Intermolecular radical CC bond formation: Synthesis of a novel dinucleoside linker for non-anionic antisense oligonucleosides

✍ Scribed by Françoise Debart; Jean-Jacques Vasseur; Yogesh S. Sanghvi; P. Dan Cook

• Book ID: 104215735
• Publisher: Elsevier Science
• Year: 1992
• Tongue: French
• Weight: 305 KB
• Volume: 33
• Category: Article
• ISSN: 0040-4039
• DOI: 10.1016/s0040-4039(00)79047-2

✦ Synopsis

Abatm& An cffkient, stmwselcclive synthesis of a thymidine (T) nwkosi~ dimes (T-3'-CH2-NH-O-S'-T) 1 has bum accanplished via an intemokxular did reaction. 'I& new dimea amd methodology is useful for the development of ba&bonemodEcdrmbense 0ligolmcleQsidw. Modulation of the expression of genetic information by an antisense oligonucleotides is an exciting new drug design concept.' Development of therapeutic agents based on this technology requires modified ollgonucleotides that arc m&ant to nucleolytic cleavage, penetrate cellular membranes, and hybridize, with appropriate affiiity and specificity, to targeted RNA. The removal of the negative charge carried by the phosphodiester linkage of oligonucleotides may enhance each of these pharmacokinetic properties. However, efforts in this direction, such as substitutions on the prochiral phosphorus atom of the phosphodiester linkage, as represented by phosphotricsters, methylphosphonatcs, phosphoramiclates, compromise biding affinity.' Several other approaches, that provide a neutral backbone, are the methylene,2 carbonyl,3 disubstituted sily14 modifications, which represent one to one atom replacements. A synthesis of a methylsulfonate as a two atom replacement, and a dimethylene sulfonate as a three atom replacement of the phosphodiester linkage has been ~ported.~ We now report the replacement of the two atom moiety -3'-0-P(O)-2-of a T-T dinucleotide by the non-anionic 3'-CH2-NI% moiety by a free radical, carbon-carbon bond formation between the nucleosides. The resulting hydroxylamine nucleoside dimer 1 is achiral, neutral,6 and is expected to mimic a natural DNA phosphodiester linkage? Scheme I outlines the synthesis of novel target dinucleoside 1, for which the key reaction is the stereoselective connection of S-O-(trityl)-3'-deoxy-3'-iodothymidine (5) and S-0-(methyleneamino)~3'-(t-butyldiphenylsilyl)thymidine (9). We chose to explore the possibility of achieving this connection via an intermolecular radical C-C bond formation. In recent years, considerable technology has been developed with radical reactions that result in a high degree of stereoselectivity.* In particular, our attention was drawn to the stereoselective synthesis of 3'-cyanomethyl-and 3'cyano-3'-deoxythymidines by Tam,9 and Parkes," respectively. It is notable that these wtre stereoselective, high yield reactions which indicates the stability of the incipient 3'-radical of 3." *we refer to modified oligonucleotides that have the Mti atom nmoved as oligonuckosides. bsiting Scientists from C.N.R.S. (France)