Novel Exocyclic Nucleoside Related to Clitocine: A Convergent Synthesis of 3′-Azido-2′,3′-dideoxy Clitocine

Abstract

The synthesis of a new clitocine derivative was achieved through a convergent strategy. A protected 4,6-diamino-5-nitro­pyrimidine was condensed with p-chlorobenzoyl (PCB)-protected methyl 3′-azido-2′,3′-dideoxyribofuranoside, followed by subsequently deprotection to give the desired product.

Key words

nucleoside analogues - exocyclic nucleosides - convergent synthesis - clitocine - antiviral drug

References and Notes

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17

The CCDC number of compound 12α is 777653.

18

6-Amino-5-nitro-4-(3′-azido-5′- O - p -chloro-benzoyl-2′,3′-dideoxy-β- d -ribofuranosylamino) Pyrimidine (16)
TMS-protected 4,6-diamino-5-nitropyrimidine 8 (0.86 g, 2.9 mmol) was dissolved in DCE (10 mL). To this solution, methyl 3′-azido-5′-O-p-chlorobenzoyl-2′,3′-dideoxy-β-d-ribofuranoside (13, 0.75 g, 2.4 mmol) and TMSOTf (0.72 mL, 4.0 mmol) were added, the mixture was stirred for 48 h at r.t., and 10% NaHCO₃ (15 mL) was added. After 20 min stirring, CH₂Cl₂ (20 mL) was added to the resulting suspension; the mixture was filtered through Hyflo Super Cel; the organic layer was separated, washed with H₂O (10 mL), and dried with Na₂SO₄. Nucleoside 16 (0.11 g) and recovered sugar 13 (0.27 g) were isolated by silica gel chromatography (elution with EtOAc-PE = 1:2). The yield was 16% based on recovered starting material. A white solid was afforded after recrystallizaion in EtOAc; mp 178-180 ˚C. IR (KBr): ν = 3440, 3332, 2109, 1389, 1344, 1290, 1245 cm^-¹. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 9.57 (1 , d, J _{NH-H1 ′} = 8.51 Hz, NH), 8.61 (2 H, d, J _NH2 = 15.10 Hz, NH₂), 8.00 (1 H, s, C2-H), 7.98 (2 H, m, ArH), 7.61 (2 H, m, ArH), 6.32 (1 H, m, C1′-H), 4.56 (1 H, m, C4′-H), 4.36 (3 H, m, C5′-H, C3′-H), 2.62 (1 H, dd, J = 5.69, 12.80 Hz, C2′-H), 2.20 (1 H, m, C2′-H) ppm. ^¹³C NMR (500 MHz, DMSO-d ₆): δ = 164.66 (C=O), 159.29 (C-2), 158.58 (C-6), 156.02 (C-4), 138.46 (CCl), 131.11 (2 C, Ar), 128.98 (2 C, Ar), 128.17 (CC=O), 112.03 (C-5), 81.11 (C-1′), 80.62 (C-4′), 64.83 (C-5′), 61.68 (C-3′), 36.77 (C-2′) ppm.

19

6-Amino-5-nitro-4-(3′-azido-2′,3′-dideoxy-β- d -ribofuranosylamino) Pyrimidine 6
To a solution of nucleoside 16 (90 mg, 0.2 mmol) in MeOH (10 mL) cooled to 0 ˚C was added 0.1 M NaOMe in MeOH (0.64 mL), and the mixture was stirred at r.t. for 18 h in the argon atmosphere. The reaction mixture was neutralized with Dowex 50 (H⁺), and the resin was rapidly filtered. After evaporation under vacuum to dry, a light yellow solid product 6 was isolated from the residue by silica gel chromatography, elution with an EtOAc-PE (3:2). The yield was 40 mg (65%). ^¹H NMR (500 MHz, DMSO-d ₆): δ = 9.39 (1 H, d, J _{NH-H1 ′} = 8.2 Hz, NH), 8.56 (2 H, br s, NH₂), 8.00 (1 H, s, C2-H), 6.22 (1 H, td, J = 6.0 Hz, J _{NH-H1 ′} = 8.2 Hz, C1′-H), 5.23 (1 H, t, J = 5.0 Hz, OH), 4.33 (1 H, td, J = 4.2 Hz, J _{H2 α ′ -H3 ′} = 7.0 Hz, C3′-H), 3.88 (1 H, q, J = 3.58, 3.58, 3.60 Hz, C4′-H), 3.51 (2 H, t, J = 4.2 Hz, C5′-H), 2.39 (1 H, ddd, J _{H2 α ′ -H1 ′} = 6.0 Hz, J _{H2 α ′ -H3 ′} = 7.0 Hz, J _{H2 β ′ -H2 α ′} = 13.0 Hz, C2′-H_α), 2.27 (1 H, ddd, J _{H2 β ′ -H3 ′} = 4.2 Hz, J _{H2 β ′ -H1 ′} = 6.0 Hz, J _{H2 β ′ -H2 α ′} = 13.0 Hz, C2′-H_β) ppm. ^¹³C NMR (500 MHz, DMSO-d ₆): δ = 159.98 (C-2), 159.29 (C-6), 156.49 (C-4), 109.99 (C-5), 84.62 (C-1′), 82.21 (C-4′), 62.14 (C-5′), 62.08 (C-3′), 38.40 (C-2′) ppm.