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Synlett 2006(9): 1339-1342  
DOI: 10.1055/s-2006-941568
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 2′,3′-Cyclohexen Bicyclic Uridine Analogues Using Ring-Closure Metathesis

Jullien Dronea, Maxim Egorova, Wilfried Hattona, Marie-Jo Bertranda, Christophe Lenb, Jacques Lebreton*a
a Laboratoire de Synthèse Organique, CNRS UMR 6513, Université de Nantes, 2 Rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France
Fax: +33(2)51125562; e-Mail: Jacques.Lebreton@univ-nantes.fr;
b Synthèse et Réactivité des Substances Naturelles, CNRS UMR 6514, FR 2703, Université de Poitiers, 40 Avenue du Recteur Pineau, 86022 Poitiers Cedex, France
Further Information

Publication History

Received 27 February 2006
Publication Date:
22 May 2006 (online)

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Abstract

The synthesis of two new 2′,3′-cyclohexen bicyclic uridine analogues is described. From 5′-protected uridine two successive tin radical-mediated allylations at 2′-C and 3′-C position followed by ring-closure olefin metathesis on the diene intermediate using Grubbs’ catalyst led to the formation of the six-membered ring.

Key words

antivirals - nucleic acid analogues - radical allylation - ring-closure metathesis

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Personal communication from Dr. Alain De Mesmaeker (Syngenta, Basel, Switzerland).

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Representative Procedure for the Preparation of 3′- C -Allyluridine 25 and 26.
A degassed solution of thiocarbonate 24 (1.0 g, 1.56 mmol), Bu3SnAll (4.83 mL, 15.58 mmol, 10 equiv), AIBN (256 mg, 1.56 mmol, 1 equiv) and Bu3SnH (45 mg, 0.16 mmol, 0.1 equiv) in distilled benzene (1.5 mL, 1 mol/L) was stirred overnight at reflux. The solvent was removed under reduced pressure and purification by flash chromatography (30% Et2O-PE) afforded a mixture of diastereoisomers 25 and 26 (420 mg, 51%) as a white foam; 75% de [determined by HPLC performed using a Chrompack Inertsil column Intersil 250 × 3 mm with a flow of rate 1 mL/min (CH2Cl2), t R = 10.5 min for minor diastereomer 26 and t R = 11.1 min for major diastereomer 25; R f = 0.66 (30% Et2O-PE, single spot with these conditions)]. MS (CI/NH3): m/z 531(100) [M + NH3]+, 548.
Data for major diastereomer 25: 1H NMR (400 MHz, CDCl3): δ = 1.03 (s, 9 H, t-Bu), 1.80-2.50 (m, 6 H, H-2′, H-3′, H-6′, H-6′′, H-10′ and H-10′′), 3.60 and 4.00 (part AB of ABX system, 2 H, J = 2.3 Hz, J = 2.4 Hz, J = 11.8 Hz, H-5′), 3.80 (m, 1 H, H-4′), 4.90-5.09 (m, 4 H, H-8′, H-9′, H-12′ and H-13′), 5.35 (d, 1 H, J = 8.2 Hz, H-5), 5.45-5.80 (m, 2 H, H-7′ and H-11′), 5.83 (d, 1 H, J = 4,3 Hz, H-1′), 7.25-7.75 (m, 10 H, 2 × Ph), 7.95 (d, 1 H, J = 8.2 Hz, H-6), 8.55 (br s, 1 H, NH-3) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.3 [(CH3)3 C-Si], 26.0 [(CH3)3C-Si], 29.6 (C-6′), 32.3 (C-10′), 38.3 (C-3′), 46.4 (C-2′), 63.5 (C-5′), 83.1 (C-4′), 87.8 (C-1′), 101.2 (C-5), 116.1 (C-8′), 116.3 (C-12′), 128.0-135.6 (2 × Ph), 129.2 (C-7′), 129.7 (C-11′), 139.4 (C-6), 149.3 (C=O), 162.1 (C=O) ppm.

