C ₂-Symmetric Chiral Sulfoxide-Mediated Intermolecular Interrupted Pummerer Reaction for Enantioselective Construction of C3a-Substituted Pyrroloindolines

Abstract

The first example of an enantioselective intermolecular interrupted Pummerer reaction has been developed by the utilization of a C ₂-symmetric chiral sulfoxide. The reaction was used for the enantioselective synthesis of C3a-substituted pyrroloindolines in a one-pot procedure starting from tryptamine. The synthetic utility of the reaction was further demonstrated by its application to the highly concise total synthesis of (+)-psychotriasine.

Key words

asymmetric synthesis - chirality - sulfoxides - indoles - total synthesis

• References and Notes

• 1a Carreño MC. Chem. Rev. 1995; 95: 1717
• 1b Fernández I, Khiar N. Chem. Rev. 2003; 103: 3651
• 1c Toru T, Bolm C. Organosulfur Chemistry in Asymmetric Synthesis . Wiley-VCH; Weinheim: 2008
• 1d Carreño MC, Hernández-Torres G, Ribagorda M, Urbano A. Chem. Commun. 2009; 6129

For reviews of chiral sulfoxides in C–C bond formation, see:
• 2a Walker AJ. Tetrahedron: Asymmetry 1992; 3: 961
• 2b Delouvrié B, Fensterbank L, Nájera F, Malacria M. Eur. J. Org. Chem. 2002; 3507
• 2c Hanquet G, Colobert F, Lanners S, Solladie G. ARKIVOC 2003; (vii): 328
• 2d Pellissier H. Tetrahedron 2006; 62: 5559

For nucleophilic additions to carbonyl groups, see:
• 3a Nakamura S, Takemoto H, Ueno Y, Toru T, Kakumoto T, Hagiwara T. J. Org. Chem. 2000; 65: 469
• 3b García Ruano JL, Aranda MT, Aguirre JM. Tetrahedron 2004; 60: 5383
• 3c Colobert F, Obringer M, Solladié G. Eur. J. Org. Chem. 2006; 1455

For nucleophilic additions to imine groups, see:
• 4a Zucca C, Bravo P, Corradi E, Meille SV, Volonterio A, Zanda M. Molecules 2001; 6: 424
• 4b Midura WH. Tetrahedron Lett. 2007; 48: 3907

For conjugate additions, see:
• 5a García Ruano JL, Cifuentes García M, Laso NM, Martín Castro AM, Rodríguez Ramos JH. Angew. Chem. Int. Ed. 2001; 40: 2507
• 5b Satoh T, Yoshida M, Ota H. Tetrahedron Lett. 2001; 42: 9241
• 5c Satoh T, Yoshida M, Takahashi Y, Ota H. Tetrahedron: Asymmetry 2003; 14: 281
• 5d Raghavan S, Rajender A. Tetrahedron 2004; 60: 5059
• 5e Maezaki N, Sawamoto H, Suzuki T, Yoshigami R, Tanaka T. J. Org. Chem. 2004; 69: 8387

For cycloadditions, see:
• 6a García Ruano JL, Fraile A, Martín MR, González G, Fajardo C. J. Org. Chem. 2008; 73: 8484
• 6b García Ruano JL, Núñez AJr, Martín MR, Fraile A. J. Org. Chem. 2008; 73: 9366
• 6c García Ruano JL, Alonso M, Cruz D, Fraile A, Martín MR, Peromingo MT, Tito A, Yuste F. Tetrahedron 2008; 64: 10546
• 6d Cruz D, Yuste F, Martín MR, Tito A, García Ruano JL. J. Org. Chem. 2009; 74: 3820
• 7 For radical additions, see: Toru T, Watanabe Y, Mase N, Tsusaka M, Hayakawa T, Ueno Y. Pure Appl. Chem. 1996; 68: 711

