Synthesis of Mono- and Bis-C-glycosylated 2,3,4-Trisubstituted 1H-Pyrroles as Cyclo- and Acyclo-C-nucleoside Analogues

Abstract

A new method for the synthesis of mono- and bis-C-glycosylated 2,3,4-trisubstituted 1H-pyrroles, a type of cyclo- and ­acyclo-C-nucleoside analogues, is described. The reaction of readily available sensitive 2H-azirines derived from carbohydrates with 1,3-dicarbonyl compounds is catalysed by tris(triphenylsilyl)vanadate under mild conditions. The reaction of 2H-azirines with vanadium enolates has not been described previously. This methodology may be suitable for the synthesis of combinatorial libraries with the trisubstituted 1H-pyrrole skeleton as a molecular scaffold.

Key words

pyrroles - heterocycles - addition reactions - C-nucleosides - C-glycosides

References and Notes

• 1a Wellington KW. Benner SA. Nucleosides, Nucleotides Nucleic Acids  2006,  25:  1309 
• 1b Wu QP. Simons C. Synthesis  2004,  1533 
• 1c Henry AA. Romesberg FE. Curr. Opin. Chem. Biol.  2003,  7:  727 
• 1d Kool ET. Acc. Chem. Res.  2002,  35:  936 
• 1e Kool ET. Morales JC. Guckian KM. Angew. Chem. Int. Ed.  2000,  39:  990 
• For a review, see:
• 2a Ramesh NG. Balasubramanian KK. Eur. J. Org. Chem.  2003,  4477 
• For recent references, see:
• 2b Bari A. Feist H. Michalik M. Peseke K. Molecules  2005,  10:  837 
• 2c Otero I. Methling K. Feist H. Michalik M. Quincoces J. Reinke H. Peseke K. J. Carbohydr. Chem.  2005,  24:  809 
• 2d Bari A. Milicevic S. Feist H. Michalik D. Michalik M. Peseke K. Synthesis  2005,  2758 
• 2e Nasr AZ. Nucleosides, Nucleotides Nucleic Acids  2004,  23:  1825 ; and references cited therein
• 3 Alonso-Cruz CR. Kennedy AR. Rodríguez MS. Suárez E. Org. Lett.  2003,  5:  3729 
• For syntheses of related 1,4-anhydro-1-(1H-pyrrol-2-yl)alditol derivatives, see:
• 4a Armitt DJ. Banwell MG. Freeman C. Parish CR. J. Chem. Soc., Perkin Trans. 1  2002,  1743 
• 4b Nishimura N. Kato A. Maeba I. Carbohydr. Res.  2001,  331:  77 
• 4c Yokoyama M. Nomura M. Togo H. Seki H. J. Chem. Soc., Perkin Trans. 1  1996,  2145 
• 4d Yokoyama M. Akiba T. Togo H. Synthesis  1995,  638 
• 4e Patil SA. Otter BA. Klein RS. Tetrahedron Lett.  1994,  35:  5339 
• 4f Casiraghi G. Cornia M. Rassu G. Delsante C. Spanu P. Tetrahedron  1992,  48:  5619 
• 4g Maeba I. Takeuchi T. Iijima T. Kitaori K. Muramatsu H. J. Chem. Soc., Perkin Trans. 1  1989,  649 
• 4h Maeba I. Takeuchi T. Iijima T. Furukawa H. J. Org. Chem.  1988,  53:  1401 
• 4i Perez JAG. Caballero RB. Ventula AC. Carbohydr. Res.  1985,  143:  129 
• For a specific review on azirines in reactions involving pyrroles, see:
• 5a Trofimov BA. Mikhaleva AI. Chem. Heterocycl. Compd. (Engl. Transl.)  1987,  23:  1037 
• For general reviews of azirines, see:
• 5b Palacios F. Ochoa de Retana AM. Martínez de Marigorta E. de los Santos JM. Org. Prep. Proced. Int.  2002,  34:  219 
