Difluoroalkylcyclopropyl amino acids and esters, and syntheses thereof

Abstract

The invention provides methods of synthesizing compounds in an asymmetric or enantioenriched fashion, wherein the compounds are useful intermediates in the synthesis of viral protease inhibitors.

1 - 16 . (canceled) 
     
     
         17 . A method, comprising
 combining a compound of formula A with a compound of formula B at a first temperature for a first period of time in the presence of a first metal, a first solvent, and optionally a first base, thereby forming a first product mixture comprising a compound of formula C,   wherein   formula A is   
       
         
           
           
               
               
           
         
         formula B is 
       
       
         
           
           
               
               
           
         
         formula C is 
       
       
         
           
           
               
               
           
         
         R is alkyl; and 
         and R′ is alkyl. 
       
     
     
         18 . The method of  claim 17 , wherein the first metal comprises TiCl 4 , TiOR 4 , CeCl 3 , Ce 2 (SO 4 ) 3 , CaCl 2 , MgCl 2 , Ti(Oi-Pr) 3 Cl or Ti(OEt) 3 Cl. 
     
     
         19 . The method of  claim 17 , wherein the first base is present; and the first base comprises (i-Pr) 2 EtN, triethylamine, EtNH 2 , Et 2 NH, or (iPr) 2 NH. 
     
     
         20 . The method of  claim 19 , wherein the first base is triethylamine. 
     
     
         21 . The method of  claim 17 , wherein the first metal is CeCl 3  or MgCl 2 ; and the first base is absent. 
     
     
         22 . The method of  claim 17 , wherein the first metal is CeCl 3  or MgCl 2 ; and the first metal is present in a catalytic quantity. 
     
     
         23 . The method of  claim 17 , wherein the first metal is TiCl 4 , TiOR 4 , Ti(Oi-Pr) 3 Cl, or Ti(OEt) 3 Cl; and the first metal is present in a stoichiometric quantity. 
     
     
         24 . The method of  claim 17 , wherein the first solvent comprises MeOH, EtOH, n-PrOH, i-PrOH, tetrahydrofuran (THF), methyl tert-butyl ether, ethyl acetate, dioxane, DMF, acetonitrile, or DMSO. 
     
     
         25 . The method of  claim 24 , wherein the first metal is TiCl 4 , TiOR 4 , Ti(Oi-Pr) 3 Cl, or Ti(OEt) 3 Cl. 
     
     
         26 . The method of  claim 24 , wherein the first metal is CeCl 3  or MgCl 2 . 
     
     
         27 . The method of  claim 17 , wherein the first temperature is from about −10° C. to about 15° C. 
     
     
         28 . The method of  claim 17 , wherein the first period of time is from about 6 h to about 18 h. 
     
     
         29 . The method of  claim 17 , further comprising heating the first product mixture at a second temperature. 
     
     
         30 . The method of  claim 29 , wherein the first product mixture is maintained at the second temperature for a second period of time. 
     
     
         31 . The method of  claim 17 , further comprising heating the first product mixture at a third temperature. 
     
     
         32 . The method of  claim 31 , wherein the first product mixture is maintained at the third temperature for a third period of time. 
     
     
         33 . The method of  claim 17 , further comprising isolating the compound of formula C from the first product mixture, thereby forming substantially pure compound of formula C. 
     
     
         34 . The method of  claim 17 , wherein R is ethyl, n-propyl, or isopropyl. 
     
     
         35 . The method of  claim 17 , wherein the compound of formula C is 
       
         
           
           
               
               
           
         
       
     
     
         36 . The method of  claim 17 , wherein the compound of formula C is