4-Thiofuranoid Glycal: Versatile Glycosyl Donor for the Selective Synthesis of -anomer of 4’-thionucleoside and its biological activities

: The first highly diastereoselective synthesis of -anomers of 4’-thionucleosides has been carried out by means of electrophilic glycosidation utilizing 3,5-O-(di-t-butylsilylene) (DTBS)-4-thiofuranoid glycal as a glycosyl donor. The resulting glycosides were transformed into ribo-, 2’-deoxy- and arabinofuranosyl nucleosides through a chemical transformation of the 2’-substituent. The additive Pummerer reaction of the glycal S-oxide gave 1,2-di-O-acetyl-3,5-O-DTBS-4-thioribofuranose. The utility of the DTBS-protected 4-thioribofuranose has been demonstrated by the preparation of 4’-thio analogues of pyrimidine- and purine-4’-thioribonucleosides on the basis of the Vorbrüggen glycosidation. Synthesis of 4’-thio-counterpart of C-nucleoside antibiotic tiazofurin has also been carried out. -Face selective hydroboration of 1-C-aryl- or 1-C-heteroaryl-glycals obtained by cross-coupling of 1-tributylstannylglycal has furnished the respective -anomer of 4’-thio-C-ribonucleosides including 4’-thio analogue of nucleoside antibiotic pseudouridine and 9-deazaadenosine. On the basis of lithiation chemistry, 1-C- and 2-C-carbon-carbon-substituted 3,5-O-(1,1,3,3-tetraisopropyldisiloxane-1,3- diyl) (TIPDS)- 4-thiofuranoid glycal were synthesized. These glycals enabled us to prepare 1’-C- and 2’--C-carbon-substituted 2’-deoxy-4’-thionucleosides which include thio-counterpart of antitumor nucleoside antibiotic angustmycin C. Furthermore, 1’-C-methyl-4’-thiothymidine emerged as potent inhibitor of angiogenesis. In addition, 1’-C-methyl-4’-thiothymidine exhibited inhibitory activity against thymidine kinase deficient mutant of herpes virus more potent than that of ganciclovir. Among the 4’-substituted 4’-thiothymidines, the 4’-C-cyano- and 4’-C-ethynyl derivatives inhibited replication of HIV variant resistant to 3TC (HIVM184V) as potent as to those of the HIV-1IIIB. In terms of the value of selectivity index (SI), 4’-C-cyano-4’-thiothymidine showed 3-fold selective index (SI) than that of the corresponding thymidine derivative. Furthermore, 4’-C-ethynyl-2’-deoxy-4’-thioguanosine has a 20-fold better value (>18,200) than that of 2’-deoxyguanosine counterpart (933). Furthermore,4’-azido-4’-thiothymidine was emerged as selective and potent anti-EBV agent. In terms of antineoplastic activity, 4’-azido- and 4’-C-fluoromethyl-2’-deoxy-4’-thiocytidine inhibited proliferation of human B-cell (CCRF-SB) and T-cell leukemia (Molt-4) cell lines although the parent compound 2’-deoxy-4’-thiocytidine did not show any cytotoxicity up to 100 M. These facts concerning the biological activities suggested that replacement of the furanose oxygen with sulfur atom is a promising approach for development of less toxic antiviral and antineoplastic nucleoside antimetabolites. 4’-Thionucleoside has also superior biological properties as monomer for oligonucleotides (ONs) therapeutics. Therefore, this review provides a wide range of potential monomer for antisense ON and siRNA.

α-C–H difluoroalkylation of alkyl sulfoxides via intermolecular Pummerer reaction

A simple and practical intermolecular Pummerer reaction using difluoroenol silyl ethers as nucleophiles is described. The protocol allows for highly efficient α-difluoroalkylation of a wide spectrum of alkyl sulfoxides.

Total synthesis of tricolorin A via interrupted Pummerer reaction-mediated glycosylation and one-pot relay glycosylation

The total synthesis of tricolorin A was achieved with high efficiency based on interrupted Pummerer reaction-mediated (IPRm) glycosylation and one-pot relay glycosylation.

Metal-Free Photoredox-Catalyzed C–H/C–H Coupling of Arenes Enabled by Interrupted Pummerer Activation

<p>Aryl–aryl cross-coupling constitutes one of the most widely used procedures for the synthesis of high-value materials, ranging from pharmaceuticals to organic electronics and conducting polymers. The assembly of (hetero)biaryl scaffolds generally requires multiple steps; coupling partners must be functionalized before the key bond-forming event is considered. Thus, the development of selective C–H arylation processes in arenes, that side-step the need for prefunctionalized partners, is crucial for streamlining the construction of these key architectures. Here we report an expedient, one-pot assembly of (hetero)biaryl motifs using photocatalysis and two non-prefunctionalized arene partners. The approach is underpinned by the activation of a C–H bond in an arene coupling partner using the interrupted Pummerer reaction. A unique pairing of the organic photoredox catalyst and the intermediate dibenzothiophenium salts enables highly selective reduction in the presence of sensitive functionalities. The utility of the metal-free, one-pot strategy is exemplified by the synthesis of a bioactive natural product and the modification of complex molecules of societal importance.</p>

Metal-Free Photoredox-Catalyzed C–H/C–H Coupling of Arenes Enabled by Interrupted Pummerer Activation

<p>Aryl–aryl cross-coupling constitutes one of the most widely used procedures for the synthesis of high-value materials, ranging from pharmaceuticals to organic electronics and conducting polymers. The assembly of (hetero)biaryl scaffolds generally requires multiple steps; coupling partners must be functionalized before the key bond-forming event is considered. Thus, the development of selective C–H arylation processes in arenes, that side-step the need for prefunctionalized partners, is crucial for streamlining the construction of these key architectures. Here we report an expedient, one-pot assembly of (hetero)biaryl motifs using photocatalysis and two non-prefunctionalized arene partners. The approach is underpinned by the activation of a C–H bond in an arene coupling partner using the interrupted Pummerer reaction. A unique pairing of the organic photoredox catalyst and the intermediate dibenzothiophenium salts enables highly selective reduction in the presence of sensitive functionalities. The utility of the metal-free, one-pot strategy is exemplified by the synthesis of a bioactive natural product and the modification of complex molecules of societal importance.</p>