Enantioselective Synthesis of r-Quaternary Amino Acid Derivatives by Sequential Enzymatic Desymmetrization and Curtius Rearrangement of r,r-Disubstituted Malonate Diesters

摘要

Aconvenient and versatile enantioselective synthesis of biologically important R-quaternary amino acid derivativeswas based on the sequential double alkylation or arylation of dimethylmalonate, followed by desymmetrization with porcine liver esterase (PLE) and Curtius rearrangement. The PLE-mediated hydrolysis of the prochiral dialkylated malonate diesters produced the corresponding chiral half-esters in high yield and with enantiomeric excesses of 43% to >98%. Curtius rearrangement of the latter products, after trapping of the intermediate isocyanates with benzyl alcohol or amines, afforded the corresponding Cbz-protected amino esters or ureas. The absolute configurations of themajor products in five examples were established by conversion to compounds with known specific rotations, or by X-ray crystallography of derivatives obtained with chiral amines of known configuration.