Removal of the N-(benzyloxycarbonyl) group from the protected dipeptide (I) by catalytic hydrogenolysis provided the dipeptide Val-Pro-O-t-Bu (II), which was N-acylated with anisoyl chloride (III) to afford anisoyl dipeptide (IV). The tert-butyl ester group of (IV) was then cleaved using trifluoroacetic acid to afford (VI). Alternatively, the intermediate (VI) could be obtained from unprotected Val-Pro-OH (V) by treatment with trimethylsilyl chloride and subsequent acylation of the silyl ester with acid chloride (III). The anisoyl dipeptide (VI) was further condensed with racemic threo-aminoalcohol (VII), either in the presence of EDC and HOBt or via conversion to the mixed anhydride with isobutyl chloroformate, to furnish the corresponding peptide amide (VIII) as a diastereomeric mixture. Subsequent oxidation of the alcohol group of (VIII) to the trifluoromethyl ketone (IX) was carried out using a modified Pfitzner-Moffat procedure in the presence of DMSO, EDC and dichloroacetic acid or with KMnO4 in basic medium. The desired S,S,S-isomer was isolated from the epimeric mixture after repeated crystallizations.

An alternative synthesis has been reported employing pure (2R,3S)-aminoalcohol (XVII). Treatment of isobutyl iodide (X) with sodium nitrite in the presence of urea in DMF afforded 2-methyl-1-nitropropane (XI). Further condensation of fluoral hydrate (XII) with this nitrocompound using K2CO3 provided a diastereomeric mixture of nitroalcohols (XIII). Fractional crystallization from pentane yielded the racemic threo-nitroalcohol (XIV), which was converted to the alredy reported racemic threo-aminoalcohol (VII) by catalytic hydrogenation. This compound (VII) was treated with triphosgene and NaOH to produce oxazolidone (XV). After conversion of (XV) to the corresponding lithium salt with BuLi at -70 C, its condensation with (-)-menthyl chloroformate gave a diastereomeric mixture of carbamates, from which the desired isomer (XVI) was isolated by fractional crystallization from ether/hexane. The chiral auxiliary and the oxazolidone ring were then cleaved by hydrolysis with KOH yielding the (2R,3S)-aminoalcohol (XVII)(1). The coupling of (XVII) with the amino protected dipeptide (XVIII) (obtained by treatment of peptide (I) with trifluoroacetic acid) afforded dipeptide amide (XIX), The N-(benzyloxycarbonyl) protecting group of (XIX) was subsequently removed by catalytic hydrogenation, and the resulting amino compound was condensed with anisoyl chloride (III) to furnish the anisoyl dipeptide (XX). Finally, oxidation of the alcohol group of (XX) using the modified Pfitner-Moffat procedure produced some epimerization of the resulting ketone, the oxidation with KMnO4 in the presence of NaOH yielded the target S,S,S-peptide.

Removal of the N-(benzyloxycarbonyl) group from the protected dipeptide (I) by catalytic hydrogenolysis provided the dipeptide Val-Pro-O-t-Bu (II), which was N-acylated with anisoyl chloride (III) to afford anisoyl dipeptide (IV). The tert-butyl ester group of (IV) was then cleaved using trifluoroacetic acid to afford (VI). Alternatively, the intermediate (VI) could be obtained from unprotected Val-Pro-OH (V) by treatment with trimethylsilyl chloride and subsequent acylation of the silyl ester with acid chloride (III). The anisoyl dipeptide (VI) was further condensed with racemic threo-aminoalcohol (VII), either in the presence of EDC and HOBt or via conversion to the mixed anhydride with isobutyl chloroformate, to furnish the corresponding peptide amide (VIII) as a diastereomeric mixture. Subsequent oxidation of the alcohol group of (VIII) to the trifluoromethyl ketone (IX) was carried out using a modified Pfitzner-Moffat procedure in the presence of DMSO, EDC and dichloroacetic acid or with KMnO4 in basic medium. The desired S,S,S-isomer was isolated from the epimeric mixture after repeated crystallizations.

An alternative synthesis has been reported employing pure (2R,3S)-aminoalcohol (XVII). Treatment of isobutyl iodide (X) with sodium nitrite in the presence of urea in DMF afforded 2-methyl-1-nitropropane (XI). Further condensation of fluoral hydrate (XII) with this nitrocompound using K2CO3 provided a diastereomeric mixture of nitroalcohols (XIII). Fractional crystallization from pentane yielded the racemic threo-nitroalcohol (XIV), which was converted to the alredy reported racemic threo-aminoalcohol (VII) by catalytic hydrogenation. This compound (VII) was treated with triphosgene and NaOH to produce oxazolidone (XV). After conversion of (XV) to the corresponding lithium salt with BuLi at -70 C, its condensation with (-)-menthyl chloroformate gave a diastereomeric mixture of carbamates, from which the desired isomer (XVI) was isolated by fractional crystallization from ether/hexane. The chiral auxiliary and the oxazolidone ring were then cleaved by hydrolysis with KOH yielding the (2R,3S)-aminoalcohol (XVII)(1). The coupling of (XVII) with the amino protected dipeptide (XVIII) (obtained by treatment of peptide (I) with trifluoroacetic acid) afforded dipeptide amide (XIX), The N-(benzyloxycarbonyl) protecting group of (XIX) was subsequently removed by catalytic hydrogenation, and the resulting amino compound was condensed with anisoyl chloride (III) to furnish the anisoyl dipeptide (XX). Finally, oxidation of the alcohol group of (XX) using the modified Pfitner-Moffat procedure produced some epimerization of the resulting ketone, the oxidation with KMnO4 in the presence of NaOH yielded the target S,S,S-peptide.