SYNTHESIS OF NOVEL NUCLEIC-ACID MIMICS VIA THE STEREOSELECTIVE INTERMOLECULAR RADICAL COUPLING OF 3'-IODO NUCLEOSIDES AND FORMALDOXIMES

A highly convergent free radical coupling of alkyl iodides and oximes, mediated by bis(trimethylstannyl) benzopinacolate (8), has been utili zed to prepare a series of dimeric nucleosides as mimics of natural nu cleic acids. The systematic optimization of the reaction conditions al lowed for the single-step conversion of the appropriate iodides and ox imes into the 2'-deoxy dimers 9 in moderate to excellent yields. For e xample, the reaction of 3'-deoxy-3'-iodo-5'-(triphenylmethyl)thymidine (6a) with butyldiphenylsilyl)-5'-O-(methyleneimino)thymidine (7a) in the presence of 8 in degassed benzene gave an 81% yield of hinico)-3'- (methyleneimino)-5'-O-(triphenylmethyl) -(3'-->5')-3'-O-(tert-butydiph enylsilyl)thymidine. (9a). Similarly prepared were dimers containing b oth pyrimidine (thymine, 5-methylcytosine) and purine (adenine, guanin e) bases. The reaction was highly stereoselective, giving only a singl e dimeric species having the ribo-configuration of the newly introduce d C-3'-branched methylene moiety. Also prepared were dimers 16, incorp orating 2'-O-methyl ribonucleosides in both halves of the dimer. This required the synthesis of 3'-deoxy-3'-iodo-2'-O-methyl nucleosides 12 as well as 2'-O-methyl-5'-O-methyleneimino nucleosides 15. For example , utyldiphenylsilyl)-3'-deoxy-3'-iodo-2'-O-methyl-5- methyluridine (12 e) was prepared in 80% yield by displacement of the corresponding trif late with Bu(4)NI. Also prepared were the suitably protected 3'-deoxy- 3'-iodo adenosine and guanosine derivatives. Compounds 15 were prepare d in high yield by a regioselective Mitsunobu reaction to give the cor responding 5'-O-phthalimido nucleosides 13, which were subsequently co nverted to the requisite oximes 15. In the 2'-O-methyl series, the pin acolate coupling reaction proceeded with efficiency equal to that obse rved for the 2'-deoxy series 9, but with slightly less stereoselectivi ty, giving predominantly the C-3'ribo products 16, contaminated with 5 -25% of the epimeric material. Mixed base dimers containing both pyrim idine and purine bases at all possible positions, including purine-pur ine dimers were prepared. The hydroxylamine or methyleneimino (MI) bac kbone of several representative dimers so prepared was converted via m ethylation to give the corresponding methylenemethylimino (MMI)-linked compounds, which are novel phosphate surrogates for use in antisense oligonucleotides.