• 5c Palacios F. Ochoa de Retana AM. Martínez de Marigorta E. de los Santos JM. Eur. J. Org. Chem.  2001,  2401 
• 5d Gilchrist TL. Aldrichimica Acta  2001,  34:  51 
• 5e Zwanenburg B. ten Holte P. Top. Curr. Chem.  2001,  216:  93 
• 5f Padwa A. Woolhouse AD. Comprehensive Heterocyclic Chemistry   Vol. 7:  Katritzky AR. Rees CW. Pergamon Press; Oxford: 1984.  p.47-93  
• 5g Anderson DJ. Hassner A. Synthesis  1975,  483 
• For recent examples of the addition of nucleophiles to azirines, see:
• 5h Hassner A. Usak D. Kumareswaran R. Friedman O. Eur. J. Org. Chem.  2004,  2421 
• 5i Pinho e Melo TMVD. Lopes CSJ. Rocha Gonsalves AM. Beja AM. Paixao JA. Silva MR. da Veiga LA. J. Org. Chem.  2002,  67:  66 
• 6 Filho PF. Schuchardt U. Angew. Chem., Int. Ed. Engl.  1977,  16:  647 
• 7 Narasimhan NS. Heimgartner H. Hansen H.-J. Schmid H. Helv. Chim. Acta  1973,  56:  1351 
• 8 Alves MJ. Gilchrist TL. Sousa JH. J. Chem. Soc., Perkin Trans. 1  1999,  1305 
• 9 Tchissambou L. Benechie M. Khuong-Huu F. Tetrahedron  1982,  38:  2687 
• For a review on vanadium in organic synthesis, see:
• 10a Hirao T. Chem. Rev.  1997,  97:  2707 
• For nucleophilic addition catalysed by vanadium, see:
• 10b Belokon YN. Green B. Ikonnikov NS. North M. Parsons T. Tararov VI. Tetrahedron  2001,  57:  771 
• 10c Trost BM. Jonasson C. Wuchrer M. J. Am. Chem. Soc.  2001,  123:  12736 
• 10d Trost BM. Oi S. J. Am. Chem. Soc.  2001,  123:  1230 
• For the synthesis of VO(OSiPh₃)₃, see:
• 11a Pauling H. Andrews DA. Hindley NC. Helv. Chim. Acta  1976,  59:  1233 
• 11b Trost BM. Jonasson C. Angew. Chem. Int. Ed.  2003,  42:  2063 
• 12a

  The catalytic activity of VO(OSiPh₃)₃ is more apparent with hindered 1,3-diketones; for example, in the absence of catalyst the reaction of 5α-cholestan-1,3-dione (see ref. 12b) with an excess of azirine 2 did not occur after 48 h in anhydrous CH₂Cl₂ at reflux temperature; notwithstanding, in the presence of 5 mol% of VO(OSiPh₃)₃ the reaction proceeded to completion in only 5 h to give a 6:4 mixture of regioisomers A and B in 96% yield (Scheme [3] ).

• 12b Win WW. Franck RW. J. Org. Chem.  1997,  62:  4510 
• For synthesis of 3-pyrrole acyclic C-nucleosides by other methods, see:
• 13a Yu M. Brian L. Pagenkopf BL. Org. Lett.  2003,  5:  5099 
• 13b Chiara J.-L. Gómez-Sánchez A. Hidalgo F.-J. Yruela I. Carbohydr. Res.  1989,  188:  55 
• 13c Gómez-Sánchez A. Hidalgo F.-J. Chiara J.-L. Carbohydr. Res.  1987,  167:  55 
• 13d González FG. Sánchez AG. Gómez JG. An. R. Soc. Esp. Fís. Quím., Ser. B  1958,  54:  513 
• 13e González FG. Sánchez AG. Gómez JG. An. R. Soc. Esp. Fís. Quím., Ser. B  1958,  54:  519 
• 13f Sánchez AG. Gómez JG. An. R. Soc. Esp. Fís. Quím., Ser. B  1958,  54:  753 
• 14a Veronese AC. Morelli CF. Tetrahedron Lett.  1998,  39:  3853 
• 14b Morelli CF. Manferdini M. Veronese AC. Tetrahedron  1999,  55:  10803 
