A New and Versatile Synthesis of 1,3-Dioxan-5-yl-pyrimidine and Purine Nucleoside Analogues

Abstract

1,3-Dioxan-5-yl pyrimidine and purine nucleoside analogues were prepared following a new and versatile synthetic strategy. These analogues were synthesized via nucleophilic addition of the selected nucleobase to a 1,3-dioxane scaffold that presents an appropriate leaving group in position 5. In particular cis and trans isomers of purine/pyrimidine nucleosides and their halogenated homologues were obtained. NMR experiments, carried out on the cis isomers, led to assignment of an equatorial orientation to the 2-hydroxymethyl group and axial orientation to the nucleobase in position 5 of the 1,3-dioxane. The trans isomers showed a diequatorial orientation of these groups. These assignments were confirmed by X-ray crystallographic studies.

Key words

nucleosides - 1,3-dioxane - purines - pyrimidines - antiviral

• References and Notes

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• 17 Benzoyloxyacetaldehyde Diethyl Acetal (1) Potassium benzoate (125.2 mmol, 20.0 g) was added to a solution of bromoacetaldehyde diethyl acetal (160.0 mmol, 24.4 mL) and 18-crown-6 ether (catalytic amount) in anhydrous DMF (25 mL), and the mixture was refluxed for 6 h. Then, after cooling to r.t., H₂O was added, and the mixture was extracted three times with EtOAc. The combined extracts were washed with H₂O, dried (Na₂SO₄), and concentrated under vacuum. The residue was dried azeotropically with toluene to give benzoyloxyacetaldehyde diethyl acetal (24.72 g, 104.0 mmol, 83%). This product was used in the next step without further purification. Dark oil. ¹H NMR (400 MHz, CDCl₃): δ = 1.22 (t, J = 7.2 Hz, 6 H, 2 × CH₃), 3.54–3.68 (m, 2 H, CH ₂CH₃), 3.68–3.80 (m, 2 H, CH ₂CH₃), 4.35 (d, J = 5.4 Hz, 2 H, CH₂OCO), 4.84 (t, J = 5.4 Hz, 1 H, CH), 7.43 (dd, J = 7.6, 7.7 Hz, 2 H, CH-3, CH-5 Ph), 7.55 (t, J = 7.6 Hz, 1 H, CH-4 Ph), 8.05 (d, J = 7.7 Hz, 2 H, CH-2, CH-6 Ph). ¹³C NMR (100 MHz, CDCl₃): δ = 15.0 (2 CH₃), 62.2 (2 CH₂), 64.1 (CH₂OCO), 99.4 (CH), 128.1 (C-3, C-5 Ph), 129.4 (C-2, C-6 Ph), 129.7 (C-1 Ph), 132.8 (C-4 Ph), 166.0 (CO). HRMS-APCI: m/z calcd for C₁₃H₁₉O₄ ⁺ [M + H]⁺: 239.1278; found: 239.1280.
• 18 (5-Hydroxy-1,3-dioxan-2-yl)methyl Benzoate (2) To a solution of CoCl₂ (9.7 g, 75.0 mmol) in anhydrous MeCN (100 mL), benzoyloxyacetaldehyde diethyl acetal (1, 33.3 g, 140.0 mmol), TMSCl (19.0 mL, 149.0 mmol), and glycerol (19.3 mL, 265.0 mmol) were added at r.t. under stirring. After 12 h the reaction was stopped, the mixture was extracted three times with EtOAc, and the extracts were collected and washed with NaHCO₃ (5%). The organic layer was dried (Na₂SO₄), filtered, and the solvent was evaporated under vacuum to give an oily residue. Purification and separation of two diastereoisomers 2a and 2b was achieved by flash column chromatography (cyclohexane–ethyl acetate, 70:30): 5.00 g of cis isomer 2a (21.0 mmol, 15%), 5.34 g of trans isomer 2b (22.4 mmol, 16%), and 10.0 g of [4-(hydroxymethyl)-1,3-dioxolan-2-yl]methyl benzoate (2c, 42.0 mmol, 30%) as an inseparable cis/trans diastereoisomeric mixture (50:50) were obtained. Molar ratio 1,3-dioxanes/1,3-dioxolanes = 55:45.
