Method and compositions for the synthesis of dioxolane nucleosides with beta-configuration

Abstract

The present invention relates to methods and compositions for preparing biologically important nucleoside analogues containing 1,3-dioxolane sugar rings. In particular, this invention relates to the stereoselective synthesis of the beta (cis) isomer by glycosylating the base with an intermediate of formula (II) below a temperature of about −10° C. wherein R 1 and L are as defined herein.

We claim:  
     
         1 . A process for producing a β-nucleoside analogue compound of formula (III):  
       
         
           
           
               
               
           
         
         and salts thereof, wherein R 1  is a hydroxyl protecting group; and R 2  is a purine or pyrimidine base or an analogue or derivative thereof, the process comprising glycosylating said purine or pyrimidine base at a temperature below about −10° C., with an intermediate of formula (II):  
         
           
             
             
                 
                 
             
           
         
         wherein L is halogen.  
       
     
     
         2 . The process according to  claim 1 , wherein L is iodo.  
     
     
         3 . The process according to  claim 2 , wherein R 1  is benzyl.  
     
     
         4 . The process according to  claim 1 , wherein R 2  is selected from the group consisting of  
       
         
           
           
               
               
           
         
         wherein  
         R 3  is selected from the group consisting of hydrogen, C 1-6  alkyl and C 1-6  acyl groups;  
         R 4  and R 5  are independently selected from the group consisting of hydrogen, C 1-6  alkyl, bromine, chlorine, fluorine, and iodine;  
         R 6  is selected from the group of hydrogen, halogen, cyano, carboxy, C 1-6  alkyl, C 1-6  alkoxycarbonyl, C 1-6  acyl, C 1-6  acyloxy, carbamoyl, and thiocarbamoyl; and  
         X and Y are independently selected from the group of hydrogen, bromine, chlorine, fluorine, iodine, amino, and hydroxyl groups.  
       
     
     
         5 . The process according to  claim 1 , wherein R 2  is  
       
         
           
           
               
               
           
         
         wherein  
         R 3  is selected from the group consisting of hydrogen, C 1-6  alkyl and C 1-6  acyl groups; and  
         R 4  is selected from the group consisting of hydrogen, C 1-6  alkyl, bromine, chlorine, fluorine, and iodine.  
       
     
     
         6 . The process according to  claim 5 , wherein R3 is H or acetyl and R4 is H or F.  
     
     
         7 . The process according to  claim 1 , wherein the glycosylation reaction occurs at a temperature below about −15° C.  
     
     
         8 . The process according to  claim 1 , wherein the glycosylation reaction occurs at a temperature below about −20° C.  
     
     
         9 . The process according to  claim 1 , wherein the glycosylation reaction occurs at a temperature below about −50° C.  
     
     
         10 . The process according to  claim 1 , wherein the glycosylation reaction occurs at about −78° C.  
     
     
         11 . The process according to any one of  claims 7  to  10  wherein L is iodo.  
     
     
         12 . The process according to  claim 11  wherein R 1  is benzyl.  
     
     
         13 . The process according to  claim 1 , wherein the compound of formula (III) is subsequently deprotected to give a compound of formula (I)  
       
         
           
           
               
               
           
         
         wherein R 2  is a purine or pyrimidine base or an analogue or derivative thereof.  
       
     
     
         14 . The process according to  claim 1 , wherein the intermediate of formula (II) is prepared by reacting an intermediate of formula (II′)  
       
         
           
           
               
               
           
         
         wherein L′ is a leaving group; with a Lewis acid of formula (IV)  
         
           
             
             
                 
                 
             
           
         
         wherein  
         R 3 , R 4  and R 5  are independently selected from the group consisting of hydrogen; C 1-20  alkyl (e.g. methyl, ethyl, ethyl, t-butyl), optionally substituted by halogens (F, Cl, Br, I), C 6-20  alkoxy (e.g., methoxy) or C 6-20  aryloxy (e.g., phenoxy); C 7-20  aralkyl (e.g., benzyl), optionally substituted by halogen, C 1-20  alkyl or C 1-20  alkoxy (e.g., p-methoxybenzyl); C 6-20  aryl (e.g., phenyl), optionally substituted by halogens, C 1-20  alkyl or C 1-20  alkoxy; trialkylsilyl; fluoro; bromo; chloro and iodo; and  
         R 6  is selected from the group consisting of halogen (F, Cl, Br, I); C 1-20  sulphonate esters, optionally substituted by halogens (e.g., trifluoromethane sulphonate); C 1-20  alkyl esters, optionally substituted by halogen (e.g., trifluoroacetate); polyvalent halides (e.g., triiodide); trisubstituted silyl groups of the general formula (R 3 ) (R 4 ) (R 5 )Si (wherein R 3 , R 4 , R 5  are as defined above); saturated or unsaturated selenenyl C 6-20  aryl; substituted or unsubstituted C 6-20  arylsulphenyl; substituted or unsubstituted C 1-20  alkoxyalkyl; and trialkylsiloxy.  
       
     
     
         15 . The process according to  claim 14 , wherein the Lewis acid is selected from TMSI and SiH 2 I 2 .  
     
     
         16 . The process according to  claim 15 , wherein the Lewis acid is TMSI.  
     
     
         17 . The process according to  claim 14 , wherein L is iodo.  
     
     
         18 . The process according to  claim 17 , wherein R 1  is benzyl.  
     
     
         19 . The process according to any one of  claims 14  to  18 , wherein the compound of formula (III) is subsequently deprotected to give a compound of formula (I)  
       
         
           
           
               
               
           
         
         wherein R 2  is a purine or pyrimidine base or an analogue or derivative thereof.  
       
     
     
         20 . The process according to  claim 19 , wherein the glycosylation reaction occurs at a temperature below about −15° C.  
     
     
         21 . The process according to  claim 19 , wherein the glycosylation reaction occurs at a temperature below about −20° C.  
     
     
         22 . The process according to  claim 19 , wherein the glycosylation reaction occurs at a temperature below about −50° C.  
     
     
         23 . The process according to  claim 19 , wherein the glycosylation reaction occurs at about −78° C.