• 15a Dhavale DD. Bhujbal NN. Joshi P. Desai SG. Carbohydr. Res.  1994,  263:  303 
• 15b Karche NP. Jachak SM. Dhavale DD. J. Org. Chem.  2001,  66:  6323 
• 16a Tegdes A. Medgyes G. Boros S. Kuszmann J. Carbohydr. Res.  2006,  341:  776 
• 16b van Delft FL. Valentijn ARPM. van der Marel GA. van Boom JH. J. Carbohydr. Chem.  1999,  18:  165 
• 17 Holmquist CR. Roskamp EJ. J. Org. Chem.  1989,  54:  3258 
• For other synthesis of C-glycoconjugates using C-glycosyl β-keto esters, see:
• 18a Dondoni A. Massi A. Sabbatini S. Bertolasi V. J. Org. Chem.  2002,  67:  6979 
• 18b Saha NN. Desai VN. Dhavale DD. J. Org. Chem.  1999,  64:  1715 

19

General Procedure for the Reaction of Azirines with 1,3-Dicarbonyl Compounds Catalyzed by VO(OSiPh ₃ ) ₃
A solution of the azirine (1 mmol) and 1,3-dicarbonyl (1-1.2 mmol) in an amount of CH₂Cl₂ depending on solubility (1-15 mL) containing VO(OSiPh₃)₃ (0.05 mmol) was stirred under nitrogen, at the temperature and for the time specified in each case in Table [1] and Scheme [2] . The reaction mixture was then concentrated under reduced pressure and the residue purified by silica gel column chromatography (hexanes-EtOAc mixtures).
Compound 6: crystalline solid, mp 161.3-163.3 °C (from n-hexane-EtOAc); [α]_D +52 (c 0.073). IR: 3456, 1735, 1646 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.98 (3 H, s), 2.09 (3 H, s), 2.43 (3 H, s), 2.51 (3 H, s), 4.20 (1 H, dd, J = 12.2, 8.7 Hz), 4.32 (1 H, dd, J = 11.9, 2.7 Hz), 5.58 (1 H, ddd, J = 8.8, 2.6, 2.6 Hz), 6.59 (1 H, d, J = 3.4 Hz), 6.63 (1 H, d, J = 1.9 Hz), 8.15 (1 H, s), 8.96 (1 H, br s). ¹³C NMR (100.6 MHz, CDCl₃): δ = 15.3 (CH₃), 20.7 (CH₃), 21.0 (CH₃), 30.5 (CH₃), 62.3 (CH₂), 70.0 (CH), 72.2 (CH), 115.9 (CH), 120.1 (C), 120.8 (C), 135.0 (C), 160.3 (CH), 169.7 (C), 170.8 (C), 194.4 (C). MS (EI): m/z (%) = 325 (3) [M⁺], 279 (5), 265 (5), 236 (19), 152 (100). HRMS: m/z calcd for C₁₅H₁₉NO₇: 325.1162; found: 325.1161. Anal. Calcd for C₁₅H₁₉NO₇: C, 55.38; H, 5.89; N, 4.31. Found: C, 55.41; H, 5.71; N, 4.12.
Compound 7: crystalline solid, mp 159-161 °C (from n-hexane-CHCl₃); [α]_D +12.3 (c 0.073). IR 3456, 1735, 1655 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.08 (3 H, s), 1.09 (3 H, s), 1.98 (3 H, s), 2.07 (3 H, s), 2.32 (2 H, br s), 2.64 (2 H, br s), 4.17 (1 H, dd, J = 12.1, 8.0 Hz), 4.31 (1 H, dd, J = 12.2, 2.7 Hz), 5.84 (1 H, ddd, J = 7.3, 3.1, 3.1 Hz), 6.50 (1 H, d, J = 4.2 Hz), 6.73 (1 H, d, J = 2.3 Hz), 8.10 (1 H, s), 9.18 (1H, br s). ¹³C NMR (100.6 MHz, CDCl₃): δ = 20.7 (CH₃), 21.0 (CH₃), 28.4 (CH₃), 28.5 (CH₃), 35.7 (C), 36.8 (CH₂), 52.4 (CH₂), 62.3 (CH₂), 68.6 (CH), 72.0 (CH), 116.1 (C), 117.1 (C), 118.0 (CH), 143.4 (C), 160.2 (CH), 169.7 (C), 170.7 (C), 194.0 (C). MS (EI): m/z (%) = 365 (<1) [M⁺], 304 (14), 276 (29), 220 (38); 192 (100). HRMS: m/z calcd for C₁₈H₂₃NO₇: 365.1475; found: 365.1459. Anal. Calcd for C₁₈H₂₃NO₇: C, 59.17; H, 6.34; N, 3.83. Found: C, 59.35; H, 6.54; N, 3.51.