For recent reports and reviews of chiral sulfoxides in metal catalysts, see:
• 8a Wang D, Cao P, Wang B, Jia T, Lou Y, Wang M, Liao J. Org. Lett. 2015; 17: 2420
• 8b Chen L.-Y, Yu X.-Y, Chen J.-R, Feng B, Qi Y.-H, Xiao W.-J. Org. Lett. 2015; 17: 1381
• 8c Trost BM, Rao M. Angew. Chem. Int. Ed. 2015; 54: 5026
• 8d Sipos G, Drinkel EE, Dorta R. Chem. Soc. Rev. 2015; 44: 3834
• 9a Jonsson E. Tetrahedron Lett. 1967; 38: 3675
• 9b Oae S, Kise M. Bull. Chem. Soc. Jpn. 1970; 43: 1416
• 9c Numata T, Itoh O, Oae S. Tetrahedron Lett. 1979; 21: 1869
• 9d Kita Y, Shibata N, Yoshida N. Tetrahedron Lett. 1993; 34: 4063
• 9e Kita Y, Shibata N, Kawano N, Fukui S, Fujimori C. Tetrahedron Lett. 1994; 35: 3575
• 9f Kita Y, Shibata N, Kawano N, Tohjo T, Fujimori C, Matsumoto K. Tetrahedron Lett. 1995; 36: 115
• 9g Crucianelli M, Bravo P, Arnone A, Corradi E, Meille SV, Zanda M. J. Org. Chem. 2000; 65: 2965
• 9h García Ruano JL, García Paredes C. Tetrahedron Lett. 2000; 41: 261
• 9i García Ruano JL, Alemán J, Padwa A. Org. Lett. 2004; 6: 1757
• 9j Feldman KS, Karatjas AG. Org. Lett. 2006; 8: 4137
• 9k Nagao Y, Miyamoto S, Miyamoto M, Takeshige H, Hayashi K, Sano S, Shiro M, Yamaguchi K, Sei Y. J. Am. Chem. Soc. 2006; 128: 9722
• 10a Kawasaki T, Suzuki H, Sakata I, Nakanishi H, Sakamoto M. Tetrahedron Lett. 1997; 38: 3251
• 10b Higuchi K, Tayu M, Kawasaki T. Chem. Commun. 2011; 47: 6728
• 10c Tayu M, Higuchi K, Inaba M, Kawasaki T. Org. Biomol. Chem. 2013; 11: 496
• 10d Tayu M, Higuchi K, Ishizaki T, Kawasaki T. Org. Lett. 2014; 16: 3613
• 10e Tayu M, Ishizaki T, Higuchi K, Kawasaki T. Org. Biomol. Chem. 2015; 13: 3863
• 11 The syntheses of C ₂-symmetric sulfoxides 3a–c are described in the Supporting Information.
• 12 The determination of the absolute configuration of 4a is described in the Supporting Information. Tentative absolute configurations of other products were estimated from that of 4a.
• 13 Synthesis of 4; General Procedure: Acid anhydride (0.20 mmol, 1.0 equiv) was added to a solution of 2 (0.20 mmol, 1.0 equiv) and sulfoxide 3c (26 μL, 0.20 mmol, 1.0 equiv) in EtCN (1.0 mL, 0.20 M) at –78 °C under an argon atmosphere. After stirring for 10 min, DTBP (90 μL, 0.40 mol, 2.0 equiv) was added and the reaction mixture was stirred for a further 10 min. N-Methylindole (25 μL, 0.20 mmol, 1.0 equiv) was added and the reaction mixture was warmed to 0 °C over 10 min with stirring. The reaction mixture was neutralized with saturated aqueous NaHCO₃ at 0 °C, and then extracted three times with DCM. The organic layer was washed with brine, dried over MgSO₄, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane–EtOAc) to afford the corresponding pyrroloindoline 4.
• 14 Analytical Data for Compound (–)-4a: The ee was determined by chiral HPLC analysis to be 94% ee {CHIRALPAK IA column; hexane–2-propanol (95:5); R_t  = 19 (+), 27 (–) min}; [α] _d ²⁸ −155.7 (c = 0.07, CHCl₃). IR (CHCl₃): 1692, 1493, 1452 cm^–1. ¹H NMR (500 MHz, DMSO-d ₆, 80 °C): δ = 2.36 (ddd, J = 12.5, 6.3, 3.5 Hz, 1 H), 2.78 (ddd, J = 12.5, 9.0, 9.0 Hz, 1 H), 3.15–3.28 (m, 1 H), 3.50 (s, 3 H), 3.70 (s, 3 H), 3.94 (ddd, J = 10.5, 7.5, 3.0 Hz, 1 H), 4.58 (d, J = 16.2 Hz, 1 H), 4.69 (d, J = 16.2 Hz, 1 H), 5.84 (s, 1 H), 6.45 (d, J = 7.6 Hz, 1 H), 6.57 (dd, J = 7.6, 7.6 Hz, 1 H), 6.83 (dd, J = 7.6, 7.6 Hz, 1 H), 6.93 (d, J = 7.6 Hz, 1 H), 6.97–7.07 (m, 2 H), 7.09 (dd, J = 7.6, 7.6 Hz, 1 H), 7.11 (s, 1 H), 7.16–7.22 (m, 1 H), 7.22–7.28 (m, 2 H), 7.28–7.32 (m, 2 H), 7.34 (d, J = 7.6 Hz, 1 H). ¹³C NMR (125 MHz, DMSO-d ₆, 80 °C): δ = 31.8, 37.6, 45.0, 49.1, 51.6, 55.1, 86.6, 105.7, 109.4, 116.3, 117.0, 118.2, 119.0, 120.8, 123.0, 125.3, 126.2, 126.48, 126.52, 126.6, 127.7, 132.6, 137.4, 138.7, 148.9, 154.6. MS (EI): m/z (%) = 437 (32) [M]⁺, 405 (22), 350 (17), 349 (100), 335 (22), 258 (20), 257 (41), 91 (10). HRMS (EI): m/z calcd for C₂₈H₂₇N₃O₂: 437.2103; found: 437.2102.
• 15a Trost BM, Arndt HC. J. Am. Chem. Soc. 1973; 95: 5288
• 15b Oae S, Furukawa N. Adv. Heterocycl. Chem. 1990; 48: 1
• 15c Sato S, Furukawa N. Top. Curr. Chem. 1999; 205: 89
• 16 One-pot oxidation was carried out because of the instability of 11 during purification.

For isolation of the natural product, see:
• 17a Zhou H, He H.-P, Wang Y.-H, Hao X.-J. Helv. Chim. Acta 2010; 93: 1650
• 17b For racemic synthesis, see: Newhouse T, Lewis CA, Eastman KJ, Baran PS. J. Am. Chem. Soc. 2010; 132: 7119
• 17c For enantioselective synthesis, see: Li Q, Xia T, Yao L, Deng H, Liao X. Chem. Sci. 2015; 6: 3599