Gamma amino acid building blocks

Patent metadata

Field	Value
Publication number	US-9796660-B2
Application number	US-201615174306-A
Country	US
Kind code	B2
Filing date	Jun 6, 2016
Priority date	Oct 14, 2009
Publication date	Oct 24, 2017
Grant date	Oct 24, 2017

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 V:

wherein
Y is NO 2 or NHA, wherein A is H, a nitrogen protecting group, an amino acid, or a chain of two or more amino acids;
R is H, an amino acid, a chain of two or more amino acids, or OB, wherein B is H or a carboxylic acid protecting group;
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, alkoxycarbonyl, protected 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.

2. A method of preparing a compound of Formula VI:

wherein
R 1 is hydrogen, 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, alkoxycarbonyl, protected amino, alkylamino, dialkylamino, acylamino, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, arylsulfonyl, cyano, or azide groups, or one nitrogen protecting group;
comprising contacting:
a compound of Formula VII:

wherein A 3 -A 6 are as defined for Formula VI; and
a compound of Formula VIII:

wherein R 1 is as defined for Formula VI;
in the presence of an organic solvent and a proline derivative, for a period of time sufficient to provide the compound of Formula VI, or a salt thereof.

3. The method of claim 2 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 Formula VI is prepared in an enantiomerically enriched form.

4. The compound of claim 1 , wherein Y is NO 2 or NH 2 .

5. The compound of claim 1 , wherein R is H or OH.

6. The compound of claim 1 , wherein Y is NO 2 or NH 2 and R is H or OH.

7. The compound of claim 1 , wherein R 1 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle.

8. The compound of claim 7 , wherein Y is NO 2 or NH 2 .

9. The compound of claim 7 , wherein R is H or OH.

10. The compound of claim 7 , wherein Y is NO 2 or NH 2 and R is H or OH.

Assignees

• Wisconsin Alumni Res Found

Inventors

• Gellman Samuel Helmer
• Guo Li
• Giuliano Michael

Classifications

• C07C269/00

  Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups [IMAGE cpc-sch-C07C-0964.gif], the nitrogen atom not being part of nitro or nitroso groups · CPC title

• C07C271/66

  Y being a hetero atom · CPC title

• C07D211/56

  Nitrogen atoms (nitro radicals C07D211/38) · CPC title

• C07C233/48

  having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a saturated carbon skeleton containing rings · CPC title

• C07C205/55

  having nitro groups or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton · CPC title