Improved Synthesis of a Salicylic Aldehyde C-Nucleoside for Metallo Base Pairs via Heck Reaction

Abstract

Salicylic aldehyde C-nucleosides, when incorporated in oligodeoxynucleotides, have been widely used to prepare DNA duplexes with metallo base pairs. Here, we report a synthesis of such nucleosides that involves diastereoselective formation of the glycosidic bond via Heck reaction.

Key words

Heck reaction - DNA - nucleobases - oligonucleotides - nucleosides

• References and Notes

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• 24 2-(5,5-Dimethyl-1,3-dioxan-2-yl)-5-iodophenol (4b) The following protocol was derived from that for a related compound described in ref. 8. Salicylic aldehyde 3 (1.50 g, 6.05 mmol, 1 equiv), 2,2-dimethyl-1,3-propanediol (2.52 g, 24.20 mmol, 4 equiv), tetrabutylammonium tribromide (0.29 g, 0.61 mmol, 0.1 equiv), and triethylorthoformate (1.10 mL, 0,99 g, 6.66 mmol, 1.1 equiv) were added to a flask. The reaction mixture was stirred at r.t. for 16 h under argon. TLC (PE–EtOAc = 9:1, v/v) showed complete conversion of the starting material. The reaction mixture was diluted with EtOAc (50 mL) and washed with sat. NaHCO₃ solution (50 mL). The organic phase was washed twice with H₂O and dried over Na₂SO₄. Solvents were evaporated and the yellow, oily crude was purified by column chromatography on silica (140 g), eluting with a step gradient of EtOAc (7–14%) in PE to give 1.94 g of 4b (5.80 mmol, 96%) as a colorless solid. TLC (PE–EtOAc = 9:1, v/v). R_f = 0.42. HRMS (ESI-TOF): m/z calcd for C₁₂H₁₅IO₃ [M + Na]⁺: 356.996; found: 356.994. ¹H NMR (300 MHz, CDCl₃): δ = 0.82 (s, 3 H), 1.27 (s, 3 H), 3.66 (d, J = 11.1 Hz, 2 H), 3.81 (d, J = 11.1 Hz, 2 H), 5.49 (s, 1 H), 6.89 (d, J = 8.2 Hz, 1 H), 7.20 (dd, J = 8.2, 1.6 Hz, 1 H), 7.28 (d, J = 1.6 Hz, 1 H), 8.08 (s, 1 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 21.9, 23.1, 30.5, 77.7, 95.5, 102.7, 121.7, 126.5, 128.9, 129.4, 156.0 ppm. IR: ν = 3278, 2958, 2869, 1605, 1558, 1478, 1386, 1214, 1093, 1016, 705 cm^–1. 2-[4-Iodo-2-(4-nitrophenylethoxy)phenyl]-5,5-dimethyl-1,3-dioxane (5b) Acetal 4b (1.00 g, 2.99 mmol, 1 equiv), Ph₃P (1.57 g, 5.98 mmol, 2 equiv), and 2-(4-nitrophenyl)ethanol (1.00 g, 5.98 mmol, 2 equiv) were added to a flask and dried in vacuo. THF (15 mL) was added, and the resulting solution was cooled to 0 °C. DIAD (1.17 mL, 1.21 g, 5.98 mmol, 2 equiv) was added dropwise, and the orange solution was stirred overnight, while the mixture was allowed to warm to 20 °C. Volatiles were removed under reduced pressure, and the resulting brown oil was purified by column chromatography on silica (100 g), eluting with a step gradient of CH₂Cl₂ (50–75%) in PE, to give 1.36 g of 5b (2.82 mmol, 94%) as a colorless solid. TLC (CH₂Cl₂–PE = 1:1, v/v). R_f = 0.22. HRMS (ESI-TOF): m/z calcd for C₂₀H₂₂INO₅ [M + Na]⁺: 506.044; found: 506.045. ¹H NMR (300 MHz, CDCl₃): δ = 0.78 (s, 3 H), 1.27 (s, 3 H), 3.22 (t, J = 6.2 Hz, 2 H), 3.52 (d, J = 10.8 Hz, 2 H), 3.81 (d, J = 10.8 Hz, 2 H,), 4.23 (t, J = 6.2 Hz, 2 H), 5.49 (s, 1 H), 7.17 (s, 1 H), 7.34–7.36 (m, 2 H), 7.44–7.50 (m, 2 H), 8.16–8.22 (m, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 22.0, 23.1, 30.4, 35.5, 68.3, 77.9, 95.1, 96.6, 121.2, 123.8, 127.0, 129.0, 130.1, 130.6, 146.3, 147.0, 155.9 ppm. IR: ν = 2949, 2866, 2833, 1593, 1513, 1341, 1245, 1093, 1020, 817 cm^–1. Enol Ether 7b A mixture of Pd(OAc)₂ (50 mg, 220 μmol, 0.2 equiv) and AsPh₃ (136 mg, 440 μmol, 0.4 equiv) was dissolved in CHCl₃ (10.3 mL) under argon. After stirring for 1 h, Ag₂CO₃ (459 mg, 1.67 mmol, 1.5 equiv) was added, followed by addition of compound 5b (700 mg, 1.45 mmol, 1.3 equiv) and glycal 6 (257 mg, 1.11 mmol, 1 equiv). The reaction mixture was stirred at 70 °C for 4 h, and then allowed to cool to r.t., followed by filtration over Celite. Volatiles were removed in vacuo, and the resulting crude was purified by chromatography, using silica (30 g), and eluting with a step gradient of Et₂O (50–75%) in PE to afford 372 mg of 7b (640 μmol, 58%) as a colorless foam. TLC (PE–Et₂O = 1:1, v/v). R_f = 0.19. ¹H NMR (300 MHz, CDCl₃): δ = 0.22 (s, 3 H), 0.23 (s, 3 H), 0.78 (s, 3 H), 0.95 (s, 9 H), 1.28 (s, 3 H), 3.21 (t, J = 6.2 Hz, 2 H), 3.53 (d, J = 10.7 Hz, 2 H), 3.67–3.77 (m, 4 H), 4.26 (t, J = 6.2 Hz, 2 H), 4.57–4.65 (m, 1 H), 4.79 (br t, J = 1.6 Hz, 1 H), 5.55 (s, 1 H), 5.70 (dd, J = 3.7, 1.6 Hz, 1 H), 6.97–7.02 (m, 2 H), 7.44–7.52 (m, 2 H), 7.63 (d, J = 8.2 Hz, 1 H), 8.14–8.21 (m, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = –4.9, –4.7, 18.2, 22.0, 23.1, 25.7, 30.4, 35.6, 62.7, 67.9, 78.0, 83.4, 84.8, 96.8, 101.4, 110.5, 120.1, 123.7, 127.1, 127.6, 128.8, 130.1, 144.9, 146.8, 146.9, 151.6, 155.7 ppm. IR: ν = 2952, 2929, 2856, 1656, 1518, 1343, 1227, 1094, 1033, 833 cm^–1. Ketone 8b To a vessel containing a solution of enol ether 7b (700 mg, 1.20 mmol, 1 equiv) in dry THF (7 mL) under argon at 0 °C was added triethylamine trihydrofluoride (292 μL, 289 mg, 1.80 mmol, 1.5 equiv). CAUTION: HF that may be