SYNTHETIC STUDIES TOWARD NEW α- GLUCOSIDASE INHIBITORS PENAROLIDE SULFATE A1, SCHULZEINES B AND C BY MR. DEBABRATA BHATTASALI DR. MUKUND K. GURJAR (RESEARCH GUIDE) DIVISION OF ORGANIC CHEMISTRY NATIONAL CHEMICAL LABORATORY PUNE-411008, INDIA OCTOBER 2008 Synthetic Studies Toward New α-Glucosidase Inhibitors Penarolide Sulfate A1, Schulzeines B And C A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY (IN CHEMISTRY) TO KALYANI UNIVERSITY BY Mr. DEBABRATA BHATTASALI Dr. Mukund K. Gurjar (Research Guide) DIVISION OF ORGANIC CHEMISTRY NATIONAL CHEMICAL LABORATORY PUNE-411008, INDIA OCTOBER 2008 DEDICATED TO MY BELOVED PARENTS DECLARATION The research work embodied in this thesis has been carried out at National Chemical Laboratory, Pune under the supervision of Dr. M. K. Gurjar, Division of Organic Chemistry, National Chemical Laboratory, Pune- 411008. This work is original and has not been submitted part or full, for any degree or diploma of this or any other University. Pune-411008 (Debabrata Bhattasali) October 2008 Candidate CERTIFICATE The research work presented in thesis entitled “Synthetic Studies Toward New α- Glucosidase Inhibitors Penarolide Sulfate A1, Schulzeines B And C” has been carried out under my supervision and is a bonafide work of Mr. Debabrata Bhattasali. This work is original and has not been submitted for any other degree or diploma of this or any other University. Pune-411008 (Dr. M. K. Gurjar) October 2008 Research Guide ACKNOWLEDGEMENTS It gives me great pleasure to express my deep sense of esteem and gratitude to my research guide, Dr. Mukund. K. Gurjar, Division of Organic Chemistry, NCL, for his inspiring guidance, never diminishing encouragement, support and his complete dedication during the progress of my work. I take this opportunity to specially thank Dr. D. K. Mohapatra for his helpful suggestions. The help of Dr. R. A. Joshi, Dr. R. R. Joshi, Dr. C.V. Ramana, Mr. I. Shivakumar, Dr. Sayam Sengupta and Dr. B. G. Hazra is greatly acknowledged. I gratefully acknowledge the training and support extended by my senior colleagues Dr. Ekambram, Dr. Sankar, Dr. Nagaprasad, Dr. Sridhar, Dr. Mahesh, Dr. Siddharth, Dr. Smritilekha, Dr. Dhananjoy, Dr. Manjusha, Dr. Srinivas. Dr. Sukhen, Dr. Bhagwat, Dr. Ramdas, Dr. Seetaram, Tushar, Gorakh, Sahoo, Raghupathi, Kulbhushan, Ramesh, Soumitrada, Rahmanda, Anuj, Sabita, Ritadi, Bhargav, Chinmoyda, Bhaskarda, Pradipda, Kiran, Nageshwar, Susheel, and Srinivas during the tenure of my Ph.D life. I would like to thank all my colleagues Indu, Abhijeet, Sharad, Alam, Ganesh, Rosy, Rambabu, Anil, Rohidas, Ankush and Anand for their cooperation and friendly attitude. I am very much indebted to my senior colleagues Dr. Anamitra Chatterjee and Dr. Pallavi Sharma for their advices, true love and care. Help from the NMR and mass spectroscopy groups is gratefully acknowledged. I sincerely thank Dr. Rajmohan for his helpful discussions and cooperation. My sincere thanks to Mrs. C. Raphel, Mrs. P. Kulkarni and all other office staff for their cooperation. I wholeheartedly thank my colleagues and friends at NCL and GJ hostel for their cheerful company, which made my stay at NCL memorable one. Especially I would like to thank the members of our bong group namely, Dr. Tarasankarda, Dr. Bivasda, Dr. Debdutda, Dr. Prabhasda, Arijit, Rahul, Kaushik, Roopa, Maitri, jayita, Sujit, Debasish Dey, Sumantra, Partha, Sumanta, Anal, Mrityunjoy, Debasish Pati, Binoy, Subrata, Himadri, Suman(IIT Bombay), Anupam, Asadullah and Shyam sundar for their help, love and support. I would like to thank my M. Sc. Classmates Rajarshi, Sudipta, joy and a close friend at NCL Sanmitra for their valuable help at all times. My special thanks to Dr. S. K. Chattopadhyay, University of Kalyani for helping me attain this degree. I also owe my sincere thanks to Dr. Ganesh Pandey, Head, Division of Organic Chemistry, National Chemical Laboratory, who have provided me sufficient support to fulfill my research work. It is impossible to express my sense of gratitude for my parents and dada in mere words. Whatever I am and whatever I will be in future is because of their commitments to my ambitions and their selfless sacrifices. I am indeed indebted to my fiance Gargi for her encouragement and support which enable me to pursue my goal wholeheartedly. Finally I thank Director, National Chemical Laboratory, Pune for providing infrastructural facilities to complete my work successfully. Financial assistance from CSIR, New Delhi in the form of fellowship is gratefully acknowledged. Debabrata Bhattasali ABBREVIATIONS AcOH - Acetic acid Ac2O - Acetic anhydride Boc - tert-Butyloxycarbonyl Bn - Benzyl BnBr - Benzyl bromide m-CPBA - meta-Chloroperbenzoic acid DBU - 1,8-diazabicyclo[5,4,0]undec-7-ene DCC - N,N/-Dicyclohexylcarbodiimide DCM - Dichloromethane DDQ - 2,3-Dichloro-5,6-dicyano-para- benzoquinone DET - Diethyl tartrate DIPT - Diisopropyl tartrate DIBAL-H - Diisobutylaluminium hydride DIPEA - Diisopropylethyl amine DME - Dimethoxyethane DMF - N,N-Dimethyl formamide DMAP - N,N-Dimethylamino pyridine DMP - Dimethoxypropane DMSO - Dimethyl sulfoxide EDC - 1-Ethyl-3-(3/-dimethylaminopropyl)- carbodiimide Eqv - Equivalent EtOAc - Ethyl acetate EtOH - Ethanol Et3N - Triethyl amine Et - Ethyl FGT - Functional group transformations HKR - Hydrolytic kinetic resolution HMPA - Hexamethylphosphoricacid triamide HOBt - 1-Hydroxybenzotriazole HWE - Horner-Wadsworth-Emmons Im-H - Imidazole LAH - Lithium aluminium hydride LDA - Lithium diisopropylamide LiHMDS - Lithium hexamethyldisilazide MeOH - Methanol MsCl - Methanesulfonyl chloride MEM - Methoxyethoxymethyl Me - Methyl MOM - Methoxymethyl NMO - N-Methylmorpholine-N-oxide PCC - Pyridinium chlorochromate Pd/C - Palladium on carbon Ph - Phenyl PMB - para-Methoxybenzyl Py - Pyridine rt - Room temperature SAD - Sharpless aymmetric dihydroxylation SAE - Sharpless asymmetric epoxidation TBAF - Tetra-n-butylammonium fluoride TBDPSCl - tert-Butyl diphenylchlorosilane TBHP - tert-Butyl hydroperoxide TBSCl - tert-Butyl dimethylchlorosilane TMEDA - N,N,N/,N/-Tetramethylethylenediamine TMSOI - Trimethylsulfoxonium iodide TMSI - Trimethylsilyl iodide TMSOTf - Trimethylsilyl triflate TPP - Triphenylphosphine p-TSA - para-Toluenesulfonic acid THF - Tetrahydrofuran GENERAL REMARKS 1H NMR spectra were recorded on AV-200 MHz, AV-400 MHz, and DRX-500 MHz spectrometer using tetramethylsilane (TMS) as an internal standard. Chemical shifts have been expressed in ppm units downfield from TMS. 13C NMR spectra were recorded on AV-50 MHz, AV-100 MHz, and DRX-125 MHz spectrometer ESI Mass spectra were recorded on Finngan MAT-1020 spectrometer at 70 eV using a direct inlet system. Infrared spectra were scanned on Shimadzu IR 470 and Perkin-Elmer 683 or 1310 spectrometers with sodium chloride optics and are measured in cm-1. Optical rotations were measured with a JASCO DIP 370 digital polarimeter. Melting points were recorded on Buchi 535 melting point apparatus and are uncorrected. All reactions are monitored by Thin Layer chromatography (TLC) carried out on 0.25 mm E-Merck silica gel plates (60F-254) with UV light, I2 and anisaldehyde in ethanol as development reagents. All solvents and reagents were purified and dried by according to procedures given in Vogel’s Text Book of Practical Organic Chemistry. All reactions were carried out under nitrogen or argon atmosphere with dry, freshly distilled solvents under anhydrous conditions unless otherwise specified. Yields refer to chromatographically and spectroscopically homogeneous materials unless otherwise stated. All evaporations were carried out under reduced pressure on Buchi rotary evaporator below 40 °C. Silica gel (60–120) used for column chromatography was purchased from ACME Chemical Company, Mumbai, India. Independent numbering of compounds, schemes and figures has been employed for Abstract and each individual chapter. CONTENTS Page No. Abstract 01 Chapter 1: An Introduction to Glycosidase Inhibitors 17 References 46 Chapter 2: Total Synthesis of Penarolide Sulfate A1 Present Work 54 Experimental 98 Spectra 132 References 164 Chapter 3: Studies Toward the Total Syntheses of Schulzeines B And C Present Work 171 Experimental 202 Spectra 231 References 261 List of Publications 267 Abstract ABSTRACT The thesis entitled “Synthetic Studies Toward New α-Glucosidase Inhibitors Penarolide Sulfate A1, Schulzeines B And C” consists of three chapters. The first chapter deals with the basic introduction regarding various glycosidase inhibitors. The second chapter deliberates the synthetic efforts toward the total synthesis of penarolide sulfate A1. The third chapter outlines the synthetic studies toward the total syntheses of schulzeines B and C. Chapter 2 and 3 are subdivided into the following sections; Present work, Experimental, Spectra and References. Chapter 1: An Introduction to Glycosidase Inhibitors The first chapter of this dissertation summarizes the role of glycosidases in hydrolyzing the most stable covalent bond found within natural biopolymers, the glycosidic bond. It presents an overview of the classification and mechanistic approach of glycosidases. However, glycosidase inhibitors are of mere current interest since they describe the mechanism of enzyme-catalysed glycoside hydrolysis which has a direct application in medicinal chemistry. Thus, the chapter outlines the importance of glycosidase inhibitors as drugs and therapeutic agents. Glycosidases are involved in the biosynthesis of the oligosaccharide chains and quality