of 60-80 ºC. 4. Organic layers were dried over anhydrous sodium sulfate. 5. TLC analysis was carried out using thin layer plates pre-coated with silica gel 60 F254 (Merck) and visualised by fluorescence quenching or Iodine or by charring after treatment with p-anisaldehyde. 6. In cases where chromatographic purification was done, silica gel (60-120 mesh) was used as the stationary phase or otherwise as stated. 7. IR spectra were recorded on Perkin-Elmer Infrared Spectrophotometer Model 68B or on Perkin-Elmer 1615 FT Infrared Spectrophotometer. 8. 1H NMR and 13C NMR were recorded on Bruker AV-200 (50 MHz) or Bruker AV-400 (100 MHz) or Bruker DRX-500 (125 MHz). Figures in the parentheses refer to 13C frequencies. Tetramethyl silane was used as the internal standard. 9. Mass spectra were recorded at an ionization energy of 70 eV on Finnigan MAT- 1020, automated GC/MS instrument and on API Q STARPULSAR using electron spray ionization [(ESI), solvent medium: a mixture of water, acetonitrile and ammonium acetate] technique and mass values are expressed as m/z. HRMS were recoreded on a micromass Q-T of micro with spray source (ESI+) mode. 10. Starting materials were obtained from commercial sources or prepared using known procedures. 11. Microanalysis data were obtained using a Carlo-Erba CHNS-O EA 1108 elemental analyzer within the limits of accuracy (± 0.4%). i Abbreviations Ac Acetyl ADD (Azodicarbonyl)dipiperidine AIBN 2,2-Azobis(isobutyronitrile) tAm tertiary amyl Ar Aryl Aq. Aqueous BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl BMS Borane-dimthyl sulfide Bn Benzyl BnBr Benzyl bromide Boc tertiary butoxy carbonyl Bu Butyl sBu secondary butyl tBu tertiary-butyl CAL Candida antarctica lipase CAN Cerric ammonium nitrate Cat. Catalytic Cbz Carbobenzyloxy mCPBA meta-chloroperbenzoic acid CSA Camphor sulfonic acid DBDMH 1,3-Dibromo-5,5-dimethylhydantoin DBN 1,5-diazabicyclo[4.3.0]non-5-ene DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCB 1,2-Dichlorobenzene DCC N,N'-Dicyclohexylcarbodiimide DCE 1,2-Dichloroethane DCM Dichloromethane DEPT Distortionless Enhancement by Polarization Transfer DIAD Diisopropylazodicarboxylate DIBAL Diisobutyl aluminium hydride DIPT Diisopropyltartrate ii DMAP 4-Dimethylamino pyridine DME 1,2-dimethoxyethane DMF N,N-Dimethylformamide DMS Dimethy sulfide DMSO Dimethyl sulfoxide dppf (Bis-diphenylphosphino)ferrocenyl Et Ethyl g gram(s) GABA Gamma-aminobutyric acid h hour(s) IPA Isopropyl alcohol IR Infra red HMPA hexamethylphosphoramide Hz