Chemical synthesis of oligonucleotides containing a naphthalene diolepoxide deoxycytidine adduct in solution and using a mixed chemistry semi-automated solid phase approach

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Abstract
I have recently reported the first total synthesis of a naphthalene diolepoxide-deoxycytidlne nudeoside adduct suitable for incorporation into synthetic oligonucleotides. The racemic synthesis yielded the modified deoxycytidine nudeoside as a mixture of diastereomers (1a,b). I now report the conversion of the modified nucleosides (1a,b) into their phosphotriester salts (2a,b) and subsequent Incorporation at a specific site into synthetic oligodeoxyribonucleotides. These syntheses yielded oligonudeotides possessing the diastereo merically modified nucleosides, N4 ± )-1(b),2(a),3(a)-trlhydroxy-4(b)-1,23,4-tetrahydronaphthyl]-2'-deoxycytidine (3a,b = C* at a specific position. A sample of the modified nudeosides (3a,b) was obtained by chemically removing the protecting groups from (la,b) and purification on C-18 reverse-phase chromatography. The structure of the modified nucleosides (3a,b) was supported by 400 MHZ 1H-NMR and fast atom bombardment MS. The modified tetramers C*pGpApT (9a,b) along with the par sequence CpGpApT were synthesized using the phosphotrlester chemistry in solution. Interestingly, the diastereomerically modified tetramers (9a) and (9b) could be resolved using C-18 reverse-phase chromatography. Using a mixed chemistry semi-automated approach on a solid support the modified oligo nucleotide 24mers, ApApTpTpGpCpApApGpTpC*pCpApT pApTpGpGpApCpTpTpGpC (10a,b), were synthesized and purified by anion exchange chromatography. The nucleoslde composition of all synthetic oligonucleolides was quantitatively examined by reverse-phase chromatography following enzymlc digestion.

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