Methods for preparing amides and amino acids
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 γ 2 -amino acids, which are essential for systematic conformational studies of γ-peptide foldamers.
1. 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 and a proline derivative;
for a period of time sufficient to provide an α-substituted-γ-nitrobutyraldehyde, wherein the beta-carbon of the α-substituted-γ-nitrobutyraldehyde is a methylene;
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.
2. The method of claim 1 wherein the aldehyde has an α-methylene group or an α-methine group.
3. The method of claim 1 further comprising protecting the amine group of the α-substituted-γ-amino acid with a nitrogen protecting group.
4. The method of claim 1 wherein the proline derivative is a chiral pyrrolidine catalyst and the α-substituted-γ-amino acid is prepared in an enantiomerically enriched form.
5. The method of claim 4 wherein the chiral pyrrolidine catalyst is an (S)- or (R)-diphenylprolinol trialkyl silyl ether.
6. The method of claim 1 wherein the contacting is carried out in the presence of a carboxylic acid.
7. The method of claim 6 wherein the carboxylic acid is acetic acid or a nitrobenzoic acid, and the organic solvent is the carboxylic acid or an aryl solvent.
8. The method of claim 6 wherein the carboxylic acid is present in about 5-20 mol % with respect to the molar amount of nitroethylene.
9. The method of claim 6 wherein the carboxylic acid is a nitrobenzoic acid.
10. The method of claim 6 wherein the carboxylic acid is 3-nitrobenzoic acid.
11. The method of claim 4 wherein about 1-10 mol % of the chiral pyrrolidine catalyst is present with respect to the molar amount of nitroethylene, and a carboxylic acid is present wherein the carboxylic acid is optionally acetic acid or a nitrobenzoic acid.
12. The method of claim 11 wherein the carboxylic acid is present in about 5-20 mol % with respect to the molar amount of nitroethylene.
13. The method of claim 1 wherein the molar amount of the aldehyde is greater than the molar amount of nitroethylene.
14. The method of claim 1 wherein aldol products are afforded in less than about 20% yield with respect to the molar amount of nitroethylene.
15. A method for preparing an amide compound comprising 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, wherein the beta-carbon of the α-substituted-γ-nitrobutyraldehyde is a methylene;
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 an α-amino acid that has a protected carboxylic acid group to form an amide compound; and
reducing the nitro moiety of the amide compound to an amine, to provide the amide compound comprising an α-substituted-γ-amino acid coupled to an α-amino acid.
16. The method of claim 15 further comprising protecting the amine group of the α-substituted-γ-amino acid with a nitrogen protecting group.
17. The method of claim 15 wherein the contacting is carried out in the presence of a carboxylic acid.
18. The method of claim 15 wherein the proline derivative is a chiral pyrrolidine catalyst and the α-substituted-γ-amino acid is prepared in an enantiomerically enriched form.
19. The method of claim 18 wherein the chiral pyrrolidine catalyst is an (S)- or (R)-diphenylprolinol trialkyl silyl ether, the organic solvent is an aryl solvent, and the carboxylic acid is a nitrobenzoic acid.