The synthesis and characterisation of N-(1-carbamoyl-1,1-dialkyl-methyl)-(S)-prolinamides and related pyrrolidin-2-yl-4,5-dihydro-1H-imidazol-5-ones as potential enantioselective organocatalysts

The acylation of substituted 2-aminopropanamides with (2S)-Boc-proline, (2S)-Cbz-proline and (2S)-Bn-proline was used to prepare substituted 1-protected N-(1-carbamoyl-1,1-dialkyl-methyl)-(S)-prolinamides (74–89%), whose subsequent deprotection gave N-(1-carbamoyl-1,1-dialkyl-methyl)-(S)-prolinamides (94–95%). The enantiomerically pure N-(1-carbamoyl-1,1-dialkyl-methyl)-(S)-prolinamides obtained were tested as organocatalysts for the aldol reaction of cyclohexanone with 4-nitrobenzaldehyde, with yields ranging from 38% to 79% ee. The highest enantioselectivity (89% ee) was achieved by catalysis with N-(1-carbamoyl-cyclopentyl)-(S)-prolinamide (methanol, l0% HCl). By the action of sodium methoxide, Boc-N-(1-carbamoyl-cyclopentyl)-(S)-prolinamide was quantitatively cyclised to 2-(1-Boc-pyrrolidin-2-yl)-1,3-diazaspiro[4.4]non-1-en-4-one, which was accompanied by racemisation at the stereogenic centre of the proline skeleton. Alternatively, the substituted 4,4-dialkyl-2-pyrrolidin-2-yl-4,5-dihydro-1H-imidazol-5-ones were prepared by oxidation of 4,4-dialkyl-2-((2S)-1-Boc-pyrrolidin-2-yl)-4,5-dihydro-1H-imidazolidin-5-ones (54–69%). In an acid medium, 2-pyrrolidin-2-yl-1,3-diazaspiro[4.4]non-1-en-4-one and (4S)-4-isopropyl-4-methyl-2-pyrrolidin-2-yl-4,5-dihydro-1H-imidazol-5-one underwent racemisation. Conversely, the free base of (2S)-2-pyrrolidin-2-yl-1,3-diazaspiro[4.4]non-1-en-4-one very easily underwent oxidation to give the achiral 2-(4,5-dihydro-3H-pyrrol-2-yl)-1,3-diazaspiro[4.4]non-1-en-4-one.

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1-Cbz-N-(1-carbamoyl-cyclopentyl)-(S)-prolinamideC19H25N3O4[α]D20=-72.2 (c 1, CH3OH)Source of chirality: (S)-Cbz-prolineAbsolute configuration: (S)

1-Cbz-N-((1S)-1-carbamoyl-1,2-dimethylpropyl)-(S)-prolinamideC19H27N3O4[α]D20=-54.7 (c 1, CH3OH)Source of chirality: (S)-Cbz-proline; (S)-2-amino-2,3-dimethylbutanamideAbsolute configuration: (S,S)

1-Cbz-N-((1S)-1-carbamoyl-2-methylpropyl)-(S)-prolinamideC18H25N3O4[α]D20=-68.3 (c 1, CH3OH)Source of chirality: (S)-Cbz-proline; (S)-2-amino-3-methylbutanamideAbsolute configuration: (S,S)

1-Boc-N-(1-carbamoyl-cyclopentyl)-(S)-prolinamideC16H27N3O4[α]D20=-68.9 (c 1, CH3OH)Source of chirality: (S)-Boc-prolineAbsolute configuration: (S)

1-Boc-N-((1S)-1-carbamoyl-1,2-dimethylpropyl)-(S)-prolinamideC16H29N3O4[α]D20=-51.0 (c 1, CH3OH)Source of chirality: (S)-Boc-proline; (S)-2-amino-2,3-dimethylbutanamideAbsolute configuration: (S,S)

1-Boc-N-((1S)-1-carbamoyl-2-methylpropyl)-(S)-prolinamideC15H27N3O4[α]D20=-74.7 (c 1, CH3OH)Source of chirality: (S)-Boc-proline; (S)-2-amino-3-methylbutanamideAbsolute configuration: (S,S)

1-Bn-N-((1S)-1-carbamoyl-1,2-dimethylpropyl)-(S)-prolinamideC18H25N3O2[α]D20=-32.1 (c 1, CH3OH)Source of chirality: (S)-Bn-prolineAbsolute configuration: (S)

N-(1-Carbamoyl-cyclopentyl)-(S)-prolinamideC11H19N3O2[α]D20=-45.4 (c 1, CH3OH)Source of chirality: (S)-Cbz-prolineAbsolute configuration: (S)

N-((1S)-1-Carbamoyl-1,2-dimethylpropyl)-(S)-prolinamideC11H21N3O2[α]D20=-48.5 (c 1, CH3OH)Source of chirality: (S)-Cbz-proline; (S)-2-amino-2,3-dimethylbutanamideAbsolute configuration: (S,S)

N-((1S)-1-Carbamoyl-2-methylpropyl)-(S)-prolinamideC10H19N3O2[α]D20=-54.2 (c 1, CH3OH)Source of chirality: (S)-Cbz-proline; (S)-2-amino-3-methylbutanamideAbsolute configuration: (S,S)

((2S)-1-Boc-2-pyrrolidin-2-yl)-1,3-diazaspiro[4.4]nonan-4-oneC16H27N3O3[α]D20=-50.0 (c 1, CHCl3)Source of chirality: (S)-Boc-prolinalAbsolute configuration: (S)

(4S)-4-Isopropyl-4-methyl-2-((2S)-1-Boc-pyrrolidin-2-yl)-imidazolidin-5-oneC16H29N3O3[α]D20=-15.6 (c 1, CH3OH)Source of chirality: (S)-Boc-prolinal; (S)-2-amino-2,3-dimethylbutanamideAbsolute configuration: (S,S)

((2S)-1-Boc-2-pyrrolidin-2-yl)-1,3-diazaspiro[4.4]non-1-en-4-oneC16H25N3O3[α]D20=-64.0 (c 1, CHCl3)Source of chirality: (S)-Boc-prolinalAbsolute configuration: (S)

(4S)-4-Isopropyl-4-methyl-2-((2S)-1-Boc-pyrrolidin-2-yl)-4,5-dihydro-1H-imidazol-5-oneC16H27N3O3[α]D20=-24.3 (c 2.9, CH3OH)Source of chirality: (S)-Boc-prolinal; (S)-2-amino-2,3-dimethylbutanamideAbsolute configuration: (S,S)

(4S)-4-Isopropyl-4-methyl-2-(pyrrolidin-2-yl)-4,5-dihydro-1H-imidazol-5-one bis(trifluoroacetate)C15H21F6N3O5[α]D20=-10.7 (c 2.9, CH3OH)Source of chirality: (S)-Boc-prolinal; (S)-2-amino-2,3-dimethylbutanamideAbsolute configuration: (4S)