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.

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.

Compounds are provided to modulate the C5a receptor. The compounds have the following Formula (I): ##STR00001## including stereoisomers and pharmaceutically acceptable salts thereof, wherein R.sup.1, R.sup.2 and R.sup.3 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

Compounds are provided to modulate the C5a receptor. The compounds have the following Formula (I): ##STR00001## including stereoisomers and pharmaceutically acceptable salts thereof, wherein R.sup.1, R.sup.2 and R.sup.3 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

A method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid represented by formula (10) below: ##STR00001##
the method including removing the protecting group from the hydroxyl group in a compound represented by formula (7) below: ##STR00002##
(wherein P represents a protecting group, R.sup.3 represents an alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms)
to synthesize a compound represented by formula (8) below: ##STR00003##
(wherein R.sup.3 represents an alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms).

A method for producing (2S,5S)/(2R,5R)-5-hydroxypiperidine-2-carboxylic acid represented by formula (10) below: ##STR00001##
the method including removing the protecting group from the hydroxyl group in a compound represented by formula (7) below: ##STR00002##
(wherein P represents a protecting group, R.sup.3 represents an alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms)
to synthesize a compound represented by formula (8) below: ##STR00003##
(wherein R.sup.3 represents an alkyl group containing 1 to 4 carbon atoms, and A represents an alkyl group containing 1 to 10 carbon atoms, an aryl group containing 6 to 12 carbon atoms, an alkyloxy group containing 1 to 4 carbon atoms, or an aralkyloxy group containing 7 to 20 carbon atoms).

A process for producing a compound represented by a Formula (III), including reacting a compound of the following formula

##STR00001##

with a compound selected from the group consisting of 1-hydroxypyrrolidine-2,5-dione, 2-hydroxy-3a,4,7,7a-tetrahydro-1H-isoindol-1,3(2H)-dione, 2-hydroxyhexahydro-1H-isoindol-1,3(2H)-dione and 4-hydroxy-4-azatricyclo[5.2.1.0.sup.2,6]dec-8-ene-3,5-dione, carrying out a carbonylation to obtain a compound of the following formula

##STR00002##

removing the NH protecting group P and treating the resultant compound with a base to produce a compound represented by the following formula

##STR00003##

wherein OBn is benzyloxy and R.sup.2 is hydrogen, ClCO— or Cl.sub.3COCO—.

A process for producing a compound represented by a Formula (III), including reacting a compound of the following formula

##STR00001##

with a compound selected from the group consisting of 1-hydroxypyrrolidine-2,5-dione, 2-hydroxy-3a,4,7,7a-tetrahydro-1H-isoindol-1,3(2H)-dione, 2-hydroxyhexahydro-1H-isoindol-1,3(2H)-dione and 4-hydroxy-4-azatricyclo[5.2.1.0.sup.2,6]dec-8-ene-3,5-dione, carrying out a carbonylation to obtain a compound of the following formula

##STR00002##

removing the NH protecting group P and treating the resultant compound with a base to produce a compound represented by the following formula

##STR00003##

wherein OBn is benzyloxy and R.sup.2 is hydrogen, ClCO— or Cl.sub.3COCO—.

Compounds are provided to modulate the C5a receptor. The compounds have the following Formula (I):

##STR00001## including stereoisomers and pharmaceutically acceptable salts thereof, wherein R.sup.1, R.sup.2 and R.sup.3 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

Compounds are provided to modulate the C5a receptor. The compounds have the following Formula (I):

##STR00001## including stereoisomers and pharmaceutically acceptable salts thereof, wherein R.sup.1, R.sup.2 and R.sup.3 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.