ENANTIOSELECTIVE SYNTHESIS OF BIOACTIVE MOLECULES VIA ASYMMETRIC HYDROXYLATIONS, AMINOALLYLATION AND SYNTHETIC METHODOLOGIES INVOLVING ACTIVATION OF C-H BONDS A THESIS SUBMITTED TO THE UNIVERSITY OF PUNE FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN CHEMISTRY By TANVEER MAHAMADALI SHAIKH UNDER THE GUIDANCE Dr. A. Sudalai Chemical Engineering and Process Development Division National Chemical Laboratory Pune-411008, INDIA November 2009 Dedicated to my beloved parents & brother Raziya Mahamadali & Sameer NATIONAL CHEMICAL LABOATORY Dr. A. Sudalai Scientist Chemical Engineering & Process Development Division, Pune – 411 008, India Phone (O) : 0091-20-25902174, Fax: 0091-20-25902676, e-mail: [email protected] CERTIFICATE Certified that the work incorporated in the thesis entitled “Enantioselective Synthesis of Bioactive Molecules via Asymmetric Hydroxylations, Aminoallylation and Synthetic Methodologies Involving Activation of C-H Bonds” was carried out by the candidate under my supervision. Such material as had been obtained from other sources has been duly acknowledged in the thesis. November 2009 (Dr. A. Sudalai) Pune Research Supervisor NATIONAL CHEMICAL LABORATORY DECLARATION I here by declare that the thesis entitled “Enantioselective Synthesis of Bioactive Molecules via Asymmetric Hydroxylations, Aminoallylation and Synthetic Methodologies Involving Activation of C-H Bonds” submitted for the degree of Doctor of Philosophy in Chemistry to the University of Pune, has not been submitted by me to any other university or institution. This work was carried out at the National Chemical Laboratory, Pune, India. November 2009 Tanveer Mahamadali Shaikh Pune CE & PD Division National Chemical Laboratory Pune – 411 008 CONTENTS Page No. Acknowledgements i Abbreviations iii General Remarks v Abstract vi CHAPTER I: ENANTIOSELECTIVE SYNTHESIS OF (+)-SERTRALINE AND (+)-LENTIGINOSINE Section I A short Enantioselective Synthesis of (+)-Sertraline via Sharpless Asymmetric Dihydroxylation 1.1.1 Introduction 1 1.1.2 Pharmacology 2 1.1.3 Review of Literature 2 1.1.4 Present Work 13 1.1.4.1 Objective 13 1.1.3.2 Asymmetric Dihydroxylation 14 1.1.4 Results and Discussion 18 1.1.5 Conclusion 26 1.1.6 Experimental Section 26 Section II Enantioselective Synthesis of (+)-Lentiginosine via aza-Cope Rearrangement 1.2.1 Introduction 33 1.2.2 Review of Literature 34 1.2.3 Present Work 48 1.2.3.1 Objective 48 1.2.4.1 Proline-Catalyzed α-Aminooxylation 49 1.2.4.2 Asymmetric aza-Cope Rearrangement 51 1.2.5 Results and Discussion 54 1.2.6 Conclusion 65 1.2.7 Experimental Section 65 1.2.8 References 75 CHAPTER II: ENANTIOSELECTIVE SYNTHESIS OF (+)-Α- CONHYDRINE, (-)-SEDAMINE, (-)-ALLOSEDRIDINE, (S)- BETAXOLOL AND (S)-METOPROLOL Section I Enantioselective Synthesis of (+)-α-Conhydrine and (-)- Sedamine via L-Proline Catalyzed α-Aminooxylation 2.1.1 Introduction 79 2.1.2 Review of Literature 80 2.1.3 Present Work 93 2.1.3.1 Objective 93 2.1.4 Results and Discussion 94 2.1.4.1 Enantioselective Synthesis (+)-α-Conhydrine 94 2.1.4.2 Enantioselective Synthesis of (-)-Sedamine 100 2.1.5 Conclusion 108 2.1.6 Experimental Section 