• 19 cis-(5-Hydroxy-1,3-dioxan-2-yl)methyl Benzoate (2a) Yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 3.10 (br s, 1 H, OH), 3.52–3.61 (m, 1 H, CH-5 diox), 3.90–4.01 (m, 2 H, CH-4_ax, CH-6_ax diox), 4.04–4.13 (m, 2 H, CH-4_eq, CH-6_eq diox), 4.40 (d, J = 4.6 Hz, 2 H, CH₂O), 4.96 (t, J = 4.6 Hz, 1 H, CH-2 diox), 7.44 (dd, 2 H, J = 7.4, 7.8 Hz, CH-3, CH-5 Ph), 7.57 (t, 1 H, J = 7.4 Hz, CH-4 Ph), 8.01 (d, 2 H, J = 7.8 Hz, CH-2, CH-6 Ph). ¹³C NMR (100 MHz, CDCl₃): δ = 64.0 (C-5 diox), 64.9 (CH₂OCO), 71.9 (C-4, C-6 diox), 98.9 (C-2 diox), 128.5 (C-3, C-5 Ph), 129.6 (C-1 Ph), 129.7 (C-2, C-6 Ph), 133.2 (C-4 Ph), 166.2 (CO). HRMS-APCI: m/z calcd for C₁₂H₁₅O₅ ⁺ [M + H]⁺: 239.0914; found: 239.0917.
• 20 trans-(5-Hydroxy-1,3-dioxan-2-yl)methyl Benzoate (2b) Yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 3.02 (br s, 1 H, OH), 3.42 (dd, J = 10.4, 10.8 Hz, 2 H, CH-4_ax, CH-6_ax diox), 3.81–3.91 (m, 1 H, CH-5 diox), 4.22 (dd, J = 4.9, 10.4 Hz, 2 H, CH-4_eq, CH-6_eq diox), 4.35 (d, J = 4.6 Hz, 2 H, CH₂O), 4.78 (t, J = 4.6 Hz, 1 H, CH-2 diox), 7.43 (dd, 2 H, J = 7.2, 7.8 Hz, CH-3, CH-5 Ph), 7.55 (t, 1 H, J = 7.2 Hz, CH-4 Ph), 8.04 (d, 2 H, J = 7.8 Hz, CH-2, CH-6 Ph). ¹³C NMR (100 MHz, CDCl₃): δ = 60.7 (C-5 diox), 64.4 (CH₂OCO), 70.8 (C-4, C-6 diox), 97.8 (C-2 diox), 128.2 (C-3, C-5 Ph), 129.2 (C-1 Ph), 129.5 (C-2, C-6 Ph), 133.1 (C-4 Ph), 166.1 (CO). HRMS-APCI: m/z calcd for C₁₂H₁₅O₅ ⁺ [M +H]⁺: 239.0914; found: 239.0915.
• 21 trans-[5-(Tosyloxy)-1,3-dioxan-2-yl]methyl Benzoate (3b) p-Toluenesulfonyl chloride (1.20 g, 6.3 mmol) was added at 0 °C to a solution of 2b (1.0 g, 4.2 mmol), Et₃N (8.4 mmol, 1.17 mL) in anhydrous CH₂Cl₂ (20 mL). The mixture was stirred at r.t. for 12 h. Ice and H₂O were added, and the mixture was extracted with CH₂Cl₂. The organic extracts were collected and dried (Na₂SO₄). Crystallization from EtOAc–cyclohexane afforded the desired compound (0.86 g, 2.2 mmol, 52%). White solid; mp 83–85 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.46 (s, 3 H, CH₃), 3.57 (dd, J = 10.4, 11.3 Hz, 2 H, CH-4_ax, CH-6_ax diox), 4.14 (dd, J = 5.3, 11.3 Hz, 2 H, CH-4_eq, CH-6_eq diox), 4.32 (d, J = 4.6 Hz, 2 H, CH₂O), 4.45–4.58 (m, 1 H, CH-5 diox), 4.78 (t, J = 4.5 Hz, 1 H, CH-2 diox), 7.31–7.45 (m, 2 H, CH-2, CH-6 Ph), 7.43–7.56 (m, 2 H, CH-3, CH-5 Ph), 7.58–7.64 (m, 1 H, CH-4 Ph), 7.81 (d, J = 8.4 Hz, 2 H, CH-3, CH-5 Ts), 8.04 (d, J = 8.4 Hz, 2 H, CH-2, CH-6 Ts). ¹³C NMR (100 MHz, CDCl₃): δ = 21.4 (CH₃), 63.9 (CH₂OCO), 67.5 (C-5 diox), 67.9 (C-4, C-6 diox), 98.1 (C-2 diox), 127.6 (C-3, C-5 Ts), 128.1 (C-3, C-5 Ph), 129.5 (C-2, C-6 Ts), 129.2 (C-1 Ph), 129.9 (C-2, C-6 Ph), 133.4 (C-4 Ph), 133.7 (C-1 Ts), 145.3 (C-4 Ts), (165.8 (CO). HRMS-APCI: m/z calcd for C₁₉H₂₁O₇S⁺ [M + H]⁺: 393.1003; found: 393.1006.
