Bioinspired Formal Synthesis of Pancracine via Selective Hydro­genation of an Indole Derivative

Abstract

A bioinspired formal synthesis of the montanine-type Amaryllidaceae alkaloid pancracine through selective hydrogenation of a 3-arylindole derivative is disclosed. The key features of this synthesis include a hexahydroindole synthesis by a chemoselective hydrogenation of an aryl-substituted indole and a diastereoselective silyl hydride reduction of an iminium intermediate generated from an enaminone through Tf₂O activation. The eight-step assembly of the 5,11-methanomorphanthridine framework represents a novel and efficient strategy that permits one of the shortest syntheses of pancracine reported so far.

Key words

bioinspired synthesis - hydrogenation - chemoselectivity - indole alkaloids - pancracine

• References and Notes

• 1 Vitaku E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257
• 2 Lovering F, Bikker J, Humblet C. J. Med. Chem. 2009; 52: 6752
• 3 Aldeghi M, Malhotra S, Selwood DL, Chan AW. E. Chem. Biol. Drug Des. 2014; 83: 450
• 4 Kim AN, Stoltz BM. ACS Catal. 2020; 10: 13834
• 5 Lubitz W, Ogata H, Rüdiger O, Reijerse E. Chem. Rev. 2014; 114: 4081
• 6 Schilter D, Camara JM, Huynh MT, Hammes-Schiffer S, Rauchfuss TB. Chem. Rev. 2016; 116: 8693
• 7 Dey S, Das PK, Dey A. Coord. Chem. Rev. 2013; 257: 42
• 8 Papish ET, Das S, Silprakob W, Boudreaux CM, Manafe S. In Comprehensive Organometallic Chemistry IV . Parkin G, Meyer K, O’hare D. Eds.; 2022; Vol. 1, 442
• 9 Zhou H, Li Z, Wang Z, Wang T, Xu L, He Y, Fan Q.-H, Pan J, Gu L, Chan AS. C. Angew. Chem. Int. Ed. 2008; 47: 8464
• 10 Wang Z.-J, Zhou H.-F, Wang T.-L, He Y.-M, Fan Q.-H. Green Chem. 2009; 11: 767
• 11 Wang T, Chen Y, Ouyang G, He Y.-M, Li Z, Fan Q.-H. Chem. Asian J. 2016; 11: 2773
• 12 Yang Z, Chen F, He Y.-M, Yang N, Fan Q.-H. Catal. Sci. Technol. 2014; 4: 2887
• 13 Ding Z.-Y, Wang T, He Y.-M, Chen F, Zhou H.-F, Fan Q.-H, Guo Q, Chan AS. C. Adv. Synth. Catal. 2013; 355: 3727
• 14 Chen Y, He Y.-M, Zhang S, Miao T, Fan Q.-H. Angew. Chem. Int. Ed. 2019; 58: 3809
• 15 Qin J, Chen F, He Y.-M, Fan Q.-H. Org. Chem. Front. 2014; 1: 952
• 16 Touge T, Arai T. J. Am. Chem. Soc. 2016; 138: 11299
• 17 Yang Z, Chen F, He Y, Yang N, Fan Q.-H. Angew. Chem. Int. Ed. 2016; 55: 13863
• 18 Kerkovius JK, Stegner A, Turlik A, Lam PH, Houk KN, Reisman SE. J. Am. Chem. Soc. 2022; 144: 15938
• 19 Lerchen A, Gandhamsetty N, Farrar EH. E, Winter N, Platzek J, Grayson MN, Aggarwal VK. Angew. Chem. Int. Ed. 2020; 59: 23107
• 20 Welin ER, Ngamnithiporn A, Klatte M, Lapointe G, Pototschnig GM, McDermott MS. J, Conklin D, Gilmore CD, Tadross PM, Haley CK, Negoro K, Glibstrup E, Grünanger CU, Allan KM, Virgil SC, Slamon DJ, Stoltz BM. Science 2019; 363: 270
• 21 Zhang Z, Wang J, Li J, Yang F, Liu G, Tang W, He W, Fu J.-J, Shen Y.-H, Li A, Zhang W.-D. J. Am. Chem. Soc. 2017; 139: 5558
• 22 Wang D.-S, Chen Q.-A, Li W, Yu C.-B, Zhou Y.-G, Zhang X. J. Am. Chem. Soc. 2010; 132: 8909
• 23 Wang D.-S, Ye Z.-S, Chen Q.-A, Zhou Y.-G, Yu C.-B, Fan H.-J, Duan Y. J. Am. Chem. Soc. 2011; 133: 8866
