Concise Total Synthesis of (+)-Aphanorphine

Abstract

A concise total synthesis of (+)-aphanorphine is described. The key features of the strategy include a Pd-catalyzed intermolecular trimethylenemethane [3+2]-cycloaddition to form ring C and a Co-catalyzed radical cyclization through a hydrogen-atom transfer to close ring B. The synthesis was completed in six steps.

Key words

aphanorphine - total synthesis - alkaloids - tert-butanesulfinimine - cycloaddition - hydrogen-atom transfer

Publication History

Received: 28 February 2021

Accepted after revision: 19 March 2021

Article published online:
08 April 2021

• References and Notes

• 1 Gulavita N, Hori A, Shimizu Y, Laszlo P, Clardy J. Tetrahedron Lett. 1988; 29: 4381
• 2a Tamura O, Yanagimachi T, Kobayashi T, Ishibashi H. Org. Lett. 2001; 3: 2427
• 2b Zhai H, Luo S, Ye C, Ma Y. J. Org. Chem. 2003; 68: 8268
• 2c Hu H, Zhai H. Synlett 2003; 2129
• 2d Tamura O, Yanagimachi T, Ishibashi H. Tetrahedron: Asymmetry 2003; 14: 3033
• 2e Bower JF, Szeto P, Gallagher T. Chem. Commun. 2005; 5793
• 2f Bower JF, Szeto P, Gallagher T. Org. Biomol. Chem. 2007; 5: 143
• 2g Ma Z, Zhai H. Synlett 2007; 161
• 2h Ma Z, Hu H, Xiong W, Zhai H. Tetrahedron 2007; 63: 7523
• 2i Yang X, Zhai H, Li Z. Org. Lett. 2008; 10: 2457
• 2j Yang X, Cheng B, Li Z, Zhai H. Synlett 2008; 2821
• 2k Yoshimitsu T, Atsumi C, Iimori E, Nagaoka H, Tanaka T. Tetrahedron Lett. 2008; 49: 4473
• 2l Mai DN, Rosen BR, Wolfe JP. Org. Lett. 2011; 13: 2932
• 2m Medjahdi M, González-Gómez JC, Foubelo F, Yus M. Eur. J. Org. Chem. 2011; 2230
• 2n Pansare SV, Kulkarni KG. RSC Adv. 2013; 3: 19127
• 2o Wang Z, Zheng H, Yang J, Xie X, She X. Adv. Synth. Catal. 2015; 357: 2082
• 2p Peterson LJ, Wolfe JP. Adv. Synth. Catal. 2015; 357: 2339
• 3a Fuchs JR, Funk RL. Org. Lett. 2001; 3: 3923
• 3b Katoh M, Inoue H, Suzuki A, Honda T. Synlett 2005; 2820
• 3c Honda T, Katoh M, Inoue H. Heterocycles 2007; 72: 497
• 3d Donets PA, Goeman JL, Van der Eycken J, Robeyns K, Van Meervelt L, Van der Eycken EV. Eur. J. Org. Chem. 2009; 793
• 4a Takano S, Inomata K, Sato T, Ogasawara K. J. Chem. Soc., Chem. Commun. 1989; 1591
• 4b Takano S, Inomata K, Sato T, Takahashi M, Ogasawara K. J. Chem. Soc., Chem. Commun. 1990; 290
• 4c Honda T, Yamamoto A, Cui Y, Tsubuki M. J. Chem. Soc., Perkin Trans. 1 1992; 531
• 4d Hulme AN, Henry SS, Meyers AI. J. Org. Chem. 1995; 60: 1265
• 4e Fadel A, Arzel P. Tetrahedron: Asymmetry 1995; 6: 893
• 4f Hallinan KO, Honda T. Tetrahedron 1995; 51: 12211
• 4g Meyers AI, Schmidt W, Santiago B. Heterocycles 1995; 40: 525
• 4h Shiotani S, Okada H, Nakamata K, Yamamoto T, Sekino F. Heterocycles 1996; 43: 1031
• 4i Node M, Imazato H, Kurosaki R, Kawano Y, Inoue T, Nishide K, Fuji K. Heterocycles 1996; 42: 811
• 4j Ogasawara K, Shimizu M, Kamikubo T. Heterocycles 1997; 46: 21
• 4k Fadel A, Arzel P. Tetrahedron: Asymmetry 1997; 8: 283
• 4l Fadel A, Arzel P. Tetrahedron: Asymmetry 1997; 8: 371
• 4m Tanaka K, Taniguchi T, Ogasawara K. Tetrahedron Lett. 2001; 42: 1049
• 4n ElAzab AS, Taniguchi T, Ogasawara K. Heterocycles 2002; 56: 39
• 4o Kita Y, Futamura J, Ohba Y, Sawama Y, Ganesh JK, Fujioka H. J. Org. Chem. 2003; 68: 5917
• 4p Taylor SK, Ivanovic M, Simons LJ, Davis MM. Tetrahedron: Asymmetry 2003; 14: 743
• 4q Li M, Zhou P, Roth HF. Synthesis 2007; 55
• 4r Zhu D.-Y, Xu M.-H, Tu Y.-Q, Zhang F.-M, Wang S.-H. Chem. Eur. J. 2015; 21: 15502
• 4s Chiou W.-H, Chen P.-C. J. Org. Chem. 2017; 82: 8213
• 5 Grainger RS, Welsh EJ. Angew. Chem. Int. Ed. 2007; 46: 5377

