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Approaches towards a total synthesis of the phomactins
[Thesis]. Manchester, UK: The University of Manchester; 2011.
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Abstract
Within this thesis are described synthetic approaches towards thephomactins which are novel platelet activating factor antagonists. The workwas carried out at the University of Manchester by Abdur Rehman Irshadfor the degree of Doctor of Philosophy for the titled work: “Approachestowards a total synthesis of the phomactins” submitted in 2010.The synthesis of known alcohol 162 is described, the two keyintermediates being aldehyde 160 and vinyl iodide 161. The key step of thesynthesis of aldehyde 160 is a [2,3]-Wittig-Still rearrangement of stannane159 which introduces the hindered C1-C2 bond present in the phomactins.The vinyl iodide 161 is made in four steps from 4-pentyn-1-ol. Addition of thevinyl ytterbium species derived from the vinyl iodide to aldehyde 160 gavesecondary alcohol 162. Subsequent transformations furnished the bisprotectedmacrocyclic sulfone 174 in four steps from alcohol 162 to give theC2 SEM protected macrocycle.Elaboration of the macrocycle to ketoaldehyde 206 was made possibleby the TPAP oxidation/rearrangement reaction. Reduction with DIBAL-Hgave diol 175. Attempts at removing the sulfone appendage proved difficultso the diol was protected as the bis-acetate to attempt a selective epoxidationof the D3,4 olefin in the presence of the D1,15 olefin. Although this lookedpromising with the formation of the mono-epoxide 213, the inefficiency ofremoving the SEM group at C2 prior to the epoxidation meant the route wasnot viable.Removing both protecting groups from macrocycle 174 was possiblewith refluxing TBAF and after incorporating the epoxide of the D3,4 olefin,the macrocycle was elaborated to the benzyl ether 217. Applying the TPAPoxidation/DIBAL-H reduction sequence furnished advanced intermediate179 which has the full carbon skeleton found in phomactin A and also hadoxygen functionality at all the required positions.