Total Chemoenzymatic Synthesis of (-)-3′-Methylaristeromycin

Abstract

Enantiopure ethyl (1S,4R)-4-hydroxy-2-methylcyclopent-2-ene-1-carboxylate, readily obtained by enzymatic kinetic resolution of the corresponding racemic derivative, provided a convenient starting building block for an 11-step chiral preparation of (-)-3′-methylaristeromycin with 23% overall yield.

Key words

aristeromycin - nucleobases - carbocyclic nucleosides - stereoselective synthesis - enzymatic regioselectivity

References and Notes

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16

9-[(1′ R ,2′ S ,3′ R ,4′ R )-4′-Acetoxymethyl-2′,3′- O -isopropyl-idene-3′-methylcyclopent-1′-yl]adenine [(-)-11]: To a stirred solution of adenine (476 mg, 3.52 mmol, 2.5 equiv) in DMF (30 mL) at 0 °C under an argon atmosphere was added NaH (113 mg, 2.82 mmol, 2.0 equiv, 60% dispersion in mineral oil). The reaction mixture was heated to 60 °C and stirred at this temperature for 2 h. After cooling the solution to 0 °C, triflate (-)-10 (530 mg, 1.41 mmol) in DMF (3 mL) was added dropwise. After stirring for 2 h at 60 °C, the reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (CH₂Cl₂-MeOH) to give compound (-)-11 (380 mg, 75%) as a foam.

17

Characterization of selected new compounds:
Compound (+)-5: oil; [α]²⁵ _D +31.7 (c = 1.0, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 4.12-4.23 (m, 3 H), 3.94 (d, J = 1.8 Hz, 1 H), 2.95 (dd, J = 7.1, 11.3 Hz, 1 H), 2.32 (dt, J = 7.1, 13.6 Hz, 1 H), 2.06 (ddd, J = 7.1, 11.3, 13.6 Hz, 1 H), 1.49 (s, 3 H), 1.40 (s, 3 H), 1.35 (s, 3 H), 1.27 (t, J = 7.2 Hz, 3 H), 0.88 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 172.2 (C), 112.0 (C), 93.5 (CH), 88.5 (C), 74.8 (CH), 60.5 (CH₂), 53.3 (CH), 36.8 (CH₂), 28.3 (Me), 26.8 (Me), 25.7 (3 × Me), 21.7 (Me), 17.9 (C), 14.3 (Me), 4.9 (Me), 5.0 (Me). Anal. Calcd for C₁₈H₃₄O₅Si: C, 60.30; H, 9.56. Found: C, 60.19; H 9.59.
Compound (-)-10: white needles; mp 59-60 °C; [α]²⁵ _D -32.1 (c = 1.0, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 5.13 (ddd, J = 5.6, 7.0, 8.8 Hz, 1 H), 4.32 (d, J = 5.6 Hz, 1 H), 4.06, 4.00 (ABX, J = 4.8, 5.0, 11.6 Hz, 2 H), 2.50 (dt, J = 8.8, 12.5 Hz, 1 H), 2.38-2.44 (m, 1 H), 2.05 (s, 3 H), 1.98-2.05 (m partially overlapped, 1 H), 1.46 (s, 3 H), 1.42 (s, 3 H), 1.41 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 170.3 (C), 118.5 (q, J = 317 Hz, CF₃), 113.1 (C), 89.2 (C), 85.2 (CH), 84.4 (CH), 63.7 (CH₂), 44.2 (CH), 32.9 (CH₂), 27.6 (Me), 27.5 (Me), 21.6 (Me), 20.7 (Me). Anal. Calcd for C₁₃H₁₉F₃O₇S: C, 41.49; H, 5.09. Found: C, 41.73; H 5.13.
Compound (-)-11: [α]²⁵ _D -15.7 (c = 1.0, MeOH). ¹H NMR (300 MHz, DMSO-d ₆): δ = 8.26 (s, 1 H), 8.15 (s, 1 H), 7.26 (br s, 2 H), 4.91 (dt, J = 3.7, 9.5 Hz, 1 H), 4.51 (d, J = 3.7 Hz, 1 H), 4.12 (d, J = 6.8 Hz, 2 H), 2.40-2.46 (m, 1 H), 2.30-2.37 (m, 2 H), 2.01 (s, 3 H), 1.53 (s, 3 H), 1.46 (s, 3 H), 1.26 (s, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 170.4 (C), 156.1 (C), 152.4 (CH), 149.3 (C), 140.0 (CH), 119.3 (C), 112.8 (C), 90.4 (CH), 87.6 (C), 62.8 (CH₂), 58.4 (CH), 46.6 (CH), 34.0 (CH₂), 28.6 (Me), 27.2 (Me), 20.7 (Me), 20.5 (Me). Anal. Calcd for C₁₇H₂₃N₅O₄: C, 56.50; H, 6.41; N, 19.38. Found: C, 56.19; H, 6.37; N, 19.59.
Compound (-)-1: white solid; mp 146-147 °C; [α]²⁵ _D -10.5 (c = 1.0, MeOH). ¹H NMR (500 MHz, CD₃OD): δ = 8.22 (s, 1 H), 8.18 (s, 1 H), 4.87 (q, partially overlapped with HDO, J = 9.6 Hz, 1 H), 4.34 (d, J = 9.6 Hz, 1 H), 3.75 (d, J = 4.8 Hz, 2 H), 2.62 (dt, J = 9.6, 13.8 Hz, 1 H), 2.17 (dq, J = 4.8, 9.6 Hz, 1 H), 2.05 (ddd, J = 4.8, 9.6, 13.8 Hz, 1 H), 1.36 (s, 3 H). ¹³C NMR (125 MHz, CD₃OD): δ = 157.1 (C), 152.9 (CH), 150.7 (C), 142.3 (CH), 120.6 (C), 81.1 (CH), 78.8 (C), 63.9 (CH₂), 61.6 (CH), 48.7 (CH), 30.3 (CH₂), 21.6 (Me). Anal. Calcd for C₁₂H₁₇O₃N₅: C, 51.60; H, 6.13; N, 25.07. Found: C, 51.99; H, 6.09; N, 24.79.