• 24 Cai X.-F, Huang W.-X, Chen Z.-P, Zhou Y.-G. Chem. Commun. 2014; 50: 9588
• 25 Lu L.-Q, Li Y, Junge K, Beller M. J. Am. Chem. Soc. 2015; 137: 2763
• 26 Zhang S.-X, Xu C, Yi N, Li S, He Y.-M, Feng Y, Fan Q.-H. Angew. Chem. Int. Ed. 2022; 61: e202205739
• 27 Wagener T, Pierau M, Heusler A, Glorius F. Adv. Synth. Catal. 2022; 364: 3366
• 28 Wiesenfeldt MP, Nairoukh Z, Li W, Glorius F. Science 2017; 357: 908
• 29 Ling L, He Y, Zhang X, Luo M, Zeng X. Angew. Chem. Int. Ed. 2019; 58: 6554
• 30 Han B, Ma P, Cong X, Chen H, Zeng X. J. Am. Chem. Soc. 2019; 141: 9018
• 31 Yang Z.-Y, Luo H, Zhang M, Wang X.-C. ACS Catal. 2021; 11: 10824
• 32 Tian J.-J, Yang Z.-Y, Liang X.-S, Liu N, Hu C.-Y, Tu X.-S, Li X, Wang X.-C. Angew. Chem. Int. Ed. 2020; 59: 18452
• 33 Geier SJ, Chase PA, Stephan DW. Chem. Commun. 2010; 46: 4884
• 34 Mahdi T, Heiden ZM, Grimme S, Stephan DW. J. Am. Chem. Soc. 2012; 134: 4088
• 35 Liu Y, Du H. J. Am. Chem. Soc. 2013; 135: 12968
• 36 Iida H, Takarai T, Kibayashi C. J. Org. Chem. 1978; 43: 975
• 37 Valls N, Bonjoch J, Bosch J. J. Org. Chem. 1992; 57: 2508
• 38 Lewin G, Schaeffer C, Dacquet C. J. Nat. Prod. 1997; 60: 419
• 39 Winkler JD, Londregan AT, Ragains JR, Hamann MT. Org. Lett. 2006; 8: 3407
• 40 Scherer M, Gademann K. Org. Lett. 2017; 19: 3915
• 41 Wildman WC, Brown CL. J. Am. Chem. Soc. 1968; 90: 6439
• 42 Cedrón J, Ravelo Á, León L, Padrón J, Estévez-Braun A. Molecules 2015; 20: 13854
• 43 Koutová D, Havelek R, Peterová E, Muthná D, Královec K, Breiterová K, Cahlíková L, Řezáčová M. Int. J. Mol. Sci. 2021; 22: 7014
• 44 Overman LE, Shim J. J. Org. Chem. 1993; 58: 4662
• 45 Ikeda M. Synlett 1998; 1246
• 46 Banwell MG, Edwards AJ, Jolliffe KA, Kemmler M. J. Chem. Soc., Perkin Trans. 1 2001; 1345
• 47 de Gracia Retamosa M, Ruiz-Olalla A, Bello T, de Cózar A, Cossío FP. Angew. Chem. Int. Ed. 2018; 57: 668
• 48 Overman LE, Shim J. J. Org. Chem. 1991; 56: 5005
• 49 Ishizaki M, Hoshino O, Iitaka Y. Tetrahedron Lett. 1991; 32: 7079
• 50 Ishizaki M, Kurihara K.-I, Tanazawa E, Hoshino O. J. Chem. Soc., Perkin Trans. 1 1993; 101
• 51 Jin J, Weinreb SM. J. Am. Chem. Soc. 1997; 119: 2050
• 52 Pandey G, Banerjee P, Kumar R, Puranik VG. Org. Lett. 2005; 7: 3713
• 53 Bao X, Cao Y.-X, Chu W.-D, Qu H, Du J.-Y, Zhao X.-H, Ma X.-Y, Wang C.-T, Fan C.-A. Angew. Chem. Int. Ed. 2013; 52: 14167
• 54 Chang M.-Y, Chen H.-P, Lin C.-Y, Pai C.-L. Heterocycles 2005; 65: 1999
• 55 Anada M, Tanaka M, Shimada N, Nambu H, Yamawaki M, Hashimoto S. Tetrahedron 2009; 65: 3069
• 56 Pansare SV, Lingampally R, Kirby RL. Org. Lett. 2010; 12: 556
• 57 Yang H, Hou S, Tao C, Liu Z, Wang C, Cheng B, Li Y, Zhai H. Chem. Eur. J. 2017; 23: 12930
• 58 Liu X, Lou M, Bai S, Sun G, Qi X. J. Org. Chem. 2022; 87: 5199
• 59 The configuration of the three newly generated stereocenters in the hydrogenated phenyl ring of compound 18c was determined to be all-cis. Compound 19c was purified as inseparable diastereomers.
• 60 Gerasimov M, Marona-Lewicka D, Kurrasch-Orbaugh DM, Qandil AM, Nichols DE. J. Med. Chem. 1999; 42: 4257
• 61 The isolated yield of 14c in a one-gram-scale reaction was 39%.
