Synthesis of novel nucleic acid mimics via the stereoselective intermolecular radical coupling of 3′-iodo nucleosides and formaldoximes

Article abstract of DOI:10.1021/jo961549c

A highly convergent free radical coupling of alkyl iodides and oximes, mediated by bis(trimethylstannyl) benzopinacolate (8), has been utilized to prepare a series of dimeric nucleosides as mimics of natural nucleic acids. The systematic optimization of the reaction conditions allowed for the single-step conversion of the appropriate iodides and oximes into the 2′-deoxy dimers 9 in moderate to excellent yields. For example, the reaction of 3′-deoxy-3′-iodo-5′-(triphenylmethyl)thymidine (6a) with 3′-O-(teri-butyldiphenylsilyl)-5′-O-(methyleneimino)thymidine (7a) in the presence of 8 in degassed benzene gave an 81percent yield of 3′-de(oxyphosphinico)-3′-(methyleneimino)-5′-O-(triphenyl- methyl)thymidylyl-(3′→5′)-3′-O-(tert-butyldiphenylsilyl) thymidine (9a). Similarly prepared were dimers containing both pyrimidine (thymine, 5-methylcytosine) and purine (adenine, guanine) bases. The reaction was highly stereoselective, giving only a single dimeric species having the riboconfiguration of the newly introduced C-3′-branched methylene moiety. Also prepared were dimers 16, incorporating 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, 5′-O-(teri-butyldiphenylsilyl)-3′-deoxy-3′-iodo-2′-O- methyl-5-methyluridine (12e) was prepared in 80percent yield by displacement of the corresponding inflate with Bu₄NI. Also prepared were the suitably protected 3′-deoxy-3′-iodo adenosine and guanosine derivatives. Compounds 15 were prepared in high yield by a regioselective Mitsunobu reaction to give the corresponding 5′-O-phthalimido nucleosides 13, which were subsequently converted to the requisite oximes 15. In the 2′-O-methyl series, the pinacolate coupling reaction proceeded with efficiency equal to that observed for the 2′-deoxy series 9, but with slightly less stereoselectivity, giving predominantly the C-3′ribo products 16, contaminated with 5-25percent of the epimeric material. Mixed base dimers containing both pyrimidine and purine bases at all possible positions, including purinepurine dimers were prepared. The hydroxylamine or methyleneimino (MI) backbone of several representative dimers so prepared was converted via methylation to give the corresponding methylenemethylimino (MMI)-linked compounds, which are novel phosphate surrogates for use in antisense oligonucleotides.