For reviews about MHAT reaction, see:
• 6a Crossley SW. M, Obradors C, Martinez RM, Shenvi RA. Chem. Rev. 2016; 116: 8912
• 6b Green SA, Crossley SW. M, Matos JL. M, Vásquez-Céspedes S, Shevick SL, Shenvi RA. Acc. Chem. Res. 2018; 51: 2628

For selected applications MHAT reaction in natural product synthesis, see:
• 7a Zhang B, Zheng W, Wang X, Sun D, Li C. Angew. Chem. Int. Ed. 2016; 55: 10435
• 7b Xu G, Elkin M, Tantillo DJ, Newhouse TR, Maimone TJ. Angew. Chem. Int. Ed. 2017; 56: 12498
• 7c Deng H, Cao W, Liu R, Zhang Y, Liu B. Angew. Chem. Int. Ed. 2017; 56: 5849
• 7d Godfrey NA, Schatz DJ, Pronin SV. J. Am. Chem. Soc. 2018; 140: 12770
• 7e Lu Z, Zhang X, Guo Z, Chen Y, Mu T, Li A. J. Am. Chem. Soc. 2018; 140: 9211
• 7f Farney EP, Feng SS, Schäfers F, Reisman SE. J. Am. Chem. Soc. 2018; 140: 1267
• 7g Ji Y, Xin Z, He H, Gao S. J. Am. Chem. Soc. 2019; 141: 16208
• 7h Xu G, Wu J, Li L, Lu Y, Li C. J. Am. Chem. Soc. 2020; 142: 15240
• 7i Chen P, Wang C, Yang R, Xu H, Wu J, Jiang H, Chen K, Ma Z. Angew. Chem. Int. Ed. 2021; 60: 5512
• 8 Yamago S, Nakamura E. Org. React. (Hoboken, NJ, U. S.) 2002; 61: 1

