Protection of D-alloisoleucine (I) with Cbz-succinimide afforded benzyl carbamate (II). Activation of the carboxyl group of (II) as the pentafluorophenyl ester (III), followed by condensation with the lithium enolate of methyl acetate, gave beta-ketoester (IV). Stereoselective reduction of (IV) with KBH4 produced alcohol (V) as the major diastereomer. The hydroxyl group of (V) was protected as the triisopropylsilyl ether (VI), and then hydrolysis of the ester group of (VI) yielded carboxylic acid (VII).

(S)-2-Hydroxyisovaleric acid (IX) was obtained from L-valine (VIII) by diazotization in the presence of sulfuric acid. After protection as the allyl ester (X), coupling with isostatine derivative (VII) using DCC and DMAP afforded (XI). Then, removal of the allyl group of (XI) by means of Pd(PPh3)4 gave acid (XIII), which was activated as the pentafluorophenyl ester (XIII).

Hydrogenolysis of the Cbz group from the fully protected tetrapeptide (XIV) gave the free amine (XV). This was coupled with the activated ester (XIII) to provide the linear precursor (XVI). Selective cleavage of the silylethoxymethyl ester of (XVI) with MgBr2.Et2O, followed by hydrogenolysis of the Cbz group furnished (XVII). Subsequent macrocyclization of (XVII) using HATU afforded the cyclic depsipeptide (XVIII).

Treatment of (XVIII) with HCl in EtOAc cleaved both Boc and triisopropylsilyl protecting groups to yield (XIX). This was finally coupled with the preformed side chain (XX) using BOP to afford the title compound.