Enantioselective synthesis of alpha-quaternary amino acid derivatives by sequential enzymatic desymmetrization and Curtius rearrangement of alpha,alpha-disubstituted malonate diesters.
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.
Department of Chemistry, University of Calgary, Calgary, AB, Canada, T2N 1N4.
Violeta
V
Iosub
Anton R
AR
Haberl
Jennifer
J
Leung
Michael
M
Tang
Kannan
K
Vembaiyan
Masood
M
Parvez
Thomas G
TG
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D000478:Alkylation; D000588:Amines / Q000737:chemistry*; D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry; D001669:Biochemical Phenomena; D002384:Catalysis; D018360:Crystallography, X-Ray; D004950:Esterases / Q000737:chemistry* / Q000378:metabolism; D004952:Esters; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy; D008314:Malonates / Q000138:chemical synthesis* / Q000737:chemistry; D013058:Mass Spectrometry; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism
D000588:Amines; D000596:Amino Acids; D004952:Esters; D008314:Malonates; D004950:Esterases; C005230:methyl malonate