liberated from this mixture is very hazardous in case of skin contact, eye contact, or ingestion. The mixture was filtered through a short silica column (10 g), eluting with CH₂Cl₂–MeOH (95:5, v/v, 50 mL). The filtrate was concentrated in vacuo, and 555 mg of the resulting product 8b (1.18 mmol, 99%) were obtained as a colorless foam. TLC (CH₂Cl₂–MeOH = 95:5, v/v). R_f = 0.44. HRMS (ESI-TOF): m/z calcd for C₂₅H₂₉NO₈ [M + Na]⁺: 494.179; found: 494.176. ¹H NMR (300 MHz, CDCl₃): δ = 0.71 (s, 3 H), 1.21 (s, 3 H), 2.36 (dd, J = 18.0, 10.4 Hz, 1 H), 2.77 (dd, J = 18.0, 5.9 Hz, 1 H), 3.15 (t, J = 6.4 Hz, 2 H), 3.45 (d, J = 11.0 Hz, 2 H), 3.64 (d, J = 11.0 Hz, 2 H), 3.83–3.87 (m, 2 H), 3.94 (t, J = 3.5 Hz, 1 H), 4.20 (t, J = 6.4 Hz, 2 H), 5.11 (dd, J = 10.4, 5.9 Hz, 1 H), 5.48 (s, 1 H), 6.89 (d, J = 1.3 Hz, 1 H), 6.93 (dd, J = 7.9, 1.3 Hz, 1 H), 7.55–7.62 (m, 2 H), 7.58 (d, J = 7.9 Hz, 1 H), 8.06–8.14 (m, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 22.0, 23.1, 30.4, 35.6, 45.5, 61.6, 68.2, 77.4, 78.0, 82.4, 96.7, 109.4, 118.9, 123.8, 127.4, 127.8, 130.1, 142.2, 146.6, 146.9, 155.8, 213.6 ppm. IR: ν = 2954, 2860, 1742, 1518, 1345, 1090, 1009, 831 cm^–1. Nucleoside 9b Ketone 8b (555 mg, 1.18 mmol, 1 equiv) was dissolved in dry MeCN (12 mL), and the solution was cooled to 0 °C. Then, NaBH(OAc)₃ (499 mg, 2.35 mmol, 2 equiv) was added, and the solution was stirred at 0 °C for 2 h. The reaction was quenched by adding MeOH (10 mL), and volatiles were removed in vacuo. The resulting crude was chromatographed on silica (25 g) with a gradient of 3–5% MeOH in CH₂Cl₂ to afford 432 mg (912 μmol, 76%) of the desired nucleoside 9b as a colorless solid. TLC (CH₂Cl₂–MeOH = 95:5, v/v). R_f = 0.14. HRMS (ESI-TOF): m/z calcd for C₂₅H₃₁NO₈ [M + Na]⁺: 496.194; found: 496.194; ¹H NMR (300 MHz, MeOD): δ = 0.76 (s, 3 H), 1.24 (s, 3 H), 1.90 (ddd, J = 13.1, 10.3, 6.0 Hz, 1 H), 1.90 (ddd, J = 13.1, 6.0, 1.7 Hz, 1 H), 3.20 (t, J = 6.1 Hz, 2 H), 3.49 (d, J = 10.8 Hz, 2 H), 3.63 (d, J = 10.8 Hz, 2 H), 3.65–3.69 (m, 2 H), 3.94 (dd, J = 5.1, 2.3 Hz, 1 H), 4.30 (m, 3 H), 5.10 (dd, J = 10.3, 6.0 Hz, 1 H), 5.47 (s, 1 H), 6.97 (dd, J = 7.7, 1.2 Hz, 1 H), 7.07 (d, J = 1.2 Hz, 1 H), 7.49 (d, J = 7.7 Hz, 1 H), 7.52–7.58 (m, 2 H), 8.14–8.20 (m, 2 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 21.9, 23.3, 31.0, 36.4, 45.0, 63.9, 69.4, 74.2, 78.7, 81.2, 89.2, 98.1, 110.8, 119.3, 124.4, 127.4, 128.2, 131.4, 146.0, 148.1, 148.6, 157.1 ppm. IR: ν = 2953, 2870, 1513, 1343, 1092, 1032, 821 cm^–1 .