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Synlett 2006(2): 324-326  
DOI: 10.1055/s-2005-923580
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Carbocyclic Pyrimidine Nucleosides Using the Mitsunobu ­Reaction - Part II: [1] Influence of the Solvent on N1- versus O2-Alkylation

Olaf R. Ludek, Chris Meier*
Institut für Organische Chemie, Universität Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Fax: +49(40)428382495; e-Mail: chris.meier@chemie.uni-hamburg.de;
Further Information

Publication History

Received 11 October 2005
Publication Date:
23 December 2005 (online)

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Abstract

The influence of the solvent on N- vs O-alkylation of N3-benzoylthymine under Mitsunobu conditions is described. The Mitsunobu reaction is an important tool in carbocyclic nucleoside chemistry for the direct coupling of alcohols with heterocyclic bases under mild conditions.

Key words

Mitsunobu reaction - carbocyclic nucleosides - regio­selectivity - antiviral agents - medicinal chemistry

    References and Notes

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12

Typical Procedure: DIAD (545 µL, 2.80 mmol) was slowly added to a suspension of PPh3 (787 mg, 3.00 mmol) in anhyd solvent (11 mL). The mixture was stirred for 0.5 h at 0 °C. This pre-formed complex was slowly added to a suspension of the N3-Bz-thymine (506 mg, 2.2 mmol) and cyclopentanol (90 µL, 1.00 mmol) in anhyd solvent (6.0 mL) at -40 °C under nitrogen. The reaction was slowly warmed to r.t. and stirred overnight. The solvent was removed from the reaction mixture and a solution of NaOH in MeOH (1%, 15 mL) was added and stirred overnight at r.t. The solution was neutralized by the addition of HCl (1 M) and then concentrated. The crude was purified by chromatography on silica gel (hexanes-EtOAc, 1:2) to yield the N1-alkylated product 2 [R f 0.26 (hexanes-EtOAc, 1:2)] and the O 2-isomer 3 [R f 0.35 (hexanes-EtOAc, 1:2)] as colorless solids. Both isomers were isolated and the product ratio was determined from integration of the H-1′ protons in the 1H NMR spectra.
Cyclopentylthymine 2. IR (KBr): 3173, 3039, 2956, 2874, 1692, 1474, 1415, 1369, 1368, 1317, 1270, 1121, 921, 585, 425 cm-1. 1H NMR (400 MHz, DMSO-d 6 ): δ = 11.20 (br s, 1 H, NH), 7.56 (q, 1 H, J = 1.2 Hz, H-6), 4.80-4.72 (m, 1 H, H-1′), 2.00-1.90 (m, 2 H, H-2′a, H-5′a), 1.82 (d, 3 H, J = 1.2 Hz, H-7), 1.80-1.55 (m, 6 H, H-2′b, H-5′b, 3′-CH2, 4′-CH2). 13C NMR (101 MHz, DMSO-d 6 ): δ = 164.23 (C-4), 152.34 (C-2), 137.45 (C-6), 111.25 (C-5), 56.05 (C-1′), 32.87 (C-2′, C5′), 25.29 (C-3′, C-4′), 12.84 (C-7). HRMS-FAB: m/z calcd for C10H14N2O2 (M + H): 195.1134; found: 195.1131.
2- O -Cyclopentylthymine 3. IR (KBr): 2960, 1650, 1581, 1498, 1380, 1327, 1163, 1042, 955, 917, 773, 750, 587 cm-1. 1H NMR (400 MHz, DMSO-d 6 ): δ = 12.10 (br s, 1 H, NH), 7.60 (q, 1 H, J = 1.0 Hz, H-6), 5.38-5.30 (m, 1 H, H-1′), 2.00-1.90 (m, 2 H, H-2′a, H-5′a), 1.88 (d, 3 H, J = 1.0 Hz, H-7), 1.80-1.55 (m, 6 H, H-2′b, H-5′b, 3′-CH2, 4′-CH2). 13C NMR (101 MHz, DMSO-d 6 ): δ = 164.23 (C-4), 157.13 (C-2), 151.37 (C-6), 118.36 (C-5), 80.09 (C-1′), 33.72 (C-2′, C5′), 24.91 (C-3′, C-4"), 12.92 (C-7). HRMS-FAB: m/z calcd for C10H14N2O2 (M + H): 195.1134; found: 195.1128.