Protection of ascomycin (I) by means of tert-butyldimethylsilyl trifluoromethanesulfonate in the presence of 2,6-lutidine provided the 14,4''-disilylated derivative (II). Selective removal of the 4''-silyl group of (II) with para-toluenesulfonic acid in MeOH-CH2Cl2 yielded the 14-protected compound (III). This was converted to allyl ether (V) upon treatment with allyl trichloroacetimidate (IV) and trifluoromethanesulfonic acid. Dihydroxylation of the allyl double bond of (V) with OsO4 and N-methylmorpholine-N-oxide, followed by oxidative cleavage of the resulting diol (VI) with sodium metaperiodate furnished aldehyde (VII).
Addition of 2-naphthylmagnesium bromide (VIII) produced the corresponding carbinol as a diastereomeric mixture, from which the required isomer (IX) was isolated by preparative TLC. Finally, the silyl protecting group was cleaved by treatment with HF in pyridine.
The condensation of the 32-OH of ascomycin (I) with the diazoketone (II) by means of a Rh catalyst gives the addition product (III), which is silylated at the 24-OH with TES-Cl yielding the silyl ether (IV). The reduction of the new carbonyl group of (IV) with the chiral reducing agent (S)-OAB/BH3 and TEA affords the silylated target compound (V), which is finally treated with HCl to eliminate the TES- group.