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Alternative Formats If You Require This Document in an Alternative Format, Please Contact: Openaccess@Bath.Ac.Uk University of Bath PHD Synthesis of novel secosteroids Ashton, Mark Richard Award date: 1994 Awarding institution: University of Bath Link to publication Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 11. Oct. 2021 SYNTHESIS OF NOVEL SECOSTEROIDS submitted by MARK RICHARD ASHTON for the degree of Ph.D. of the University of Bath 1994 "Attention is drawn to the fact that copyright of this thesis rests with its author. This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with its author and that no quotation from the thesis and no information derived from it may be published without prior written consent of the author". "This thesis may be made available for consultation within the University Library and may be photocopied or lent to other libraries for the purpose of consultation". UMI Number: U540219 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U540219 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 UNIVERSITY OF BATH LiE'>Anv 2.} 3 0 JAN 1995 | f HO I I I........ ... ? ° f ? ? 4 * 1 “Oh, ttop moaning! It** bad though th# ante* thedst didn’t turn up this morning." The importance of anaesthesia. Dedicated to my parents and grandma for their constant love and support ACKNOWLEDGEMENTS The work described in this thesis was carried out in the organic chemistry department at the University of Bath and Organon Teknika laboratories between October 1990 and March 1994. I would like to thank Organon Teknika for their financial support throughout this period. I am grateful to Professor Malcolm M. Campbell for his help and support. I am indebted to my industrial supervisor, Dr. Alex Campbell, for his interest and advice during and after my research, and also to the staff of Organon, Newhouse for their advice and friendship throughout my stay in Glasgow. My appreciation goes to the technical staff at the University of Bath for their invaluable services. Special thanks go to Mr. John Bradley and Mr. Russel Barlow (Organic Stores), Mr. David Wood and Mr. Harry Hartell (NMR spectroscopy), Mr. Alan Carver (Elemental Analysis), Mr. Chris Cryer (Mass Spectroscopy), and also to June and Freda. I would also like to thank Mrs. Jo Curtis for her excellent typing of this thesis and help during my research, Dr. Mary Mahon and Dr. Kieran Molloy for the X-ray crystal structures, and Dave Evans for his invaluable help and advice. Last, but by no means least, I would like to thank everybody in the department for making my time spent here a lively and great one. Especially Steve Walford, Matt Sage, Gwo-Sen and the rest of the guys and galls for all their help and friendship throughout. I would like to thank my girlfriend Sarah for her constant support and patience throughout the writing of this thesis, when even the most sane of us began to go mad. To all of you, cheers and all the best for the future. - i v - ABSTRACT It was hoped that secosteroids of the type 107, and to a lesser degree secosteroids such as 60 and 65, and flbeosteroids 117 and 128 would probe conformational requirements for inducing and maintaining general anaesthesia after intravenous administration. The 3-acetoxy-5a-hydroxy steroid 38 underwent fragmentation of the C(5)-C(10) bond after treatment with eerie ammonium nitrate in refluxing acetonitrile, with the formation of 10-membered ring containing 5,10-secosteroidal compounds with a A1,10 double bond. The synthesis afforded exclusively the (E)-form 39, the configuration of the double bond being assigned by means of NMR spectrometry. Epoxidation of the A1,10 double bond occurred stereoselectively to give the ip,10a-epoxide, which served as a protecting group for the olefin and allowed deoxygenation of the 5-carbonyl. Selective hydrolysis of the 3-acetate in the presence of the 20-acetate allowed manipulation of both the head and tail ends of the seco- and abeosteroids to afford the 3a-hydroxyl and 20-keto moieties, required for optimum anaesthetic potency (detailed in the review of steroidal anaesthetics , see Appendix). It was hoped that the 3a-hydroxyl and 20-keto moieties would be less constrained and thus more free to adopt a suitable conformation for GABAa receptor binding. Cyclization of the (E)-5,10-secosteroids of the type 