Download PDF
Synlett 2012; 23(9): 1349-1352
DOI: 10.1055/s-0031-1291047
letter
© Georg Thieme Verlag Stuttgart · New York

Asymmetric Synthesis of (–)-9-epi-Metazocine

Qiang Chen
a   State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China, Fax: +86(931)8912582   Email: shexg@lzu.edu.cn
,
Xing Huo
a   State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China, Fax: +86(931)8912582   Email: shexg@lzu.edu.cn
,
Huaiji Zheng
a   State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China, Fax: +86(931)8912582   Email: shexg@lzu.edu.cn
,
Xuegong She*
a   State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China, Fax: +86(931)8912582   Email: shexg@lzu.edu.cn
b   State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, P. R. of China
› Author Affiliations
Further Information

Publication History

Received: 08 March 2012

Accepted after revision: 28 March 2012

Publication Date:
08 May 2012 (online)

    Permissions and Reprints All articles of this category


Abstract

(–)-9-epi-Metazocine was synthesized through an Evans syn aldol reaction, ring-closing metathesis reaction and intramolecular radical cyclization.

Key word

asymmetric - drug development - aldol - ring-closing ­metathesis - radical cyclization

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
  • Supporting Information
 

  • References

    • 1a Novak BH, Hudlicky T, Reed JW, Mulzer J, Trauner D. Curr. Org. Chem. 2000; 4: 343
      Crossref
    • 1b Hudlicky T, Butora G, Fearnley SP, Gum AG, Stabile MR. Stud. Nat. Prod. Chem. 1996; 18: 43
    • 1c Blakemore PR, White JD. Chem. Commun. 2002; 1159
    • 2a Clarke EG. C. Nature 1959; 184: 451
    • 2b Ager JH, Fullerton SE, May EL. J. Med. Chem. 1963; 6: 322
      Crossref
    • 2c Archer S, Albertson NF, Harris LS, Pierson AK, Bird JG. J. Med. Chem. 1964; 7: 123
      CrossrefPubMed
    • 2d Tullar BF, Harris LS, Perry RL, Pierson AK, Soria AE, Wetterau WF, Albertson NF. J. Med. Chem. 1967; 10: 383
      Crossref
    • 2e Kametani T, Kigasawa K, Hiiragi M, Wagatsuma N. Heterocycles 1974; 2: 79
      Crossref
    • 2f Rice KC, Jacobson AE. J. Med. Chem. 1976; 19: 430
      Crossref
    • 2g Palmer DC, Strauss MJ. Chem. Rev. 1977; 77: 1
      Crossref
    • 3a Grewe R, Mondon A. Chem. Ber. 1948; 81: 279
      Crossref
    • 3b Genisson Y, Marazano C, Das BC. J. Org. Chem. 1993; 58: 2052
      Crossref
    • 3c Meyers AI, Dickman DA, Bailey TR. J. Am. Chem. Soc. 1985; 107: 7974
      Crossref
    • 3d Comins DL, Zhang Y, Joseph SP. Org. Lett. 1999; 1: 657
      CrossrefPubMed
    • 3e Anada M, Tanaka M, Washio T, Yamawaki M, Abe T, Hashimoto S. Org. Lett. 2007; 9: 4559
      CrossrefPubMed
    • 3f Yang X, Zhai H, Li Z. Org. Lett. 2008; 10: 2457
      CrossrefPubMed
    • 4a Parker KA, Fokas D. J. Am. Chem. Soc. 1992; 114: 9688
      Crossref
    • 4b Parker KA, Fokas D. J. Org. Chem. 2006; 71: 449
      Crossref
  • 5 Trost BM, Tang W. J. Am. Chem. Soc. 2003; 125: 8744
    CrossrefPubMed
    • 6a Trost BM, Tang W. J. Am. Chem. Soc. 2002; 124: 14542
      CrossrefPubMed
    • 6b Trost BM, Tang W, Toste FD. J. Am. Chem. Soc. 2005; 127: 14785
      Crossref
    • 6c Omori AT, Finn KJ, Leisch H, Carroll RJ, Hudlicky T. Synlett 2007; 2859
      Article in Thieme Connect
    • 6d Leisch H, Omori AT, Finn KJ, Gilmet J, Bissett T, Ilceski D, Hudlicky T. Tetrahedron 2009; 65: 9862
