Synthesis of a New Dual Metalloprotease Inhibitor. I. Diastereoselective Alkylation of Protected 6-Oxopipecolic Acid Esters

Diastereoselective methylation of the enolate generated from various protected 6-oxopipecolic acid esters (3aa-3cd) was studied. The protecting groups on the carboxylic acid and amino groups significantly influenced the trans/cis selectivity in the methylation reaction. The optimal substrate (3ca), bearing benzhydryl ester and carbobenzyloxy moieties gave a trans/cis isomer ratio of ca. 4 : 1. Investigation of the reaction conditions revealed that the reaction solvent, alkylating reagent, and base employed to generate the enolate, were decisive factors for diastereoselectivity. Further optimization of reaction conditions, including the amounts of the reagents and their addition sequence enabled maximization of reaction conversion and minimization of by-products to produce the trans rich 5-methyl-6-oxopipecolic acid ester (4ca) on a large scale.