Synthetic approaches to proposed biosynthetic intermediates of the polyther ionophore monensin

Russell, Simon Thomas (1987) Synthetic approaches to proposed biosynthetic intermediates of the polyther ionophore monensin. University of Southampton, Doctoral Thesis.

Abstract

This thesis describes progress towards the synthesis of putative biosynthetic precursors of monensin B. It also contains a synthetic investigation into the hypothetical polyepoxide cyclisations proposed in the biosynthesis. The synthesis of (5E, 9E, HS)-13-benzyloxy-5,9-11-trimethyltrideca-5,9-dien-2-yl triethylsilylether (24) is described. Using a stereoselective alkylation process, (2'S, 4R 5S)-(+)-4-methyl-3-(2'-methyl-1'-oxopent-4'-enyl)-5-phenyl-2-oxazolidone (33) was prepared, containing the required chiral centre. This strategy, however, was not found to be viable at multigram scales. An alternative method utilised R-(+)-pulegone (27) as a chiral precursor to the key synthetic intermediate (2S)-4-benzyloxy-2-methylbutan-1-al (25). Conversion to (4S)-6-benzyloxy-2,4-dimethylhex-1-en-3-ol (49), followed by a ketal Claisen rearrangement produced (6E, 8S)-(+)-10-benzyloxy-2,6,8-trimethyldeca-1,6-dien-3-one (58) containing one of the two required (E)-trisubstituted double bonds. The second double bond was constructed using an orthoester Claisen rearrangement on (6E, 8S)-10-benzyloxy-2,6,8-trimethyldeca-1,6-dien-3-ol (50) which gave (4E, 8E, 10S)-(+)-ethyl-12-benzyloxy-4,8,10-trimethyldodeca-4,8-dienoate (77). This was converted into the required silyl ether (24), which is a useful intermediate in the synthesis of a proposed triene precursor (140) monensin B. The preparation of two fragments of monensin B with appropriate relative and absolute stereochemistry, namely, (+)-(5S)-5-[(2S, 5R, 1'R)-2-(1',2'-dihydroxyethyl)-2-methyltetrahydrofuran-5-yl]-5-methyldihydrofuran-2-one (194), and (-)-(5S)-5-[(2S, 5R, 5'R)-2-(dihydrofuran-2'-one-5'-yl)-2-methyltetrahydrofuran-5-yl]-5-methyldihydrofuran-2-one (200), is described. This involved the use of an unusual polyepoxide cyclisation procedure which has been implicated in the biosynthesis of monensin. (4R, 5R, 8R, 9R)-(+)-Methyl-4,5-8,9-diepoxy-4,8-dimethyl-10-hydroxydecanoate (166) was prepared from geraniol (72) using Sharpless asymmetric epoxidations as the key steps. Incubation with pig liver esterase gave the bicyclic lactone (194). Similarly (4R, 5R, 8R, 9R)-(+)-methyl-4,5-8,9-diepoxy-4,8-dimethyl-11-formylundecanoate (169) was prepared from the diepoxide (166) and underwent cyclisation with pig liver esterase to give (5S)-5-[(2S, 5R, 5'R)-2-(tetrahydrofuran-2'-ol-5'-yl)-2-methyltetrahydrofuran-5-yl]-5-methyldihydrofuran-2-one (197). This was converted into the tricyclic dilactone (200) and the assigned relative stereochemistry confirmed by a single crystal X-ray diffraction analysis. An n.m.r. study of the cyclisation of (166) into (194) revealed that a monocyclic intermediate (201) was involved in the process. These results enhance the relevance of polyepoxide cyclisations to polyether biosynthesis and present new methodology for polyether synthesis. (D82124)

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