      Crossref
    • 7a Tanimoto H, Saito R, Chida N. Tetrahedron Lett. 2008; 49: 358
      Crossref
    • 7b Chida N. Top. Curr. Chem. 2011; 299: 1
  • 8 Sun Y, Yu B, Wang X, Tang S, She X, Pan X. J. Org. Chem. 2010; 75: 4224
    Crossref
  • 9 Cheng X, Fu C. Chin. J. Chem. 2007; 25: 1762
    Crossref
  • 10 Smith K, El-Hiti GA, Al-Shamali M. Catal. Lett. 2006; 109: 77
    Crossref
    • 11a Crimmins MT, Chaudhary K. Org. Lett. 2000; 2: 775
      Crossref
    • 11b Crimmins MT, Slade DJ. Org. Lett. 2006; 8: 2191
      Crossref
  • 12 Compound 5: To a solution of thiazolidinethione propionate 7 (4.27 g, 16.1 mmol) in CH2Cl2 (100 mL) at 0 °C, was added TiCl4 (1.86 mL, 16.9 mmol); a characteristic orange slurry formed. After 10 min, (–)-sparteine (3.78 g, 16.1 mmol) was added, and the color changed to a deep red. After stirring for 30 min, the mixture was cooled to –78 °C, N-methylpyrrolidinone (NMP; 1.6 mL, 16.1 mmol) was added and the mixture was stirred for an additional 10 min. Aldehyde 6 (4.06 g, 17.7 mmol) in CH2Cl2 (20 mL) was added and the mixture was stirred at –78 °C for 1 h. After a further 2.5 hours stirring at 0 °C, the reaction was quenched with sat. NH4Cl. After separation of layers, the aqueous layer was further extracted with CH2Cl2 (2 × 30 mL) and the combined organic extract was dried over anhydrous Na2SO4 and evaporated in vacuo. The residue was purified by chromatography (petroleum ether–EtOAc, 10:1) to afford 5 (6.0 g, 76%) as yellow liquid; [α] d 18 –79.3 (c 2.0, CHCl3); 1H NMR (CDCl3, 400 MHz): δ = 7.37–7.33 (m, 2 H), 7.29–7.27 (m, 3 H), 7.19 (d, J = 8.4 Hz, 1 H), 7.11 (d, J = 2.8 Hz, 1 H), 6.82 (dd, J = 2.4, 8.4 Hz, 1 H), 5.37–5.31 (m, 1 H), 4.62–4.56 (m, 1 H), 4.24 (br s, 1 H), 3.77 (s, 3 H), 3.37 (dd, J = 6.8, 11.2 Hz, 1 H), 3.21 (dd, J = 3.6, 13.2 Hz, 1 H), 3.07–3.00 (m, 1 H), 2.90–2.86 (m, 3 H), 1.38 (d, J = 6.8 Hz, 3 H); 13C NMR (CDCl3, 100 MHz): δ = 201.0, 177.6, 158.8, 136.3, 131.9, 129.3, 129.2, 128.8, 127.1, 124.9, 118.0, 113.5, 71.9, 68.6, 55.4, 42.7, 39.6, 36.7, 31.9, 10.8; HRMS (ESI): m/z [M + H]+ calcd for C22H25BrNO3S2: 494.0454; found: 494.0463
  • 13 Crimmins MT, Caussanel F. J. Am. Chem. Soc. 2006; 128: 3128
    CrossrefPubMed
  • 14 Cossy J, Willis C, Bellosta V, BouzBouz S. J. Org. Chem. 2002; 67: 1982
    CrossrefPubMed
  • 15 Compound 16: To a solution of alcohol 15 (0.68 g, 2.3 mmol) in THF (30 mL) was added Ph3P (0.65 g, 2.5 mmol), DIAD (0.51 g, 2.5 mmol), and diphenylphosphoryl azide (0.96 g, 2.7 mmol) at 0 °C and stirring was continued for 12 h. The solvent was removed in vacuo and the residue was purified by chromatography (petroleum ether–EtOAc,100:1) to afford 16 (0.6 g, 80%) as a colorless liquid; [α] d 18 +74.0 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): δ = 7.21 (d, J = 8.4 Hz, 1 H), 7.12 (d, J = 2.8 Hz, 1 H), 6.84 (dd, J = 2.8, 8.4 Hz, 1 H), 4.91 (s, 1 H), 4.90 (s, 1 H), 3.80 (s, 3 H), 3.62–3.57 (m, 1 H), 3.12 (dd, J = 2.8, 14.0 Hz, 1 H), 2.58 (dd, J = 10.8, 14.4 Hz, 1 H), 2.52–2.45 (m, 1 H), 1.81 (s, 3 H), 1.22 (d, J = 6.8 Hz, 3 H); 13C NMR (CDCl3, 100 MHz): δ = 159.0, 146.3, 132.3, 129.5, 124.5, 118.0, 113.6, 112.7, 65.5, 55.5, 45.7, 37.6, 20.0, 16.1; IR: 3366, 2961, 2925, 2853, 2102, 1604, 1492, 1243, 1034 cm–1; HRMS (ESI): m/z [M + H]+ calcd for C14H19BrN3O: 324.0706; found: 324.0718
