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A Synthetic Approach to Determine the Stereochemistry of Diepomuricanin A

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A Synthetic Approach to Determine the Stereochemistry of Diepomuricanin A University of Southampton Research Repository ePrints Soton Copyright © and Moral Rights for this thesis are retained by the author and/or other copyright owners. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the copyright holder/s. The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the copyright holders. When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given e.g. AUTHOR (year of submission) "Full thesis title", University of Southampton, name of the University School or Department, PhD Thesis, pagination http://eprints.soton.ac.uk UNIVERSITY OF SOUTHAMPTON FACULTY OF NATURAL AND ENVIRONMENTAL SCIENCES CHEMISTRY A synthetic approach to determine the stereochemistry of diepomuricanin A by Mohammed Hussain Geesi Thesis for the degree of Doctor of Philosophy May 2014 UNIVERSITY OF SOUTHAMPTON ABSTRACT FACULTY OF NATURAL AND ENVIRONMENTAL SCIENCES Synthetic Organic Chemistry Thesis for the degree of Doctor of Philosophy A SYNTHETIC APPROACH TO DETERMINE THE STEREOCHEMISTRY OF DIEPOMURICANIN A Mohammed Hussain Geesi The total synthesis of bis-epoxide acetogenin, diepomuricanin, has been investigated in order to determine the absolute stereochemistry within the bis-epoxide region. Two approaches (linear and tethered-metathesis) were attempted. In the linear approach, two routes were investigated. In the first one an intermediate aldehyde 248 was created in six steps in order to investigate the asymmetric α-oxidation and diastereoselective additions of organometallic reagents. Model studies using octanal met with moderate success, and highlighted the sensitivity of the α-oxidation products. The instability of the -oxidation products prevented a proper study of the additions of Grignard and organozinc reagents. In a second route, hydrolytic kinetic resolution of terminal epoxides was investigated in order to obtain optically enriched 1,2-diols suitable for elaboration to diepomuricanins. A revised, convergent approach to diepomuricanin A stereoisomers was developed based on a silicon-tethered metathesis of allylic alcohol fragments. Sharpless asymmetric kinetic resolution (SAKR) of allylic alcohols (±)-305 and (±)-306 was the key step towards the left hand fragments (19S,20S)-302, and (19R,20R)-302, and the right hand fragments (15S,16S)-303, and (15R,16R)-303. Combining them together via a tethered alkene metathesis, led to the key siloxytriene 308. An investigation of the Alder-ene reactions of right hand fragment (15S,16S)-303 display the low selectivity of the less hindered and more electron-rich C27-C28 doble bond. Therefore, the route was modified to proceed by new right hand fragment epoxyalcohols (15S,16S)-354, and (15R,16R)-354, which allowed formation of butenolide 363 towards the synthesis of the diepomuricanin A stereoisomer (anti-5d). The synthesis was optimised using an asymmetric allylic esterification of trichloroacetimidate (Z)-370 in the re-synthesis of the left hand fragment (19S,20S)-302 on large scale. Coupling of (19S,20S)-302 with the right hand fragment (15S,16S)-354 allowed formation of the key butenolide intermediate 392 towards the synthesis of the diepomuricanin A stereoisomer (syn-5c). Contents ABSTRACT ...................................................................................................................... i Contents ............................................................................................................................ i DECLARATION OF AUTHORSHIP .......................................................................... v Acknowledgements ........................................................................................................ vii Definitions and Abbreviations ...................................................................................... ix 1. Chapter 1: Introduction ........................................................................................... 1 1.1 General introduction ........................................................................................... 1 1.2 Classification of acetogenins .............................................................................. 2 1.3 Biological activity of acetogenins ...................................................................... 3 1.4 Biosynthesis of acetogenins ............................................................................... 6 1.5 Structural elucidation of acetogenins ................................................................. 7 1.5.1 Determining the primary structure of acetogenins ...................................... 