Synthesis of New 3‘-, 5-, andN⁴-Modified 2‘-O-Methylcytidine Libraries on Solid Support

Abstract

A versatile solid phase combinatorial approach was developed and utilized for the rapid synthesis of new 2'-O-methylcytidine nucleoside libraries 1-7 containing 672 compounds with 3'-deoxy-3'-C-methyl, 3'-deoxy-3'-C-hydroxymethyl, and 5-alkyl/alkynyl modifications. The modified uridine scaffolds 8-10, 23-25, and 31 were loaded onto the 4-methoxytrityl chloride (MMT-Cl) polystyrene resin through the hydroxyl groups at the 5'-position as well as on the substituents at the 3'- and 5-positions. The scaffolds loaded on the resin were orthogonally protected by MMT group on the resin itself and TBDMS or acetyl protecting groups. The 4-position of the uridine derivatives was activated by 2,4,6-triisopropyl benzene sulfonyl chloride for further derivatization. The resins 14-16, 28-30, and 32 loaded with the corresponding activated scaffolds were reacted with the selected and validated amino building blocks in the 96 well format on the semiautomated synthesizer. The high-quality 2'-O-methylcytidine libraries 1-7 were thus generated and characterized by liquid chromatography-mass spectrometry (LC-MS) analysis with 63-99% successful rates.

Facile Modifications at the C4 Position of Pyrimidine Nucleosides via In Situ Amide Activation with 1H‐Benzotriazol‐1‐yloxy‐tris(dimethyl‐amino)phosphonium Hexafluorophosphate

“…On the other hand, C4 triazol‐1‐yl (Divakar & Reese, ; Reese & Skone, ; Reese & Ubasawa, ; Sung, ) and tetrazol‐1‐yl (Ariza & Vilarrasa, ; Kamaike, Takahashi, Utsugi, Tomizuka, & Ishido, ; Kobori, Miyata, Ushioda, Seio, & Sekine, ; Mahto & Chow, ; Sung & Narang, ) pyrimidine nucleoside derivatives are stable and reactive intermediates among all the electrophilic pyrimidine nucleosides and hence, are widely useful. Various C4 aryl sulfonates such as p ‐toluenesulfonyl, 2‐mesitylensulfonyl, and 2,4,6‐isopropylbenzenesulfonyl derivatives have been investigated for their stability and reactivity (Bischofberger, ; Cismaş & Gimisis, ; Ding et al., ; Holmes & Gait, ; Verma & Miller, ). Among these, the 2,4,6‐isopropylbenzenesulfonates displayed relatively higher stability (Bischofberger, ).…”

Oligonucleosides with Integrated Backbone and Base: Foldamers with a Novel Architecture

“…The strongest motives for the design and synthesis of oligonucleotide mimics have been the search for antisense or antigene activities [1][2][3][4][5][6][7][8][9][10][11][12][13][14] and the quest for a rational insight into the prebiotic origin of nucleic acids [15]. They led to the synthesis of numerous analogues, modifying nucleobases, ribose or deoxyribose units, and the phos-swers.…”

A General Route to 4-C-Substituted Pyrimidine Nucleosides

“…5 Both 4-N-and 4-O-substituted pyrimidines can be easily prepared from uridines by conversion of the O4 into a suitable leaving group (for example a chloride or an arylsulfonate) and substitution of this leaving group by a nitrogen or oxygen nucleophile. 6,7 For carbon nucleophiles, however, this reaction is limited to extremely nucleophilic compounds such as malonic diesters. 8 Organometallic nucleophiles like organolithium or organocopper compounds react only sluggishly or, like alkyl Grignard reagents, add preferentially to the 6-position without substituting the leaving group.…”