Synthesis of 2-C-Substituted 5-Deoxyglucals from d-Ribose: ­Access to 2-C-Substituted 5-Deoxyglycosides and -Nucleosides

Abstract

The synthesis of 2-C-substituted 5-deoxyglucals from d-ribose, by using a nickel-catalyzed cross-coupling reaction of 2-iodo-5-deoxyglucals with Grignard reagents, is reported. The obtained 2-C-substituted 5-deoxyglucals were then transformed into 2-C-substituted 5-deoxyglycosides and 2-C-substituted 5-deoxynucleosides. During this work, structures published in the literature were reassigned.

Key words

d-ribose - 5-deoxyglucal - 2-iodo-5-deoxyglucal - 2-C-substituted 5-deoxyglycoside - 2-C-substituted 5-deoxynucleoside - Grignard reagent - nickel catalysis.

Publication History

Received: 19 May 2022

Accepted after revision: 07 July 2022

Article published online:
08 August 2022

• References and Notes

• 1a Seley-Radtke KL, Yates MK. Antiviral Res. 2018; 154: 66
• 1b Tzioumaki N, Manta S, Tsoulaka E, Van Voorde J, Liebens S, Komiotis D, Balzarini J. Eur. J. Med. Chem. 2011; 46: 993
• 1c Tsoukala E, Tziuomaki N, Mana S, Riga A, Balzarini J, Komiotis D. Bioorg. Chem. 2010; 38: 285
• 1d De Clercq E. Mini-Rev. Med. Chem. 2002; 2: 163
• 2a Huryn DM, Okabe M. Chem. Rev. 2002; 92: 1745
• 2b De Clercq E. Curr. Med. Chem. 2001; 8: 1543
• 3a Li X, Dumbre SG, Lescrinier E, Groaz E, Herdewijn P. J. Org. Chem. 2019; 84: 6589
• 3b Wang J, Froeyen M, Hendrix C, Andrei G, Snoeck R, De Clercq E, Herdewijn P. J. Med. Chem. 2000; 43: 736
• 3c Pérez-Pérez M.-J, Balzarini J, Rozenski J, De Clercq E, Herdewijn P. Bioorg. Med. Chem. Lett. 1995; 5: 1115
• 4a Pruijssers AJ, Denison MR. Curr. Opin. Virol. 2019; 35: 57
• 4b Serpi M, Ferrari V, Pertusati F. J. Med. Chem. 2016; 59: 10343
• 5a Manta S, Xipnitou A, Kiritsis C, Kantsadi AL, Hayes JM, Skamnaki VT, Lamprakis C, Kontou M, Zoumpoulakis P, Zographos SE, Leonidas DD, Komiotis D. Chem. Biol. Drug Des. 2012; 79: 663
• 5b Tzioumaki N, Manta S, Tsoukala E, Vande Voorde J, Liekens S, Komiotis D, Balzarini J. Eur. J. Med. Chem. 2011; 46: 993
• 5c Agelis G, Tzioumaki N, Botic T, Cencic A, Komiotis D. Bioorg. Med. Chem. 2007; 15: 5448
• 5d Votruba I, Krecmerova M, Hrebabecky H, Holy A. Nucleosides Nucleotides 1999; 18: 2551

