New syntheses of 2',3'-dideoxy-2',3'-di-substituted & -2'-mono-substituted uridines & adenosines by michael addition reactions

Abstract

Michael addition reactions of the 3'-enesulfones 5, 6 and 18 with ammonia, primary amines (methylamine, benzylamine, glycine methyl ester), secondary amines (dimethylamine, pyrrolidine, piperidine, morpholine) and carbon-nucleophiles (sodium methylmalonate, conjugate base of nitromethane and pyrrolidin-1 -cyclohexene) have been used as means to synthesize new 2', 3'-dideoxy-2',3'-disubstituted- or 2'-substituted nucleosides. Most of these nucleophilic addition reactions have given exclusively trans-adducts [7c-j, 19d-g & 20] owing to the regiospecific protonation of the intermediary chiral α-sulfonyl cabanion at C-3'; a few of the above reactions have however produced a mixture of cis- and trans-adducts, although the latter is overwhelmingly a major product, depending upon the nature of the 2'-substituent and the type of the 3'-enesulfone [5,6 or 18]. The Michael adducts [7,9,19,24] have been deprotected at the 5'-end to produce 2',3'-disubstituted-2',3'-dideoxy-β-D-nucleosides [8a-k, 10a,b,k & 21a-g, 22j, 25a-c]. Some of the Michael adducts have been C-3' desulfonated to produce 5'-protected-2',3'-dideoxy-2'-substituted nucleosides [11a-g, 26a,f,g] which are not easily accessible through any other routes. Finally these compounds have been also deprotected to give nucleosides [12a-g & 33] in good yields. Compounds described herein, with free 5'-hydroxyl function, are potential inhibitors of the HIV-reverse transcriptase promoted c-DNA synthesis.