AROMATIC NONPOLAR NUCLEOSIDES AS HYDROPHOBIC ISOSTERES OF PYRIMIDINE AND PURINE NUCLEOSIDES

Described are the design, synthesis, and structures of three nonpolar nucleoside isosteres to be used as probes of noncovalent bonding in DN A and as isosteric replacements for the natural nucleosides in designe d nucleic acid structures. Reaction of substituted aryl Grignards with 3',5'bis-O-toluoyl-alpha-deoxyibofuranosyl chloride and subsequent de protection with sodium methoxide in methanol afforded the two beta-C-n ucleoside pyrimidine analogs 1 and 2. The dimethylindolyl nucleoside 3 , a purine isostere, was obtained by a nucleophilic displacement on al pha-chlorodeoxyribofuranose by the sodium salt of 4,6-dimethylindole, followed by deprotection. Regio- and stereochemistry of the products w ere established with NOE difference spectra and H-1 NMR splitting patt erns. Analogs 1 and 2 are nonpolar isosteres of thymidine, and nucleos ide 3 is an isostere of 2-aminodeoxyadenosine, the triply-bonded Watso n-Crick partner of thymidine. Semiempirical AM1 calculations were carr ied out to provide bond length information to assess structural simila rities between the isosteres and their natural counterparts.