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Selected physico-chemical data for major diastereomer 19: R f = 0.23 (5% EtOH-CH2Cl2). 1H NMR (300 MHz, CD3COCD3): δ = 9.98 (br s, 1 H, NH), 8.30 (d, 1 H, J = 8.1 Hz, H6), 5.76-5.72 (m, 2 H, H7 ′ and H8 ′), 5.69 (d, 1 H, J = 2.5 Hz, H1 ′), 5.54 (d, 1 H, J = 8.1 Hz, H5), 4.38 (br s, 1 H, OH), 3.98 (dd, 1 H, J 4 ′-5 ′ = 2.6 Hz and J5 ′-5 ′= 12.1 Hz, H5 ′), 3.90 (dt, 1 H, J 4 ′-5 ′ = 2.6 Hz, J 3 ′-4 ′ = 7.9 Hz, H4 ′), 3.82 (dd, 1 H, J 4 ′-5 ′= 2.6 Hz and J 5 ′-5 ′ = 12.1 Hz, H5 ′), 2.56 (m, 1 H, H2 ′), 2.54 (m, 1 H, H3 ′), 2.43-2.27 (m, 2 H, H6 ′eq and H9 ′eq), 2.09-1.96 (m, 2 H, H6 ′ax and H9 ′ax) ppm. 13C NMR (75 MHz, CD3SOCD3): δ = 163.2 (C4), 150.6 (C2), 140.5 (C6), 125.0 (C8′ or C7′), 124.3 (C8′ or C7′), 100.6 (C5), 89.2 (C1′), 84.9 (C4′), 60.5 (C5′), 40.2 (C2′), 32.2 (C3′), 22.9 (C6′), 22.9 (C9′) ppm. HRMS (ESI): m/z calcd for C13H16N2O4Na [M + Na+]: 287.1008; found: 287.1004.

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Selected physico-chemical data for minor diastereomer 20: R f = 0.26 (5% EtOH-CH2Cl2). 1H NMR (300 MHz, CD3COCD3): δ = 9.98 (br s, 1 H, NH), 8.15 (d, 1 H, J = 8.1 Hz, H6), 5.88 (d, 1 H, J = 7.9 Hz, H1 ′), 5.77 (m, 1 H, J = 11.9 Hz, H8 ′), 5.71 (m, 1 H, J = 11.9 Hz, H7 ′), 5.60 (d, 1 H, J = 8.1 Hz, H5), 4.27 (br s, 1 H, OH), 4.22 (dt, 1 H, J 4 ′-5 ′ = 2.6, 3.3 Hz, J 3 ′-4 ′ = 6.6 Hz, H4 ′), 3.89 (dd, 1 H, J 4 ′-5 ′ = 3.3 Hz and J 5 ′-5 ′ = 11.9 Hz, H5 ′), 3.76 (dd, 1 H, J 4 ′-5 ′ = 2.6 Hz and J 5 ′-5 ′ = 11.9 Hz, H5 ′), 2.38-2.28 (m, 2 H, H2 ′ and H3 ′), 2.28 (m, 1 H, H6 ′eq), 2.30-2.20 (m, 2 H, H9 ′ax and H9 ′ eq), 2.00 (m, 1 H, H6 ′ax) ppm. 13C NMR (75 MHz, CD3SOCD3): δ = 163.0 (C4), 150.8 (C2), 140.6 (C6), 126.8 (C8′), 125.7 (C7′), 101.8 (C5), 87.5 (C1′), 79.7 (C4′), 61.6 (C5′), 42.9 (C2′), 40.6 (C3′), 26.8 (C6′), 25.3 (C9′) ppm. HRMS (ESI): m/z calcd for C13H16N2O4Na [M + Na+]: 287.1008; found: 287.0995.

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Preparative HPLC was performed using a Chrompack Inertsil column Intersil 250 × 10 mm with a flow of rate 1 mL/min (CH2Cl2-MeOH, 95:5) with t R = 31.0 min for minor diastereomer 20 and t R = 34.8 min for major diastereomer 19.