Enantioselective Synthesis of (–)-Pentazocine and (–)-Metazocine

Abstract

We have accomplished an efficient asymmetric synthesis of (–)-pentazocine and (–)-metazocine from the readily available d-tyrosine, featuring a ring-closing metathesis (RCM) reaction for the formation of the C ring and an intramolecular Friedel–Crafts reaction for the assembly of the B ring. The new strategy established herein should be applicable to enantioselective synthesis of a broad range of chiral benzomorphan analogues, thereby facilitating the biological and medicinal chemistry studies of these clinically important molecules.

Key words

benzomorphans - pentazocine - metazocine - asymmetric synthesis - ring-closing metathesis reaction

• References and Notes

• 1a Novak BH, Hudlicky T, Reed JW, Mulzer J, Trauner D. Curr. Org. Chem. 2000; 4: 343
• 1b Hudlicky T, Butora G, Fearnley PS, Gum AG, Stabile MR. Stud. Nat. Prod. Chem. 1996; 18: 43
• 1c Blakemore PR, White JD. Chem. Commun. 2002; 1159
• 2a Eddy NB, May EL. Synthetic Analgesics, Part B . Pergamon Press; Oxford, London: 1966
• 2b Palmer DC, Strauss MJ. Chem. Rev. 1977; 77: 1
• 2c Lednicer D. Strategies for Organic Drug Synthesis and Design . John Wiley and Sons; New York: 1998: 161-184
• 3a Clarke EG. C. Nature (London, U.K.) 1959; 184: 451
• 3b Archer S, Albertson FN, Harris LS, Pierson AK, Bird JG. J. Med. Chem. 1964; 7: 123
• 3c Kametani T, Kigasawa K, Hiiragi M, Wagatsuma N. Heterocycles 1974; 2: 79
• 3d Tullar BF, Harris LS, Perry RL, Pierson AK, Soria AE, Wetterau WF, Albertson NF. J. Med. Chem. 1967; 10: 383
• 4a Boulanger WA. Synth. Commun. 1999; 29: 2201
• 4b Brine GA, Berrang B, Hayes JP, Carroll FI. J. Heterocycl. Chem. 1990; 27: 2139
• 4c Rice KC, Jacobson AE. J. Med. Chem. 1976; 19: 430
• 5a Comins DL, Zhang Y.-M, Joseph SP. Org. Lett. 1999; 1: 657
• 5b Genisson Y, Marazano C, Das BC. J. Org. Chem. 1993; 58: 2052
• 5c Meyers AI, Dickman DA, Bailey TR. J. Am. Chem. Soc. 1985; 107: 7974
• 5d Chen Q, Huo X, Zhang H, She X. Synlett 2012; 23: 1349
• 5e Chen Q, Huo X, Zhang H, She X. Chem. Asian J. 2012; 7: 2543
• 6 Trost BM, Tang W. J. Am. Chem. Soc. 2003; 125: 8744
• 7 Coppola GM, Schuster HF. Asymmetric Synthesis – Construction of Chiral Molecules Using Amino Acids. John Wiley and Sons; New York: 1987
• 8 Yang X, Zhai H, Li Z. Org. Lett. 2008; 10: 2457
• 9a Hu H, Zhai H. Synlett 2003; 2129
• 9b Ma Z, Zhai H. Synlett 2007; 161
• 10a Grubbs RH, Miller SJ, Fu GC. Acc. Chem. Res. 1995; 28: 446
• 10b Prunet J. Angew. Chem. Int. Ed. 2003; 42: 2826
• 10c Nicolaou KC, Bulger PG, Sarlah D. Angew. Chem. Int. Ed. 2005; 44: 4490
• 11a Jafarpour L, Nolan SP. Org. Lett. 2000; 2: 4075
• 11b Louie J, Grubbs RH. Angew. Chem. Int. Ed. 2001; 40: 247
• 11c Fürstner A, Ackermann L, Beck K, Hori H, Koch D, Langemann K, Liebl M, Six C, Leitner W. J. Am. Chem. Soc. 2001; 123: 9000
• 11d Andreana PR, McLellan JS, Chen Y, Wang PG. Org. Lett. 2002; 4: 3875
