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

1a Ezzitouni A. Russ P. Marquez VE. J. Org. Chem.  1997,  62:  4870 

1b Shin KJ. Moon HR. George C. Marquez VE. J. Org. Chem.  2000,  65:  2172 

1c Yoshimura Y. Moon HR. Choi Y. Marquez VE. J. Org. Chem.  2002,  67:  5938 

1d Choi Y. George C. Comin MJ. Barchi JJ. Kim HS. Jacobsen KA. Balzarini J. Mitsuya H. Boyer PL. Hughes SH. Marquez VE. J. Med. Chem.  2003,  46:  3292 

1e Comin MJ. Parrish DA. Deschamps JR. Marquez VE. Org. Lett.  2006,  8:  705 

2a Marquez VE. Ezzitouni A. Russ P. Siddiqui MA. Ford H. Feldman RJ. Mitsuya H. George C. Barchi JJ. J. Am. Chem. Soc.  1998,  120:  2780 

2b Marquez VE. Choi Y. Comin MJ. Russ P. George C. Huleihel M. Ben-Kasus T. Agbaria R. J. Am. Chem. Soc.  2005,  127:  15145 

3a Paquette LA. Seekamp CK. Kahane AL. J. Org. Chem.  2003,  68:  8614 

3b Paquette LA. Kahane AL. Seekamp CK. J. Org. Chem.  2004,  69:  5555 

3c Paquette LA. Seekamp CK. Kahane AL. Hilmey DG. Gallucci J. J. Org. Chem.  2004,  69:  7442 

4 Obika S. Nanbu D. Hari Y. Morio K.-i. In Y. Ishida T. Imanishi T. Tetrahedron Lett.  1997,  38:  8735 

5 Singh SK. Nielsen P. Koshkin AA. Wengel J. Chem. Commun.  1998,  455 

6a Yoshimura Y. Sano T. Matsuda A. Ueda T. Chem. Pharm. Bull.  1988,  36:  162 

6b Yoshimura Y. Matsuda A. Ueda T. Nucleosides Nucleotides  1988,  7:  409 

6c Yoshimura Y. Matsuda A. Ueda T. Chem. Pharm. Bull.  1989,  37:  660 

6d Yoshimura Y. Matsuda A. Ueda T. Chem. Pharm. Bull.  1990,  38:  389 

7a Matsuda A. Muneyama K. Nishida T. Sato T. Ueda T. Nucleic Acids Res.  1976,  3:  3349 

7b Ueda T. Usui H. Shuto S. Inoue H. Chem. Pharm. Bull.  1984,  32:  3410 

7c Ueda T. Shuto S. Satoh M. Inoue H. Nucleosides Nucleotides  1985,  4:  401 

7d Suzuki Y. Matsuda A. Ueda T. Chem. Pharm. Bull.  1987,  35:  1808 ; and references cited therein

7e Yoshimura Y. Ueda T. Matsuda A. Tetrahedron Lett.  1991,  32:  4549 

7f Yoshimura Y. Otter BA. Ueda T. Matsuda A. Chem. Pharm. Bull.  1992,  40:  1761 

8a Ueda T. Usui H. Shuto S. Inoue H. Chem. Pharm. Bull.  1984,  32:  3410 

8b Yamagata Y. Tomita K. Usui H. Sano T. Ueda T. Chem. Pharm. Bull.  1989,  37:  1971 

1,5-Hydrogen-transfer-radical cyclization, see:

9a Curran DP. Kim D. Liu HT. Shen W. J. Am. Chem. Soc.  1988,  110:  5900 

9b Snieckus V. Cuevas J.-C. Sloan CP. Liu H. Curran DP. J. Am. Chem. Soc.  1990,  112:  896 

9c Kittaka A. Asakura T. Kuze T. Tanaka H. Yamada N. Nakamura KT. Miyasaka T. J. Am. Chem. Soc.  1999,  64:  7081 

9d Sha C.-K. Hsu C.-W. Chen Y.-T. Cheng S.-Y. Tetrahedron Lett.  2000,  41:  9865 

9e Takasu K. Ohsato H. Ihara M. Org. Lett.  2003,  5:  3017 

9f Beaufils F. Dénès F. Renaud P. Org. Lett.  2004,  6:  2563 

9g Sukeda M. Matsuda A. Shuto S. Tetrahedron  2005,  61:  7865 

10a Mastuda A. Tezuka M. Ueda T. Tetrahedron  1978,  34:  2449 

10b G ani D. Johnson AW. Lappert MF. J. Chem. Soc., Perkin Trans. 1  1981,  3065 

10c Flyunt R. Bazzanini R. Chatgilialoglu C. Mulazzani QC. J. Am. Chem. Soc.  2000,  122:  4225 

10d Chatgilialoglu C. Guerra M. Mulazzani QC. J. Am. Chem. Soc.  2003,  125:  3839 

10e Chatgilialoglu C. Duca M. Ferreri C. Guerra M. Ioele M. Mulazzani QC. Strittmatter H. Giese B. Chem. Eur. J.  2004,  10:  1249 

10f Navacchia ML. Chatgilialoglu C. Montevecchi PC. J. Org. Chem.  2006,  71:  4445 

10g Otter BA. Falco EA. Fox JJ. J. Org. Chem.  1976,  41:  3133 

11 Yoshimura Y. Kumamoto H. Baba A. Takeda S. Tanaka H. Org. Lett.  2004,  6:  1793 

12 Tanaka H. Hayakawa H. Obi K. Miyasaka T. Tetrahedron Lett.  1985,  26:  6229 

13

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.

14 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 

15 Otter BA. Falco EA. Fox JJ. J. Org. Chem.  1976,  41:  3133