39 under thermal conditions afforded compounds of the 5(10—>lpH)< 2Z?e<? type 117, exclusively the trans lp,5a-configuration. Also incorporation of a good leaving group at position C(5) facilitated the facile transannular reaction to afford 5(10—*lpH)fl&e 0 Steroids of the type 117. The ease of the transannular reaction plus results of conformational studies indicates that the transannular interaction of the double bond with the — V — carbonyl group may strongly influence the thermodynamic stability of the system. Conformational studies on the (E)-5,10-seco-pregnene 39 showed the cyclodecenone ring to adopt an extended crown conformation, and analysis of the lH-NMR data of the 3a-silyl ether revealed that in solution the 10-membered ring exists in at least 2 distinct forms. X-ray analysis of the 5(10—*1 pH )abeo diol 117 revealed the unusual configuration of the 19a-methyl group plus a solid state molecular packing dominated by intermolecular hydrogen bonds through the corresponding hydroxyl groups. The consequence of these hydrogen bonds is an array of infinite herringbone polymers, unique to this type of structure. - v i - ABBREVIATIONS A - angstrom Ac - acetyl AFU - anaesthetic fish unit AIBN - azobisisobutyronitrile Ar - aryl ATP - adenosine triphosphate BI - benz[e]indene Bu - butyl Bz - benzyl CAN - eerie ammonium nitrate C.I. - chemical ionisation CNS - central nervous system CTMS - chlorotrimethylsilane 2D COSY - two dimensional correlated spectroscopy DCA - desoxycorticosterone acetate DDQ - 2,3-dichloro-5,6-dicyano-1,4-benzoquionone DEAD - diethyl azodicarboxylate DEG - diethylene glycol DHP - dehydropregnenolone DMAP - 4-dimethylaminopyridine DMF - dimethylformamide DMPC - dimyristoylphosphatidylcholine DMSO - dimethyl sulphoxide DPPC - dipalmitoylphosphatidylcholine e d 50 (AD50) - 50 percent effective dose - v i i - E.I. - electron ionisation Et - ethyl FAB - Fast Atom Bombardment GABA - gamma-amino-rt-butyric acid GAD - glutamic acid decarboxylase h - hour HCG - human chorionic gonadotrophin HMPA - hexamethyl phosphoric acid Hz - Hertz Im - Imidazole IR - infrared J - coupling constant Kd - dissociation constant for a given drug KJ - kilo joule LD50 - 50 percent lethal dose LH - luteinizing hormone MAC - minimum alveolar concentration Me - methyl min - minute m.p. - melting point NMDA - N-methyl-D-aspartate NMO - 4-methylmorpholine N-oxide NMR - nuclear magnetic resonance PCC - pyridinium chlorochromate PCN - 3(B-hydroxy-20-oxo-5a-pregnan-16a-carbonitrile Ph - phenyl PMS - pregnant mare serum ppm - parts per million p-TSA - para-toluenesulphonic acid - v i i i - rbf - round bottomed flask REM - rapid eye movement Rf - retention factor rt - room temperature SAR - structure activity relationship t - tert- TBAF - tetrabutylammonium fluoride tBDMS - r-butyldimethylsilyl TBPS - r-butyl bicyclophosphorothionate Tf - triflate THF - tetrahydrofuran T.I. - therapeutic index tic - thin layer chromatography TPAP - tetrapropylammonium perruthenate Ts - tosyl U.V. - ultraviolet W - Watt - i x - NOMENCLATURE General The chemical name of a compound specifies its stereochemistry but not the conformation. Though all steroids can be assigned a unique systematic name based on IUPAC nomenclature1, trivial and non-systematic names are used persistantly. For example, the trivial name for pregn-4-ene-3,20-dione is progesterone. The systematic names are based on certain fundamental stem names and the stereochemistry implied in them. Substituents are indicated by systematic application of the rules of general organic chemical nomenclature. According to the IUPAC rules hydroxyl and keto groups appear after the name of the parent compound, characterized by the ending "-ol" or "-one" respectively, added to the number of the carbon atom to which it is attached, while all other substituents are listed before the parent name in order of their position on the steroid skeleton. Prefixes and suffixes are added to the parent name, their positions being indicated by the number of the carbon atoms to which they are attached. The prefix A is used as an alternative to denote a double bond. The standard atom numbering scheme and the lettering of the rings of the steroid skeleton are shown in Figure 1. The carbon atoms are numbered around the rings, starting from the top of ring A.
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