• 22 cis-{5-[5-Chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]-1,3-dioxan-2-yl}methyl Benzoate (5b) To a suspension of 5-chlorouracil (1.2 mmol) and K₂CO₃ (1.2 mmol), in anhydrous DMF (10 mL), was added portionwise, under nitrogen, the tosylated compound 3b (1 mmol) and 18-crown-6 (catalytic amount). The resulting mixture was stirred and heated to reflux for 24 h. After cooling to r.t. the mixture was concentrated under vacuum. The residue was partitioned between EtOAc and H₂O. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The extracts were combined, washed with H₂O, and dried (Na₂SO₄). The suspension was filtered and the solvent evaporated under vacuum. The residue obtained was purified by flash chromatography to yield the desired compound (0.046 g, 0.125 mmol, 12%). Yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 4.19–4.37 (m, 4 H, CH₂-4, CH₂-6 diox), 4.50 (br s, 1 H, CH-5 diox), 4.53 (d, J = 3.8 Hz, 2 H, CH₂O), 5.11 (t, J = 3.8 Hz, CH-2 diox), 7.53 (dd, J = 7.5, 8.0 Hz, 2 H, CH-3, CH-5 Ph), 7.69 (dd, J = 1.3, 7.5 Hz, 1 H, CH-4 Ph), 7.94 (dd, J = 1.3, 8.0 Hz, 2 H, CH-2, CH-6 Ph), 8.65 (s, 1 H, CH-6 uracil). ¹³C NMR (100 MHz, CDCl₃): δ = 48.5 (C-5 diox), 64.0 (CH₂OCO), 68.5 (C-4, C-6 diox), 99.0 (C-2 diox), 108.7 (C-5 uracil), 128.3 (C-3, C-5 Ph), 129.6 (C-2, C-6 Ph), 129.9 (C-1 Ph), 133.2 (C-4 Ph), 139.6 (C-6 uracil), 149.2 (C-2 uracil), 157.8 (C-4 uracil), 166.1 (CO). ESI-HRMS: m/z calcd for C₁₆H₁₆ClN₂O₆ ⁺ [M + H]⁺: 367.0691; found: 367.0692.
• 23 cis-[5-(6-Chloro-9H-purin-9-yl)-1,3-dioxan-2-yl]methyl Benzoate (12b) The compound was obtained from 3b and 6-chloropurine, following the procedure described for 5b (0.059 g, 0.158 mmol, 15%). Dark-brown oil. ¹H NMR (400 MHz, CDCl₃): δ = 4.30–4.38 (m, 2 H, CH-4_ax, CH-6_ax diox), 4.39–4.46 (m, 2 H, CH-4_eq, CH-6_eq diox), 4.49 (d, J = 4.3 Hz, 2 H, CH₂O), 4.82 (br s, 1 H, CH-5 diox), 5.21 (t, J = 4.3 Hz, 1 H, CH-2 diox), 7.48 (dd, J = 7.5, 7.8 Hz, 2 H, CH-3, CH-5 Ph), 7.60 (dd, J = 1.2, 7.5 Hz, 1 H, CH-4 Ph), 8.07 (dd, J = 1.2, 7.8 Hz, 2 H, CH-2, CH-6 Ph), 8.73 (s, 1 H, CH-2 purine), 8.92 (s, 1 H, CH-8 purine). ¹³C NMR (100 MHz, CDCl₃): δ = 48.5 (C-5 diox), 64.6 (CH₂OCO), 69.0 (C-4, C-6 diox), 99.4 (C-2 diox), 128.5 (C-3, C-5 Ph), 129.3 (C-1 Ph), 129.8 (C-2, C-6 Ph), 131.0 (C-5 purine), 133.5 (C-4 Ph), 145.4 (C-8 purine), 151.1 (C-4 purine), 151.5 (C-6 purine), 151.8 (C-2 purine), 166.1 (CO). ESI-HRMS: m/z calcd for C₁₇H₁₆ClN₄O₄ ⁺ [M + H]⁺: 375.0855; found: 375.0862.
