Gamma amino acid building blocks
The invention provides compounds and methods, for example, to carry out organocatalytic Michael additions of aldehydes to cyclically constrained nitroethylene compounds catalyzed by a proline derivative to provide cyclically constrained α-substituted-γ-nitro-aldehydes. 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 to >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 cyclically constrained protected γ-amino acid residues, which are essential for systematic conformational studies of γ-peptide foldamers. New methods are also provided to prepare other γ-amino acids and peptides. These new building blocks can be used to prepare foldamers, such as α/γ-peptide foldamers, that adopt specific helical conformations in solution and in the solid state.
1. A peptide comprising one or more γ-amino acid residues, wherein at least one γ-amino acid residue is a residue of Formula IX or a residue of Formula X, wherein the structure of Formula IX is:
wherein
A is H, a nitrogen protecting group, an amino acid, or a chain of two or more amino acids;
B is H, or a carboxylic acid protecting group, or —OB is an amino acid, or a chain of two or more amino acids;
R 1 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle;
A 3 is carbon;
A 4 is carbon or nitrogen;
A 5 is carbon, or nitrogen provided A 6 is not a direct bond;
A 6 is carbon or a direct bond; and
each of A 3 -A 6 are optionally substituted with one or two alkyl, alkoxy, fluoro, optionally protected hydroxy, aryl, (aryl)alkyl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, optionally protected amino, optionally protected aminoalkyl, optionally protected alkylamino, dialkylamino, acylamino, trifluoromethyl, trifluoromethoxy, optionally protected carboxy, optionally protected carboxyalkyl, keto, arylsulfonyl, cyano, or azide groups, or when nitrogen, one nitrogen protecting group; and
wherein each alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle is optionally substituted with one to five alkyl, alkoxy, fluoro, optionally protected hydroxy, aryl, (aryl)alkyl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, optionally protected amino, optionally protected aminoalkyl, optionally protected alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, acylamino, trifluoromethyl, trifluoromethoxy, optionally protected carboxy, optionally protected carboxyalkyl, keto, arylsulfonyl, cyano, or azide groups; and
the structure of Formula X is:
wherein
A is H, a nitrogen protecting group, an amino acid, or a chain of two or more amino acids;
B is H, or a carboxylic acid protecting group, or —OB is an amino acid, or a chain of two or more amino acids;
R 1 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle, or hydrogen provided that the peptide comprises a residue of Formula IX; wherein the alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle of R 1 is optionally substituted with one to five alkyl, alkoxy, fluoro, protected hydroxy, aryl, (aryl)alkyl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, protected amino, alkylamino, dialkylamino, acylamino, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, arylsulfonyl, cyano, or azide groups;
A 3 is carbon;
A 4 is carbon;
A 5 is carbon; and
A 6 is carbon, or a direct bond.
2. The peptide of claim 1 wherein the peptide comprises three or more residues and the peptide forms a 12-helix, a 13-helix, or a 14-helix.
3. The peptide of claim 2 wherein the peptide comprises alternating α- and γ-amino acid residues and the peptide forms a 12-helix.
4. The peptide of claim 2 wherein the peptide comprises one or more γαα peptide sequences and the peptide forms a 12-helix.
5. The peptide of claim 2 wherein the peptide comprises alternating β- and γ-amino acid residues and the peptide forms a 13-helix.
6. The peptide of claim 2 wherein the peptide comprises three or more γ-amino acid residues and the peptide forms a 14-helix.
7. The peptide of claim 1 wherein A 4 is carbon.
8. The peptide of claim 1 wherein A 4 is nitrogen.
9. The peptide of claim 1 wherein A 5 is carbon.
10. The peptide of claim 1 wherein A 5 is nitrogen.
11. The peptide of claim 1 wherein A 6 is carbon.
12. The peptide of claim 1 wherein A 6 is a direct bond.
13. The peptide of claim 1 wherein A 3 -A 6 of Formula IX are each carbon.
14. The peptide of claim 1 wherein A 3 -A 5 of Formula IX are each carbon and A 6 is a direct bond.
15. The peptide of claim 1 wherein A of Formula IX or Formula X is a chain of two or more amino acids, wherein the two or more amino acids comprise α-amino acids, β-amino acids, γ-amino acids, or a combination thereof.
16. The peptide of claim 1 wherein B of Formula IX or Formula X is a chain of two or more amino acids, wherein the two or more amino acids comprise α-amino acids, β-amino acids, γ-amino acids, or a combination thereof.
17. The peptide of claim 1 wherein at least one γ-amino acid residue is a residue of Formula IX and R 1 of Formula IX is alkyl.
18. The peptide of claim 1 wherein at least one γ-amino acid residue is a residue of Formula X.
19. The peptide of claim 18 wherein R 1 of Formula X is alkyl.
20. A peptide comprising a γ-amino acid residue, wherein at least one γ-amino acid residue is a residue of Formula IX or a residue of Formula X, wherein the structure of Formula IX is:
wherein
A is H, a nitrogen protecting group, an amino acid, or a chain of two or more amino acids;
B is H, or a carboxylic acid protecting group, or —OB is an amino acid, or a chain of two or more amino acids;
R 1 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle;
A 6 is carbon or a direct bond; and
the structure of Formula X is:
wherein
A is H, a nitrogen protecting group, an amino acid, or a chain of two or more amino acids;
B is H, or a carboxylic acid protecting group, or —OB is an amino acid, or a chain of two or more amino acids;
R 1 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle, or hydrogen provided that the peptide comprises a residue of Formula IX;
A 3 is carbon;
A 4 is carbon;
A 5 is carbon; and
A 6 is carbon, or a direct bond; and
the peptide comprises three to about 20 amino acid residues.