A Concise Total Synthesis of (±)-Mesembrine

Abstract

A concise total synthesis of (±)-mesembrine has been successfully accomplished in seven steps and 24% overall yield from commercially available 3-ethoxy-2-cyclohexen-1-one. Central to the assembly of the skeleton of mesembrine are a Johnson–Claisen rearrangement for the formation of the benzylic quaternary stereocenter and direct allylic oxidation to generate the substrate for the amidation/transannular aza-conjugate addition reaction.

Key words

mesembrine - natural products - total synthesis - allylic transfer - benzylic quaternary stereogenic center - 3a-(aryl)octahydro­indole.

• References and Notes

• 1 Jeffs PW. In The Alkaloids . Vol. 19. Rodrigo RG. A. Chap. Academic Press; New York: 1981
• 2 Bodendorf K. Krieger W. Arch. Pharm. 1957; 290: 441
• 3a Popelak A. Haack E. Lettenbauer G. Spingler H. Naturwissenschaften 1960; 47: 156
• 3b Popelak A. Lettenbauer G. Haack E. Spingler H. Naturwissenschaften 1960; 47: 231
• 4 Harvey AL. Young LC. Viljoen AM. Gericke NP. J. Ethnopharmacol. 2011; 137: 1124
• 5a Pelletier SW. Alkaloids: Chemical and Biological Perspectives . Vol. 15. Elsevier Science; Oxford: 2001: 34
• 5b Smith MT. Crouch NR. Gericke N. Hirst M. J. Ethnopharmacol. 1996; 50: 119
• 5c Jeffs PW. Archie WC. Hawks RL. Farrier DS. J. Am. Chem. Soc. 1971; 93: 3752

For representative reviews on the synthesis of quaternary all-carbon-sterecenter, see:
• 6a Martin SF. Tetrahedron 1980; 36: 419
• 6b Douglas CJ. Overman LE. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 5363
• 6c Christoffers J. Baro A. Adv. Synth. Catal. 2005; 347: 1473
• 6d Trost BM. Jiang C. Synthesis 2006; 369
• 7 Claisen L. Ber. Dtsch. Chem. Ges. 1912; 45: 3157

For recent reviews on the Claisen rearrangement, see:
• 8a Martín Castro AM. Chem. Rev. 2004; 104: 2939
• 8b Majumdar KC. Nandi RK. Tetrahedron 2013; 69: 6921
• 8c Rehbein J. Hiersemann M. Synthesis 2013; 45: 1121
• 9a Chida N. Sugihara K. Amano S. Ogawa S. J. Chem. Soc., Perkin Trans. 1 1997; 0: 275
• 9b Bohno M. Sugie K. Imase H. Yusof YB. Oishib T. Chida N. Tetrahedron 2007; 63: 6977
• 9c Tanimoto H. Kato T. Chida N. Tetrahedron Lett. 2007; 48: 6267
• 9d Tanimoto H. Saito R. Chida N. Tetrahedron Lett. 2008; 49: 358
• 9e Ichiki M. Tanimoto H. Miwa S. Saito R. Sato T. Chida N. Chem. Eur. J. 2013; 19: 264
• 10a Shamma M. Rodriguez HR. Tetrahedron Lett. 1965; 6: 4847
• 10b Shamma M. Rodriguez HR. Tetrahedron 1968; 24: 6583
• 11 Yamada S. Otani G. Tetrahedron Lett. 1971; 12: 1133

