Stereocontrol in organic synthesis using silicon-containing compounds. A synthesis of nonactin

The enantiomeric purity of (1R)-1-(1'-naphthyl)ethanol 7 was raised by Horeau's method by separating its oxalate 11 from its diastereoisomer by crystallisation. The alcohol 7 was used to open the anhydride of (3RS,4SR)-3,4-bis[dimethyl(4-methylphenyl)silyl]hexane-1,6-dioic acid with selectivity of 96:4 for one of the enantiotopic carbonyl groups, allowing the synthesis of (3R,4S)-3,4-bis[dimethyl(4-methylphenyl)silyl]hexane-1,6-dioic acid 6-(2-trimethylsilylethyl) ester 10. This acid was converted into the allylsilane methyl (E)-(3S,4R)-3,4-bis[dimethyl(4-methylphenyl)silyl]-7-(2-methyldioxolan-2-yl)hept-5-enoate 15, the carboxylic acid derived from which underwent epoxidation with unexpected silyl migration to give (3S,4S,5S,6R)-3,5-bis[dimethyl(4-methylphenyl)silyl]-6-hydroxy-7-(2-methyldioxolan-2-yl)heptano-4-lactone 17. Desilylative elimination and hydrogenation then gave the alcohol (3R,6R)-3-[dimethyl(4-methylphenyl)silyl]-6-hydroxy-7-(2-methyldioxolan-2-yl)heptanoic acid 19, in which the relative and absolute configuration at C-3 and C-6 have been controlled. The relative configuration at C-8 was controlled by anti-selective reduction of a 6-hydroxy-8-ketone using Evans' method, and at C-2 by anti-selective enolate methylation of the beta-silyl lactone 20. Silyl-to-hydroxy conversion with retention at C-3 and displacement of the tosylate with inversion at the same centre gave the correct relative and absolute configuration, completing a synthesis of methyl (+)-nonactate 4. The relative configuration at CS was controlled in the opposite sense by syn-selective reduction of a 6-hydroxy-8-ketone using Prasad's conditions, and at C-2 in the opposite sense by anti-selective enolate methylation of the open-chain beta-silyl ester 22. Silyl-to-hydroxy conversion with retention at C-3 and displacement of the tosylate with inversion at C-6 gave the correct relative and absolute configuration completing a synthesis of the pseudo-enantiomer, benzyl (-)-nonactate 25. Some protecting group changes and coupling of these two-fragments gave the "dimers" 28 and 29, coupling of which gave the "tetramer" 30. Ring closure of this material using Yamaguchi's method gave nonactin in 73% yield, substantially better than in any previous synthesis.