• 24 cis-[5-(2-Amino-6-chloro-9H-purin-9-yl)-1,3-dioxan-2-yl]methyl Benzoate (13b) The compound was obtained from 3b and 6-chloro-2-amino-purine, following the procedure described for 5b (0.063 g, 0.162 mmol, 16%). Dark-brown oil. ¹H NMR (400 MHz, CDCl₃): δ = 4.30–4.44 (m, 4 H, CH₂-4, CH₂-6 diox), 4.50 (d, J = 4.2 Hz, 2 H, CH₂O), 4.69 (br s, 1 H, CH-5 diox), 5.05 (br s, 2 H, NH₂), 5.18 (t, J = 4.2 Hz, 1 H, CH-2 diox), 7.51 (dd, J = 7.4, 7.8 Hz, 2 H, CH-3, CH-5 Ph), 7.62 (t, J = 7.4 Hz, 1 H, CH-4 Ph), 8.09 (d, J = 7.8 Hz, 2 H, CH-2, CH-6 Ph), 8.77 (s, 1 H, CH-8 purine). ¹³C NMR (100 MHz, CDCl₃): δ = 48.8 (C-5 diox), 64.4 (CH₂OCO), 68.8 (C-4, C-6 diox), 99.5 (C-2 diox), 128.9 (C-3, C-5 Ph), 129.4 (C-1 Ph), 129.9 (C-2, C-6 Ph), 130.8 (C-5 purine), 133.5 (C-4 Ph), 139.6 (C-8 purine), 151.5 (C-6 purine), 152.7 (C-4 purine), 159.1 (C-2 purine), 166.0 (CO). ESI-HRMS: m/z calcd for C₁₇H₁₇ClN₅O₄ ⁺ [M + H]⁺: 390.0964; found: 390.0969.
• 25 cis-5-Chloro-1-[2-(hydroxymethyl)-1,3-dioxan-5-yl]pyrimidine-2,4(1H,3H)-dione (15b) Compound 5b (0.046 g, 0.125 mmol) was dissolved in concentrated aq NH₃ (15 mL) and stirred for 5 h in a Pyrex pressure tube. After evaporation of the solvent under vacuum, the residue was crystallized from MeOH–Et₂O to give the desired compound (0.026 g, 0.099 mmol, 79%). White solid; mp 207–209 °C. ¹H NMR (400 MHz, DMSO): δ = 3.34–3.47 (m, 2 H, CH ₂OH), 4.01–4.12 (m, 2 H, CH-4_ax, CH-6_ax diox), 4.13–4.21 (m, 2 H, CH-4_eq, CH-6_eq diox), 4.31 (br s, 1 H, CH-5 diox), 4.71 (t, J = 4.1 Hz, 1 H, CH-2 diox), 4.95 (t, J = 6.0 Hz, 1 H, OH), 8.47 (s, 1 H, CH-6 uracil), 11.30 (br s, 1 H, NH). ¹³C NMR (100 MHz, DMSO): δ = 47.5 (C-5 diox), 62.4 (CH₂OH), 68.0 (C-4, C-6 diox), 100.6 (C-2 diox), 108.3 (C-5 uracil), 141.2 (C-6 uracil), 160.3 (C-2 uracil), 163.4 (C-4 uracil). Anal. Calcd for C₉H₁₁ClN₂O₅: C, 41.16; H, 4.22; N, 10.67. Found: C, 41.05; H, 4.14; N, 10.41. ESI-HRMS: m/z calcd for C₉H₁₂ClN₂O₅ ⁺ [M + H]⁺: 263.0429; found: 263.0428.
