Clean, high-yield preparation of s,s and r,s amino acid isosteres

Abstract

The present invention provides compounds and methods that can be used to convert the intermediate halomethyl ketones (HMKs), e.g., chloromethyl ketones, to the corresponding S,S- and R,S-diastereomers. More particularly, the present invention provides: (1) reduction methods; (2) inversion methods; and (3) methods involving the epoxidation of alkenes. Using the various methods of the present invention, the R,S-epoxide and the intermediary compounds can be prepared reliably, in high yields and in high purity.

1 .- 75 . (canceled) 
     
     
         76 . A composition comprising an R,S-halomethyl alcohol (R,S-HMA) compound having the following general formula: 
       
         
           
           
               
               
           
         
       
       said composition prepared by a method comprising:
 reducing a halomethyl ketone (HMK) compound having the following general formula: 
 
       
         
           
           
               
               
           
         
         with a non-chelating, bulky reducing agent to form said R,S-HMA compound; 
       
       wherein:
 R 1  is an amino acid side chain; 
 R 2  is a blocking group; and 
 X 1  is a leaving group. 
 
     
     
         77 . The composition in accordance with  claim 76 , wherein said non-chelating, bulky reducing agent used in said method is a member selected from the group consisting of lithium aluminum t-butoxyhydride (LATBH) and sodium tris-t-butoxyborohydride (STBH). 
     
     
         78 . The method in accordance with  claim 77 , wherein said non-chelating, bulky reducing agent is lithium aluminum t-butoxyhydride (LATBH). 
     
     
         79 . The composition in accordance with  claim 76 , wherein R 1  is a member selected from the group consisting of a benzyl group, an S-phenyl group, an alkyl group and para-nitrobenzene. 
     
     
         80 . The composition in accordance with  claim 76 , wherein X 1  is a halogen. 
     
     
         81 . The composition in accordance with  claim 80 , wherein X 1  is chloro or bromo. 
     
     
         82 . The composition in accordance with  claim 76 , wherein R 2  is a blocking group selected from the group consisting of BOC, MOC and CBZ. 
     
     
         83 . The composition in accordance with  claim 76 , wherein the reduction is carried out in a solvent selected from the group consisting of diethyl ether, THF, MTBE, glyme and diglyme. 
     
     
         84 . The composition in accordance with  claim 83 , wherein said solvent is diethyl ether. 
     
     
         85 . The composition in accordance with  claim 76 , wherein the reduction is carried out at a temperature ranging from about −30° C. to about 25° C. 
     
     
         86 . The composition in accordance with  claim 85 , wherein the reduction is carried out at a temperature ranging from about −5° C. to about 5° C. 
     
     
         87 . The composition in accordance with  claim 76 , wherein the composition is a 8:1 mixture of R,S-HMA:S,S-HMA. 
     
     
         88 . A composition comprising an R,S-halomethyl alcohol (R,S-HMA) compound having the following general formula: 
       
         
           
           
               
               
           
         
       
       said composition prepared by a method comprising:
 reducing a halomethyl ketone (HMK) compound having the following general formula: 
 
       
         
           
           
               
               
           
         
         with a reducing agent selected from the group consisting of sodium cyanoborohydride, cerium chloride/sodium borohydride, K-Selectride®, KS-Selectride® and (+)-Dip Chloride™ to form said R,S-HMA compound; 
       
       wherein:
 R 1  is an amino acid side chain; 
 R 2  is a blocking group; and 
 X 1  is a leaving group. 
 
     
     
         89 . The composition in accordance with  claim 88 , wherein the composition is a 2:1 mixture of R,S-HMA:S,S-HMA. 
     
     
         90 . An R,S-epoxide compound having the following general formula: 
       
         
           
           
               
               
           
         
       
       prepared by a method comprising:
 reducing a halomethyl ketone (HMK) compound having the following general formula: 
 
       
         
           
           
               
               
           
         
         with a non-chelating, bulky reducing agent to form an R,S-halomethyl alcohol (R,S-HMA) compound having the following general formula: 
       
       
         
           
           
               
               
           
         
       
       and
   contacting said R,S-HMA compound of Formula II with an alkali metal base to form said R,S-epoxide compound;   
 
       wherein:
 R 1  is an amino acid side chain; 
 R 2  is a blocking group; and 
 X 1  is a leaving group. 
 
     
     
         91 . The compound in accordance with  claim 90 , wherein R 1  is a benzyl group; R 2  is a BOC blocking group; and X 1  is chloro or bromo. 
     
     
         92 . The compound in accordance with 88, wherein said non-chelating, bulky reducing agent is a member selected from the group consisting of lithium aluminum t-butoxyhydride (LATBH) and sodium tris-t-butoxyborohydride (STBH). 
     
     
         93 . The compound in accordance with  claim 90 , wherein the reduction is carried out in diethyl ether. 
     
     
         94 . The compound in accordance with  claim 90 , wherein said alkali metal base is a member selected from the group consisting of NaOH, KOH, LiOH, NaOCH 3 , NaOCH 2 CH 3  and KOtBu. 
     
     
         95 . A composition comprising a mixture of R,S-halomethyl alcohol (R,S-HMA) and S,S-halomethyl alcohol (S,S-HMA), wherein said mixture is at least 2:1R,S-HMA:S,S-HMA. 
     
     
         96 . The composition in accordance with  claim 95 , wherein said mixture is about 8:1 R,S-HMA:S,S-HMA.