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Download (6MB) https://theses.gla.ac.uk/ Theses Digitisation: https://www.gla.ac.uk/myglasgow/research/enlighten/theses/digitisation/ This is a digitised version of the original print thesis. Copyright and moral rights for this work are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This work cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given Enlighten: Theses https://theses.gla.ac.uk/ [email protected] Development and Application of the One-pot Julia Olefination Paul Richard Blakemore Thesis Submitted for the Degree of Doctor of Philosophy University of Glasgow, Chemistry Department February 1999 © Paul Richard Blakemore 1999 ProQuest Number: 10992306 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 com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 10992306 Published by ProQuest LLO (2018). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLO. ProQuest LLO. 789 East Eisenhower Parkway P.Q. Box 1346 Ann Arbor, Ml 4 8 1 0 6 - 1346 GLASGOW UNIVERSITY LIBRARY Abstract The influence of heterocycle, base and solvent on the recently reported one-pot Julia olefination^"^ was investigated. 1-Phenyl-l//-tetrazol-5-yl (FT) sulfones emerged as a promising alternative to the previously reported benzothiazol-2-yl (BT) sulfones for use in the olefin synthesis. For both BT and FT systems an increase in solvent polarity resulted in a heightened trans selectivity for the synthesis of simple 1,2-disubstituted monoenes. However, only for the new FT variant was the stereochemical outcome also dependent on base counter cation. Potassium derivatives of FT sulfones react with saturated aldehydes in 1,2- dimethoxyethane (DME) to produce 1,2-disubstituted alkenes with excellent selectivity"^. A partial synthesis of vitamin D2 was achieved employing fragments derived from a new improved degradation procedure. Condensation of the sodium derivative of BT sulfone 230 with aldehyde 198 yielded 70% of vitamin D2 (163, 1E:Z = 72:28) after deprotection. (a) NaHMDS, EtaO -78°C, 1 h TBSO,. SO2 198 -100°C ^ rt, 0/N 230 (0) TBAF-3H20 HO' THF, rt, 0/N vitamin D 2 (163) 70%, 7 E;Z= 72:28 The first total synthesis of the polyketide herboxidiene (233) was completed in 22 linear steps from cyclohexanone^. Both BT and FT one-pot Julia methodologies were used at pivotal junctures in the synthesis. The new FT variant was employed to access a simple 1,2- disubstituted olefin (327) prior to subsequent Sharpless asymmetric dihydroxylation. The established BT technology was used to conjoin two late stage intermediates, 332 and 238, to yield 81% of the protected herboxidiene derivative 394 with \OE:Z =91:9. (a) LDA,THF,-78°C, 15min MeO 238 CO2 AII MeO PCBO -78°C ^ -2 0 °C , 1.5 h 332 RO PCB = 4-chlorobenzoyl 394, R = PCB, R' = All , deprotection 81%, 10E;Z=91:9 herboxidiene (233), R = R' = H 3 Dedicated to the loving memory of my mother. Acknowledgements Firstly, I would like to thank my supervisor. Prof. Philip Kocienski, for allowing me immense freedom in controlling the direction of my studies and for providing helpful advice and insight. Dr W. J. Cole for completing an enormous number of GC analyses to a very strict deadline. Dr Cole's extraordinary efforts were much appreciated by me at a personally difficult time. Dr A. Morley, my industrial supervisor, for taking a keen interest in my work and for his continued support. Prof. J. Wicha and Dr S. Marzcek for a most fruitful and rewarding collaboration involving the D vitamins. All my friends and colleagues in the Kocienski group, past and present, for providing much inspiration and many good times. The EPSRC and Rhône-Poulenc Rorer for funding. Lastly, I would like to thank everyone at Glasgow University for their warm welcome and subsequent friendship after I first moved to Scotland from the remoteness of Southampton University in November 1996. s Contents Abbreviations 6 1. The One-pot Julia Olefination 7 2. Development of the One-pot Julia Olefination 22 3. Vitamin D Fragment Linkage Strategies 42 4. Partial Synthesis of Vitamin D 49 5. The Herbicidal Polyketide Herboxidiene 56 6. Total Synthesis of Herboxidiene 68 1. Summary of Results and Conclusion 88 8. Experimental Section 93 9. Appendix - Crystal Structure of Diol 365 189 10. References 194 Abbreviations Ac - acetyl NaHMDS - sodium acac - acetylacetonate hexamethyldisilazide All - allyl NMO A-methylmorpholine Bn - benzyl A-oxide Boc - /err-butyloxycarbonyl PCB 4-chlorobenzoyl BT - benzothiazol-2-yl PCC pyridinium chlorochromate Bz - benzoyl PMB 4-methoxybenzyl m-CPBA - 3-chloroperoxybenzoic acid PPTS pyridinium dba - dibenzylideneacetone /7-toluenesulfonate DDQ - 2,3-dichloro-5,6-dicyano- proton 1,8-bis(dimethylamino)- 1,4-benzoquinone