A practical synthetic route to triene synthons of putative intermediates in polyether biosynthesis

Dyer, Ulrich Conrad (1986) A practical synthetic route to triene synthons of putative intermediates in polyether biosynthesis. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

A synthetic study has been made to assist in the elucidation of the mechanisms of polyether antibiotic biosynthesis. Previous biochemical investigations into these pharmacologically important metabolites have suggested that a general route may exist to account for their construction. It was proposed, in the case of monensin biosynthesis, that its array of tetrahydrofuran and tetrahydropyran rings may be formed from a triene intermediate which undergoes biological epoxidation and a subsequent cascade of ring closures to form the polyether. Current efforts to establish this proposal, using a variety of biochemical techniques, are dependent upon the availability, through synthesis, of the putative triene intermediate. The development of a practical synthetic route to such triene systems is reported in this thesis. The synthesis of a suitably functionalised (3R^*, 5S^* ,6E,10E,14E)-3,5,11,15-tetramethyl-6,10,14-nonadecatriene skeleton was investigated. Commencing from geraniol, which possesses the two trisubstituted double bonds present in the target molecule, methods for the construction of the (E)-disubstituted double bond were examined. Initial attempts using the Wittig-Schlosser methodology failed. Therefore the alternative methodology of the Julia olefination reaction was examined, but it was found that the yields of this coupling reaction to form the target molecule were unacceptably low. However, by using a modification of the Julia olefination reaction, (1RS,4E,8E,12RS)-12-tert-butyldimethylsiloxy-5,9-dimethyl-1-lithio-1-(phenylsulphonyl)-4,8-tridecadiene (109) and (2S^*,4R^*)-methyl 2-methyl-4-(2-methyl-1,3-dioxolan-2-yl)-pentanoate (97) were successfully coupled and the product was converted through to (2R^*,4S^*,5E,9E,13E,17RS)-17-tert-butyldiethylsiloxy-2-(methyl-1,3-dioxolan-2-yl)-4,10,14-trimethyl-5,9,13-octadecatriene (105) in high yield. This optimised route to the triene (105) proceeds in 23% yield from geraniol. The synthesis of a tritium labelled triene (105T) has also been achieved. (D72238/87)