For recent syntheses of mesembrine, see:
• 12a Zhao Y. Zhou Y. Liang L. Yang X. Du F. Li L. Zhang H. Org. Lett. 2009; 11: 555
• 12b Gu Q. You S.-L. Chem. Sci. 2011; 2: 1519
• 12c Honda T. Arai H. Yamamoto N. Takahashi K. Heterocycles 2012; 84: 327
• 12d Zhang Q.-Q. Xie J.-H. Yang XH. Xie J.-B. Zhou Q.-L. Org. Lett. 2012; 14: 6158
• 12e Geoghegan K. Evans P. J. Org. Chem. 2013; 78: 3410
• 12f Geoghegan K. Evans P. Tetrahedron Lett. 2014; 55: 1431
• 12g Ozaki T. Kobayashi Y. Org. Chem. Front. 2015; 2: 328
• 12h Nunokawa S. Minamisawa M. Nakano K. Ichikawa Y. Kotsuki H. Synlett 2015; 26: 2301
• 12i Gan P. Smith MW. Braffman NR. Snyder SA. Angew. Chem. Int. Ed. 2016; 55: 3625
• 12j Spittler M. Lutsenko K. Czekelius C. J. Org. Chem. 2016; 81: 6100
• 12k Bhosale VA. Ukale DU. Waghmode SB. New J. Chem. 2016; 40: 9432
• 12l Wang L.-N. Cui Q. Yu Z.-X. J. Org. Chem. 2016; 81: 10165
• 13 Reformatsky S. Ber. Dtsch. Chem. Ges. 1887; 20: 1210
• 14 Keck GE. Webb RR. J. Org. Chem. 1982; 47: 1302
• 15 Johnson WS. Werthemann L. Bartlett WR. Brocksom TJ. Li T. Faulkner DJ. Petersen MR. J. Am. Chem. Soc. 1970; 92: 741
• 16 For a review of the Johnson–Claisen rearrangements, see: Fernandes RA. Chowdhury AK. Kattanguru P. Eur. J. Org. Chem. 2014; 2833
• 17 Procedure for the Preparation of Compound 3 A sealed tube charged with alcohol 5 (205 mg, 0.876 mmol) in triethyl orthoacetate (17.5 mL, 0.05 M) was treated with 2-nitrophenol (3.65 mg, 0.026 mmol, 3 mol%). After stirring for 20 h at 140 °C, the resulting mixture was cooled to room temperature and quenched with the addition of sat. aq NaHCO₃ and diluted with H₂O and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with sat. aq NaCl, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, 10% EtOAc/hexanes) to provide 3 (193 mg, 73%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃): δ = 6.89–6.83 (m, 2 H), 6.80–6.76 (m, 1 H), 6.13–6.05 (m, 1 H), 5.92 (dt, J = 10.2, 3.5 Hz, 1 H), 3.96 (dq, J = 7.1, 0.7 Hz, 1 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 2.76 (d, J = 14.1 Hz, 1 H), 2.65 (d, J = 14.2 Hz, 1 H), 2.06–1.95 (m, 2 H), 1.95–1.78 (m, 2 H), 1.60–1.47 (m, 1 H), 1.44–1.26 (m, 1 H), 1.08 (t, J = 7.1 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 171.2, 148.2, 147.0, 139.4, 132.2, 128.3, 119.1, 110.4, 110.3, 59.8, 55.8, 55.7, 46.9, 41.5, 37.1, 25.0, 18.6, 14.0. IR (film): ν_max = 2934, 2834, 1730, 1517, 1255, 1149, 1029, 467 cm^–1. HRMS (ESI): m/z calcd for C₁₈H₂₄O₄: 304.1675; found: 304.1677 [M⁺].
• 18 Corey EJ. Fleet GW. J. Tetrahedron Lett. 1973; 14: 4499
• 19a Hackett S. Livinghouse T. J. Org. Chem. 1986; 51: 1629
• 19b Yamada O. Ogasawara K. Tetrahedron Lett. 1998; 39: 7747
• 20 Procedure for the Synthesis of Mesembrine (1) A cooled (0 °C) solution of ketal 11 (252 mg, 0.726 mmol) in THF (9 mL, 0.08 M) was treated with LiAlH₄ (3.6 mL, 1.0 M in THF, 3.63 mmol, 5 equiv). After refluxing for 5 h, the resulting mixture was quenched with the addition of MeOH and cooled to room temperature. The resulting mixture was added 1 M HCl (9 mL, 0.08 M) and stirred at reflux. After stirring for 4 h, the resulting mixture was basified with the addition of 1 M NaOH and diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with sat. aq NaCl, dried over anhydrous Na₂SO₄, and concentrated in vacuo. The residue was purified by flash chromatography (SiO₂, 2% Et₃N gradient elution: 5% MeOH/CH₂Cl₂ to 10% MeOH/CH₂Cl₂) to provide (±)-mesembrine (1, 204 mg, 97%) as a white foam. ¹H NMR (500 MHz, CDCl₃): δ = 6.93 (dd, J = 8.4, 2.1 Hz, 1 H), 6.89 (d, J = 1.9 Hz, 1 H), 6.84 (d, J = 8.4 Hz, 1 H), 3.90 (s, 3 H), 3.88 (s, 3 H), 3.16–3.10 (m, 1 H), 2.94 (t, J = 3.4 Hz, 1 H), 2.60 (t, J = 3.1 Hz, 2 H), 2.48–2.38 (m, 1 H), 2.37–2.28 (m, 1 H), 2.31 (s, 3 H), 2.26–2.03 (m, 5 H).¹³C NMR (125 MHz, CDCl₃): δ = 211.5, 149.0, 147.4, 140.2, 117.9, 110.9, 109.9, 70.4, 56.0, 55.9, 54.8, 47.5, 40.5, 40.1, 38.8, 36.2, 35.2. IR (film): ν_max = 3468, 2941, 2835, 2782, 1716, 1519, 1254, 1148, 1027 cm^–1. HRMS (ESI): m/z calcd for C₁₇H₂₃NO₃: 289.1678; found: 289.1677 [M⁺].