The amino acid building block (XI) was prepared as follows. Friedel-Crafts condensation of dimethylacrylic acid (I) with benzene in the presence of AlCl3 afforded 3-methyl-3-phenylbutanoic acid (II). After activation of acid (II) as the mixed anhydride (IV) by treatment with pivaloyl chloride (III) and Et3N, coupling with the lithium salt of (S)-4-isopropyl-2-oxazolidinone (V) furnished the chiral N-acyl oxazolidinone (VI). Diastereoselective introduction of an azido group into the lithium enolate of (VI) by means of 2,4,6-triisopropylbenzenesulfonyl azide led to the (S,S)-azido compound (VII). Catalytic hydrogenation of azide (VII) in the presence of Boc2O provided the Boc-protected amine (VIII). The chiral auxiliary of (VIII) was removed by hydrolysis with lithium hydroperoxide, and the resultant carboxylic acid was further converted to the methyl ester (IX) upon treatment with an ethereal solution of diazomethane. The N-methyl derivative (X) was then prepared by alkylation of the tert-butyl carbamate (IX) with iodomethane in the presence of NaH. Basic hydrolysis of ester (X) provided the target N-Boc amino acid (XI).

N-Boc-N-Methyl-L-valine (XII) was condensed with N,O-dimethylhydroxylamine by means of PyBOP as the coupling reagent. The resultant Weinreb amide (XIII) was then reduced to aldehyde (XIV) using LiAlH4. Wittig condensation of the valinal derivative (XIV) with (carbethoxyethylidene)triphenylphosphorane provided the unsaturated amino ester (XV). The N-Boc protecting group of (XV) was subsequently removed by treatment with trifluoroacetic acid, giving (XVI). Coupling of amino ester (XVI) with N-Boc-tert-leucine (XVII) was carried out via formation of the mixed anhydride of (XVII) with pivaloyl chloride. The resultant N-Boc dipeptide (XVIII) was further deprotected with trifluoroacetic acid, yielding (XIX). Coupling of dipeptide (XIX) with the N-Boc amino acid (IX) provided tripeptide (XX). The title compound was then obtained by sequential deprotection of the ethyl ester and N-Boc groups of (XX) using LiOH and trifluoroacetic acid, respectively.

An alternative synthetic method employed the racemic amino acid (XXIX). The phenylpyruvic acid precursor (XXVII) was prepared from benzaldehyde (XXI) by several procedures. Condensation of benzaldehyde (XXI) with hydantoin (XXII) yielded the benzylidene hydantoin (XXIV), which was converted to (XXVII) by basic hydrolysis. Alternatively, aldehyde (XXI) was condensed with N-acetyl glycine or with the phosphonoacetate reagent (XXIII) to produce (XXV) or (XXVI), respectively. Basic hydrolysis of either (XXV) or (XXVI) led to the desired phenylpyruvic acid (XXVII). Dialkylation of keto acid (XXVII) with iodomethane and NaOH furnished the dimethyl derivative (XXVIII). Then, reductive amination of (XXVIII) with methylamine yielded the racemic amino acid (XXIX). Coupling of amino acid (XXIX) with the intermediate dipeptide (XIX) gave rise to tripeptide (XXX) as an epimeric mixture. After chromatographic isolation of the desired isomer, basic hydrolysis of the ethyl ester provided the title compound.