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Synlett 2006(14): 2215-2218  
DOI: 10.1055/s-2006-949635
LETTER
© Georg Thieme Verlag Stuttgart · New York

Conformationally Locked Carbocyclic Nucleosides: Synthesis of the 1-Methyl-6-oxabicyclo[3.1.0]hexane Scaffold

Yoann Aubin, Gérard Audran*, Honoré Monti*
Laboratoire de Réactivité Organique Sélective, U.M.R. 6180 ‘Chirotechnologies: catalyse et biocatalyse’, Université Paul Cézanne, Aix-Marseille III, 13397 Marseille cedex 20, France
Fax: +33(4)91288862; e-Mail: g.audran@univ-cezanne.fr; e-Mail: honore.monti@univ-cezanne.fr;
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Publication History

Received 16 June 2006
Publication Date:
24 August 2006 (online)

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Abstract

This paper describes the racemic and stereoselective ­synthesis of novel conformationally locked 3′-methyl-2′,3′-oxirane-fused carbocyclic nucleosides (nucleosides numbering). The key step is the direct coupling of an alcohol bearing the 1-methyl-6-oxa­bicyclo[3.1.0]hexane scaffold with diversely substituted purine ­nucleobases under Mitsunobu reaction conditions providing only the N9 target molecules.

Key words

carbocyclic nucleosides - conformationally locked ­nucleosides - Mitsunobu reaction - stereoselective synthesis - lipase regioselectivity

8

Nucleoside numbering.

