Enantioselective Synthesis of Unsymmetrically-Substituted Organophosphorus Compounds with Stereogenic Phosphorus Atoms

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Asymmetric synthesis of optically active organophosphorus compounds via the phosphoramidite method using an optically active promoter, where the enantioselection is caused by kinetic resolution of the intermediates, was investigated. A number of enantioselective syntheses of an unsymmetrically substituted trialkyl phosphite were attempted using an optically pure tetrazole compound such as (R) - (-) -2-methoxy-2'- (1H-tetrazol-5-yl) -l, l'-binaphthyl or (lR, 2R) - (+) - 1-trimethylsilyl-2- (1H-tetrazol-5-yl) ferrocene, or an optically pure imidazole derivative such as (S)- 1 - [2- (6-methoxynaphthyl) ] -1- (2-benzimidazolyl) ethane or (S) -l- (2- imidazolyl) -l- (tert-butyldimethylsiloxy) ethane as the promoter. However, little selectivity was observed in all attempts.Although the intended objective has not been achieved, this research disclosed that imidazole triflate and benzimidazolium triflate serve as highly reactive promoters in the synthesis of oligonucleotides via the phosphoramidite approach. Particularly, imidazole triflate is a useful reagent which allows 0-selective phosphitylation, i.e, intemucleotide-linkage formation of N-unprotected nucleosides and has opened an ideal synthesis of oligodeoxyribonucleotides without nucleoside-base protection. This novel method allows low-cost supply of the products and accordingly will be useful for large-scale synthesis of DNA-related compounds including DNA phosphorothioates important as antisense molecules.