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

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.

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

References and Notes

1 Ludek OR. Meier C. Synlett  2005,  3145 

2 Marquez VE. In Advances in Antiviral Drug Design   Vol. 2:  De Clercq E. JAI Press; Greenwich: 1996.  p.89-146  

3 Agrofoglio LA. Challand SR. Acyclic, Carbocyclic and l-Nucleosides   Kluwer Academic Publishers; Dordrecht, Boston, London: 1998. 

4 Vince R. Hua M. J. Med. Chem.  1990,  33:  17 

5 Daluge SM. Martin MT. Sickles BR. Livingston DA. Nucleosides, Nucleotides Nucleic Acids  2000,  19:  297 

6 Bisacchi GS. Chao ST. Bachard C. Daris JP. Innaimo S. Jacobs GA. Kocy O. Lapointe P. Martel A. Merchant Z. Slusarchyk WA. Sundeen JE. Young MG. Colonno R. Zahler R. Bioorg. Med. Chem. Lett.  1997,  7:  127 

7a Balzarini J. Baumgartner H. Bodenteich M. De Clercq E. Griengl H. Nucleosides Nucleotides  1989,  8:  855 

7b Wyatt PG. Anslow AS. Coomber BA. Cousins RPC. Evans DN. Gilbert VS. Humber DC. Paternoster IL. Sollis SL. Tapolczay DJ. Weingarten GG. Nucleosides Nucleotides  1995,  14:  2039 

8a Borthwick AD. Biggadike K. Tetrahedron  1992,  48:  571 

8b Agrofoglio L. Suhas E. Farese A. Condom R. Challand SR. Earl RA. Guedj R. Tetrahedron  1994,  50:  10611 

8c Crimmins MT. Tetrahedron  1998,  54:  9229 

9a Jenny TF. Previsani N. Benner SA. Tetrahedron Lett.  1991,  32:  7029 

9b Jenny TF. Horlacher J. Previsani N. Benner SA. Helv. Chim. Acta  1992,  75:  1944 

9c Bonnal C. Chavis C. Lucas M. J. Chem. Soc., Perkin Trans. 1  1994,  1401 

9d Pérez-Pérez MJ. Rozenski J. Busson R. Herdewijn P. J. Org. Chem.  1995,  60:  1531 

9e Borthwick AD. Crame AJ. Exall AM. Weingarten GG. Mahmoudian M. Tetrahedron Lett.  1995,  36:  6929 

9f Schmitt L. Caperelli CA. Nucleosides Nucleotides  1997,  16:  2165 

9g Choo H. Chong Y. Chu CK. Org. Lett.  2001,  3:  1471 

10a Ludek OR. Meier C. Synthesis  2003,  13:  2101 

10b Ludek OR. Balzarini J. Meier C. Eur. J. Org. Chem.  2005,  in press 

11 Cruickshank KA. Jiricny J. Reese CB. Tetrahedron Lett.  1984,  25:  681 

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.

13 Reichardt C. Solvents and Solvent Effects in Organic Chemistry   2nd Ed.:  VCH-Verlagsgesellschaft GmbH; Weinheim: 1988.