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Characterization of Selected New Compounds.
Compound (±)-7: IR (neat): ν = 3321, 1752, 1148, 1053 cm-1. 1H NMR (400 MHz, CDCl3): δ = 4.27 (t, J = 7.8 Hz, 1 H), 3.95 (ABX, J = 11.4, 5.4, 4.9 Hz, 2 H), 3.28 (s, 1 H), 2.79 (br s, OH), 2.38 (dt, J = 9.0, 4.7 Hz, 1 H), 1.98 (s, 3 H), 1.76 (dd, J = 13.4, 7.8 Hz, 1 H), 1.48 (dt, J = 13.4, 8.3 Hz, 1 H), 1.32 (s, 3 H). 13C NMR (400 MHz, CDCl3): δ = 170.7 (C), 72.3 (CH), 65.3 (CH), 65.0 (CH2), 64.0 (C), 41.4 (CH), 33.1 (CH2), 20.7 (CH3), 15.5 (CH3). Anal. Calcd for C9H14O4: C, 58.05; H, 7.58. Found: C, 57.91; H, 7.61. Compound (±)-1a: white solid; mp 150 °C (dec.). IR (KBr): ν = 3291, 3115, 1667, 1609 cm-1. 1H NMR (400 MHz, CDCl3): δ = 8.42 (s, 1 H), 7.95 (s, 1 H), 6.14 (br s, 1 H), 5.00 (dd, J = 9.5, 2.9 Hz, 1 H), 3.81 and 3.72 (ABX, J = 10.9, 4.5, 3.5 Hz, 2 H), 3.56 (s, 1 H), 3.01 (m, 1 H), 2.61 (dt, J = 14.5, 9.5 Hz, 1 H), 2.49-2.42 (m, 1 H), 2.25 (dt, J = 14.5, 2.9 Hz, 1 H), 1.62 (s, 3 H), 0.93-0.87 (m, 2 H), 0.65-0.59 (m, 2 H). 13C NMR (400 MHz, CDCl3): δ = 155.9 (C), 152.9 (CH), 148.5 (C), 139.6 (CH), 120.0 (C), 69.3 (C), 66.2 (CH), 62.8 (CH2), 55.6 (CH), 44.5 (CH), 34.4 (CH2), 23.7 (CH), 15.4 (CH3), 2 × 7.4 (CH2). Anal. Calcd for C15H19N5O2: C, 59.79; H, 6.36; N, 23.24. Found: C, 59.98; H, 6.33; N, 23.04.
Compound (±)-1b: white solid; mp 170 °C (dec.). IR (KBr): ν = 3278, 3107, 1678, 1600 cm-1. 1H NMR (500 MHz, DMSO-d 6): δ = 8.19 (s, 1 H), 8.13 (s, 1 H), 7.21 (br s, 2 H), 4.91 (d, J = 7.2 Hz, 1 H), 4.77 (t, J = 4.5 Hz, 1 H), 3.79 (s, 1 H), 3.55 (m, 1 H), 3.38 (m, 1 H), 2.27-2.18 (m, 2 H), 1.88 (d, J = 12.6 Hz, 1 H), 1.49 (s, 3 H). 13C NMR (400 MHz, DMSO-d 6): δ = 156.2 (C), 152.5 (CH), 149.6 (C), 139.2 (CH), 118.9 (C), 68.1 (C), 64.1 (CH), 61.6 (CH2), 54.2 (CH), 44.5 (CH), 33.6 (CH2), 15.5 (CH3). Anal. Calcd for C12H15N5O2: C, 55.16; H, 5.79; N, 26.80. Found: C, 54.85; H, 5.84; N, 26.59.
Compound (±)-1c: white solid; mp 190 °C (dec.). IR (KBr): ν = 3305, 3172, 1676, 1615 cm-1. 1H NMR (400 MHz, DMSO-d 6): δ = 7.76 (s, 1 H), 7.28 (br d, J = 3.6 Hz, 1 H), 5.86 (br s, 2 H), 4.78 (t, 4.9 Hz, 1 H), 4.72 (d, J = 7.2 Hz, 1 H), 3.70 (s, 1 H), 3.49 (dt, J = 10.8, 4.9 Hz, 1 H), 3.30 (dt, J = 10.8, 4.9 Hz, 1 H), 3.02 (br s, 1 H), 2.27-2.07 (m, 2 H), 1.86 (d, J = 14.0 Hz, 1 H), 1.47 (s, 3 H), 0.69-0.61 (m, 2 H), 0.60-0.53 (m, 2 H). 13C NMR (400 MHz, DMSO-d 6): δ = 160.3 (C), 156.1 (C), 151.5 (C), 135.3 (CH), 113.6 (C), 68.0 (C), 64.2 (CH), 61.7 (CH2), 53.6 (CH), 44.6 (CH), 33.3 (CH2), 24.0 (CH), 15.6 (CH3), 2 × 6.6 (CH2). Anal. Calcd for C15H20N6O2: C, 56.95; H, 6.37; N, 26.56. Found: C, 57.23; H, 6.39; N, 26.35.

14

General Procedure.
Diisopropyl azodicarboxylate (DIAD, 0.72 mL, 3.6 mmol, 1.5 equiv) was added dropwise to a solution of PPh3 (950 mg, 3.6 mmol, 1.5 equiv) in fresly distilled THF (50 mL) kept under Ar atmosphere at 0 °C. The mixture was stirred for 30 min and then the purine base was added (3.6 mmol, 1.5 equiv). The mixture was stirred for an additional 30 min and then a solution of epoxide 7 (450 mg, 2.4 mmol, 1 equiv) in dry THF (5 mL) was added slowly. The cooling bath was removed and the mixture allowed to warm to r.t. The mixture was stirred for 12 h at r.t.(chloropurine) or 12 h at r.t. then 4 h at 40 °C (adenine, 2-aminochloropurine). The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column (gradients hexane-EtOAc as eluent). Compounds 8 (66% yield) and 9 (56% yield) were obtained pure as white solids, but 10 was contaminated with inseparable triphenylphosphine oxide.

15

Triphenylphosphine oxide present with 10 was conveniently eliminated during this ammonia deprotective step by triturating the insoluble alcohol 12 with CH2Cl2 before aminocyclopropanation. Using this protocol, pure 12 was obtained in 53% overall yield from 7.