The Total Synthesis of Herbimycin A

The first total synthesis of herbimycin A (1), the benzoquinonoid ansamycin antibiotic, is described. (2E,4S,5R,6S,8S)-5,6-Dimethoxy-9-(4-methoxybenzyl)oxy-2,4,8-trimethyl-2-nonenal (40), corresponding to the C7–C15 portion of the ansa-chain of 1, was prepared from methyl 3,4-anhydro-2-deoxy-2-C-methyl-6-O-(triphenylmethyl)-α-d-altropyranoside (16), which had been previously prepared from methyl α-d-mannopyranoside according to our developed procedure, by using a regioselective epoxide opening [bis(1,2-dimethylpropyl)borane–NaBH4] and a stereoselective hydroboration (BH3·SMe2) as the key steps. This aldehyde 40 was subjected to the Brown’s diastereo- and enantioselective allylation conditions [[(Z)-3-methoxyallyl]diisopinocampheylborane] to afford the desired syn 3-methoxy-1,5-dodecadien-4-ol derivative. Subsequent three-step conversion of this alcohol furnished the synthesis of the C5–C15 ansa-chain aldehyde, (2S,4S,5R,6S,7E,9S,10S)-9-[(t-butyldimethylsilyl)oxy]-4,5,10-trimethoxy-2,6,8-trimethyl-7,11-dodecadienal (7). Union of 7 and the lithiated aromatic chromophore, prepared from N-(triphenylmethyl)-3-bromo-2,5-dimethoxyaniline and butyllithium, provided the coupling product, which was transformed to herbimycin A (1) through elongation of the C1–C4 carbon unit and macrolactamization. This fully enantiospecific synthesis elucidates the absolute stereochemistry of 1.