Synthesis of 6,5′-C-Cyclouridine by a Novel Tandem Radical 1,6-Hydrogen Transfer and Cyclization Reaction

Abstract

C-Cyclonucleosides are conformational mimics and, as such, are suitable for investigating steric interactions between nucleosides and the enzymes that utilize them. To achieve the synthesis of C-cyclouridine, we developed a novel tandem radical 1,6-hydrogen transfer and cyclization of a 6-phenylselenouridine derivative, which gave 5,6-dihydro-C-cyclouridine in good yields. The synthesis of 6,5′-C-cyclouridine was accomplished by recovery of the double bond of 5,6-dihydro-C-cyclouridine and subsequent deprotection.

nucleosides - radical reactions - tandem reactions - cyclizations - selenium

References and Notes

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Tandem 1,6-HT-Radical Cyclization of 5a; Typical Procedure To a refluxing solution of 5a (2.00 g, 2.97 mmol) in toluene (200 mL) was added slowly a solution of TTMSS (2.29 mL, 7.43 mmol) and AIBN (488 mg, 2.97 mmo) in toluene (30 mL) over 1 h by using a syringe pump. After the mixture was kept under reflux for 6 h, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (10-20% EtOAc in hexane) to give 6a (920 mg, 60%), 4a (370 mg, 24%), and 7a (160 mg, 11%) in order of fractions eluted.
Data for 6a ¹H NMR (400 MHz, CDCl₃): δ = 7.34 (2 H, d, J = 8.7 Hz), 6.82 (2 H, d, J = 8.2 Hz), 6.04 (1 H, s), 4.91 (1 H, d, J = 14.0 Hz), 4.82 (1 H, d, J = 14.0 Hz), 4.79 (1 H, d, J = 5.8 Hz), 4.49 (1 H, d, J = 5.8 Hz), 4.22 (1 H, d, J = 4.3 Hz), 3.78 (3 H, s), 3.59 (1 H, dd, J = 4.4, 8.3 Hz), 3.08 (1 H, ddd, J = 4.1, 8.7, 12.6 Hz), 2.96 (1 H, dd, J = 4.1, 16.2 Hz), 2.46 (1 H, dd, J = 12.3, 16.2 Hz), 1.50 (3 H, s), 1.33 (3 H, s), 0.90 (9 H, s), 0.13 (3 H, s), 0.10 (3 H, s). ¹³C NMR (100 MHz, CDCl₃): δ = 167.1, 159.0, 151.4, 130.4, 129.5, 113.7, 113.0, 86.7, 83.4, 83.0, 78.0, 69.6, 55.2, 51.4, 43.3, 35.9, 25.9, 25.6, 24.7, 17.7, -4.4, -4.9. HRMS (EI): m/z calcd for C₂₆H₃₈N₂O₇Si [M⁺]: 518.2448; found: 518.2444. Anal. Calcd for C₂₆H₃₈N₂O₇Si: C, 60.21; H, 7.38; N, 5.40. Found C, 60.49; H, 7.49; N, 5.41.
Data for 7a ¹H NMR (400 MHz, CDCl₃): δ = 7.35 (2 H, d, J = 8.7 Hz), 6.81 (2 H, d, J = 8.7 Hz), 6.10 (1 H, s), 4.89 (1 H, d, J = 14.0 Hz), 4.85 (1 H, d, J = 14.0 Hz), 4.56 (1 H, d, J = 5.8 Hz), 4.54 (1 H, d, J = 5.3 Hz), 4.31 (1 H, d, J = 2.4 Hz), 3.77 (3 H, s), 3.48 (1 H, t, J = 2.9 Hz), 3.39 (1 H, dt, J = 4.0, 10.5 Hz), 2.95 (1 H, dd, J = 11.1, 16.4 Hz), 2.46 (1 H, dd, J = 4.8, 16.9 Hz), 1.51 (3 H, s), 1.31 (3 H, s), 0.91 (9 H, s), 0.13 (3 H, s), 0.10 (3 H, s). ¹³C NMR (100 MHz, CDCl₃): δ = 168.2, 158.9, 152.4, 130.4, 129.6, 113.7, 113.2, 86.9, 84.7, 82.8, 79.3, 65.6, 55.2, 49.2, 43.2, 33.0, 25.8, 25.7, 24.6, 18.1, -4.6, -4.8. HRMS (EI): m/z calcd for C₂₆H₃₈N₂O₇Si [M⁺]: 518.2448; found: 518.2435. Anal. Calcd for C₂₆H₃₈N₂O₇Si: C, 60.21; H, 7.38; N, 5.40. Found C, 60.23; H, 7.56; N, 5.40.

<A NAME="RU10306ST-14">14</A> The stereochemistry of 9a was determined by comparison of ¹H NMR spectrum of 2′,3′-O-isopropylidene-6,5′-C-cyclo-5,6-dihydrouridine reported previously: Sugawara T. Otter BA. Ueda T. Tetrahedron Lett.  1988,  29:  75 

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