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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)

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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

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  • 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
  • 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