sponge® naphthalene DEAD - diethyl azodicarboxylate PT 1 -phenyl- l//-tetrazol-5-yl DET - diethyl tartrate PYM pyrimidin-2-yl DHP - 3,4-dihy dro-27f-pyran PYR pyridin-2-yl DIAD - diwopropyl Red-Al® - sodium bis(2-methoxy- azodicarboxylate ethoxy)aluminum hydride DIBAL-H - difjobutylaluminum hydride TBAF tetra-M-butylammonium DMAD - dimethyl azodicarboxylate fluoride DMAP - 4-(dimethylamino)pyridine TBAI tetra-n-butylammonium DME - 1,2-dimethoxyethane iodide DME - A, A-dimethy Iformamide TBDPS rgyf-butyldiphenylsilyl DMP - Dess-Martin periodinane TBHP fgrr-butylhydroperoxide DMPU - A,A'dimethylpropylene TBS rarr-butyldimethylsilyl urea TES triethylsilyl DMSO - dimethylsulfoxide Tf trifluoromethanesulfonyl Het - heterocycle TEA trifluoroacetic acid HMPA - hexamethylphosphoramide THE tetrahydrofuran IM - 1 -methylimidazol-2-yl TIPS triwopropylsilyl IQ - woquinolin-l-yl TMS trimethylsilyl KHMDS - potassium Ts p-toluenesulfonyl hexamethyldisilazide TZ 4-methyl-1,2,4-triazol-3-yl LDA - lithium diwopropylamide LiEMDS - lithium hexamethyldisilazide Ms - methanesulfonyl 1. The One-pot Julia Olefination The organic chemist now has a vast array of reactions in his/her arsenal^, but unfortunately still relatively few procedures which are at once both mild and selective enough to effect the linkage of complex multi-functional fragments. Of those at our disposal, connective olefination processes^’^ are amongst the most powerful, provided that chemo-, regio- and stereoselection can all be under complete control. Until the advent of the Wittig reaction^'in the early 1950's, alkenes were typically prepared via classical elimination methods. Under the relatively harsh conditions required for such reactions, double bond formation is frequently under thermodynamic control and thus doomed to yield Saytzeff-type products^^ The following example provided by Inhoffen*^ exemplifies some of the problems facing chemists in the pre-Wittig era (Scheme 1). Ionic elimination of water from diene 2 not surprisingly failed to yield the desired vitamin D model triene 1, but instead yielded the higher substituted endocyclic olefin 3. OH Schem e 1 1 2 3 The Wittig reaction offered for the first time a mild connective olefination method which not only enabled precise positioning of the newly formed double bond but often also gave an enormous degree of stereocontrol. A large variety of the olefination methods available today employ the same basic paradigm laid down by Georg Wittig over 45 years ago: condensation of a carbanion (or ylide) stabilised by an adjacent third row heteroatom (Si, P or S) with a carbonyl group initiates a cascade of reactions ultimately leading to the formation of an alkene. Olefination procedures belonging to this general class include: the phosphorus-based Wittig^’^®, Homer-Wittig^^’^'^ and Homer-Wadsworth-Emmons (HWE)^^’^^ reactions (all three have been comprehensively reviewed by Maryanoff and Reitz*^); the silicon-based Peterson** reaction and the sulfur-based Johnson*^ and classical Julia^** reactions. The aforementioned processes all rely on the variable valency of the key stabilising heteroatom and many are thermodynamically driven by the formation of a strong heteroatom oxygen bond. A new variant of the classical Julia reaction, the one-pot Julia olefination^, is the main focus of this PhD thesis. 1.1. Phosphorus hased olefination methods: the Wittig, Horner-Wittig and Horner-W ads worth-Emmons reactions 1.1.1. The Wittig reaction The very well known Wittig reaction involves the addition of a phosphonium ylide 5 (phosphorane) to a carbonyl compound 4, resulting in the formation of an olefin 8 (always at the site of the original carbonyl group) and a phosphine oxide 9 (Scheme 2)*^’^*, Although zwitterionic betaines were originally thought to be intermediates in the reaction, it is now the accepted view (certainly in the case of unstabilised ylides^^) that the reaction occurs via diastereomeric oxaphosphetane entities (6 and 7). Their formation is thought to be the result of a [2+2] cycloaddition between the ylide and carbonyl; a syn cycloreversion process can then either return the starting materials or yield the products irreversibly. Schem e 2 0 -PPh3 *'"R‘ O PPha 6 + + Ph3P=0 0 -PPh3 R' "R" 7 Although regiochemistry is precisely controlled, the stereochemical outcome of the Wittig reaction depends upon several factors, being particularly sensitive to the type of ylide used. Generally, stabilised ylides yield predominately E-olefins whereas the contrary is true of unstabilised ylides. Indeed, in the absence of soluble lithium salts (so called 'salt-free' conditions) extremely high Z-selectivity can result from the use of unstabilised ylides^^.
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