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The synthesis of an ionomycin fragment

University of British Columbia

This thesis concerns studies directed towards the synthesis of the polyether antibiotic ionomycin (1). Specifically, the aims were to prepare optically active fragments A and B, corresponding to C-l to C-9 and to C-10 to C-15 of ionomycin, and to couple these intermediates. A model study was conducted to develop chemistry central to the synthesis of fragment A from methyl α-D-glucopyranoside (73). A Wadsworth-Emmons cyclization of the phosphonate aldehyde 69 furnished α,β-unsaturated lactone 70, the second reported urono-8,4-lactone. A stereoselective conjugate addition with the higher order mixed organo-cuprate, Me₂Cu(CN)Li₂, yielded as the major product, lactone 82 with an axial methyl group at C-6. The minor product of the cuprate reaction, lactone 83 with an equatorial methyl group at C-6, was also prepared via a separate route. The synthesis of the fragment A precursor for ionomycin involved the introduction of three pendent methyl groups at positions C-2, C-4, and C-6 on the D-glucose frame work. Notably, the C-6 methyl group was introduced by a highly stereoselective conjugate addition analogous to the model study. Thus, the cuprate, Me₂Cu(CN)Li₂, added to α,β -unsaturated lactone 110 to yield lactone 112 as the sole reaction product. The lactone ring was then opened to allow the stereoselective introduction of the methyl group at C-4 after which the pyranoside ring was opened. Subsequent synthetic manipulations yielded the optically active fragment A precursor 138. Fragment B was prepared from meso-2,4-dimethylglutaric anhydride (5). An intermediate, acid ester 6, was resolved and was then modified to yield the optically active mixture of epimeric epoxides 15. The fragment A precursor 138 and the fragment B mixture 15 were coupled to yield the epimeric mixture of β-hydroxy ketones 140 which contains C-2 to C-15 of ionomycin.[See Thesis for Diagrams]

Text

2010-08-07

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http://hdl.handle.net/2429/27174

Chemistry

University of British Columbia

Graduate