Synthesis of keto‐methylene and dehydro‐keto‐methylene pseudo‐dipeptides

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Abstract
A new synthetic pathway is proposed for the preparation of keto‐methylene and dehydro‐keto‐methylene dipeptide isosteres bearing the general formulas (RS)XxxΨ(COCH2)(RS)Yyy and (RS)XxxΨ(COCH2)ΔYyy. The method involves the condensation of an oxazolone derived from an N‐benzoyl amino acid (3a, b) via a modified Dakin‐West reaction with the appropriately α‐substituted succinoyl chloride half ester (2a, b). This last compound is obtained from a Stobbe condensation followed by reaction with oxalyl chloride. The fully protected pseudo‐dehydro dipeptides (41, b) thus obtained can then be catalytically hydrogenated to the desired pseudo‐dipeptides (5a, b). Acid hydrolysis of (4) and (5) gives the pure fully deblocked dipeptide surrogates which are then N‐protected for coupling into the desired peptide analogs. For preparative applications, the prior isolation of intermediates is not required throughout the procedure up to the final products. In this manner, the following compounds were prepared: Boc‐(RS)PheΨ(COCH2)(E, Z)Δ Phe‐OH (9), Boc‐(RS)Pheψ(COCH2)(RS)Phe‐OH (7a), and Boc‐Glyψ(COCH2)(RS)Leu‐OH (7b). Characterization of isolated intermediates and final products was carried out.