Asymmetric Mannich reactions catalyzed by proline and 4-hydroxyproline derived organocatalysts in the presence of water

The ability of amphiphilic catalysts based on proline and 4-hydroxyproline to catalyze the Mannich reaction in aqueous media is reported. With a 4-tert-butyldimethylsiloxy-substituted organocatalyst derived from N-prolylsulfonamide, the reaction of cyclohexanone with iminoglyoxylate proceeds with high enantioselectivity (>99% ee for the syn-diastereomer). This catalyst was also successfully applied in a reaction of an iminoglyoxylate with an aqueous tetrahydro-2H-pyran-2,6-diol to give the corresponding 2,3-disubstituted tetrahydropyridine with up to 95:5 dr and 98% ee.

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trans-1-Benzyloxycarbonyl-4-(R)-tert-butyldimethylsilyloxy-N-(p-butylbenzenesulfonyl)-2-(S)-pyrrolidinecarboxamideC29H42N2O6SSi[α]D20=-61(c 0.2, CHCl3)Source of chirality: chiral poolAbsolute configuration: (S,R)

trans-4-tert-(R)-Butyldimethylsilyloxy-N-(p-butylbenzenesulfonyl)-(S)-proline amideC21H36N2O4SSi[α]D20=-50 (c 0.2, CHCl3)Source of chirality: chiral poolAbsolute configuration: (S,R)

(S)-Ethyl 2-((4-methoxyphenyl)amino)-2-((S)-2-oxocyclohexyl)acetateC17H23NO498% ee (by HPLC on chiral column)[α]D20=-33.4 (c 1.0, CHCl3).Source of chirality: asymmetric synthesisAbsolute configuration: (S,S)

Ethyl 3-(S)-formyl-1-(4-methoxyphenyl)-1,2,3,4-tetrahydropyridine-2-(S)-carboxylateC16H19NO498% ee (by HPLC on chiral column)[α]D20=-131.8 (c 1.0, CHCl3).Source of chirality: asymmetric synthesisAbsolute configuration: (S,S)