• 62 Procedure for the Selective Hydrogenation of 11c A solution of compound 11c (100 mg, 0.29 mmol, 1.0 equiv) in 50:1 HFIP–TFA (2.5 mL) was stirred in the presence of 50 wt % Pd/C at 50 ℃ under H₂ at atmospheric pressure for 24 h. The mixture was then cooled to r.t. and filtered through Celite. The filtrate was basified with sat. aq NaHCO₃, and the mixture was extracted with CH₂Cl₂ (×3). The combined organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure to give a crude residue that was purified by column chromatography (silica gel, 0.5–5% MeOH–CH₂Cl₂) to give 14c as a light-red solid; yield: 36 mg (48%). ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.30 (s, 1 H), 6.76 (d, J = 7.9 Hz, 1 H), 6.64 (d, J = 1.5 Hz, 1 H), 6.59 (dd, J = 8.0, 1.6 Hz, 1 H), 5.94 (s, 2 H), 4.06 (dd, J = 11.0, 4.5 Hz, 1 H), 3.87 (t, J = 10.9 Hz, 1 H), 3.22 (dd, J = 10.7, 4.7 Hz, 1 H), 2.43 (t, J = 5.8 Hz, 1 H), 2.38 (t, J = 6.6 Hz, 1 H), 2.11–2.03 (m, 2 H), 1.89 (p, J = 6.3 Hz, 2 H). ¹³C NMR (101 MHz, DMSO-d ₆): δ = 188.86, 169.32, 147.10, 145.22, 139.92, 119.67, 110.98, 107.81, 107.30, 100.54, 54.99, 43.12, 36.31, 23.24, 22.20. Procedure for the Tf₂O-Induced Diastereoselective Activation/Reduction Tf₂O (28 mg, 0.1 mmol, 2.0 equiv) and EtMe₂SiH (8.8mg, 0.1 mmol, 2.0 equiv) were added successively to a stirred solution of compound 21 (21 mg, 0.05 mmol, 1.0 equiv) in anhydrous CH₂Cl₂ (4 mL) at r.t. The mixture was stirred at r.t. for 24 h then quenched with sat. aq NaHCO₃ and extracted with CH₂Cl₂ (×3). The combined organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue that was purified by column chromatography (silica gel, 1–5% EtOAc–PE) to give compound 22 (79 mg, 36% yield) and dia-22 (108 mg, 49% yield) in a combined 85% yield. 22 ¹H NMR (400 MHz, CDCl₃): δ = 7.57 (d, J = 8.2 Hz, 2 H), 7.21 (d, J = 8.4 Hz, 2 H), 6.53 (d, J = 8.0 Hz, 1 H), 6.34 (dd, J = 8.0, 1.8 Hz, 1 H), 6.22 (d, J = 1.7 Hz, 1 H), 5.90 (d, J = 0.8 Hz, 2 H), 4.16–4.04 (m, 1 H), 3.90 (dd, J = 10.7, 7.5 Hz, 2 H), 3.35 (dd, J = 10.7, 4.0 Hz, 1 H), 2.65 (dq, J = 12.1, 3.9 Hz, 1 H), 2.41 (s, 3 H), 2.39–2.37 (m, 2 H), 2.09 (d, J = 14.1 Hz, 1 H), 1.79–1.63 (m, 1 H), 1.50 (dd, J = 25.6, 11.5 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 147.76, 146.53, 144.08, 143.92, 133.13, 132.99, 129.58, 127.47, 120.20, 118.0 (q, J _C–F = 308.2 Hz), 108.24, 107.08, 101.02, 59.91, 56.39, 42.85, 29.11, 26.44, 21.46, 20.36. ¹⁹F NMR (376 MHz, CDCl₃): δ = –74.74. dia-22 ¹H NMR (400 MHz, CDCl₃) δ = 7.68 (d, J = 8.3 Hz, 2 H), 7.39 (d, J = 7.9 Hz, 2 H), 6.75 (d, J = 1.0 Hz, 1 H), 6.70 (dd, J = 2.3, 1.0 Hz, 2 H), 5.94 (dd, J = 3.4, 1.5 Hz, 2 H), 3.80 (d, J = 8.1 Hz, 1 H), 3.48 (dd, J = 9.8, 2.4 Hz, 1 H), 3.39–3.35 (m, 1 H), 3.17 (dd, J = 9.8, 8.3 Hz, 1 H), 2.75–2.70 (m, 1 H), 2.47 (s, 3 H), 2.33–2.30 (m, 2 H), 2.15–2.09 (m, 1 H), 1.71–1.65 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 147.84, 146.68, 144.46, 143.30, 135.17, 134.99, 130.82, 129.88, 128.18, 121.22, 118.0 (q, J _C–F = 321.6 Hz), 107.98, 107.62, 100.99, 61.27, 57.25, 43.36, 28.09, 26.63, 21.57, 20.48. ¹⁹F NMR (376 MHz, CDCl₃): δ = –74.68.