108 Section II Enantioselective Synthesis of (-)-Allosedridine via Sharpless Asymmetric Epoxidation 2.2.1 Introduction 124 2.2.2 Review of Literature 125 2.2.3 Present Work 128 2.2.3.1 Objective 128 2.2.3.2 Sharpless Asymmetric Epoxidation 129 2.2.4. Results and Discussion 131 2.2.5 Conclusion 142 2.2.6 Experimental Section 142 Section III Asymmetric Synthesis of β-Blockers: (S)-Betaxolol and (S)- Metoprolol 2.3.1 Introduction 152 2.3.2 Pharmacology 153 2.3.3 Review of Literature 153 2.3.4 Present Work 157 2.3.4.1 Objective 157 2.3.4.2 Kinetic Resolution 158 2.3.5 Results and Discussion 161 2.3.5.1 Asymmetric Synthesis of (S)-Betaxolol 161 2.3.5.2 Asymmetric Synthesis of (S)-Metoprolol (159) 165 2.3.6 Conclusion 169 2.3.7 Experimental Section 169 2.3.8 References 176 CHAPTER III NaIO4 MEDIATED C-H ACTIVATION OF ALKYLARENES AND OXIDATIVE FUNCTIONALIZATION OF C-H, C-Br, C-O BONDS Section I NaIO4-Mediated C-H Activation of Alkylarenes: Oxyfunctionalization at the Benzylic Position 3.1.1 Introduction 180 3.1.2 Review of Literature 181 3.1.3 Present Work 184 3.1.3.1 Objective 184 3.1.4 Results and Discussion 185 3.1.6 Conclusion 192 3.1.7 Experimental Section 192 Section II NaIO4-Mediated Selective Oxidation of Benzylic Bromides and Alkylarenes to Benzoic acids in Water as Solvent 3.2.1 Introduction 197 3.2.2 Review of Literature 198 3.2.3 Present Work 202 3.2.3.1 Objective 202 3.2.4 Results and Discussion 202 3.2.6 Conclusion 208 3.2.7 Experimental Section 209 Section III NaIO4-Mediated Selective Oxidation of Benzylic alcohols: High Yield Preparation of Aromatic Aldehydes and Esters 3.3.1 Introduction 213 3.3.2 Review of Literature 213 3.3.3 Present Work 223 3.3.3.1 Objective 223 3.3.4 Results and Discussion 223 3.3.5 Conclusion 231 3.3.6 Experimental Section 231 3.3.7 References 236 CHAPTER IV HETEROGENEOUS CATALYSTS FOR OXIDATIVE TRANSFORMATION OF C-H, C-O AND C=C BONDS Section I WO3-Catalyzed Selective Oxidation of Alkylarenes and Arylketones: High Yield Preparation of Benzoic Acids 4.1.1 Introduction 239 4.1.2 Review of Literature 240 4.1.3 Present Work 243 4.1.3.1 Objective 243 4.1.4 Results and Discussion 243 4.1.6 Conclusion 250 4.1.7 Experimental Section 250 Section II Titanium Superoxide: A Heterogeneous Catalyst for Aminobromination of Olefin 4.2.1 Introduction 252 4.2.2 Review of Literature 252 4.2.3 Present Work 261 4.2.3.1 Objective 261 4.2.4 Results and Discussion 261 4.2.5 Conclusion 268 4.2.6 Experimental Section 268 4.2.7 References 274 ACKNOWLEDGEMENT I wish to express my heartfelt gratitude towards my research supervisor Dr. A. Sudalai sir, whose knowledge and vast experience has inspired me at every stage of my tenure and helped me to achieve this target. His suggestions, criticisms and constant encouragement helped me immensely to grow as a chemist. My everlasting gratitude goes to him. I thank Dr. B. D. Kulkarni sir, Deputy Director and Head, CE-PD division, for his help and support. My special thanks go to Dr. S. Gurunath for his constant encouragement and moral support. I thank Dr. Ganesh Pandey sir, Head, OCD and Drs. Suresh Iyer, S. N. Kotwal, R. A. Kulkarni, V. G. Kulakarni, S. S. Pardhy, Mrs. S. Mayadevi