Photoredox-Catalyzed Deformylative 1,4-Addition of 2′-Deoxy-5′-O-phthalimidonucleosides for Synthesis of 5′-Carba Analogs of Nucleoside 5′-Phosphates

Abstract

A concise approach for the synthesis of the 5'-carba analogs of nucleoside 5'-phosphates from 2'-deoxy-5'- O-phthalimidonucleosides by a visible-light-mediated deformylative 1,4-addition was developed. This method enabled rapid and facile generation of 4'-carbon radicals of nucleosides. Moreover, this synthetic strategy was applicable to the 5'-carba analogs of nucleoside 5'-phosphates as well as other 5'-carba nucleosides bearing methoxycarbonyl, cyano, and N-methylsulfamoyl groups.

Visible-Light-Induced Alkoxyl Radicals Enable α-C(sp3)-H Bond Allylation

“…Our investigation was initiated by the serendipitous discovery with N-alkoxylphthalimide 1 as the alkoxyl radical precursor, which can be readily prepared from alcohols and are bench-stable (Scheme 2) (Zhu et al., 2009, Kim et al., 1998, Zhang et al., 2016, Zhang et al., 2017, Wang et al., 2016, Ito et al., 2018, Han et al., 2019, Deng et al., 2019, Shi et al., 2019). Under the reaction conditions of fac -Ir(ppy) 3 and Hantzsch ester known to generate alkoxyl radicals (Zhang et al., 2016, Zhang et al., 2017, Wang et al., 2016, Ito et al., 2018, Han et al., 2019, Deng et al., 2019, Shi et al., 2019), the ester-derived N-alkoxylphthalimide 1 gave no δ-C(sp 3 )-H allylation adduct 3 with allyl sulfone 2 under blue LED irradiation. Instead, the α-C(sp 3 )-H allylation adduct 4 was observed in 41% yield, together with the hydrogenation adduct alcohol 5 in 52% yield (entry 1 in Table 1) (Zhang et al., 2016).…”

Synthesis of the Methyl Analog of 2′-O,4′-C-Ethylene-Bridged 5-Methyluridine via Intramolecular Radical Cyclization and Properties of Modified Oligonucleotides

“…Anhydrous, dichloromethane (DCM), 1,4-dioxane, MeCN, MeOH, pyridine and tetrahydrofuran (THF) were used as purchased. 1 H NMR, 13 C{ 1 H} NMR, and 31 P{ 1 H} NMR spectra were recorded on a Bruker AVANCE III HD 500 equipped with a BBO cryoprobe or Varian Mercury plus 300. Chemical shift values were reported in ppm, relative to internal tetramethylsilane (δ = 0.00 ppm) or solvent residual signals (δ = 3.31 ppm for CD 3 OD) for 1 H NMR, solvent residual signals (δ = 77.0 ppm for CDCl 3 and δ = 49.0 ppm for CD 3 OD) for 13 C{ 1 H} NMR, and external 5% H 3 PO 4 (δ = 0.00 ppm) for 31 P{ 1 H} NMR.…”

“…1 H NMR (500 MHz, CDCl 3 ): δ 7.62 (dd, J = 8.0, 1.0 Hz, 2H), 7.59 (dd, J = 8.0, 1.0 Hz, 2H), 7.50 (s, 1H), 7.43−7.20 (m, 21H), 6.16 (d, J = 4.5 Hz, 1H), 5.48 and 5.44 (ABq, J = 9.5 Hz, 2H), 5.38 (dd, J = 6.0, 5.5 Hz, 1H), 4.66 (s, 1H), 4.57−4.50 (m, 4H), 4.41 (d, J = 5.5 Hz, 1H), 3.94 and 3.73 (ABq, J = 11.0 Hz, 2H), 3.82 and 3.70 (ABq, J = 10.0 Hz, 2H), 1.93 (s, 3H), 1.52 (s, 3H), 1.04 (s, 9H). 13 C{ 1 H} NMR (126 MHz, CDCl 3 ): δ 170.0, 163.3, 151.2, 138.0, 137.5, 137.3, 135.7, 135.5, 134.5, 133.0, 132.7, 129.9, 129.7, 128.6, 128.4, 128.2, 128.1, 127.9, 127.7, 127.7, 127.7, 127.7, 127.6, 127.5, 110.5, 87.9, 86.5, 77.4, 74.9, 74.5, 73.7, 72.0, 70.5, 63.9, 26.9, 20.6, 19.2, 12.7. IR (ATR) cm −1 : 3068, 3030, 2930, 2858, 1747, 1713, 1666, 1453, 1363, 1228.…”

“…As part of our ongoing research aimed at developing novel methods for the synthesis of useful nucleoside analogs, we had recently reported the concise synthesis of 5′-carba analogs of nucleosides from 2′-deoxy-5′-O-phthalimidonucleosides by the photoredox-catalyzed deformylative 1,4-addition reaction (Scheme 2a). 13 It is known that oligonucleotides containing six-membered ENA exhibit higher nuclease resistance than that containing five-membered LNA, without the loss of hybridization affinity toward the ssRNA. 8 Furthermore, oligonucleo- tides containing S-cEt, which possesses a methyl group at the 6′-position, not only increased nuclease resistance but also reduced the risk of hepatotoxicity, compared to that containing LNA.…”

From d- to l-Monosaccharide Derivatives via Photodecarboxylation–Alkylation

“…Photoredox catalysis has been utilized in the synthesis of natural products − and even to derivatize complex biomolecules. ,, Its application in the field of carbohydrate chemistry enables the synthesis of derivatives that are difficult to access via existing synthesis routes. We showcased this by employing photocatalytic HAT for the site-selective alkylation of unprotected glucosides .…”