6 Total Synthesis of Antimycin A_3
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The first total synthesis of antifungal antibiotic antimycin A_3 (blastmycin) in a form of diastereomeric mixture was reported in 1969 from our laboratory. We have now synthesised the natural antimycin A_3 (1). The modified Reformatsky reaction of 2-benzyloxypropanal with t-butyl 2-bromo-hexanoate afforded the mixture of the diastereomeric t-butyl 4-benzyloxy-2-hutyl-3-hydroxypentanoate which contained ca. 55% of the major racemic diastereomer (2). The chromatographically separated fraction consisting of 2 contaminated by a small amount of the minor diastereomer was O-isovalerylated. The product was purified by silica gel column chromatography to give the O-acylated derivative of 2, which was hydrogenolyzed to afford t-butyl 2-butyl-4-hydroxy-3-(isovaleryloxy)pentanoate (3). Condensation of 3 with N-benzyloxycarbonyl-O-t-butyl-L-threonine yielded two kinds of diastereomeric t-butyl 4-(N-benzyloxycarbonyl-O-t-butyl-L-threonyloxy)-2-butyl-3-(isovaleryloxy)pentanoate. The less polar (+)-diastereomer (4) of the two was separated by silica gel column chromatography of the mixture. Lithium aluminium hydride reduction of 4 followed by hydrolysis and O-isovalerylation afforded the (+)-blastmycinone which was identified with the natural blast-mycinone obtained by mild alkaline degradation of blastmycin (antimycin A_3). De-t-butylation of 4 followed by cyclization with trifluoroacetic anhydride in benzene afforded the intramolecular cyclization product, 3-benzyloxycarboxamido-7-butyl-4, 9-dimethyl-1, 5-dioxa-8-(isovaleryloxy)cyclononane-2, 6-dione (5). Removal of the N-protecting group of 5 followed by N-acylation with O-benzyl-3-nitrosalicylic acid N-hydroxysuccinimide ester yielded 3-(O-benzyl-3'-nitrosalicylamido)-7-butyl-4, 9-dimethyl-1, 5-dioxa-8-(isovaleryloxy)cyclononane-2, 6-dione (6). The product (6) was again hydrogenolyzed and then N-formylated to afford the final product, antimycin A_3 (1).
