Highly enantioselective synthesis of α-methylene-δ-valerolactones by an asymmetric Michael reaction

The synthesis of α-methylene-δ-valerolactones 7, 13, and 19 with enantiomeric excesses of 90–97% was achieved by the asymmetric Michael reaction of chiral imines 3, 9, and 15 with the acrylate 1. Reduction of the carbonyl group of the resulting adducts followed by lactonization and HWE reaction with formaldehyde yielded the lactones as mixtures of diastereoisomers.

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(4aR,8aR)-4a-Methoxy-3-methylene-octahydrochromen-2-oneC11H16O3Ee = 96%[α]D25=+80.0 (c 0.65, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (4aR,8aR)

(4aR,8aS)-4a-Methoxy-3-methylene-octahydrochromen-2-oneC11H16O3Ee = 96%[α]D25=+4.2 (c 1.12, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (4aS,8aS)

(4aS,7aS)-Ethyl 3-methylene-2-oxo-octahydrocyclopenta[b]pyran-4a-carboxylateC12H16O4Ee = 97%[α]D25=-40.0 (c 0.28, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (4aS,7aS)

(4aS,7aR)-Ethyl 3-methylene-2-oxo-octahydrocyclopenta[b]pyran-4a-carboxylateC12H16O4Ee = 97%[α]D25=-46.3 (c 0.82, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (4aS,7aR)

(5R,6S)-6-Methyl-9-methylene-2,7-dioxa-spiro[4.5]decane-1,8-dioneC12H16O4Ee = 90%[α]D25=−62.7 (c 0.69, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (5R,6S)

(5R,6R)-6-Methyl-9-methylene-2,7-dioxa-spiro[4.5]decane-1,8-dioneC12H16O4Ee = 90%[α]D25=+40.4 (c 0.48, MeOH)Source of chirality: asymmetric synthesisAbsolute configuration: (5R,6R)