• 11e Yao Q, Zhang Y. J. Am. Chem. Soc. 2004; 126: 74
• 11f Michrowska A, Bujok R, Harutyunyan S, Sashuk V, Dolgonos G, Grela K. J. Am. Chem. Soc. 2004; 126: 9318
• 11g Berlin JM, Campbell K, Ritter T, Funk WT, Chlenov A, Grubbs RH. Org. Lett. 2007; 9: 1339
• 11h Stewart LC, Ung T, Pletnev AA, Berlin JM, Grubbs RH, Schrodi Y. Org. Lett. 2007; 9: 1589
• 11i Yoshida K, Kawagoe F, Iwadate N, Takahashi H, Imamoto T. Chem. Asian J. 2006; 1: 611
• 11j Vorfalt T, Leuthaeusser S, Plenio H. Angew. Chem. Int. Ed. 2009; 48: 5191
• 11k Anada M, Tanaka M, Washio T, Yamawaki M, Abe T, Hashimoto S. Org. Lett. 2007; 9: 4559
• 11l Stenne B, Timperio J, Savoie J, Dudding T, Collins SK. Org. Lett. 2010; 12: 2030
• 11m Heppekausen J, Fürstner A. Angew. Chem. Int. Ed. 2011; 50: 7829
• 12a Chandrasekhar S, Chandrashekar G. Tetrahedron: Asymmetry 2005; 16: 2209
• 12b Yonezawa Y, Shimizu K, Yoon K, Shin C. Synthesis 2000; 634
• 13 The ratio was deduced by ¹H NMR analysis.
• 14 Neipp CE, Martin SF. J. Org. Chem. 2003; 68: 8867
• 15 Kametani T, Kigasawa K, Hüragi M, Hayasaka T, Wagatsuma N, Wakisaka K. J. Heterocycl. Chem. 1969; 6: 43
• 16 Ji S, Gortler LB, Waringlo A, Battisti A, Bank S, Closson WD. J. Am. Chem. Soc. 1967; 89: 5311
• 17 Synthesis of 3 To a solution of 13 (31.0 mg, 0.101 mmol) in EtOAc (1 mL), EtOH (1 mL), and 2.5 N HCl (0.25 mL) was added 10% Pd/C (10.7 mg, 10.1 μmol). The mixture was stirred under H₂ (1 atm) overnight (16 h) and filtered. The filtrate was concentrated to give a crude secondary amine as slurry, which was used for the next step without purification. The above crude secondary amine was dissolved in DMF (1.5 mL). NaHCO₃ (67.9 mg, 0.808 mmol) and prenyl bromide (30.1 mg, 0.202 mmol) were successively added. The mixture was stirred at r.t. for 2 h, diluted with H₂O (3 mL), and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated to give a residue, which was chromatographed (MeOH–CH₂Cl₂, 1:10) to afford (–)-pentazocine (22.0 mg, 76%) as a white solid: [α]_D ²⁰ = –135.3 (c 0.44, CHCl₃). IR (film): ν = 3287, 2965, 2919, 2574, 1740, 1673, 1610, 1581, 1498, 1459, 1376, 1259, 1236, 1066, 933, 849, 807, 757 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.84 (d, J = 7.2 Hz, 3 H), 1.20–1.39 (m, 1 H), 1.31 (s, 3 H), 1.66 (s, 3 H), 1.71 (s, 3 H), 1.90 (dt, J = 12.8, 4.0 Hz, 1 H), 1.95–2.06 (m, 1 H), 2.15 (dt, J = 12.4, 2.4 Hz, 1 H), 2.59–2.71 (m, 1 H), 2.71 (dd, J = 18.8, 6.4 Hz, 1 H), 2.93 (d, J = 18.4 Hz, 1 H), 3.04–3.13 (m, 1 H), 3.22 (d, J = 6.4 Hz, 2 H), 5.27–5.38 (m, 1 H), 6.63 (dd, J = 8.0, 2.4 Hz, 1 H), 6.71 (d, J = 2.4 Hz, 1 H), 6.94 (d, J = 8.4 Hz, 1 H). ¹³C NMR (75.47 MHz, CDCl₃): δ = 14.0, 18.1, 23.3, 25.2, 26.0, 36.2, 40.7, 41.2, 45.6, 52.2, 57.1, 112.5, 113.4, 120.1, 127.0, 128.1, 136.2, 142.8, 154.9. ESI-MS: m/z = 286.1 [M + H], 308.1 [M + Na]. HRMS (MALDI): m/z calcd for C₁₉H₂₇NO + H: 286.2165; found: 286.2170.
• 18 Gottlieb L, Meyers AI. J. Org. Chem. 1990; 55: 5659