The synthesis of FK-463 can be performed as follows: The enzymatic deacylation of FR-901379 with Streptomyces anulatas No. 4811, S. anulatas No. 8703, Streptomyces strain No. 6907 or A. utahensis IFO13244 gives the deacylated lipopeptide FR-179642 (1), which is then reacylated with 1-[4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoyl]benzotriazole 3-oxide (VI) by means of dimethylaminopyridine (DMAP) in DMF. The acylating compound (VI) can be obtained as follows: The cyclization of 4-pentyloxyphenylacetylene (I) with 4-(hydroxyiminomethyl)benzoic acid methyl ester (II) by means of triethylamine in hot THF gives 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoic acid methyl ester (III), which is hydrolyzed with NaOH in hot THF/water yielding the corresponding free acid (IV). Finally, this compound is condensed with 1-hydroxybenzotriazole (V) by means of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDMCA) in dichloromethane.
The cyclization of the benzoic ester (I) with phenylacetylene (II) by means of triethylamine in THF gives the diphenyl isoxazole (III), which is hydrolyzed with NaOH in ethanol/THF yielding 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoic acid (IV). The activation of (IV) with HOBT and WSC in dichloromethane affords the benzotriazol-1-yl ester (V), which is finally condensed with the cyclic peptide (VI) by means of DMAP in DMF.