Compound 8: crystalline solid, mp 66.4-68.4 °C (from n-hexane-EtOAc); [α]_D -13.5 (c 0.07). IR: 3467, 1717, 1655 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.03 (9 H, s), 1.10 (9 H, s), 2.466 (3 H, s), 2.474 (3 H, s), 4.01 (1 H, dd, J = 10.9, 9.0 Hz), 4.15 (1 H, dd, J = 10.6, 4.0 Hz), 5.14 (1 H, ddd, J = 8.7, 8.7, 4.0 Hz), 5.77 (1 H, d, J = 8.2 Hz), 6.70 (1 H, d, J = 2.7 Hz), 7.86 (1 H, s), 8.90 (1 H, br s). ¹³C NMR (125.7 MHz, CDCl₃): δ = 15.1 (CH₃), 20.4 (C), 22.6 (C), 27.1 (3 × CH₃), 27.4 (3 × CH₃), 30.8 (CH₃), 65.1 (CH₂), 71.1 (CH), 72.2 (CH), 114.9 (CH), 120.5 (C), 125.7 (C), 135.0 (C), 159.6 (CH), 195.3 (C). MS-FAB: m/z (%) = 382 (12) [M⁺ + 1], 324 (10). HRMS: m/z calcd for C₁₉H₃₂NO₅Si: 382.2050; found: 382.2086. Anal. Calcd for C₁₉H₃₁NO₅Si: C, 59.81; H, 8.19; N, 3.67. Found: C, 60.16; H, 8.41; N, 3.32.
Compound 9: oil; [α]_D +23 (c 0.09). IR: 3455, 1747, 1640 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.95 (6 H, s), 1.96 (3 H, s), 2.11 (3 H, s), 2.12 (3 H, s), 2.41 (3 H, s), 2.51 (3 H, s), 3.81 (1 H, dd, J = 6.9, 6.9 Hz), 3.97 (1 H, dd, J = 10.9, 6.9 Hz), 4.05 (1 H, dd, J = 10.9, 6.4 Hz), 4.10 (1 H, dd, J = 12.2, 9.0 Hz), 4.28 (1 H, dd, J = 12.2, 2.2 Hz), 4.73 (1 H, d, J = 8.0 Hz), 5.02 (1 H, dd, J = 10.3, 3.5 Hz), 5.22 (1 H, dd, J = 10.3, 8.0 Hz), 5.35 (1 H, dd, J = 3.4, 1.1 Hz), 5.45 (1 H, ddd, J = 9.0, 2.1, 2.1 Hz), 5.54 (1 H, dd, J = 2.9, 1.1 Hz), 6.71 (1 H, dd, J = 2.2, 0.8 Hz), 8.18 (1 H, s), 8.75 (1 H, br s). ¹³C NMR (100.6 MHz, CDCl₃): δ = 15.5 (CH₃), 20.48 (CH₃), 20.50 (CH₃), 20.6 (CH₃), 20.7 (CH₃), 20.8 (CH₃), 30.5, (CH₃), 60.9 (CH₂), 62.3 (CH₂), 67.0 (CH), 69.1 (CH), 70.6 (CH), 70.8 (CH), 74.5 (CH), 77.5 (CH), 101.6, (CH), 116.8 (CH), 119.6 (C), 122.2 (C), 134.8 (C), 160.5 (CH), 169.9 (C), 170.0 (C), 170.2 (C), 170.3 (C), 170.8 (C), 194.3 (C). MS (EI): m/z (%) = 613 (1) [M⁺], 567 (<1), 508 (<1), 482 (<1), 331 (100), 282 (38). HRMS: m/z calcd for C₂₇H₃₅NO₁₅: 613.2007; found: 613.2023. Anal. Calcd for C₂₇H₃₅NO₁₅: C, 52.85; H, 5.75; N, 2.28. Found: C, 52.86; H, 5.92; N, 2.10.
