First stereoselective synthesis and assignment of the absolute configuration of the nebracetam eutomer and derivatives

(−)-Nebracetam 1 was stereoselectively prepared for the first time, allowing the determination of its absolute configuration as (R). The pivotal intermediate in the synthesis, 1-benzyl-4-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-pyrrolidin-2-one 6, was previously obtained in 60% yield and 90% ee from an enoate derived from d-mannitol. Two approaches were investigated to synthesize (R)-(−)-nebracetam 1 and analogues 4 and 5 from 6. Compound 6 was transformed into WEB-1868 2. Mesylation of the hydroxyl group in 2, followed by nucleophilic substitution with azide and reduction led to target 1. Compounds 4 and 5 were synthesized by using morpholine and N-methyl piperazine as nucleophiles. Compounds 4 and 5 were also prepared, in higher yields and similar ee, through the reductive amination of aldehyde 10, obtained in two steps from 6.

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N-Benzyl-(4S)-4-methanesulfonylmethyl-pyrrolidin-2-oneC13H17NO4S[α]D25=-3.0 (c 2.36, CHCl3)Source of chirality: d-(+)-mannitolAbsolute configuration: (4S)

N-Benzyl-(4S)-4-azidomethyl-pyrrolidin-2-oneC12H14N4O[α]D25=+2.2 (c 0.90, CHCl3)Source of chirality: d-(+)-mannitolAbsolute configuration: (4S)

N-Benzyl-(4R)-4-aminomethyl-pyrrolidin-2-oneC12H16N2O[α]D25=-6.3 (c 1.90, CHCl3)Source of chirality: d-(+)-mannitolAbsolute configuration: (4R)

N-Benzyl-(4R)-4-morpholylmethyl-pyrrolidin-2-oneC16H22N2O2[α]D25=-4.0 (c 2.76, CHCl3)Source of chirality: d-(+)-mannitolAbsolute configuration: (4R)

N-Benzyl-(4S)-4-E-carbadolxime-pyrrolidin-2-oneC12H14N2O2[α]D25=+14.0 (c 1.00, CHCl3), mixture of E:Z isomers (84:16)Source of chirality: d-(+)-mannitolAbsolute configuration: (4S)

N-Benzyl-(4R)-4-(N-methylpiperazyl)pyrrolidin-2-oneC17H25N3O[α]D25=-5.7 (c 1.3, CHCl3)Source of chirality: d-(+)-mannitolAbsolute configuration: (4R)