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2030-12-31
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CHEMOENZYMATIC ENANTIOSELECTIVE SYNTHESIS OF THE HANCOCK ALKALOIDS (S)- AND (R)-GALIPEINE, (S)-CUSPAREINE, (S)-GALIPININE, AND (S)-ANGUSTUREINE
Enzymatic kinetic resolution
Candida antarctica lipase
Wittig olefination
Author
Affilliation
Department of Chemistry. Federal University of Minas Gerais. Belo Horizonte, MG, Brazil.
Department of Chemistry. Federal University of Minas Gerais. Belo Horizonte, MG, Brazil.
Department of Chemistry. Federal University of Minas Gerais. Belo Horizonte, MG, Brazil.
Oswaldo Cruz Foundation. René Rachou Institute. Chemistry of Bioactive Natural Products. Belo Horizonte, MG, Brazil.
Department of Biochemistry and Molecular Biology. Federal University of Viçosa. Viçosa, MG, Brazil.
Department of Biochemistry and Molecular Biology. Federal University of Viçosa. Viçosa, MG, Brazil.
Department of Chemistry. Federal University of Minas Gerais. Belo Horizonte, MG, Brazil.
Department of Chemistry. Federal University of Minas Gerais. Belo Horizonte, MG, Brazil.
Department of Chemistry. Federal University of Minas Gerais. Belo Horizonte, MG, Brazil.
Oswaldo Cruz Foundation. René Rachou Institute. Chemistry of Bioactive Natural Products. Belo Horizonte, MG, Brazil.
Department of Biochemistry and Molecular Biology. Federal University of Viçosa. Viçosa, MG, Brazil.
Department of Biochemistry and Molecular Biology. Federal University of Viçosa. Viçosa, MG, Brazil.
Department of Chemistry. Federal University of Minas Gerais. Belo Horizonte, MG, Brazil.
Abstract
The enantioselective synthesis of the Hancock 1,2,3,4-tetrahydroquinoline alkaloids (S)-galipeine, (S)-cuspareine, (S)-galipinine, and (S)-angustureine and the nonnatural enantiomer (R)-galipeine is described herein. The target compounds were obtained in five steps from a racemic quinaldinic acid derived α-amino ester in overall yields of 21.2% to 37.5%. The synthetic route comprised two key steps: an enzymatic kinetic resolution to control the C-2 stereocenter, affording (R)- and (S)-α-amino esters as key chiral intermediates with 94% and 72% ee, respectively, and Wittig olefination of (R)- and (S)-α-amino aldehyde synthons with the corresponding phosphonium salts using a phase-transfer system (t-BuOH/CH2Cl2), thereby allowing the introduction of alkyl substituents at C-2. Finally, the enantioselective synthesis was concluded with the catalytic hydrogenation of olefinic bonds on the Wittig adducts to furnish the target Hancock alkaloids, including (R)-galipeine, whose synthesis is described here for the first time.
Keywords
Hancock alkaloidsEnzymatic kinetic resolution
Candida antarctica lipase
Wittig olefination
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