Synthesis of nitroalcohol diastereomers

Abstract

The present invention relates to a method of preparing a 1-nitro-3-substituted-3-amino-2-propanol diastereomer represented by Structural Formula I: In Structural Formula I, R is an amine protecting group, and R 1 is an amino acid side-chain, a protected amino acid side-chain, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted aralkyl or a substituted or unsubstituted heteroaralkyl group. The method involves contacting a 1-nitro-3-substituted-3-amino-2-propanone with a reducing agent to form a mixture of 1-nitro-3-substituted-3-amino-2-propanol diastereomers. The 1-nitro-3-substituted-3-amino-2-propanol diastereomers are then separated by simulated moving bed chromatography to obtain one or more 1-nitro-3-substituted-3-amino-2-propanol diastereomer.

What is claimed is:  
     
         1 . A method of preparing a 1-nitro-3-substituted-3-amino-2-propanol diastereomer represented by the following structural formula:  
       
         
           
           
               
               
           
         
         wherein: 
 R is an amine protecting group; and  
 R 1  an amino acid side-chain, a protected amino acid side-chain, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted aralkyl or a substituted or unsubstituted heteroaralkyl group, comprising the steps of: 
 a) contacting a 1-nitro-3-substituted-3-amino-2-propanone with a carbonyl reducing agent to form a mixture of 1-nitro-3-substituted-3-amino-2-propanol diastereomers; and  
 b) separating the 1-nitro-3-substituted-3-amino-2-propanol diastereomers by simulated moving bed chromatography to obtain one or more 1-nitro-3-substituted-3-amino-2-propanol diastereomer.  
 
 
       
     
     
         2 . The method of  claim 1 , wherein the 1-nitro-3-substituted-3-amino-2-propanone is a 3S or 3R enantiomer and a mixture of two 1-nitro-3-substituted-3-amino-2-propanol diastereomers is formed.  
     
     
         3 . The method of  claim 2 , wherein R 1  a phenylalanine amino acid side-chain.  
     
     
         4 . The method of  claim 3 , wherein R is a carbamate protecting group.  
     
     
         5 . The method of  claim 4 , wherein the carbamate protecting group is an ethyloxycarbonyl.  
     
     
         6 . The method of  claim 4 , wherein the carbamate protecting group is tert-butoxycarbonyl.  
     
     
         7 . The method of  claim 2 , wherein the simulated moving bed has a reverse phase solid support.  
     
     
         8 . The method of  claim 7 , wherein the reverse phase solid support is a C18 solid support.  
     
     
         9 . The method of  claim 2 , wherein the simulated moving bed has a normal phase solid support.  
     
     
         10 . The method of  claim 2 , wherein the simulating moving bed has a chiral solid support.  
     
     
         11 . The method of  claim 2 , wherein the simulating moving bed has an ion-exchange solid support.  
     
     
         12 . The method of  claim 2 , wherein the first and the second 1-nitro-3-substituted-3-amino-2-propanol diastereomers are each recovered in at least 95% diastereomeric excess.  
     
     
         13 . The method of  claim 12 , further comprising the step of contacting at least one of the 1-nitro-3-substituted-3-amino-2-propanol diastereomers with a nitro reducing agent under conditions which maintain the diastereomeric excess of the diastereomer, thereby forming a 1,3-diamino-3-substituted-2-propanol diastereomer having at least about 95% diastereomeric excess.  
     
     
         14 . The method of  claim 2 , wherein a first 1-nitro-3-substituted-3-amino-2-propanol diastereomer is recovered in at least 95% diastereomeric excess, and the second 1-nitro-3-substituted-3-amino-2-propanol diastereomer or a mixture of the first 1-nitro-3-substituted-3-amino-2-propanol diastereomer and the second 1-nitro-3-substituted-3-amino-2-propanol diastereomer is recovered.  
     
     
         15 . The method of  claim 14 , further comprising the step of contacting the first 1-nitro-3-substituted-3-amino-2-propanol diastereomer with a nitro reducing agent under conditions which maintain the diastereomeric purity of the diastereomer, thereby forming a 1,3-diamino-3-substituted-2-propanol diastereomer having at least about 95% diastereomeric excess.  
     
     
         16 . A method of preparing a 1-nitro-3-substituted-3-amino-2-propanol diastereomer represented by the following structural formula:  
       
         
           
           
               
               
           
         
         wherein: 
 R is an amine protecting group; and  
 R 1  an amino acid side-chain, a protected amino acid side-chain, a substituted or unsubstituted aliphatic group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted aralkyl or a substituted or unsubstituted heteroaralkyl group, by contacting a 1-nitro-3-substituted-3-amino-2-propanone with a carbonyl reducing agent to form a mixture of 1-nitro-3-substituted-3-amino-2-propanol diastereomers, the improvement being separating the 1-nitro-3-substituted-3-amino-2-propanol diastereomers by simulated moving bed chromatography.