Asymmetric Total Synthesis of (–)-Galanthamine via Intramolecular Heck Reaction of Conjugated Diene

Abstract

Asymmetric total synthesis of (–)-galanthamine was accomplished starting from an epoxide. Intramolecular Heck reaction of a conjugated diene system was employed to construct the key quaternary carbon center. The cyclohexene-1,3-diol unit of (–)-galanthamine is derived from an optically active epoxy alkenol.

Key words

epoxides - (–)-galanthamine - Heck reaction - meta­thesis - total synthesis

• References and Notes

• 1a Martin SF In The Alkaloids . Vol. 30. Brossi A. Academic Press; New York: 1987: 251
• 1b Hoshino O In The Alkaloids . Vol. 51. Cordell GA. Academic Press; New York: 1998: 323
• 1c Jin Z. Nat. Prod. Rep. 2003; 20: 606
• 2a Unni LK. CNS Drugs 1998; 10: 447
• 2b Nordberg A, Svensson A.-L. Drug Safety 1998; 19: 465
• 2c Thatte U. Curr. Opin. CPNS Invest. Drugs 1999; 1: 357
• 2d Weinstock M. CNS Drugs 1999; 12: 307
• 2e Maelicke A, Albuquerque EX. Eur. J. Pharmacol. 2000; 393: 165
• 2f Lilienfeld S. CNS Drug Rev. 2002; 8: 159
• 2g Popa RV, Pereira EF. R, Lopes C, Maelicke A, Albuquerque EX. J. Mol. Neurosci. 2006; 30: 227
• 3a Mikhno VV. Farm. Zh. (Kiev) 1966; 21: 28
• 3b Bastida J, Viladomat F, Llabrés JM, Quiroga S, Codina C, Rubiralta M. Planta Med. 1990; 56: 123
• 3c Shieh W.-C, Carlson JA. J. Org. Chem. 1994; 59: 5463
• 3d Küenburg B, Czollner L, Fröhlich J, Jordis U. Org. Process Res. Dev. 1999; 3: 425

