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Synthesis of Epiboxidine and Various X-Azatricyclo

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Synthesis of Epiboxidine and Various X-Azatricyclo [3+2] CYCLOADDITION OF NONSTABILIZED AZOMETHINE YLIDES: SYNTHESIS OF EPIBOXIDINE AND VARIOUS X-AZATRICYCLO[m.n.0.0 a,b]ALKANES A THESIS SUBMITTED TO THE UNIVERSITY OF POONA FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN CHEMISTRY BY AKHILA KUMAR SAHOO Division of Organic Chemistry (Synthesis) National Chemical Laboratory PUNE - 411 008 Acknowledgement I take this opportunity with immense pleasure to express my deep sense of gratitude to my teacher and research guide Dr. Ganesh Pandey, who has helped me a lot to learn and think more about chemistry. I thank him for his excellent guidance, constant encouragement, sincere advice, friendship and unstinted support during all the tough times of my Ph. D. life. I do sincerely acknowledge the freedom rendered to me by him for independent thinking, planning and executing the research. I consider very fortunate for my association with him which has given a decisive turn and a significant boost in my career. I gratefully acknowledge the guidance, training, and support extended by my senior colleague Dr. Trusar D. Bagul during the total tenure of my Ph.D life. Special thanks to all my senior colleagues and my present colleagues Dr. (Mrs.) Gadre, Laha, Nagesh, Murugan, Kapur, Tiwari, Rani, Late Mal, Utpal, Prabal, Srinivas, Sanjay, Balakrishna, and Inderesh for maintaining a warm and a very cheerful atmosphere in the lab. They made working the lab very enjoyable. Special acknowledgements to Laha, Nagesh, Kapur, Tiwari, Amar (Kallu), Raghu (Ingle), Gadre Madam, Utpal, Muruga, Jayanthi and Sreenivas for taking trouble in bringing out the thesis. Help from the spectroscopy and mass groups is gratefully acknowledged. I sincerely thank Mr. A. G. Samuel and Dr. Rajmohan for helpful discussions and Mrs. Phalgune, Dr. Sanjayan, Mr. Sathe and Mrs. Shanta kumari for their kind cooperation. I would like to specially thank to my senior colleagues Abhay, Seshu Babu, Manasda, Ravi, Prasad, Selva, Parthabhai, Sochan, Debendrabhai, Nayakbhai, RajPatel and my all friends in NCL campus and GJ hostel for their cheerful company which made my stay at NCL memorable one. My due regards to all of my old friends and well wishers Atal, Suresh, Mana, Raman and Raja. I would like to thank Dr. H. R. Sonawane, Dr. A. Sarkar, Dr. N. N. Joshi and Dr. S. P. Chavan for stimulating discussions. Special thanks are due to my professors Dr. S. Jena, Dr. S. N. Mohanty, Dr. Amar Mohanty and Dr. M. Patra who taught me the basics of chemistry in my college days. It is my great pleasure to thank my parents, sisters, sister-in-laws, brothers, late maternal grandfather (Alekha Sahoo) late uncles (Braja mamu and Biswanath bawa) and my other family members for their blessings, love, care and continuous encouragements throughout my education. Finally I thank Dr. K. N. Ganesh, Head, Division of Organic Chemistry (Syn.) and Director, National Chemical Laboratory, Pune for providing infrastructural facilities to complete my work successfully. I am also thankful to CSIR, New Delhi and DST for the financial assistance. Akhila Kumar Sahoo TO MY BELOVED PARENTS AND ALMIGHTY CONTENTS Abbreviations I Abstract III