Chemoenzymatic synthesis of optically active α-methylene-γ-carboxy-γ-lactams and γ-lactones

Three α-methylene-γ-carbomethoxy-γ-butyrolactams (methyl α-methylene-pyroglutamates) 11, 12 and 13, differing in the substitution at the heterocyclic nitrogen, as well as the structurally related γ-lactones 14 and 15 were synthesised and resolved enzymatically by hydrolysis of their ester function, mediated by commercially available hydrolytic enzymes. In particular, the α-chymotrypsin proved to be active to all the substrates examined, displaying a different degree of activity and enantioselectivity, this latter increasing significantly towards the substrate with an aromatic substituent at the nitrogen.

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Methyl (S)-(+)-4-methylene-5-oxo-pyrrolidin-2-carboxylateC7H9NO3Ee = 72%[α]D25=+8.6 (c 1.3, AcOEt)Δ208 −0.4, Δ233 +1.4 (MeOH).Source of chirality: enzymatic resolutionAbsolute configuration: (S)

Methyl (S)-(+)-1-(methylphenyl)-4-methylene-5-oxo-pyrrolidin-2-carboxylateC14H15NO3Ee >99%[α]D25=+36 (c 0.95, AcOEt)Δ213 −0.4, Δ239 +1.1 (MeOH)Source of chirality: enzymatic resolutionAbsolute configuration: (S)

Methyl (S)-(+)-1-[methyl(2,4-dimethoxyphenyl)]-4-methylene-5-oxo-pyrrolidin-2-carboxylateC16H19NO5Ee >99%[α]D25=+88.0 (c 1, AcOEt)Δ221 −0.5, Δ240 +1.3, Δ279 +0.4 (MeOH)Source of chirality: enzymatic resolutionAbsolute configuration: (S)

Ethyl (S)-(+)-4-methylene-tetrahydro-5-oxo-2-furancarboxylateC8H10O4Ee = 99%[α]D25=+19.5 (c 0.45, EtOH)Δ221 +1.1 (MeOH)Source of chirality: enzymatic resolutionAbsolute configuration: (S)