Electrophilic nitration of p-tolunitrile (I) afforded the 3-nitro derivative (II), which was condensed with diethyl oxalate in the presence of sodium ethoxide to produce the sodium enolate of the alpha-keto ester (III). Compound (III) was then subjected to Reissert indole synthesis by means of Zn and HOAc to furnish ethyl 6-cyanoindole-2-carboxylate (IV). N-alkylation of indole (IV) with iodoethane and NaH in DMF gave (V), whose carboxylate group was reduced to alcohol (VI) employing in situ-generated calcium borohydride (obtained from NaBH4 and CaI2 in THF in the presence of NaHCO3). Treatment of alcohol (VI) with PBr3 in methylene chloride yielded the corresponding bromide (VII), which was then converted into the phosphonium salt (VIII) by means of triphenylphosphine in refluxing toluene.

Fischer esterification of L-proline (IX) with MeOH and HCl gave (X). Treatment of (X) with di-tert-butyl dicarbonate provided N-Boc-proline methyl ester (XI). The ester function of (XI) was then reduced to aldehyde (XII) by employing DIBAL in toluene at -78 C. Wittig condensation between aldehyde (XII) and phosphonium bromide (VIII) in the presence of DBU yielded the (indolylvinyl)pyrrolidine (XIII), which was further hydrogenated to (XIV) in the presence of Pd/C. The N-Boc group of (XIV) was then cleaved by treatment with trifluoroacetic acid to furnish (XV).

Pyrrolidine (XV) was coupled with N-Boc-D-proline (XVI) using EDC to provide amide (XVII). After acid cleavage of the Boc protecting group of (XVII), the resultant amine (XVIII) was further coupled with N-Boc-L-aspartic acid alpha-benzyl ester (XIX) to yield peptide (XX). Pinner reaction of nitrile (XX) with EtOH and HCl, with concomitant transesterification and Boc group cleavage, furnished imidate (XXI). Subsequent treatment of the imidate (XXI) with methanolic ammonia produced the corresponding amidine ester (XXII) along with some amide analogue (XXIII). Finally, basic hydrolysis of this mixture yielded the desired amidino acid.