Diastereoselective Synthesis of Arabino- and Ribo-like Nucleoside Analogues Bearing a Stereogenic C3′ All-Carbon Quaternary Center

Abstract

The synthesis of novel nucleoside analogues bearing a C3′ all-carbon quaternary center and a C2′-hydroxy substituent is described. The all-carbon stereogenic center was generated through an intramolecular 7-endo attack of a silyltethered allyl moiety on a tertiary radical using photoredox catalysis. Subsequent allylic oxidation and diastereoselective hydride reductions provided the hydroxy substituent at C2′, which then controls the stereoselective introduction of pyrimidine nucleobases on the corresponding furanose scaffold. Density functional theory (DFT) calculations provided insights into the origin of the high syn diastereoselectivity resulting from the radical cyclization. This original methodology grants access to a wide range of 1′,2′-cis and 1′,2′-trans arabino-and ribo-like analogues bearing an all-carbon quaternary center at C3′. These molecules are currently being tested for their antiviral and anticancer properties.

Nucleotide Analogues Bearing a C2′ or C3′-Stereogenic All-Carbon Quaternary Center as SARS-CoV-2 RdRp Inhibitors

“…Hydrogen and allylation transfer reactions have previously been studied both experimentally and theoretically by our group [20,21]. We recently prepared radical precursor 2 using an enantioselective Mukaiyama aldol reaction in good yield and with high diastereoselectivity in favor of the 3R isomer (Figure 2) [14]. The secondary alcohol was then transformed into dimethylallysilyl ether 3.…”

“…Allylic oxidation of 6 using SeO 2 led to a modest 50% yield of the corresponding ketone 7 (Figure 2) [14]. The 2,4-syn diol 8 was then obtained from ketone 7 by reduction using catecholborane in the presence of cesium chloride.…”

“…Optical rotations were measured at room temperature from the sodium D line (589 nm) using the formula: [α] D = (100)α obs //( •(c)), where c = (g of substrate/100 mL of solvent) and = 1 dm. The sequence from 35 to 40 in the Scheme 5, and compounds 5 and 47 [13] were prepared as reported in our previous publications [13,14]. (17).…”

“…(17). To a solution of secondary alcohol 5 [14] (3.90 g, 9.14 mmol, 1.00 equiv.) in anhydrous DCM (45 mL, 0.20 M), imidazole (1.56 g, 22.9 mmol, 2.50 equiv.)…”

“…In parallel, we have been studying carbon-centered free radicals on acyclic molecules and their reactivity in atom transfer reactions, leading to the generation of all carbon stereogenic quaternary centers. Together, these findings [10][11][12][13][14][15][16] led to the conceptualization and synthesis of novel nucleoside analogues bearing a quaternary all-carbon stereogenic center at C3 or C2 [16][17][18].…”