Stereoselective syntheses of alpha, beta-diamino acids

Abstract

A method for the threo-stereoselective synthesis of (alpha),(beta)-diamino acids has been developed. This method was applied to the synthesis of (5-chloro-2-piperidinyl)glycine (streptolutine) and analogs of streptolutine. These amino acids, especially streptolutine, are similar in structure to the well-known antineoplastic compound 593-A, and may possess significant biological activity. Acylation of the lithio-dianion of methyl hippurate with 4-pentenoyl chloride gave methyl 2-benzoylamino-3-oxo-6-heptenoate. The (beta)-keto ester was converted to methyl 2-benzoylamino-3-amino-6-heptenoate via a reductive amination process using NH(,4)OAc and NaBH(,3)CN. This (beta)-amino ester was formed in a 2:1 erythro:threo ratio of diastereomers rather than the desired threo-selective direction. This shortcoming was circumvented by incorporating the alpha benzamide and beta amino groups into an imidazolidinone ring system, which can be epimerized at the alpha center to give the more stable trans-substituted system (threo). Cleavage of the ring and protection of the amine and acid groups gave methyl 2,3-di-(benzyloxycarbonylamino)-6-heptenoate with a ratio of threo to erythro isomers of approximately 4:1. Treatment with mercuric acetate followed by reduction and protecting group cleavage led to 2-amino-2-(trans-5-methyl-2-pyrrolidinyl)-acetic acid. Treatment of the same (alpha),(beta)-CBz ester with Hg(OAc)(,2), followed by refunctionalization of the resulting organomercurial intermediate and CBz group cleavage resulted in methyl 2-amino-2-(trans-5-iodomethyl-2-pyrrolidinyl)acetate dihydrobromide. This derivative of a potentially biologically active amino acid was converted to streptolutine methyl ester and a 5-membered ring isomer of streptolutine methyl ester by treatment of the iodomethyl amino ester with base to form the corresponding bicyclic azirdine, and ring-opening with HCl gas.