Efficient Synthesis of Clitocine via 1,3-N (endo) to N (exo) Migration: A Revision to Kini’s Work

 

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Abstract

Efficient synthesis of clitocine has been accomplished via unprecedented 1,3-N (endo) to N (exo) migration as a key transformation. Incorporation of p-chlorobenzoyl (PCB) group as a protecting group led to the easy solidification of the intermediate of 7, thus making the isolation very facile and to the minimization of the epimerization of the anomeric center at the final deprotection stage.

References

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We observed peaks at δ = 9.61 (s, 1 H), 9.43 (s, 1 H), and 9.35 (s, 1 H) in DMSO-d ₆ , which are typical peaks of the endo-product 6. Since 6 was not solidified under various conditions, it was difficult to purify the product thoroughly.

X-ray data for the compound 7: C₃₀H₂₂Cl₃N₅O₉, monoclinic, space group P2₁ with cell parameters: a = 14.6041 (11) Å, b = 6.8064 (5) Å, c = 16.1106 (12) Å; α = 90°, β = 108.0770 (10)°, γ = 90°; V = 1522.4 (2) ų; D _c = 1.533 mg/m³; Z = 2.

4-Amino-6-imino-5-nitro-1- N -(2,3,5-tri- O - para -chlorobenzoyl-β- d -ribofuranosyl)pyrimidine ( 7).
A suspension of 4, 6-diamino-5-nitropyrimidine (1.0 g, 6.45 mmol) in HMDS (30 mL) was treated with pyridine (4.8 mL), H₂SO₄ (0.2 mL) and ammonium sulfate (60 mg). The mixture was refluxed at 130 °C for 18 h, and HMDS was evaporated in vacuo. The residual solid was dissolved in MeCN (50 mL), cooled to 0 °C, and treated with 1-O-acetyl-2,3,5-tri-O-para-chlorobenzoyl-d-ribofuranose (5, 4.5 g, 7.42 mmol) and TMSOTf (2.0 mL, 11.0 mmol). The mixture was stirred at 0 °C for 23 h, and it turned into dark clear solution. Then, MeCN was evaporated in vacuo, and the residue was treated with sat. NaHCO₃ (100 mL). The aqueous layer was extracted with CH₂Cl₂ (100 mL × 2), and the combined organic phase was dried over anhyd MgSO₄. After concentration, the residue was triturated with EtOAc (4 mL) and enough amount of Et₂O. The resulting solid was filtered and washed with Et₂O to give the endo-product 7 (2.44 g, 55%) as a yellow powder. ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.61 (1 H, s), 9.44 (1 H, s), 9.36 (1 H, s), 8.33 (1 H, s), 7.98 (2 H, dd, J = 6.8, 2.0 Hz), 7.94 (2 H, dd, J = 6.8, 2.0 Hz), 7.81 (2 H, dd, J = 6.8, 2.0 Hz), 7.57 (4 H, 2 dd, J = 6.8, 2.0 Hz), 7.50 (2 H, dd, J = 6.8, 2.0 Hz), 6.33 (1 H, d, J = 2.4 Hz), 6.12 (1 H, dd, J = 6.4, 2.4 Hz), 6.06 (1 H, dd, J = 7.2, 6.4 Hz), 4.60-4.80 (3 H, m). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 164.8, 164.0, 163.9, 158.5, 152.3, 148.5, 139.0, 138.9, 138.7, 131.4, 131.3, 131.2, 129.2, 129.1, 128.2, 127.7, 127.5, 111.3, 91.2, 78.7, 74.1, 70.4, 63.7. IR: 3424, 3300, 1713, 1632, 1589, 1478, 1396, 1252, 1087, 1009, 752 cm^-1. UV/Vis (CH₂Cl₂): λ_max = 243, 374 nm.
6-Amino-5-nitro-4-[(2,3,5-tri- O - para -chlorobenzoyl-β- d -ribofuranosyl)amino]pyrimidine ( 9). A solution of 7 (2.166 g, 3.08 mmol) in methylene chloride (60 mL) was stirred with silica gel (2.2 g) for 20 h. Silica gel was filtered off and washed with CH₂Cl₂. The filtrate was concentrated to give 9 (2.06 g, 95%) as an yellow foam. ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.60 (1 H, d, J = 8.0 Hz), 8.58 (2 H, br s), 8.05 (1 H, s), 8.00 (2 H, dd, J = 6.8, 2.0 Hz), 7.90 (2 H, dd, J = 6.8, 2.0 Hz), 7.84 (2 H, dd, J = 6.8, 2.0 Hz), 7.55 (6 H, m), 6.35 (1 H, dd, J = 8.4, 4.8 Hz), 5.97 (1 H, dd, J = 5.6, 4.8 Hz), 5.89 (1 H, dd, J = 6.0, 5.2 Hz), 4.65 (2 H, m), 4.55 (1 H, m). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 165.5, 164.8, 164.7, 160.0, 159.4, 157.4, 139.8, 139.7, 139.4, 132.0, 131.9, 129.9, 129.8, 129.7, 128.9, 128.3, 128.2, 113.4, 84.8, 78.7, 75.1, 72.1, 64.8. UV/Vis (CH₂Cl₂): λ_max = 240, 331 nm.

Clitocine ( 1). 6-Amino-5-nitro-4-[(2,3,5-tri-O-para-chlorobenzoyl-β-d-ribofuranosyl)amino]pyrimidine (9, 1.93 g, 2.75 mmol) was dissolved in 1,4-dioxane (26 mL) and diluted with MeOH (65 mL). After cooling to 0 °C, the solution was treated with MeONa (0.55 mmol, 0.1 mL of 28% MeOH soln was diluted with 0.4 mL of MeOH) and stirred at 0 °C for 2 h. The resulting solution was stirred with Amberlite IR-120 (900 mg, 3.96 mol equiv, acidic resin was washed with distilled H₂O and MeOH before use) for 30 min. The resin was filtered off and the filtrate was concentrated in vacuo. The residue was triturated with Et₂O and washed with Et₂O (10 mL × 3). The solid was recrystallized from hot MeOH (135 mL) to give 1 (>98% of β-anomer, 400 mg, 51%) as a slightly yellow solid. More clitocine (1, >98% of β-anomer, 255 mg, 32%) was obtained from the mother liquor. ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.28 (1 H, d, J = 7.6 Hz), 8.56 (2 H, s), 8.00 (1 H, s), 5.79 (1 H, dd, J = 7.6, 3.6 Hz), 5.20 (1 H, d, J = 5.2 Hz), 5.06 (1 H, t, J = 4.8 Hz), 4.92 (1 H, d, J = 6.0 Hz), 4.05 (1 H, m), 3.93 (1 H, m), 3.79 (1 H, m), 3.53 (1 H, m), 3.47 (1 H, m). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 160.2, 159.5, 156.8, 112.8, 87.0, 84.8, 75.9, 70.8, 61.3.