Substrate control by means of the chiral cavity of prolinamide derivatives of cholic acid in the organocatalyzed Michael addition of cyclohexanone to nitroolefins

Different prolinamide and bis-prolinamide derivatives were checked as organocatalysts in the asymmetric Michael addition of cyclohexanone to aromatic nitroolefins, and the derivative bearing a d-prolinamide moiety linked at the 7-position emerged as the most efficient, giving the Michael adducts in satisfactory yield and ees of up to 95%. The corresponding system having a free OH group at the 3-position of the cholestanic backbone afforded the opposite enantiomer of the product, suggesting that the transition state is developed at the inner part of the cholestanic cavity, which is responsible for the substrate control determining the stereochemical outcome of the reaction.

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Methyl 3α-acetyloxy-12α,7α-diamino-5α-cholan-24-oateC27H46N2O4[α]D22=+35.0 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl 3α-acetyloxy-7α,12α-bis(Boc-d-prolinoyl)amino-5α-cholan-24-oateC47H76N4O10[α]D22=+79.5 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl 3α-acetyloxy-12α,7α-bis(d-prolinoyl)amino-5α-cholan-24-oateC37H60N4O6[α]D22=+43.4 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl 3α-hydroxy-12α,7α-bis(d-prolinoyl)amino-5α-cholan-24-oateC35H58N4O5[α]D22=+112.7 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl 3α-hydroxy-12α-acetyloxy-7α-(d-prolinoyl)amino-5α-cholan-24-oateC32H52N2O6[α]D22=+132.6 (c 1.00, CH2Cl2)Source of chirality: natural source