The synthesis of pyranoside derivatives can be achieved from sugars or by construction of the oxygenated heterocycle. For example, see:
• 6a Ikemoto N, Schreiber SL. J. Am. Chem. Soc. 1992; 114: 2524
• 6b Stauffer CS, Datta A. J. Org. Chem. 2008; 73: 4166
• 6c Yu B, Wang S. Chem. Rec. 2021; 21: 3015
• 7a Nisic F, Speciale G, Bernardi A. Chem. Eur. J. 2012; 18: 6895
• 7b Allavudeen SS, Kuberan B, Loganathan D. Carbohydr. Res. 2002; 337: 965
• 8 Chen H, Xian T, Zhang W, Si W, Luo X, Zhang B, Zhang M, Wang Z, Zhang J. Carbohydr. Res. 2016; 431: 42
• 9 Dharuman S, Vankar YD. Org. Lett. 2014; 16: 1172
• 10a Singh AK, Kandasamy J. Org. Biomol. Chem. 2018; 16: 5107
• 10b Malinowski M, Van Tran T, Robichon M, Lubin-Germain N, Ferry A. Adv. Synth. Catal. 2020; 362: 1184
• 11 Cossy J, Polak P. Chem. Eur. J. 2022; 28: e202104311
• 12 MnCl₂ can induce the in situ formation of an organomanganese derivative which can be coupled with 4. See, for example: Cahiez G, Moyeux A. Grignard Reagents and Transition Metal Catalysts. Formation of C–C Bonds by Cross-Coupling. Cossy J. De Gruyter; Berlin/Boston: 2016: 210-243
• 13 On a 2–3 mmol scale, the products resulting from the dimerization and reduction of 4 as well as a nonidentified product were observed.
• 14 Synthesis of Compound 5d Compound 4 (131 mg, 0.4 mmol) was dried by azeotropic removal of water with toluene. NiCl₂(dme) (4.4 mg, 5 mol%), dtbpy (5.4 mg, 5 mol%) and MnCl₂ (10.1 mg, 20 mol%) were introduced in the flask which was placed under high vacuum for 15 min. The flask was filled with argon (3 cycles) and THF (6 mL) was added. The reaction mixture was cooled to 0 °C and cyclopropylmagnesium bromide (1.79 mL, 0.38 M, 1.7 equiv) was slowly added by a syringe pump (0.66 mL/h). After the addition was complete (approx. 2.8 h) the completion of the reaction was indicated by a change in color of the reaction mixture from red to dark purple. The reaction was diluted with diethyl ether, quenched with 1 M HCl (1 mL), washed with brine twice, and dried over MgSO₄. Flash column chromatography on silica gel (hexane/EtOAc = 9:1) afforded 5d in 61% yield (59 mg) as a white crystalline solid. R_f = 0.31 (hexane/EtOAc = 9:1); [α]_D ²⁵+226 (0.50, CHCl₃); mp 63.5–64.2 °C. IR (ATR): 1736, 1659, 1467, 1317, 1238, 1218, 1179, 1137, 1041, 938 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.37 (d, J = 1.4 Hz, 1 H), 5.57–5.51 (m, 1 H), 5.14 (dt, J = 10.6, 4.1 Hz, 1 H), 3.92 (ddd, J = 10.3, 4.3, 1.5 Hz, 1 H), 3.85 (dd, J = 10.6, 10.3 Hz, 1 H), 2.10 (s, 3 H), 2.04 (s, 3 H), 1.28–1.14 (m, 1 H), 0.64–0.49 (m, 2 H), 0.37 (m, 1 H), 0.26 (m, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 170.80, 169.88, 144.17, 110.95, 66.47, 65.45, 62.21, 21.13, 20.87, 10.58, 4.52, 3.91. HRMS (ESI): m/z calcd for C₁₂H₁₆O₅ + Na⁺: 263.0890 [M + Na]⁺; found: 263.0890.
• 15a Haraguchi K, Konno K, Yamada K, Kitagawa Y, Nakamura KT, Tanaka H. Tetrahedron 2010; 66: 4587
• 15b Pal P, Singh P, Kumar B, Guniyal HM, Shaw AK. Tetrahedron: Asymmetry 2011; 22: 992
• 16 The cleavage of the C-I bond failed under radical conditions at elevated temperature (nBu₃SnH, AIBN, toluene, 120 °C) and rapid decomposition of the starting material was observed.
• 17 Synthesis of Compound 7 Compound 5a (100 mg, 0.37 mmol) was introduced in a flask and dried by azeotropic removal of water with toluene then placed under high vacuum for 15 min. An argon atmosphere was introduced in the flask, and then dry MeCN (4 mL) was added. NIS (166 mg, 2.0 equiv) and bis-TMS-thymine (200 mg, 2.0 equiv) were then added at once. The reaction flask was purged with argon, covered with aluminium foil, and stirred for 72 h at rt. Celite was introduced in the flask, and the solvent was evaporated. Flash column chromatography on silica gel of the crude adsorbed on Celite (hexane/EtOAc = 1:1) afforded 7 in 46% yield (89 mg) as a yellow solid foam. R_f = 0.33 (hexane/EtOAc = 1:1); [α]_D ²⁵–111 (0.42, CHCl₃); mp 110.7–113.7 °C. IR (ATR): 2959, 2871, 1748, 1688, 1671, 1465, 1371, 1288, 1230, 1097, 1075, 1030, 963, 937, 902 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.44 (br s, 1 H), 7.31 (q, J = 1.2 Hz, 1 H), 6.20 (s, 1 H), 5.47 (d, J = 3.4 Hz, 1 H), 5.19 (dt, J = 3.4, 1.6 Hz, 1 H), 4.13 (dd, J = 13.4, 1.4 Hz, 1 H), 4.05 (dd, J = 13.5, 2.0 Hz, 1 H), 2.37 (dd, J = 11.7, 8.8 Hz, 1 H), 2.15 (s, 3 H), 2.12 (s, 3 H), 1.96 (d, J = 1.2 Hz, 3 H), 1.69 (dd, J = 12.0, 9.8 Hz, 2 H), 1.63–1.52 (m, 1 H), 1.41–1.25 (m, 5 H), 0.93 (t, J = 6.8 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 169.73, 169.16, 163.28, 150.62, 136.51, 110.56, 87.19, 78.14, 69.60, 68.88, 54.30, 36.55, 32.71, 29.75, 22.74, 21.10, 20.87, 14.27, 12.70. HRMS (APCI): m/z calcd for C₁₉H₂₇IN₂O₇ + H⁺: 523.0936 [M + H]⁺; found: 523.0937.