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Enantioselective synthesis of alpha-quaternary amino acid derivatives by sequential enzymatic desymmetrization and Curtius rearrangement of alpha,alpha-disubstituted malonate diesters

Enantioselective synthesis of alpha-quaternary amino acid derivatives by sequential enzymatic desymmetrization and Curtius rearrangement of alpha,alpha-disubstituted malonate diesters

Journal of Organic Chemistry 75(5): 1612-1619

A convenient and versatile enantioselective synthesis of biologically important alpha-quaternary amino acid derivatives was based on the sequential double alkylation or arylation of dimethyl malonate, 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 the major 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.

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Accession: 052954896

Download citation: RISBibTeXText

PMID: 20131857

DOI: 10.1021/jo902584r

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