Salinomycin : the bis-spiroacetal moiety

Brimble, Margaret Ann (1985) Salinomycin : the bis-spiroacetal moiety. University of Southampton, Doctoral Thesis, 167pp.

Record type: Thesis (Doctoral)

Abstract

The synthesis of (Z)-7,8-epoxy-7-methyl-1-(tetrahydro-2-methoxypyran-2-yl)-1-octen-4-one (87) and 7,8-epoxy-7-methyl-1-(tetrahydro-2-methoxy- pyran-2-yl)-octan-4-one (115) are described. In both cases, the key step was the addition of the lithium acetylide prepared from 7-methyl-4- trimethylsilyloxy-7-octen-1-yne (98) to δ-valerolactone (97). The attempted acid catalysed cyclization of (Z)-7,8-epoxy-7-methyl-1-(tetrahydro-2-methoxypyran-2-yl)-1-octen-4-one (87) failed to yield the desired l,6,8-trioxadispiro[4.1.5.3]pentadec-13-ene ring system (26) found in the salinomycin series of polyether antibiotics. The successful acid catalysed cyclization of 7,8-epoxy-7-methyl-1-(tetrahydro-2-methoxypyran-2-yl)-octan-4-one (115) to 1-(2-methyl,1,6,8-trioxadispiro[4.1.5.3]pentadec-2-yl)–methanol (118), however, highlighted a means of constructing the corresponding 1,6,8-trioxadispiro[4.1.5.3]pentadecane ring system. An alternative strategy for the preparation of the required 1,6,8-trioxadispiro[4.1.5.3]pentadec-13-ene ring system via a Barton-type reaction of an hydroxyspiroacetal derivative was developed. This was exemplified by the successful synthesis of 2,2-dimethyl-1,6,8-trioxadispiro[4.1.5.3]pentadec-13-ene (119) from 4-(1,7-dioxaspiro[5.5]undec-4-en-2-yl)-2-methyIbutan-2-ol (121). The stereochemistry of 2,2-dimethyl-1,6,8-trioxadispiro[4.1.5.3]pentadec-13-ene (119) was found to be identical to that found in the analogous ring system of epi-17-deoxy-(0-8)-salinomycin (8) using high field ¹H n.m.r. spectroscopy, in particular, nuclear Overhauser effect (NOE) difference and proton homonuclear correlation (COSY) experiments.

The preparation of two key intermediates required for the synthesis of the bis-spiroacetal moiety of epi-17-deoxy-(0-8)-salinomycin (125) namely, (1'S,3R,5S,6S)-(+)—tetrahydro—6-[1-(acetoxymethyl)propyl]-3,5-dimethylpyran-2-one (206) and (3R,4'S)- or (3S,4'S)-1-(2,2,4-trimethyl- 1,3-dioxolan-4-yl)-5-hexyn-3-ol (128), is described. Lactone (206) was prepared enantioselectively from the optically active building block (R)-(-)-methyl 3-hydroxy-2-methylpropionate (177). Acetylene (128) was prepared from levulinic acid (213) incorporating the 'classical' resolution of (±)-(tetrahydro-2-methyl-5-oxofuran-2-yl)carboxylic acid (212) as a key step. An alternative synthesis of 4-(1,7-dioxaspiro[5-5]undec- 4-en-2-yl)-2-methylbutan-2-ol (121) from acetylene (128) and δ-valero- lactone (97) demonstrates the potential of the lactone (206) and acetylene (128) to be converted into an hydroxyspiroacetal derivative suitable for the synthesis of the bis-spiroacetal moiety of epi-17-deoxy-(0-8)- salinomycin (125) via a Barton-type cyclization.

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Brimble 1985 Thesis - Version of Record

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