Condensation of 4-methylpentanoyl chloride (I) with (S)-4-benzyl-2-oxazolidinone using n-BuLi afforded the N-acyloxazolidinone (III). Asymmetric alkylation of (III) with tert-butyl bromoacetate and LDA gave (IV), and subsequent removal of the chiral auxiliary by hydrolysis with lithium peroxide yielded (R)-2-isobutylsuccinic acid mono tert-butyl ester (V). This was further alkylated with allyl bromide (VI) and LDA to provide the (R,R)-2,3-disubstituted succinate (VII). Epimerization of (VII) to the required (2R,3S)-isomer (VIII) was accomplished by treatment with LDA and Et2AlCl. Benzyl ester (IX) was then prepared by reaction of (VIII) with benzyl bromide and DBU. Hydroboration of the olefinic double bond of (IX) by means of 9-borabicyclononane, followed by oxidative treatment with H2O2 gave rise to the primary alcohol (X). This was converted to carbonate (XI) upon reaction with p-nitrophenyl chloroformate and N-methylmorpholine (NMM). Coupling of (XI) with lysine derivative (XII) then yielded carbamate (XIII).

Simultaneous deprotection of the benzyl ester and the N-carbobenzoxy group of (XIII) by hydrogenolysis over Pd/C gave amino acid (XIV), which was cyclized by means of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and diisopropyl ethylamine (DIEA), yielding macrocycle (XV). Cleavage of the tert-butyl ester of (XV) with trifluoroacetic acid produced carboxylic acid (XVI), and this was converted to the O-benzyl hydroxamate (XVII) by coupling with O-benzyl hydroxylamine. Further hydrolysis of the methyl ester group of (XVII) to acid (XVIII) was followed by coupling with glycine morpholide (XIX) affording diamide (XX). The O-benzyl group of (XX) was finally removed by hydrogenation in the presence of Pd/C.

Condensation of 4-methylpentanoyl chloride (I) with (S)-4-benzyl-2-oxazolidinone using n-BuLi afforded the N-acyloxazolidinone (III). Asymmetric alkylation of (III) with tert-butyl bromoacetate and LDA gave (IV), and subsequent removal of the chiral auxiliary by hydrolysis with lithium peroxide yielded (R)-2-isobutylsuccinic acid mono tert-butyl ester (V). This was further alkylated with allyl bromide (VI) and LDA to provide the (R,R)-2,3-disubstituted succinate (VII). Epimerization of (VII) to the required (2R,3S)-isomer (VIII) was accomplished by treatment with LDA and Et2AlCl. Benzyl ester (IX) was then prepared by reaction of (VIII) with benzyl bromide and DBU. Hydroboration of the olefinic double bond of (IX) by means of 9-borabicyclononane, followed by oxidative treatment with H2O2 gave rise to the primary alcohol (X). This was converted to carbonate (XI) upon reaction with p-nitrophenyl chloroformate and N-methylmorpholine (NMM). Coupling of (XI) with lysine derivative (XII) then yielded carbamate (XIII).

Simultaneous deprotection of the benzyl ester and the N-carbobenzoxy group of (XIII) by hydrogenolysis over Pd/C gave amino acid (XIV), which was cyclized by means of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and diisopropyl ethylamine (DIEA), yielding macrocycle (XV). Cleavage of the tert-butyl ester of (XV) with trifluoroacetic acid produced carboxylic acid (XVI), and this was converted to the O-benzyl hydroxamate (XVII) by coupling with O-benzyl hydroxylamine. Further hydrolysis of the methyl ester group of (XVII) to acid (XVIII) was followed by coupling with glycine morpholide (XIX) affording diamide (XX). The O-benzyl group of (XX) was finally removed by hydrogenation in the presence of Pd/C.