Synthesis of proline derivatives of bile acids and their evaluation as organocatalysts in the asymmetric direct aldol reaction

A new family of bile acid derived organocatalysts was obtained by linking l- or d-proline to amino derivatives of cholic and deoxycholic acids, which were used to promote the asymmetric direct aldol reaction between acetone and 4-nitrobenzaldehyde. Both the activity and enantioselectivity of the organocatalytic systems were dependent not only on the position of the proline moiety on the cholestanic backbone and its absolute configuration, but also on the presence of free hydroxyl group on the steroidal skeleton. The cholic acid derivative bearing a d-prolinamide moiety at the 12-position and free hydroxyl groups at the 3- and 7-positions emerged as the best organocatalytic system giving complete conversion of the substrate, even when using only 2% of catalyst loading and ee up to 80%.

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Methyl-3,7-diacetyloxy-12-oxime-5-cholan-24-oateC29H45NO7[α]D22=+130.0 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-3,12-diacetyloxy-7-oxime-5-cholan-24-oateC29H45NO7[α]D22=+12.0 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-3,7-diacetyloxy-12-amine-5-cholan-24-oateC29H47NO6[α]D22=+35.0 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-3,12-diacetyloxy-7-amine-5-cholan-24-oateC29H47NO6[α]D22=+68.0 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-3-acetyloxy-12-N-(l-Boc-prolinoyl)amino-5-cholan-24-oateC37H60N2O7[α]D22=+31.0 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-3-acetyloxy-12-N-(d-Boc-prolinoyl)amino-5-cholan-24-oateC37H60N2O7[α]D22=+176.0 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-12-hydroxy-3-N-(l-Boc-prolinoyl)amino-5-cholan-24-oateC35H58N2O6[α]D22=+65.0 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-12-hydroxy-3-N-(d-Boc-prolinoyl)amino-5-cholan-24-oateC35H58N2O6[α]D22=+102.0 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-3,7-diacetyloxy-12-N-(d-Boc-prolinoyl)amino-5-cholan-24-oateC39H62N2O9[α]D22=+113.0 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-3,12-diacetyloxy-7-N-(l-Boc-prolinoyl)amino-5-cholan-24-oateC39H62N2O9[α]D22=+23.0 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-3,12-diacetyloxy-7-N-(d-Boc-prolinoyl)amino-5-cholan-24-oateC39H62N2O9[α]D22=+103.0 (c 1.00, CH2Cl2)ource of chirality: natural source

Methyl-3,7-dihydroxy-12-N-(d-Boc-prolinoyl)amino-5-cholan-24-oateC35H58N2O7[α]D22=+97.4 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-3,12-dihydroxy-12-N-(l-Boc-prolinoyl)amino-5-cholan-24-oateC35H58N2O7[α]D22=-3.6 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-3-acetyloxy-12-N-(l-prolinoyl)amino-5-cholan-24-oateC32H52N2O5[α]D22=+73.0 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-3-acetyloxy-12-N-(d-prolinoyl)amino-5-cholan-24-oateC32H52N2O5[α]D22=+171.0 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-12-hydroxy-3-N-(l-prolinoyl)amino-5-cholan-24-oateC30H50N2O4[α]D22=+36.0 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-12-hydroxy-3-N-(d-prolinoyl)amino-5-cholan-24-oateC30H50N2O4[α]D22=+54.0 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-3,7-diacetyloxy-12-N-(d-prolinoyl)amino-5-cholan-24-oateC34H54N2O7[α]D22=+69.5 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-3,7-hydroxy-12-N-(d-prolinoyl)amino-5-cholan-24-oateC30H50N2O5[α]D22=+79.9 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-3,12-diacetyloxy-7-N-(l-prolinoyl)amino-5-cholan-24-oateC34H54N2O7[α]D22=+84.0 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-3,12-diacetyloxy-7-N-(d-prolinoyl)amino-5-cholan-24-oateC34H54N2O7[α]D22=+131.0 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-3,12-dihydroxy-7-N-(l-prolinoyl)amino-5-cholan-24-oateC30H50N2O5[α]D22=+3.7 (c 1.00, CH2Cl2)Source of chirality: natural source

Methyl-3-hydroxy-12-N-(d-prolinoyl)amino-5-cholan-24-oateC30H50N2O4[α]D22=+69.6 (c 1.00, CH2Cl2)Source of chirality: natural source