Chapter-1 7-Azabicyclo[2.2.1]heptane Skeleton as Nicotinic Acetylcholine Receptors 1 Introduction Strategies towards the construction of basic 7-azabicyclo- [2.2.1]heptane skeleton 5 References 30 Chapter-2 Synthesis of Epiboxidine Introduction 36 Reported Approaches for the synthesis of N-protected-2-exo- (carboalkoxy) -7-azabicyclo[2.2.1]heptane 41 Results and Discussion 44 Conclusion 63 Experimental 64 References 80 Spectra 82 Chapter-3 Construction of Various X-azatricyclo[m.n.0.0a,b]alkanes Introduction 98 Results and Discussion 108 Summary 130 Experimental 131 References 152 Spectra 155 List of Publications 182 I ABBREVIATIONS Ac acetyl Ar aryl aq aqueous Bn benzyl bp boiling point Bu butyl t-Bu tert-butyl n-BuLi n-butyllithium s-BuLi s-butyllithium (Boc)2O di-tert-butyldicarbonate t-Boc tert-butyloxycarbonyl CBZ benzyloxycarbonyl CH3CN acetonitrile CHCl3 chloroform DCM dichloromethane DMF N,N-dimethyl formamide Et ethyl Et3N triethyl amine EtOAc ethyl acetate EtOH ethanol g gram h hour IR infrared K2CO3 potassium carbonate KOH potassium hydroxide LDA lithium diisopropylamide LAH lithium aluminium hydride m molar MeOH methanol mL millilitre mmol millimole mp melting point NaBH4 sodium borohydride NaBH3CN sodium cyanoborohydride NaHCO3 sodium bicarbonate NaOH sodium hydroxide Na2SO4 sodium sulphate rt room temperature THF tetrahydrofuran TFA trifluoroacetic acid TLC thin layer chromatography TMEDA N,N,N’,N’-tetramethylethylenediamine TMS trimethylsilane TMSCl chlorotrimethylsilane III Abstract [3+2] Cycloaddition of NonStabilized Azomethine Ylides: Synthesis of Epiboxidine and Various X-Azatricyclo[m.n.0.0a, b]Alkanes Chapter I Introduction This chapter presents a concise reports from literature on the synthesis of biologically relevant molecules possessing 7-azabicyclo[2.2.1]heptane skeleton. The synthesis of epibatidine, a potent nicotinic acetylcholine receptor, by the [3+2] cycloaddition reaction of cyclic non-stabilized azomethine ylide with appropriate dipolarophile is highlighted. Chapter II Synthesis of Epiboxidine This chapter describes the synthesis of epiboxidine {exo -2-(3-methyl-5-isoxazolyl)- 7-azabicyclo[2.2.1]heptane} as a synthetic analog of the alkaloid epibatidine. Biological and pharmacological studies exhibited epibatidine to be an extremely potent agonist of the acetylcholine receptor with antinociceptive activity. However, due to high toxicity of epibatidine (causing death in mice at 10 mL/Kg scale), the development of a pharmacophore related to the structure of 1, exhibiting better ratios of pharmacological to toxicological activity was considered of great interest. In this context, Badio et al. [Eur. J. Pharmacol. 1997, 321, 189.] designed a pharmacophore by combining the structural features of the known nicotinic receptor antagonist ABT -418 (2) and 1 and named it as epiboxidine (3) (Fig. 1). Epiboxidine was shown to be a potent nicotinic receptor agonist, proved to be equipotent at the ganglionic type receptor in PC12 cells and about 5-fold less potent in TE671 cells than epibatidine. In hot-plate antinociceptive assay with mice, 3 showed 10-fold less potency with 20-fold less IV toxicity than 1. Owing to the promising pharmacological properties, epiboxidine drew a great deal of attention in context of its synthetic and biological studies. Fig. 1 H H 4' 3' Me Cl 7 7N N 1 1 N Me 