For selected applications of N-tert-butanesulfinimines in natural-product synthesis, see:
• 9a Chuang KV, Navarro R, Reisman SE. Angew. Chem. Int. Ed. 2011; 50: 9447
• 9b Zhao S, Andrade RB. J. Am. Chem. Soc. 2013; 135: 13334
• 9c Chogii I, Njardarson JT. Angew. Chem. Int. Ed. 2015; 54: 13706
• 9d Tian M, Yan M, Baran PS. J. Am. Chem. Soc. 2016; 138: 14234
• 9e Hugelshofer CL, Palani V, Sarpong R. J. Am. Chem. Soc. 2019; 141: 8431
• 9f Li Y, Wang C, Ma Z, Zhang K, Xu X.-T. Org. Lett. 2020; 22: 8589
• 10 Yao Q, Yuan C. J. Org. Chem. 2013; 78: 6962
• 11 Procopiou G, Lewis W, Harbottle G, Stockman RA. Org. Lett. 2013; 15: 2030
• 12a Trost BM, Chan DM. T. J. Am. Chem. Soc. 1979; 101: 6432
• 12b Trost BM, Chan DM. T. J. Am. Chem. Soc. 1983; 105: 2326
• 12c Trost BM, Bringley DA, O’Keefe BM. Org. Lett. 2013; 15: 5630
• 13 Shigehisa H, Ano T, Honma H, Ebisawa K, Hiroya K. Org. Lett. 2016; 18: 3622
• 14 Obradors C, Martinez RM, Shenvi RA. J. Am. Chem. Soc. 2016; 138: 4962
• 15 Methyl (1S,4S)-8-methoxy-1-methyl-1,2,4,5-tetrahydro-3H-1,4-methanobenzo[d]azepine-3-carboxylate (18) A 4 mL vial was charged with sulfinimine 17 (13 mg, 0.05 mmol, 1.0 equiv), catalyst C7 (1.5 mg, 0.0025 mmol, 0.05 equiv), and oxidant O1 (29 mg, 0.1 mmol, 2.0 equiv). PhCF₃ (0.5 mL), previously dried in vacuo for 0.5 h, was then added and the solution was bubbled with N₂ for 10 min. PMHS (22 µL, 0.1 mmol, 2.0 equiv) was added, and the resulting mixture was stirred at 25 °C for 20 h then diluted with EtOAc (2 mL). The solution was washed with H₂O (0.5 mL) and brine (3 × 0.5 mL), then dried (Na₂SO₄) and concentrated in vacuo. The residue was purified by preparative TLC (PE–EtOAc, 5:1) to give a yellow solid: yield; 10.8 mg (83%); mp 89–92 °C; [α]_D ²⁵ +167.3 (c 0.55, CHCl₃). IR (KBr): 3795, 2957, 1701, 1612, 1495, 1453, 1389, 863, 805, 769, 741, 698 cm^–1. Rotamer ¹H NMR (500 MHz, CDCl₃): δ = 7.03 (d, J = 8.4 Hz, 0.5 H), 6.99 (d, J = 8.3 Hz, 0.5 H), 6.85–6.80 (m, 1 H), 6.72 (td, J = 8.3, 2.5 Hz, 1 H), 4.50–4.43 (m, 0.6 H), 4.39–4.32 (m, 0.4 H), 3.82–3.74 (m, 3 H), 3.72–3.66 (m, 1.3 H), 3.63–3.58 (m, 1.7 H), 3.42 (d, J = 10.1 Hz, 0.5 H), 3.36 (d, J = 9.9 Hz, 0.5 H), 3.28 (d, J = 10.0 Hz, 0.5 H), 3.22 (d, J = 9.9 Hz, 0.5 H), 3.18 (d, J = 16.6 Hz, 0.5 H), 3.04 (d, J = 16.6 Hz, 0.5 H), 2.90 (d, J = 16.6 Hz, 1 H), 2.02–1.86 (m, 2 H), 1.57–1.45 (m, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 157.9, 157.8, 155.1, 154.9, 145.8, 145.7, 130.5, 130.3, 125.7, 125.4, 111.6, 111.4, 109.89, 109.86, 61.6, 61.2, 55.29, 55.27, 54.8, 54.6, 52.2, 52.0, 42.2, 41.7, 41.6, 40.8, 36.4, 35.7, 20.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₂₀NO₃: 262.1443; found: 262.1437.