The total synthesis of (±)- and (+)-biocyclomycin
Date
1984
Authors
Armstrong, Robert W., author
Williams, Robert M., advisor
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Abstract
The completely regio- and stereocontrolled total synthesis of bicyclomycin (1) is described in 12 chemical steps. A new carbon-carbon bond-forming reaction of 1,4-dibenzyl- and 1,4-di-p-methoxybenzyl-3,6'-bis-(2'-thiopyridyl)-2,5-piperazinediones (234 and 275) has been discovered involving complexation of 234 or 275 with silver(I)triflate followed by addition of the trimethylsilyl ketene acetal of γ-butyrolactone to afford 1,4-dibenzyl- and l,4-di-p-methoxybenzyl-3-(2'-thiopyridyl)-6-(2"- γ-butyrolactonyl)-2,5-piperazinediones (236, 237, and 276-279) in good yield. The reaction proceeds in THF at 25°C with predominant syn-stereospecificity. LiA1H4 reduction of lactones 276-279 provides the corresponding diols 280-282 which are cyclized to the bicyclo[4.2.2]nucleus 284 in the presence of silver(I)triflate in THF at 25°C. Dehydration of 284 in three steps affords the key olefinic intermediate 8,10-di-p-methoxybenzyl-8,10-diaza-5-(methylene)-2-oxabicyclo[4.2.2]decane-7,9-dione (294) which is regio- and stereoselectively elaborated at the bridgehead positions via: 1) C-6-bridgehead carbanion formation followed by quenching with O2; and 2) C-1-bridgehead carbanion formation followed by aldol condensation with 2,2,4-trimethyl-l,3-dioxolane-4-carboxyaldehyde to afford a single diastereomer (279a) possessing the correct relative configuration at C-1', C-2'. Protection of the secondary hydroxyl at C-1' as the trifluoroacetate followed by oxidative removal of all the protecting groups with ceric ammonium nitrate in MeCN/H2O affords directly, totally synthetic bicyclomycin. Condensation of the racemic bicyclic nucleus 296 with optically active S-2,2,4-trirnethyl-1,3-dioxolane-4-carboxaldehyde (83% ee) provides after protection and deprotection, (+)-bicyclornycin in 78% ee. Preliminary results establishing a structure-activity correlation requiring an obligate partnership of the C-6 hydroxyl and the C-4, C-5 exomethylene are described.
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Subject
Organic compounds -- Synthesis
Antibiotics