Compound 11: colourless oil; [α]_D +20.2 (c 0.143). IR (neat): 3405, 1729 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.09 (9 H, s), 1.13 (9 H, s), 1.17 (3 H, t, J = 6.8 Hz), 4.00 (1 H, dd, J = 9.7, 9.7 Hz), 4.13 (1 H, dddd, J = 10.7, 7.3, 7.3, 7.3 Hz), 4.15 (1 H, dd, J = 10.6, 4.4 Hz), 4.21 (1 H, dddd, J = 10.7, 7.3, 7.3, 7.3 Hz), 4.70 (1 H, ddd, J = 7.8, 4.4, 2.4 Hz), 4.74 (1 H, dd, J = 12.1, 2.4 Hz), 4.79 (1 H, dd, J = 12.6, 4.8 Hz), 5.02 (1 H, ddd, J = 9.2, 9.2, 4.4 Hz), 5.72 (1 H, dd, J = 7.8, 4.9 Hz), 5.85 (1 H, dd, J = 4.9, 2.4 Hz), 5.87 (1 H, d, J = 8.7 Hz), 5.93 (1 H, d, J = 1.9 Hz), 6.70 (1 H, d, J = 2.4 Hz), 7.28 (2 H, dd, J = 7.8, 7.8 Hz), 7.45 (2 H, dd, J = 7.8, 7.8 Hz), 7.49 (3 H, dd, J = 7.8, 7.8 Hz), 7.60 (2 H, dd, J = 7.3, 7.3 Hz), 7.79 (1 H, s), 7.80 (2 H, m), 8.07 (4 H, m), 9.65 (1 H, br s). ¹³C NMR (125.7 MHz, CDCl₃): δ = 14.3 (CH₃), 20.5 (C), 22.7 (C), 27.2 (3 × CH₃), 27.5 (3 × CH₃), 59.8 (CH₂), 63.6 (CH₂), 65.5 (CH₂), 70.3 (CH), 70.9 (CH), 72.8 (CH), 77.3 (CH), 78.5 (CH), 78.8 (CH), 110.0 (C), 116.2 (CH), 127.5 (C), 128.3 (2 × CH), 128.5 (2 × CH), 128.8 (2 × CH), 129.4 (3 × C), 129.8 (2 × CH), 129.8 (2 × CH), 129.9 (2 × CH), 133.4 (CH), 133.4 (CH), 133.7 (CH), 134.6 (C), 159.5 (CH), 164.5 (C), 165.1 (C), 165.3 (C), 166.9 (C). MS (EI): m/z (%) = 841 (<1) [M⁺], 784 (26), 738 (6), 719 (8), 662 (6), 418 (22), 105 (100). HRMS: m/z calcd for C₄₅H₅₁NO₁₃Si: 841.3130; found: 841.3135. Anal. Calcd for C₄₅H₅₁NO₁₃Si: C, 64.19; H, 6.11; N, 1.66. Found: C, 64.24; H, 6.16; N, 1.83.