For recent reviews on the synthesis of galanthamine and its analogues, see:
• 4a Marco-Contelles J, do Carmo Carreiras M, Rodríguez C, Villarroya M, García AG. Chem. Rev. 2006; 106: 116
• 4b Marco-Contelles J, Perez-Mayoral E, van Nhien AN, Postel D. Targets Heterocycl. Syst. 2007; 11: 365
• 4c Jin Z. Nat. Prod. Rep. 2009; 26: 363
• 5a Barton DH. R, Kirby GW. Proc. Chem. Soc. London 1960; 392
• 5b Barton DH. R, Kirby GW. J. Chem. Soc. 1962; 806
• 5c Kametani T, Yamaki K, Yagi H, Fukomuto K. Chem. Commun. 1969; 425
• 5d Shimizu K, Tomioka K, Yamada S.-I, Koga K. Chem. Pharm. Bull. 1978; 26: 3765
• 5e Szewczyk J, Lewin AH, Carroll FI. J. Heterocycl. Chem. 1988; 25: 1809
• 5f Vlahov R, Krikorian D, Spassov G, Chinova M, Vlahov I, Parushev S, Snatzke G, Ernst L, Kieslich K, Abraham W.-R, Sheldrick WS. Tetrahedron 1989; 45: 3329
• 5g Szewczyk J, Wilson JW, Lewin AH, Carroll FI. J. Heterocycl. Chem. 1995; 32: 195
• 5h Czollner L, Frantsits W, Küenburg B, Hedenig U, Fröhlich J, Jordis U. Tetrahedron Lett. 1998; 39: 2087
• 5i Kita Y, Arisawa M, Gyoten M, Nakajima M, Hamada R, Tohma H, Takada T. J. Org. Chem. 1998; 63: 6625
• 5j Krikorian D, Tarpanov V, Parushev S, Mechkarova P. Synth. Commun. 2000; 30: 2833
• 5k Kodama S, Hamashima Y, Nishide K, Node M. Angew. Chem. Int. Ed. 2004; 43: 2659
• 6a Trost BM, Toste FD. J. Am. Chem. Soc. 2000; 122: 11262
• 6b Pilger C, Westermann B, Flörke U, Fels G. Synlett 2000; 1163
• 6c Parsons PJ, Charles MD, Harvey DM, Sumoreeah LR, Shell A, Spoors G, Gill AL, Smith S. Tetrahedron Lett. 2001; 42: 2209
• 6d Guillou C, Beunard J.-L, Gras E, Thal C. Angew. Chem. Int. Ed. 2001; 40: 4745
• 6e Trost BM, Tang W. Angew. Chem. 2002; 114: 2919
• 6f Trost BM, Tang W, Toste FD. J. Am. Chem. Soc. 2005; 127: 14785
• 6g Satcharoen V, McLean NJ, Kemp SC, Camp NP, Brown RC. D. Org. Lett. 2007; 9: 1867
• 7 Recently, a reductive intramolecular Heck reaction approach using the type b cyclization mode has been reported: Chen J.-Q, Xie J.-H, Bao D.-H, Liu S, Zhou Q.-L. Org. Lett. 2012; 14: 2714
• 8a Kim Y.-J, Tae J. Synlett 2006; 61
• 8b Lee J, Jung Y.-H, Tae J. Bull. Korean Chem. Soc. 2007; 28: 513
• 8c Jung Y.-H, Kim Y.-J, Lee J, Tae J. Chem. Asian J. 2007; 2: 656
• 8d Kim M.-Y, Kim H, Tae J. Synlett 2009; 1303
• 8e Kim H, Kim M.-Y, Tae J. Synlett 2009; 2949
• 8f Kim H, Choi K, Tae J. Synlett 2012; 23: 1832
• 9 Alcaraz L, Harnett JJ, Mioskowski C, Martel JP, Gall TL, Shin D.-S, Falck JR. Tetrahedron Lett. 1994; 35: 5449
• 10a Brotherton RJ, Hazlet SE. J. Org. Chem. 1962; 27: 3253
• 10b O’Bara EJ, Balsley RB, Starer I. J. Org. Chem. 1970; 35: 16
• 10c Cheng B, Zhang S, Zhu L, Zhang J, Li Q, Shan A, He L. Synthesis 2009; 2501
• 11a Wovkulich PM, Shankaran K, Kiegiel J, Uskoković MR. J. Org. Chem. 1993; 58: 832
• 11b Kaufman TS. Tetrahedron Lett. 1996; 37: 5329
• 12a Walker MA. J. Org. Chem. 1995; 60: 5352
• 12b Myers AG, Zheng B. Tetrahedron Lett. 1996; 37: 4841
• 12c Walker MA. Tetrahedron Lett. 1996; 37: 8133
• 13 Tsunoda T, Yamamiya Y, Itô S. Tetrahedron Lett. 1993; 34: 1639
• 14a Paquette LA, Schloss JD, Efremov I, Fabris F, Gallou F, Méndez-Andino J, Yang J. Org. Lett. 2000; 2: 1259
• 14b Ahn YM, Yang K, Georg GI. Org. Lett. 2001; 3: 1411
• 14c Cho JH, Kim BM. Org. Lett. 2003; 5: 531
• 15 Miller RA, Li W, Humphrey GR. Tetrahedron Lett. 1996; 37: 3429
• 16 Salvador JA. R, Clark JH. Chem. Commun. 2001; 33
• 17a Chidambaram N, Chandrasekaran S. J. Org. Chem. 1987; 52: 5048
• 17b Parish EJ, Wei T.-Y. Synth. Commun. 1987; 17: 1227
• 18 Liu C.-H, Li F, Tang R.-R. Bull. Korean Chem. Soc. 2010; 31: 1723
• 19a Bhalerao UT, Rapoport H. J. Am. Chem. Soc. 1971; 93: 4835
• 19b Sharpless KB, Lauer RF. J. Am. Chem. Soc. 1972; 94: 7154
• 19c Umbreit MA, Sharpless KB. J. Am. Chem. Soc. 1977; 99: 5526
• 19d Warpehoski MA, Chabaud B, Sharpless KB. J. Org. Chem. 1982; 47: 2897
• 20a Shibasaki M, Vogl EM, Ohshima T. Adv. Synth. Catal. 2004; 346: 1533
• 20b Omori AT, Finn KJ, Leisch H, Carroll RJ, Hudlicky T. Synlett 2007; 2859
• 21 Procedure for the Heck Cyclization To a solution of 19 (210 mg, 0.37 mmol) was added Pd(OAc)₂ (12 mg, 0.055 mmol), Ag₂CO₃ (303 mg, 1.10 mmol), and dppp (23 mg, 0.055 mmol) in freshly distilled toluene (4 mL), and the solution was refluxed. After 17 h, the mixture was concentrated and diluted with THF (1.2 mL) and H₂O (40 μL) and then treated with NaBH₄ (35 mg, 0.92 mmol) at 0 °C. After stirring for 2 h at r.t., the mixture was quenched with sat. aq NH₄Cl and extracted with EtOAc (2 × 10 mL) and CH₂Cl₂ (2 × 10 mL). The combined organic layers were dried over anhyd MgSO₄ and condensed in vacuo. The crude mixture was purified by silica gel chromatography (hexane–EtOAc = 2:1) to give 84 mg of 20 (46%) as a pale yellow oil.
• 22 Spectral Data for (–)-Galanthamine (1) R_f = 0.25 (silica gel, CH₂Cl₂–MeOH = 9:1); [α]_D ²⁰ –84.57 (c 0.50, CHCl₃); mp 127–129 °C. ¹H NMR (400 MHz, CDCl₃): δ = 6.67–6.62 (m, 2 H), 6.08–5.99 (m, 2 H), 4.62 (s, 1 H), 4.16–4.07 (m, 2 H), 3.84 (s, 3 H), 3.69 (d, J = 15.2 Hz, 1 H), 3.27 (t, J = 13.0 Hz, 1 H), 3.06 (d, J = 14.8 Hz, 1 H), 2.69 (m, 1 H), 2.41 (s, 3 H), 2.12–1.99 (m, 2 H), 1.64–1.58 (m, 2 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 146.1, 144.4, 133.2, 129.3, 127.8, 127.0, 122.2, 111.4, 88.9, 62.3, 60.9, 56.1, 54.0, 48.4, 42.3, 34.0, 30.1. IR (film): 3380, 3020, 2912, 1628, 1505, 1433, 1282 cm^–1. HRMS: m/z calcd for C₁₇H₂₁NO₃Na [M + Na]⁺: 310.1419; found: 310.1405.