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TRANSFORMATIVE REACTIONS ON CARBOCYCLIC COMPOUNDS A Thesis submitted to the University of North Bengal For the Award of Doctor of Philosophy (Ph.D.) in Chemistry By Jayanta Das Research Guide Prof. Pranab Ghosh DEPARTMENT OF CHEMISTRY UNIVERSITY OF NORTH BENGAL December, 2015 To my parents... i DECLARATION I hereby declare that the thesis entitled “ TRANSFORMATIVE REACTIONS ON CARBOCYCLIC COMPOUNDS ” has been prepared by myself under the guidance of Prof. Pranab Ghosh, Department of Chemistry, University of North Bengal, Drjeeling- 734013. No part of this thesis has formed the basis for the award of any degree or fellowship previously. Jayanta Das Department of Chemistry University of North Bengal Darjeeling – 734 013, India Date: 15.12.2015 ii UNIVERSITY OF NORTH BENGAL Prof. P. Ghosh , Ph: +91 3532776 381 (off) DEPARTMENT OF CHEMISTRY +91 9474441468 (M) University of North Bengal, Fax: +91 353 2699 001 Darjeeling – 734 013, India. Email: [email protected] Date: December 15 , 2015 CERTIFICATE This is to certify that Sri Jayanta Das has prepared the thesis entitled “TRANSFORMATIVE REACTIONS ON CARBOCYCLIC COMPOUNDS ”, for the award of PhD degree of the University of North Bengal, under my guidance. He has carried out the work at the Department of Chemistry, University of North Bengal, Darjeeling, West Bengal-734013. Professor Pranab Ghosh (Research Supervisor) Department of Chemistry University of North Bengal iii Abstract The thesis entitled “Transformative reactions on carbocyclic compounds” comprises four chapters and a brief of their contents are as follows: Chapter I: Carbocyclic compounds and their transformative reactions: A general perspective on natural products chemistry Natural products include any substance produced by life. Now, due to the large extent of catenation capability of carbon, it can produce a large number of molecules made solely by them which in turn, implies that nature provides a huge number of carbocyclic compounds. And in virtue, nature itself is the richest source of a variety of carbocyclic compounds. Two or more carbocycles can be joined together in a number of different fashions to produce a number of different groups of carbocyclic compounds. And among the broad spectrum of all kinds of natural products, if we look for more abundant, easily available and highly useful carbocyclic natural products, we found mainly the steroids and terpenoids. Thus, having the opportunity of working in the field of natural products chemistry, the various known / new transformative reactions were carried out on some selective major steroids (cholesterol, b- sitosterol, ergosterol, diosgenin) and comparatively less-explored but highly potential pentacyclic triterpenoid- friedelin. iv As a consequence, to have a general and very brief overview on the transformative reactions on these substrates, the present chapter demonstrates the important findings revealed so far. Chapter II: First report of solvent selective steroidal aromatization, efficient access to 4b,7 a-dihydroxy steroids, and syntheses of natural diaromatic ergosterols This chapter elaborates the syntheses of natural diaromatic ergosterol derivatives and other steroidal analogues in an unprecedented simple, one-pot and convenient synthetic route. In the process, the key factor- the selectivity of the solvents (having 1,4-ethereal oxygens) towards aromatization has been established. Of note, only ethereal solvents with two oxygens such as 1,4-dioxane, 1,3-dioxalane, 1,2-dimethoxy ethane and 1,2-diethoxy ethane were found able to result selective aromatization. Thorough solvent-dependant study of the model reaction reveals valuable product composition which may be exploited, specially, for the synthesis of biologically important steroid molecules. Efficient access to 4 b,7 a-dihydroxy cholesterol is also described. By using the established solvent-selective steroidal methodology, the yield of the natural product, diaromatic ergosterol was optimized at 12%. Analogous chemistry of b-sitosterol and diosgenin is also reported. Furthermore, single crystal X-ray crystallography has resolved the molecular structures, for the first time in their class, of similar diaromatic cholesterol derivative and triacetylated 4 b,7 a-dihydroxy cholesterol derivative. Chapter III: Polyhydroxy and epoxy-polyhydroxy steroids: design, synthesis and study of their preliminary gelation behaviour The present work associated with this chapter demonstrates basically two aspects of some new polyhydroxy steroids - designed synthesis and their preliminary gelation behavior. v Altogether sixteen polyhydroxy steroids (PHS, 12 new) of cholesteryl and b-sitosteryl series were synthesized and characterized. Among them eight (all new) are, in precise, epoxy- polyhydroxy steroids (5,6-epoxy-3b,4 a-dihydroxy- and 5,6-epoxy-3b,4 a,7 a-trihydroxy-), of which the a-diastereomers were utilized further to synthesize novel new tetraols (3 b,4 b,5 a,6 b-tetrahydroxy-) and pentaols (3 b,4 b,5 a,6 b,7a -pentahydroxy steroids). Thus, epoxidation followed by alkaline-opening of the oxirane-ring of appropriate steroidal 5-ene- 3b,4 b-diols and -5-ene-3b,4 b,7 a-triols, to furnish novel steroidal tetrols and pentols respectively consequences, in practical, a three-step synthetic route for the transformation of 3b,4 b,5 a,6 b-tetrahydroxy- and 3 b,4 b,5 a,6 b,7a -pentahydroxy steroids starting directly from their corresponding basic steroids, cholesterol and b-sitosterol. As a new class of polyhydroxy steroids, preliminary gelation behavior of the molecules was evaluated. At 1% or below CGC (critical gelation concentration), five PHS derivatives were found to be gelators of some selective organic solvents. Some selective organogels were characterized through T gel (gel melting temperature) and related physical parameters ( DH etc.), rheological data, and by morphology analysis (electron microscopes). vi Chapter IV: Syntheses of new friedelane triterpenoids: A-ring modifications including 2-homo derivatives Syntheses of a number of A-ring modified friedelane triterpenoids have been accomplished. These also include the 2-homo derivatives for which, as the key step, the transformation of friedelin with Vilsmeyer-Haack reagent was used. 3-Chloro-2-formylfriedel-2-ene, the main product isolated from the reaction was transformed suitably into various derivatives and hence, following two or three simple steps starting from friedelin, it rendered possible to produce a library of C2,C3-, C3,C4-, and C2,C3,C4- functionalized friedelane triterpenoids. Besides, some useful methodologies were thus established during the various transformative attempts. These include a two-step aromatization of friedelin by N-bromosuccinimide, a one- pot dechlorination with simultaneous C-23 activation, and selective 4 a-hydroxylation with simultaneous oxidation of allylic alcohol by selenium dioxide. Again, syntheses of some friedelane derivatives, viz. , 3b-amino-4a-hydroxy-, 2-carboxamide, 2,3-seco diol, 4a- hydroxy-3-chloro-2-formylfriedel-2-ene and 3-chloro-4a-hydroxy-2-hydroxymethylfriedel- 2-ene, in a few steps, were found very much effective to enrich the A-ring modifications of friedelane triterpenoids. On the other hand, heterocycle-linked (to C3 of friedelanes) 2- homofriedelane derivatives were achieved. We believe to use these friedelane triterpenoids for future biological applications as well as to explore more interesting and usefull multifunctionalized derivatives of the particular class of pentacyclic triterpenoids. vii Preface The thesis is the compilation of the research work carried out by the author under the supervision of Professor Pranab Ghosh in the Department of Chemistry, University of North Bengal during the period 2008 to 2015. It comprises a number of transformative reactions on different carbocyclic compounds. And as the author had privilege to work in the natural products laboratory, the carbocyclic compounds chosen as the starting substrates are some selective steroids and pentacyclic triterpenoids having immense practical utilizations. In short, a chemical compound or substance produced by a living organism —thus found in nature, is a natural product. Within the periphery of organic chemistry, we consider natural products, typically, as pure organic compounds (thus pure molecules) isolated from natural sources related to lives, directly or indirectly. Due to the widespread and increasingly demandable applications of these natural molecules, supply at a required amount has lead their preparation in the laboratory by the process of chemical synthesis, which indeed has enriched organic chemistry enormously by following a huge number of challenging targets. And considering the prime importance of steroids and pentacyclic triterpenoids in medicinal chemistry as well as in materials science, we have taken an opportunity to enrich this particular area of the natural products chemistry by synthesizing a number of interestingly useful molecules through different known/ new transformative protocols. I feel it an imperative, in my first opportunity, to express my heartfelt and sincere gratitude to my supervisor, Professor Pranab Ghosh, Department of Chemistry, University of North Bengal, West Bengal for providing me the opportunity to carry out my research work with all the marvellous supervision and utmost important suggestions. His continuous encouragement and guidance has played a pivotal role in furnishing a good basis for the present thesis. I would like to thank all the faculty members of the Department

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