Compound 13: colourless oil; [α]_D -55.3 (c 0.19). IR (neat): 3353, 1728 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.07 (3 × 3 H, s), 1.13 (3 × 3 H, s), 1.28 (1 H, t, J = 7.2 Hz), 1.35 (3 H, s), 1.53 (3 H, s), 4.02 (1 H, dd, J = 10.6, 9.3 Hz), 4.06 (1 H, d, J = 11.7 Hz), 4.16-4.27 (4 H, m), 4.29 (1 H, d, J = 2.9 Hz), 4.67 (1 H, d, J = 4.0 Hz), 5.13 (1 H, ddd, J = 9.0, 9.0, 4.8 Hz), 5.81 (1 H, d, J = 2.9 Hz), 5.90 (1 H, d, J = 8.8 Hz), 6.03 (1 H, d, J = 3.7 Hz), 6.91 (1 H, d, J = 2.7 Hz), 6.97 (2 H, m), 7.26 (3 H, m), 7.70 (1 H, s), 8.99 (1 H, br s). ¹³C NMR (100.4 MHz, CDCl₃): δ = 14.4 (CH₃), 20.5 (C), 22.67 (C), 26.4 (CH₃), 26.94 (CH₃), 27.2 (3 × CH₃), 27.5 (3 × CH₃), 59.7 (CH₂), 65.4 (CH₂), 70.6 (CH), 72.3 (CH₂), 72.8 (CH), 76.8 (CH), 82.2 (CH), 83.6 (CH), 104.5 (CH), 110.1 (C), 112.1 (C), 116.1 (CH), 126.3 (C), 127.6 (2 × CH), 128.0 (CH), 128.4 (2 × CH), 133.0 (C), 137.1 (C), 159.4 (CH), 164.7 (C). MS (EI): m/z (%) = 645 (1) [M⁺], 630 (2), 588 (44), 496 (11), 91 (100). HRMS: m/z calcd for C₃₃H₄₇NO₁₀Si: 645.2969; found: 645.2985. Anal. Calcd for C₃₃H₄₇NO₁₀Si: C, 61.37; H, 7.34; N, 2.17. Found: C, 61.55; H, 7.40; N, 2.29.
Compound 15: A solution of the crude 14 (17.2 mg, 0.0335 mmol) and VO(OSiPh₃)₃ (3 mg, 0.003 mmol) in anhyd benzene (1.2 mL) was heated at reflux temperature for 30 min under nitrogen. Azirine 2 (20 mg, 0.067 mmol) in anhyd benzene (1.2 mL) was then added and heating at this temperature was continued for 2 h. The reaction mixture was then concentrated and the residue purified by rapid chromatotron chromatography on neutral alumina (Merck 150, Type T) to minimise decomposition (toluene-EtOAc, 98:2) to give pyrrole 15 (19 mg, 0.018 mmol, 46%) as a colourless oil: [α]_D -13.9 (c 0.14). IR (CHCl₃): 3456, 1720 cm^-1. The C ₂ axis of symmetry lead to simplified NMR spectra. ¹H NMR (500 MHz, CDCl₃): δ = 1.05 (18 H, s), 1.10 (18 H, s), 1.34 (6 H, t, J = 7.3 Hz), 3.99 (2 H, dd, J = 10.7, 9.2 Hz), 4.15 (2 H, dd, J = 10.7, 4.1 Hz), 4.25 (2 H, s), 4.28 (2 H, dddd, J = 10.7, 6.9, 6.9, 6.9 Hz), 4.30 (2 H, dddd, J = 10.7, 6.9, 6.9, 6.9 Hz), 4.51 (2 H, d, J = 11.7 Hz), 4.70 (2 H, d, J = 11.7 Hz), 4.99 (2 H, ddd, J = 9.1, 9.1, 4.4 Hz), 5.78 (2 H, d, J = 8.5 Hz), 6.09 (2 H, s), 6.67 (2 H, d, J = 2.5 Hz), 7.18 (4 H, m), 7.30 (6 H, m), 7.72 (2 H, s), 9.28 (2 H, br s). ¹³C NMR (100.4 MHz, CDCl₃): δ = 14.5 (CH₃), 20.5 (C), 22.7 (C), 27.2 (3 × CH₃), 27.5 (3 × CH₃), 59.8 (CH₂), 65.4 (CH₂), 71.1 (CH), 71.9 (CH₂), 73.2 (CH), 81.0 (CH), 86.8 (CH), 110.2 (C), 115.9 (CH), 125.7 (C), 128.0 (2 × CH), 128.1 (CH), 128.5 (2 × CH), 137.0 (C), 137.1 (C), 159.5 (CH), 165.3 (C). MS (EI): m/z (%) = 1017 (<1) [M⁺ - C₄H₉], 836 (<1), 736 (5), 509 (27). HRMS: m/z calcd for C₅₂H₆₉N₂O₁₅Si₂: 1017.4237; found: 1017.4208. Anal. Calcd for C₅₆H₇₈N₂O₁₅Si₂: C, 62.54; H, 7.31; N, 2.60. Found: C, 62.71; H, 7.28; N, 2.51.