Asymmetric Michael addition of aldehydes to nitroolefins catalyzed by l-prolinamide derivatives using phenols as co-catalysts

The asymmetric Michael addition of aldehydes to nitroolefins was investigated using l-prolinamide derivatives of 2-(2′-piperidinyl)pyridine as catalyst and a variety of phenols as co-catalyst. Extensive screening toward the effect of prolinamides, phenols, and solvents on this transformation revealed that a combination of (S)-2-(2′-piperidinyl)pyridine-derived trans-4-hydroxy-l-prolinamide 2c, (S)-1,1′-bi-2-naphthol, and dichloromethane was a promising system. This system was shown to be amenable to a rich variety of aldehydes and nitroolefins and afforded the nitroaldehyde products with excellent yield, enantiomeric excess (up to 99%) and diastereoselectivity ratio (up to 99/1), even in the case of 1 mol % catalyst loading and 1.5 equiv of aldehydes.

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(S)-2-(2′-Piperidinyl)pyridine derived l-prolinamideC15H21N3O[α]D20=-198.4 (c 0.64, CH2Cl2)Source of chirality: l-proline and (S)-2-(2′ piperidinyl) pyridineAbsolute configuration: (S, 2S)

(R)-2-(2′-Piperidinyl)pyridine derived l-prolinamideC15H21N3O[α]D20=+70.0 (c 1, CH2Cl2)Source of chirality: l-proline and (R)-2-(2′-piperidinyl) pyridineAbsolute configuration: (R, 2S)

(S)-2-(2′-Piperidinyl)pyridine derived trans-4-hydroxy-l-prolinamideC15H21N3O2[α]D20=-100.0 (c 0.1, CH2Cl2)Source of chirality: trans-4-hydroxy-l-proline and (S)-2-(2′-piperidinyl) pyridineAbsolute configuration: (S, 2S, 4R)

(R)-2-(2′-Piperidinyl)pyridine derived trans-4-hydroxy-l-prolinamideC15H21N3O2[α]D20=+61.7 (c 0.47, CH2Cl2)Source of chirality: trans-4-hydroxy-l-proline and (R)-2-(2′-piperidinyl) pyridineAbsolute configuration: (R, 2S, 4R)