• 26 cis-[5-(6-Amino-9H-purin-9-yl)-1,3-dioxan-2-yl]methanol (22b) Compound 12b (0.055 g, 0.147 mmol) was dissolved in concentrated aq NH₃ (15 mL) and placed in a reactor at 100 °C for 12 h. After solvent evaporation under vacuum, the residue was crystallized from MeOH–Et₂O to give the desired compound (0.025 g, 0.100 mmol, 68%). Yellow solid; mp 255–257 °C. ¹H NMR (400 MHz, DMSO): δ = 3.47 (dd, 2 H, J = 4.0, 6.2 Hz, CH ₂O), 4.02–4.16 (m, 2 H, CH-4_ax, CH-6_ax diox), 4.18–4.32 (m, 2 H, CH-4_eq, CH-6_eq diox), 4.51 (br s, 1 H, CH-5 diox), 4.69 (t, J = 4.0 Hz, 1 H, CH-2 diox), 4.90 (t, J = 6.2 Hz, 1 H, OH), 7.17 (br s, 2 H, NH₂), 8.08 (s, 1 H, CH-2 purine), 8.40 (s, 1 H, CH-8 purine). ¹³C NMR (100 MHz, DMSO): δ = 49.3 (C-5 diox), 62.5 (CH₂OH), 67.9 (C-4, C-6 diox), 101.3 (C-2 diox), 118.9 (C-5 purine), 139.4 (C-8 purine), 149.5 (C-4 purine), 153.0 (C-2 purine), 156.3 (C-6 purine). Anal. Calcd for C₁₀H₁₃N₅O₃: C, 47.81; H, 5.22; N, 27.87. Found: C, 47.86; H, 5.44; N, 28.03. ESI-HRMS: m/z calcd for C₁₀H₁₄N₅O₃ ⁺ [M + H]⁺: 252.1091; found: 252.1093.
• 27 cis-2-Amino-9-[2-(hydroxymethyl)-1,3-dioxan-5-yl]-1H-purin-6(9H)-one (23b) Compound 13b (0.060 g, 0.154 mmol) was dissolved in MeOH and 40% NaOH aq solution was added. The reaction mixture was heated to reflux at 100 °C for 5 h, after which the solvent was removed under vacuum. The solid residue was then dissolved in DMF, and insoluble material was removed by filtration. The DMF was evaporated under vacuum to give a black oil. Crystallization from MeOH–Et₂O afforded the desired compound (0.035 g, 0.131 mmol, 85%). Yellow solid; mp 280–282 °C. ¹H NMR (400 MHz, DMSO): δ = 3.41–3.49 (m, 2 H, CH ₂OH), 4.01–4.13 (m, 2 H, CH-4_ax, CH-6_ax diox), 4.19–4.31 (m, 3 H, CH-5, CH-4_eq, CH-6_eq diox), 4.69 (t, J = 4.2 Hz, 1 H, CH-2 diox), 4.81–4.92 (m, 1 H, OH), 6.52 (br s, 2 H, NH₂), 7.88 (s, 1 H, CH-8 purine). ¹³C NMR (100 MHz, DMSO): δ = 49.3 (C-5 diox), 62.5 (CH₂OH), 67.9 (C-4, C-6 diox), 101.3 (C-2 diox), 116.6 (C-5 purine), 134.9 (C-8 purine), 151.3 (C-4 purine), 155.8 (C-6 purine), 158.6 (C-2 purine). Anal. Calcd for C₁₀H₁₃N₅O₄: C, 44.94; H, 4.90; N, 26.21. Found: C, 44.97; H, 5.16; N, 26.49. ESI-HRMS: m/z calcd for C₁₀H₁₄N₅O₄ ⁺ [M + H]⁺: 268.1040; found: 268.1041.
• 28 Experimental procedures and analytical data of all compounds reported in this work can be found in the Supporting Information.