  • 16 Vaultier M, Knouzi N, Carrie R. Tetrahedron Lett. 1983; 24: 763
    Crossref
  • 17 Staudinger H, Meyer J. Helv. Chim. Acta 1919; 2: 635
    Crossref
    • 18a Danieli B, Lesma G, Passarella D, Sacchetti A, Silvani A, Virdis A. Org. Lett. 2004; 6: 493
      CrossrefPubMed
    • 18b Shigeyama T, Katakawa K, Kogure N, Kitajima M, Takayama H. Org. Lett. 2007; 9: 4069
      Crossref
    • 18c Yoshida K, Kawagoe F, Hayashi K, Horiuchi S, Imamoto T, Yanagisawa A. Org. Lett. 2009; 11: 515
      Crossref
  • 19 Compound 17: To a stirred solution of 4 (200 mg, 0.57 mmol) in CH2Cl2 (60 mL) Hoveyda–Grubbs II (28 mg, 0.045 mmol, 8 mol%) was added under an argon atmosphere. The mixture was heated at reflux for 24 h, then the solvent was removed in vacuum and the residue was purified by chromatography (EtOAc) to afford 17 (46 mg, 25%) as a colorless solid; [α] d 16 +172 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): δ = 7.11 (d, J = 2.4 Hz, 1 H), 7.03 (d, J = 8.8 Hz, 1 H), 6.81 (dd, J = 2.4, 8.8 Hz, 1 H), 5.71 (s, 1 H), 5.49 (s, 1 H), 3.78 (s, 3 H), 3.50–3.45 (m, 1 H), 2.96–2.84 (m, 2 H), 2.18 (q, J = 6.8 Hz, 1 H), 1.96 (s, 3 H), 1.19 (d, J = 6.8 Hz, 3 H); 13C NMR (CDCl3, 100 MHz): δ = 165.2, 159.0, 156.0, 132.0, 128.8, 124.8, 118.8, 118.4, 113.7, 55.6, 55.5, 40.6, 37.6, 22.0, 17.7; IR: 3242, 2965, 2929, 2866, 1675, 1606, 1492, 1241, 1031 cm–1; HRMS (ESI): m/z [M + H]+ calcd for C15H19BrNO2: 324.0594; found: 324.0596
    • 20a Ishibashi H, Kobayashi T, Nakashima S, Tamura O. J. Org. Chem. 2000; 65: 9022
      Crossref
    • 20b Tamura O, Yanagimachi T, Kobayashi T, Ishibashi H. Org. Lett. 2001; 3: 2427
      Crossref
  • 21 Preparation of compound 18 (Scheme 4): To a solution of 3 (43 mg, 0.12 mmol) in benzene (10 mL) at reflux, was added dropwise a solution of Bu3SnH (51 mg, 0.18 mmol) and AIBN (30 mg, 0.18 mmol) in benzene (10 mL) over 1 h by using a syringe. The mixture was then heated at reflux for 3 h. After evaporation of the solvent, the residue was purified by chromatography on silica gel (hexane–EtOAc, 2:1) to give 18 (27 mg, 87%); [α] d 22 –77 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz): δ = 6.96 (d, J = 8.0 Hz, 1 H), 6.90 (d, J = 2.4 Hz, 1 H), 6.72 (dd, J = 2.4, 8.0 Hz, 1 H), 3.78 (s, 3 H), 3.53 (s, 1 H), 2.96 (s, 2 H), 2.93 (s, 3 H), 2.48 (d, J = 17.6 Hz, 1 H), 2.30 (d, J = 19.2 Hz, 1 H), 2.04 (q, J = 6.8 Hz, 1 H), 1.38 (s, 3 H), 1.19 (d, J = 7.2 Hz, 3 H); 13C NMR (CDCl3, 100 MHz): δ = 169.0, 158.6, 145.3, 130.6, 123.7, 112.4, 111.5, 61.0, 55.3, 43.4, 36.9, 36.9, 34.2, 33.8, 24.1, 14.4; HRMS (ESI): m/z [M + H]+ calcd for C16H22NO2: 260.1645; found: 260.1657
  • 22 (–)-9-epi-metazocine (2b): [α] d 17 +22.0 (c 0.5, CHCl3); 1H NMR (CDCl3, 400 MHz): δ = 6.95 (d, J = 8.0 Hz, 1 H), 6.80 (d, J = 2.4 Hz, 1 H), 6.61 (dd, J = 2.4, 8.0 Hz, 1 H), 3.13 (d, J = 17.6 Hz, 1 H), 2.92 (d, J = 5.6 Hz, 1 H), 2.67 (dd, J = 5.6, 17.6 Hz, 1 H), 2.44 (d, J = 6.8 Hz, 1 H), 2.36 (s, 3 H), 2.03 (d, J = 8.4 Hz, 2 H), 1.88 (q, J = 6.8 Hz, 1 H), 1.29 (s, 3 H), 1.26 (d, J = 7.2 Hz, 3 H), 1.10 (d, J = 9.6 Hz, 1 H); 13C NMR (CDCl3, 100 MHz): δ = 154.1, 146.4, 129.1, 128.6, 113.0, 111.5, 60.1, 47.6, 43.0, 38.2, 34.9, 34.8, 27.3, 24.0, 15.0; IR: 3254, 2932, 2865, 1610, 1496, 1485, 1360, 769 cm–1; HRMS (ESI): m/z [M + H]+ calcd for C15H22NO: 232.1696; found: 232.1692