Amino acids and catalytic preparatory methods
AssigneeWARF - Wisconsin Alumni Research Foundation
InventorsSamuel Helmer Gellman, Yonggui Chi, Li Guo
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Abstract
The invention provides novel compounds and methods to carry out organocatalytic Michael additions of aldehydes to nitroethylene catalyzed by a proline derivative to provide α-substituted-γ-nitroaldehydes. The reaction can be rendered enantioselective when a chiral pyrrolidine catalyst is used, allowing for Michael adducts in nearly optically pure form (e.g., 96-99% e.e.). The Michael adducts can bear a single substituent or dual substituents adjacent to the carbonyl. The Michael adducts can be efficiently converted to protected γ2-amino acids, which are essential for systematic conformational studies of γ-peptide foldamers.
Claims21
A compound of formula I:
- wherein
- R is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle;
- R′ is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle, provided that R′ is not methyl or butyl;
- and
- the alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle is optionally substituted with one to five alkyl, alkoxy, halo, hydroxy, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, arylsulfonyl, cyano, or azide groups;
- or a salt thereof.
A compound of formula II:
- wherein
- R and R′ are each independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle, provided that R and R′ are not both methyl;
- R″ is an amino acid side chain;
- P is hydrogen or a carboxylic acid protecting group;
- Y is nitro, amino, or protected amino;
- and
- the alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle is optionally substituted with one to five alkyl, alkoxy, halo, hydroxy, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, arylsulfonyl, cyano, or azide groups.
A method for preparing an α-substituted-γ-nitrobutyraldehyde comprising contacting nitroethylene and an aldehyde that has at least one α-hydrogen, in the presence of an organic solvent, a proline derivative, and optionally a carboxylic acid, for a period of time sufficient to provide the α-substituted-γ-nitrobutyraldehyde.
A method for preparing a compound of formula III:
- wherein R and R′ are each independently hydrogen or optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle;
- comprising contacting a compound of formula IV:
- wherein R and R′ are as defined for formula III, and nitroethylene, in the presence of an organic solvent, a proline derivative, and optionally a carboxylic acid, for a period of time sufficient to provide the compound of formula III.
A method for preparing an α-substituted-γ-amino acid comprising:
- contacting nitroethylene and an aldehyde that has at least one α-hydrogen, in the presence of an organic solvent, a proline derivative, and optionally a carboxylic acid;
- for a period of time sufficient to provide an α-substituted-γ-nitrobutyraldehyde;
- reducing the aldehyde of the α-substituted-γ-nitrobutyraldehyde to an alcohol;
- oxidizing the alcohol to a carboxylic acid;
- and
- reducing the nitro moiety of the α-substituted-γ-nitrobutyraldehyde to an amine, to provide the α-substituted-γ-amino acid.
A method for preparing an amide compound comprised of an α-substituted-γ-amino acid coupled to an α-amino acid, the method comprising:
- contacting nitroethylene and an aldehyde that has at least one α-hydrogen, in the presence of an organic solvent and a proline derivative, for a period of time sufficient to provide an α-substituted-γ-nitrobutyraldehyde;
- reducing the aldehyde of the α-substituted-γ-nitrobutyraldehyde to an alcohol;
- oxidizing the alcohol to a carboxylic acid;
- forming a peptide bond with the carboxylic acid and the nitrogen moiety of a α-amino acid that has a protected carboxylic acid group;
- and
- reducing the nitro moiety of the α-substituted-γ-nitrobutyraldehyde to an amine, to provide the enantiomerically pure amide compound.
A method for preparing a α-substituted-γ-nitrobutyraldehyde comprising contacting nitroethylene and an aldehyde that has an α-methylene group, in the presence of an organic solvent, an (S)- or (R)-diphenylprolinol trialkyl silyl ether, and optionally a carboxylic acid;
- for a period of time sufficient to provide the α-substituted-γ-nitrobutyraldehyde, wherein the α-substituted-γ-nitrobutyraldehyde is prepared in at least about 90% enantiomeric purity.
Dependencies are inferred from the claim text.