and S. A. R. Mulla for their help and support. I am immensely thankful to my seniors Drs. Vinay, Iliyas, Gajanan, Abhimanyu, Shivakumar, Shriram, Srinivas Rao, Ramesh Kumar, Victor Paul, Arun for useful training in the initial phase of my career. I would like to thank my teachers Zhipre sir, Shirsat, Mrs. Dange, Drs. Patil, Modi sir. I am also grateful to Dr. Md. Qudrathullah Principal, Poona College, Dr. G. M. Nazeruddin, Dr. Alamgir Shaikh, Dr. Rafique Sarkhwas, Dr. Ejazuddin Khan, Dr. Mrs. Mulla, Aziz Mohinuddin for inspiring me towards research. I thank NMR group Dr. Rajmohan, Jima, Hilda and elemental analysis group for their help in obtaining the analytical data. I am very thankful to Dr. Mrs. S. S. Kulkarni her help in GC-MS analysis and Dr. Vilas Chavan his help in the HPLC analysis. I thank library staff, chemical stores, purchase staff, glass blowing section NCL for their cooperation. I thank PD office staff Mr. Bhosale, Mrs. Puranik and Mr. Kakade for their cooperation. I also thank PG section of Pune University and Dr. Mrs. R. Kusurkar for their cooperation and help. It’s my privilege to thank the Director, NCL for giving me this opportunity and providing all necessary infrastructure and facilities. Financial assistance from CSIR, New Delhi is greatly acknowledged. It’s my pleasure to thank all my lab mates Pandurang, Emmanuvel, Shyla, Santhosh, Pratibha, Varun, Dayanand, Narsimha, Chaithanya, Senthil kumar, Dattatraya, Ashish, Venkat, Shukla, Ramachandra, Balaji, Shaheen, Vijay, Hari, Kuppu, Sawant, Divya, i Santosh, Satish, Deepali, Aparna, Nagesh, Nana, Rana for providing a cheerful atmosphere in the lab and in every aspect through out this research. I am very thankful to project students Alka, Mudassir, Baba, Ruchi and Charuta for helping me in this work. I thank my friends at NCL Bhargava, Raghupati, Bharat, Mehraj, Shafi, Sachin, Nagendra, Amrut, Swaroop, Deepak, Ravi, Nishant, Abhijeet, Sharad, Girish, Namdev, Imran, Muzahid, Suleman, Jayprakash, Tanpreet and Shivranjani for their help. I acknowledge all my college friends Iqbal, Asgar, Shahbaj, Zubair, Rashid, Khalil, Shabir, Hamid, Hussain. I thank Wasif for his support during my work. I am greatly indebted to all my childhood friends Pramod, Shivsharan and Pintoo. I am indeed very grateful to my my parents whose constant love, care, support and encouragement have been the main force and motivation for me. The love and affection showered by my brother on me is magnanimous. My Bhabhi sisterin-law Mehjabeen always supports and encourage me. I have known Arshiya from my childhood days and got married to her. The love, dedication, support and encouragement I received from her helped me to complete this work. My brothers kid Naumaan, Izhaan and my daughter Tasmiya are angels and made my life more beautiful. I am very thankful to my sisters and my brotherin-law, Ishrat-Abdul Sattar, Yasmin-Ayub, Nasreen-Maqdum for their belief in my abilities and constant encouragement. My sister’s kids Fahim, Mazhar, Farheen, Naeem, Azahar, Zulfin, Shazia, Sara, Ikra and Tanzim, Asim who always bought a smile on my face.