7 1.5.2 UV Spectroscopy ........................................................................................ 8 1.5.3 Thin layer chromatography (TLC) .............................................................. 8 1.5.4 IR Spectroscopy .......................................................................................... 8 1.5.5 Mass spectrometry ...................................................................................... 9 1.6 Determining the stereochemistry of mono-THF and epoxy acetogenins ........... 9 1.6.1 Determining the relative stereochemistry in mono-THF acetogenins ....... 10 1.6.1.1 Hoye’s method (1988) and application ................................................. 11 1.6.1.2 Born’s rule (1990) and application ........................................................ 15 1.6.1.3 Harmange’s method (1992) and application ......................................... 17 1.6.1.4 Cassady’s rule (1993) and application .................................................. 19 1.6.1.5 Fujimoto’s work (1994) and application ............................................... 22 1.6.1.6 Formal acetal derivatisation method and application ............................ 25 1.6.1.7 Acetonide derivatives to determine the relative stereochemistry of 1,2- diols in acetogenins and application ..................................................................... 27 1.6.2 Determining the relative stereochemistry of lactones and butenolide unit in acetogenins ........................................................................................................... 29 1.6.2.1 Hoye’s method for determination of the relative stereochemistry between C2 and C4 in acetonylbutenolides .......................................................... 29 1.6.2.2 Application of NOESY experiments and coupling constant data ......... 31 1.6.3 Methods for determining the absolute stereochemistry in acetogenins .... 32 1.6.3.1 Determining the absolute stereochemistry in mono-THF acetogenins.. 32 1.6.3.1.1 Mosher’s method ............................................................................ 32 i 1.6.3.1.2 Stereochemical determination based on libraries of murisolin isomers 43 1.6.3.1.3 2-Naphthylmethoxy acetic esters derivatives (2-NMA) method .... 50 1.6.3.1.4 p-Bromophenylurethane derivatisation method ............................. 51 1.6.3.1.5 Application of total synthesis for determination of the absolute stereochemistry in mono-THF acetogenins ...................................................... 54 1.6.3.2 Determining the absolute stereochemistry of butenolide and lactone units in acetogenins ............................................................................................... 59 1.6.3.2.1 Optical rotation data ....................................................................... 59 1.6.3.2.2 Determination of the absolute stereochemistry in mono-THF acetogenins using circular Dichroism (CD) spectroscopy technique ............... 60 1.6.4 Assigning the relative and absolute stereochemistry in mono-THF acetogenins (full structure assignment) .................................................................... 61 1.6.4.1 Assigning the stereochemistry of cis-gigantrionenin (77) .................... 61 1.6.4.2 Assigning the absolute stereochemistry of longifolicin (187)............... 62 1.6.4.3 Assigning the absolute stereochemistry of (2,4-cis- and trans)- gigantetroneninone (44) ........................................................................................ 64 1.6.4.4 Assigning the stereochemistry of donnaienin (193) .............................. 66 1.6.5 Determining the stereochemistry of epoxy acetogenins ........................... 67 1.6.5.1 Assigning the relative configuration of epoxy acetogenins by transformation of epoxides to mono-THF acetogenins ......................................... 67 1.6.5.1.1 Assigning the stereochemistry of sabadeline (196) ........................ 67 1.6.5.1.2 Assigning the stereochemistry of corepoxylone (200) ................... 68 1.6.5.1.3 Assigning the stereochemistry of anti-dieposabadelin (202) ......... 69 1.6.5.2 Assigning the absolute configuration of epoxy acetogenins by total synthesis 70 1.7 Summary from the previous work .................................................................... 74 1.8 An introduction to the proposed work .............................................................. 75 1.8.1 Total synthesis of syn-diepomuricanin A (syn-5a) by Makabe ................ 81 1.8.1.1 Synthesis of alkyne 228 ......................................................................... 82 1.8.1.2 Synthesis of lactone 229 .......................................................................
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