Chemoenzymatic total synthesis and determination of the absolute configuration of (S)-nebracetam

We have developed an asymmetric total synthesis of nebracetam 3 by a chemoenzymatic strategy. Diastereoselective Michael addition of nitromethane to the chiral lactam (S)-9d (>99% ee), which was prepared by lipase-catalyzed kinetic resolution, afforded the Michael product 10d in 99% yield with 86% de. Chemical transformations of 10d including recrystallization furnished the chiral nebracetam 3 and its derivative. The absolute configuration of the chiral (−)-nebracetam was determined to be an (S)-configuration.

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(R)-1-Benzyl-5-oxo-2,5-dihydro-1H-pyrrol-2-yl acetateC13H13NO3Ee = >99% (chiral HPLC)[α]D27=-44.7 (c 0.97, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (R)

(S)-1-Benzyl-5-hydroxy-1H-pyrrol-2(5H)-oneC11H11NO2Ee = >99% (chiral HPLC)[α]D27=-35.0 (c 1.08, CHCl3)Source of chirality: enzymatic resolutionAbsolute configuration: (S)

(S)-1-Benzyl-5-(tert-butyldiphenylsilyloxy)-1H-pyrrol-2(5H)-oneC27H29NO2SiEe = >99% (chiral HPLC)[α]D25=+15.5 (c 1.00, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(R)-1-Benzyl-4-(nitromethyl)pyrrolidin-2-oneC12H14N2O3Ee = >99% (chiral HPLC)[α]D29=+13.7 (c 0.50, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

(S)-Nebracetam ((S)-4-(aminomethyl)-1-benzylpyrrolidin-2-one)C12H16N2O[α]D26=-8.0 (c 1.00, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-1-Benzyl-4-((isopropylamino)methyl)pyrrolidin-2-oneC15H22N2O[α]D30=-7.5(c 1.01, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (S)