Synlett 2011(15): 2245-2247  
DOI: 10.1055/s-0030-1261203
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

An Inverse Electron-Demand Diels-Alder-Based Total Synthesis of Urolithin M7

Ian R. Pottie, Penchal Reddy Nandaluru, Graham J. Bodwell*
Department of Chemistry, Memorial University, St. John’s, NL, A1B 3X7, Canada
Fax: +1(709)8643702; e-Mail: gbodwell@mun.ca;
Further Information

Publication History

Received 30 May 2011
Publication Date:
30 August 2011 (eFirst)

Abstract

Urolithin M7 was synthesized from 2-hydroxy-4-methoxybenzaldehyde in 8 steps and 48% overall yield. The key step was an inverse electron demand Diels-Alder (IEDDA) reaction between diene 10 and the enamine (7) derived from dimethoxyacetaldehyde and pyrrolidine, which generated the 6H-dibenzo[b,d]pyran-6-one skeleton.

    References and Notes

  • 2 Clifford MN. Scalbert A. J. Food Sci. Agric.  2000,  80:  1118 
  • 3a Funatogawa K. Hayashi S. Shimomura H. Yoshida T. Hatano T. Ito H. Hirai Y. Microbiol. Immunol.  2004,  48:  251 
  • 3b Shito S. Shimizu M. Mizusima T. Ito H. Hatano T. Yoshida T. Tsuchiya T. FEMS Microbiol. Lett.  2000,  185:  135 
  • 3c Nakashima H. Murakami T. Yamamoto N. Sakagami H. Tanuma S. Hatano T. Yoshida T. Okuda T. Antiviral Res.  1992,  18:  91 
  • 3d Okuda T. Yoshida T. Hatano T. Planta Med.  1989,  55:  117 
  • 3e Okuda T. Mori K. Hayatsu H. Chem. Pharm. Bull.  1984,  32:  3755 
  • 3f Ito H. Miyake M. Nishitani E. Mori K. Hatano T. Okuda T. Konoshima T. Takasaki M. Kozuka M. Mukainaka T. Tokuda H. Nishino H. Yoshida T. Cancer Lett.  1999,  143:  5 
  • 3g Okabe S. Suganuma M. Imayoshi Y. Taniguchi S. Yoshida T. Fujiki H. Biol. Pharm. Bull.  2001,  24:  1145 
  • 4a Cerdá B. Llorach R. Cerón JJ. Espín JC. Tomás-Barberán FA. Eur. J. Nutr.  2003,  42:  18 
  • 4b Cerdá B. Tomás-Barberán FA. Espín JC. J. Agric. Food Chem.  2005,  53:  227 
  • 4c Espín JC. González-Barrio R. Cerdá B. López-Bote C. Tomás-Barberán FA. J. Agric. Food Chem.  2007,  55:  10476 
  • 4d González-Barrio R. Trunchado P. Ito H. Espín JC. Tomás-Barberán FA. J. Agric. Food Chem.  2011,  59:  1152 
  • 4e Ito H. Iguchi A. Hatano T. J. Agric. Food Chem.  2008,  56:  393 
  • 4f Doyle B. Griffiths LA. Xenobiotica  1980,  10:  247 
  • 5 Jeong S.-J. Kim N.-Y. Kim D.-H. Kang T.-H. Ahn N.-H. Miyamoto T. Higuchi R. Kim Y.-C. Planta Med.  2000,  66:  76 
  • 6 The Dictionary of Chinese Drugs   Shanghai Scientific and Technical Publishers; Shougakukan Tokyo: 1985.  p.875-877  
  • 7 Bodwell GJ. Pi Z. Pottie IR. Synlett  1999,  477 
  • 8 Dang A.-T. Miller DO. Dawe LN. Bodwell GJ. Org. Lett.  2008,  10:  233 
  • 10 Zanka A. Ohmori H. Okamoto T. Synlett  1999,  1636 
  • 11 Fétizon M. Golfier M. Louis J.-M. Tetrahedron  1975,  31:  171 
  • For examples of the Dakin reaction, see:
  • 12a Schönberg A. Badran N. Starowsky NA. J. Chem. Soc.  1995,  1019 
  • 12b Kabalka GW. Reddy NK. Narayana C. Tetrahedron Lett.  1992,  33:  865 
  • 12c Varma RS. Naicker KP. Org. Lett.  1999,  2:  189 
  • 12d Bodwell GJ. Hawco KM. Satou T. Synlett  2003,  879 
  • 12e Bernini R. Coratti A. Provenzano G. Fabrizi G. Tofani D. Tetrahedron  2005,  61:  1821 
  • 13 Grey RA. J. Org. Chem.  1984,  49:  2288 
  • For examples of the Baeyer-Villiger reaction reaction, see:
  • 14a Suginome H. Yamada S. J. Org. Chem.  1985,  50:  2489 
  • 14b de Azevedo MBM. Murta MM. Greene AE. J. Org. Chem.  1992,  57:  4567 
  • 14c Kametani T. Kotoh T. Fujio J. Nogiwa I. Tsubuki M. Honda T. J. Org. Chem.  1988,  53:  1982 
  • 14d Syper L. Synthesis  1989,  167 
  • 14e Smissman EE. Li JP. Israili ZH. J. Org. Chem.  1968,  33:  4231 
1

Present address: Department of Chemistry, Mount St. Vincent University, Halifax, NS, B3M 2J6, Canada.

9

Experimental Procedure for 9
A solution of dimethoxyacetaldehyde (60 wt% solution in H2O, 19.6 mL, 0.130 mol) and pyrrolidine (9.76 mL, 0.117 mol) in benzene (150 mL) was heated at reflux with azeotropic removal of H2O for 1 h. The resulting mixture was allowed to cool for 10 min, and solid 10 (3.38 g, 13.0 mmol) was added in one portion. The resulting mixture was heated at reflux for 7 d. The reaction mixture was cooled to r.t. and then concentrated under reduced pressure. The residue was taken up in CH2Cl2 (150 mL) and washed with aq 1 M HCl solution (5 50 mL), dried over MgSO4, gravity filtered, and concentrated under reduced pressure to afford 9 (4.08 g, 100%) as a tan solid: mp 195-196 ˚C. IR (Nujol): ν = 1735 (s), 1715 (s), 1607 (m), 1121 (s) cm. ¹H NMR (500 MHz, CDCl3): δ = 8.76 (d, J = 9.3 Hz, 1 H), 8.57 (d, J = 1.1 Hz, 1 H), 7.80 (d, J = 1.0 Hz, 1 H), 6.81 (dd, J = 9.6, 3.0 Hz, 1 H), 6.76 (d, J = 2.6 Hz, 1 H), 4.08 (s, 3 H), 3.96 (s, 3 H), 3.87 (s, 3 H). ¹³C NMR (125.8 MHz, CDCl3): δ = 165.6, 161.3, 160.7, 156.4, 152.7, 130.0, 129.1, 128.0, 124.0, 121.3, 116.1, 111.7, 110.0, 101.3, 56.1, 55.3, 52.4. MS (EI): m/z (%) = 314 (100) [M+], 299 (53), 283 (13), 212 (4), 157 (4). Anal. Calcd for C17H14O6: C, 64.97; H, 4.49. Found C, 65.03; H, 4.61.