Gamma amino acid building blocks

Patent metadata

Field	Value
Publication number	US-9382291-B2
Application number	US-201414166007-A
Country	US
Kind code	B2
Filing date	Jan 28, 2014
Priority date	Oct 14, 2009
Publication date	Jul 5, 2016
Grant date	Jul 5, 2016

Abstract

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.

First claim

What is claimed is:

1. A compound of Formula I:

wherein
R 1 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle;
R 2 is H, OH, an amino acid or peptide, or OR x wherein R x is alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, or an oxygen protecting group;
Y is nitro, amino, a nitrogen bonded to an amino acid, —NHR y , or —N(R y ) 2 , wherein each R y is independently alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, or a nitrogen protecting group;
Z is O, S, or H, and the dashed line to Z is an optionally present bond that is absent when Z is H;
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;
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 of any R 1 , R 2 , R x , or R y 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;
or a salt or solvate thereof.

2. The compound of claim 1 wherein the compound is a compound of Formula IA:

wherein
R 1 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle; wherein the alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle of R 1 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;
R 2 is H, OH, an amino acid or peptide, or OR x wherein R x is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle; wherein the alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle of R x 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;
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;
or a salt or solvate thereof.

3. The compound of claim 1 wherein the compound is a compound of Formula II:

wherein
R 1 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle; wherein the alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle of R 1 is optionally substituted with one to five alkyl, alkoxy, fluoro, hydroxy, aryl, (aryl)alkyl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, acylamino, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, arylsulfonyl, cyano, or azide groups;
Y is nitro, amino, protected amino, or a nitrogen bonded to an amino acid;
R 3 is an amino acid side chain;
P is hydrogen, a carboxylic acid protecting group, or —OP is an amino acid residue or peptide;
A 3 is carbon;
A 4 is carbon or nitrogen;
A 5 is carbon or nitrogen;
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, hydroxy, aryl, (aryl)alkyl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, acylamino, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, arylsulfonyl, cyano, or azide groups, or one nitrogen protecting group;
or a salt or solvate thereof.

4. The compound of claim 3 wherein R 1 is alkyl, A 3 -A 6 are each carbon, R 3 is H or alkyl, P is H, methyl or acetyl, and Y is nitro or protected amino.

5. A method for preparing a compound of claim 1 wherein R 2 is H comprising:
contacting a cyclic compound of 5 or 6 ring atoms that includes a nitroethylene moiety within the ring and that optionally includes one or two nitrogen atoms in the ring, wherein the carbon atoms in the ring are optionally substituted and the optional nitrogen atom or atoms in the ring are optionally substituted by a nitrogen protecting group; 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 the compound of claim 1 .

6. The method of claim 5 wherein the aldehyde has an α-methylene group or an α-methine group.

7. The method of claim 5 wherein the contacting is carried out in the presence of a carboxylic acid, the proline derivative is a chiral pyrrolidine catalyst, and the compound of claim 1 is prepared in at least about 80% enantiomeric purity.

8. The method of claim 5 further comprising reducing an aldehyde moiety of the compound of claim 1 to an alcohol, oxidizing the resulting alcohol to a carboxylic acid, reducing the nitro moiety of the compound of claim 1 to an amine, or a combination thereof.

9. A method for preparing a compound of Formula III:

wherein
R 1 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle; 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 or nitrogen;
A 5 is carbon, or nitrogen provided that 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, halo, protected hydroxy, aryl, (aryl)alkyl, heteroaryl, heterocycle, cycloalkyl, alkanoyl

Assignees

• Wisconsin Alumni Res Found

Inventors

• Gellman Samuel Helmer
• Guo Li
• Giuliano Michael

Classifications

• C07C2601/08

  the ring being saturated · CPC title

• C07C2601/14

  The ring being saturated · CPC title

• C07C205/44 Primary

  the carbon skeleton being further substituted by —CHO groups · CPC title

• C07K7/06 Primary

  having 5 to 11 amino acids · CPC title

• C07C237/24

  having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton · CPC title