6 2 N N 5' 4 2 Me O N O 4 1' 5 3 3 Epibatidine (1) ABT-418 (2) Epiboxidine (3) We opted two protocols either by employing [3+2] cycloaddition approach or by [4+2] cycloaddition approach towards the preparation of common precursor 4, for the synthesis of epiboxidine as shown retrosynthetically in Scheme 1. Scheme 1 CO2Et - + H P + N Me N N Bn N CO2R 5 6 O CO Me 3 4 2 + N CO2Me CO2Me 7 8 [3 + 2] Cycloaddition approach: The in situ generation of 6 from the precursor 9 was achieved, utilizing the known protocol developed in our laboratory, by the sequential one electron oxidation of 9 employing Ag(I)F as one electron oxidant. The key [3+2] cycloaddition reaction of 9 with ethyl acrylate gave st ereoisomeric cycloadducts 10 (60 %) and 11 (15 %) in 4 : 1 ratio V (Scheme - 2). The stereochemistry of cycloadducts 10 and 11 were determined by detailed 1H NMR decoupling and 1H COSY experiments. Scheme 2 Bn Bn N N CO2Et Ag(I)F DCM, RT CO Et 6 + 2 + TMS TMS N 75 % CO2Et Bn 5 10 (4 : 1) 11 9 It was felt necessary to cleave the N-benzyl moiety from 10 and 11 prior to the construction of oxazolidine moiety to avoid the complication at the later stage of the synthesis of 3. In this context, N-debenzylation of the cycloadducts were carried out by hydrogenation using 10 % Pd (OH) 2 at 40 psi of hydrogen. After Boc protection of crude amine, the undesired endo isomer 12 was epimerized quantitatively to 13 by treating with o K2CO3 in MeOH at 80 C. The carboethoxy moiety of 13, was transformed to 2-methyloxazolidine by treating with the dianion of acetone oxime at 0 oC, followed by reacting the mixture with 11 M HCl at 80 oC to afford product 3 in 41 % yield (Scheme - 3). Compound 3 was confirmed as epiboxidine by 1H and 13C NMR and mass spectral analysis and was found to be in comp lete agreement with the data reported by Badio et al. [Eur. J. Pharmacol. 1997, 321, 189.]. Scheme 3 Boc Boc OH H Me N N N N CO Et N i, ii + 2 11 + 10 O 90 % v, vi CO2Et 12 (1 : 4) 13 41 % 3 iii, iv epimerization 95 % o Reagents and conditions: i) 10 % Pd(OH)2/H2, 50 psi; ii) (Boc)2O, THF, TEA, rt; iii) K2CO3, MeOH, 80 C, 1 o o h; iv) SOCl2, EtOH, rt, 3 h; v) n-BuLi (2 eq.), THF, 0 C; vi) 11M HCl, 80 C, 4 h. VI [4 + 2] Cycloaddition Strategy: The azanorbornadiene 14 was obtained by the [4+2]-cycloaddition of N-carbomethoxy pyrrole (7) with dimethyl acetylene dicarboxylate (8) in DCM in the presence of AlCl 3. Compound 14 was hydrogenated using 10 % Pd/C at 45 psi to afford 15. The hydrolysis of 15 gave 16 in 90 % yield. Reductive radical monodecarboxylation of compound 16 was carried out by following Barton’s procedure [Tetrahedron. 1985, 41, 3901] via the pyrrolysis of the corresponding thiohydroximate ester in presence of radical scavenger tert-butyl mercaptan, which gave stereoisomeric products 17 (52 %) and 18 (13 %) in 4 : 1 ratio (Scheme - 4). Scheme 4 CO2Me CO Me CO Me 2 2 N N i CO Me ii iii + 2 N CO Me CO Me 2 CO2Me 2 CO2Me CO2Me 7 8 14 15 CO2Me CO2Me CO2Me N N N iv, v, vi + 3 65 % CO Me CO2H 2 CO Me CO2Me 2 16 17 (4 : 1) 18 epimerization 95 % o Reagents and conditions: i) AlCl3, DCM, 40 C, 1 h, 90 %; ii) 10 % Pd/C, H2, 40 psi, 6 h, 95 %; iii) LiOH (1 eq.), MeOH/H2O (3:1), rt, 3 h, 90 %; iv) (COCl)2, DCM, rt, 2 h; v) 2-Mercaptopyridine-N-Oxide, PhH, TEA, rt, 6 h; vi) PhH, t-BuSH, D, rt, 4 h.
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