Efficient One-Step Synthesis of Optically Pure (Adenin-8-yl)phenylalanine Nucleosides

Abstract

An efficient single-step synthesis of optically pure (adenin-8-yl)phenylalanine nucleosides, a new type of purine amino acid conjugate, by palladium-catalyzed cross-coupling reactions of unprotected 8-bromoadenosines with 4-(borono)phenylalanine was developed.

Key words

cross-coupling - purines - nucleosides - palladium - ­amino acids

References

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15

Typical Procedure - Preparation of Compound 13.
A H₂O-MeCN mixture (1.5:1, 3 mL) was added through septum to an argon purged vial containing adenosine 11 (69 mg, 0.2 mmol), boronic acid 10 (52 mg, 0.26 mmol), Pd(OAc)₂ (2.3 mg, 0.01 mmol), P(m-C₆H₄SO₃Na)₃ (14.2 mg, 0.025 mmol), Na₂CO₃ (42 mg, 0.4 mmol). The mixture was stirred at 90 °C on oil bath for 2 h. The pH of the reaction mixture was adjusted to 7 by HCl (2%) and solvents were evaporated in vacuo. The solid was dissolved in hot H₂O-DMSO mixture (1:1, 6 mL), and the product was isolated by HPLC on C18 column with 0.3% aq AcOH-MeOH gradient to give 66 mg (71%) of 13 as white solid after lyophilization from H₂O. MS (FAB): m/z (%) = 432 (28) [M + 1], 299 (100) [M - ribofuranose + 2]. HRMS (FAB): m/z calcd for C₁₉H₂₃N₆O₆: 431.1679; found: 431.1701. ¹H NMR (400 MHz, D₂O, ref_dioxane = 3.75 ppm): δ = 3.20 (dd, 1 H, J _gem = 14.4 Hz, J _bCH2,CH = 7.5 Hz, bCH₂), 3.32 (dd, 1 H, J _gem = 14.4 Hz, J _aCH2,CH = 5.3 Hz, aCH₂), 3.82 (dd, 1 H, J _gem = 12.9, J _{5 ′ b,4 ′} = 3.0 Hz, H-5′b), 3.88 (dd, 1 H, J _gem = 12.9 Hz, J _{5 ′ a,4 ′} = 2.4 Hz, H-5′a), 4.04 (dd, 1 H, J _CH,bCH2 = 7.5 Hz, J _CH,aCH2 = 5.3 Hz, CH), 4.20 (q, 1 H, J _{4 ′ ,5 ′ b} = 3.0 Hz, J _{4 ′ ,5 ′ a} = 2.4 Hz, J _{4 ′ ,3 ′} = 2.3 Hz, H-4′), 4.40 (dd, 1 H, J _{3 ′ ,2 ′} = 5.5 Hz, J _{3 ′ ,4 ′} = 2.3 Hz, H-3′), 5.07 (dd, 1 H, J _{2 ′ ,1 ′} = 7.2 Hz, J _{2 ′ ,3 ′} = 5.5 Hz, H-2′), 5.92 (d, 1 H, J _{1 ′ 2 ′} = 7.2 Hz, H-1′), 7.42 (m, 2 H, H-m-phenylene), 7.63 (m, 2 H, H-o-phenylene), 8.19 (s, 1 H, H-2). ¹³C NMR (100.6 MHz, D₂O, ref_dioxane = 67.19 ppm): δ = 36.87 (CH₂), 56.38 (CH), 62.77 (CH₂-5′), 71.56 (CH-3′), 72.71 (CH-2′), 87.08 (CH-4′), 89.88 (CH-1′), 119.29 (C-5), 127.29 (C-i-phenylene), 130.54 and 130.77 (CH-phenylene), 138.96 (C-p-phenylene), 149.78 (C-4), 151.04 (CH-2), 153.46 (C-8), 154.83 (C-6), 174.15 (CO). IR (KBr): 3335, 3191, 1641, 1484, 1397, 1336, 1085, 1034, 799. [α]_D ²⁰ -41.0 (c 3.50, DMSO).

16

Compound 14: white solid by lyophilization. MS (FAB): m/z (%) = 415 (70) [M + 1], 299 (100) [M - deoxyribo-furanose + 2]. HRMS (FAB): m/z calcd for C₁₉H₂₃N₆O₅: 415.1730; found: 415.1716. ¹H NMR (400 MHz, D₂O, ref_dioxane = 3.75 ppm): δ = 2.29 (ddd, 1 H, J _gem = 14.0, J _{2 ′ b,1 ′} = 6.2 Hz, J _{2 ′ b,3 ′} = 2.2 Hz, H-2′b), 3.01 (ddd, 1 H, J _gem = 14.0, J _{2 ′ a,1 ′}= 8.9 Hz, J _{2 ′ a,3 ′} = 6.2 Hz, H-2′b), 3.22 (dd, 1 H, J _gem = 14.4 Hz, J _bCH2,CH = 7.5 Hz, bCH₂), 3.32 (dd, 1 H, J _gem = 14.4 Hz, J _aCH2,CH = 5.4 Hz, aCH₂), 3.81 (dd, 1 H, J _gem = 12.6 Hz, J _{5 ′ b,4 ′} = 3.5 Hz, H-5′b), 3.87 (dd, 1 H, J _gem = 12.6 Hz, J _{5 ′ a,4 ′} = 2.7 Hz, H-5′a), 4.05 (dd, 1 H, J _CH,bCH2 = 7.5 Hz, J _CH,aCH2 = 5.4 Hz, CH), 4.10 (q, 1 H, J _{4 ′ ,5 ′} = 3.5, 2.7 Hz, J _{4 ′ ,3 ′} = 2.2 Hz, H-4′), 4.63 (dt, 1 H, J _{3 ′ ,2 ′} = 6.2, 2.2 Hz, J _{3 ′ ,4 ′} = 2.2 Hz, H-3′), 6.29 (dd, 1 H, J _{1 ′ 2 ′} = 8.9, 6.2 Hz, H-1′), 7.44 (m, 2 H, H-m-phenylene), 7.55 (m, 2 H, H-o-phenylene), 8.17 (s, 1 H, H-2). ¹³C NMR (100.6 MHz, D₂O, ref_dioxane = 67.19 ppm): δ = 36.87 (CH₂), 38.82 (CH₂-2′), 56.37 (CH), 62.95 (CH₂-5′), 72.52 (CH-3′), 87.13 (CH-1′), 88.53 (CH-4′), 119.36 (C-5), 127.57 (C-i-phenylene), 130.48 and 130.58 (CH-phenylene), 138.95 (C-p-phenylene), 149.73 (C-4), 150.76 (CH-2), 152.91 (C-8), 154.79 (C-6), 174.17 (CO). IR (KBr): 3354, 3205, 1642, 1526, 1483, 1406, 1337, 1091, 1055, 1032, 798. [α]_D ²⁰ -35.0 (c 4.15, DMSO).