Direct Preparation of Pyrrolizidines Using Imines and Isonitriles

Abstract

An acid-mediated annulation reaction for the formation of 7a-substituted unnatural pyrrolizidines is described. To reach this goal, the pyrroline 3-(3,4-dihydro-2H-pyrrol-5-yl)propan-1-ol is reacted with a large variety of isonitriles directly resulting in the target compounds. The reaction is operationally simple and tolerates air and water, and the resulting pyrrolizidines can be further transformed to the corresponding oxidized and reduced derivatives.

Key words

pyrrolizidines - isonitriles - cyclizations - pyrrolines

• References

• 1 Review: Robertson J, Stevens K. Nat. Prod. Rep. 2014; 31: 1721
• 2a Niwa H, Ogawa T, Okamoto O, Yamada K. Tetrahedron Lett. 1991; 32: 927
• 2b Tepe JJ, Williams RM. J. Am. Chem. Soc. 1999; 121: 2951
• 2c Kosogof C, Tepe JJ, Williams RM. Tetrahedron Lett. 2001; 42: 6641
• 3a Miyano S, Sumoto K, Satoh F, Shima K, Hayashimatsu M, Morita M, Aisaka K, Noguchi T. J. Med. Chem. 1985; 28: 714
• 3b Suzuki T, Oka M, Maeda K, Furusawa K, Mitani T, Kataoka T. Chem. Pharm. Bull. 1997; 45: 1218
• 3c Cordero FM, Pisaneschi F, Meschini Batista K, Valenza S, Machetti F, Brandi A. J. Org. Chem. 2005; 70: 856
• 3d Salcedo A, Neuville L, Zhu J. J. Org. Chem. 2008; 73: 3600
• 3e Mancebo-Aracil J, Nájera C, Sansano JM. Chem. Commun. 2013; 49: 11218
• 4a Jessen HJ, Schumacher A, Shaw T, Pfaltz A, Gademann K. Angew. Chem. Int. Ed. 2011; 50: 4222
• 4b Hoecker J, Liffert R, Burch P, Wehlauch R, Gademann K. Org. Biomol. Chem. 2013; 11: 3314
• 5a Garcia-Delgado N, Bertrand S, Nguyen KT, van Deursen R, Bertrand D, Reymond J.-L. ACS Med. Chem. Lett. 2010; 1: 422
• 5b Bréthous L, Garcia-Delgado N, Schwartz J, Bertrand S, Bertrand D, Reymond J.-L. J. Med. Chem. 2012; 55: 4605
• 5c Reymond J.-L, Awale M. ACS Chem. Neurosci. 2012; 3: 649
• 6a Hattori Y, Inomata N. Jpn. J. Pharmacol. 1992; 58: 365
• 6b Carmeliet E, Nilius B, Vereecke J. J. Physiol. 1989; 409: 241
• 7 Review: Dömling A, Ugi I. Angew. Chem. Int. Ed. 2000; 39: 3168
• 8 Nenajdenko VG, Gulevich AV, Balenkova ES. Tetrahedron 2006; 62: 5922
• 9a Sorgi KL, Maryanoff CA, McComsey DF, Maryanoff BE. Org. Synth. 1998; 75: 215
• 9b Machida S, Kato N, Harada K, Ohkanda J. J. Am. Chem. Soc. 2011; 133: 958
• 9c Udagawa S, Sakami S, Takemura T, Sato M, Arai T, Nitta A, Aoki T, Kawai K, Iwamura T, Okazaki S, Takahashi T, Kaino M. Bioorg. Med. Chem. Lett. 2013; 23: 1617
• 10 Ethylene oxide was used as a solution in THF.
• 11a Cristau P, Vors J.-P, Zhu J. Org. Lett. 2001; 3: 4079
• 11b Janvier P, Sun X, Bienaymé H, Zhu J. J. Am. Chem. Soc. 2002; 124: 2560
• 12 No product formation was observed with strong electron-withdrawing groups such as NO₂ and CF₃.
• 13 Carney DW, Truong JV, Sello JK. J. Org. Chem. 2011; 76: 10279
• 14a Zhu J, Wu X, Danishefsky SJ. Tetrahedron Lett. 2009; 50: 577
• 14b For a review on isocyanoacetates: Gulevich AV, Zhdanko AG, Orru RV. A, Nenajdenko VG. Chem. Rev. 2010; 110: 5235
• 15a Leonard NJ, Hay AS. J. Am. Chem. Soc. 1956; 78: 1984
• 15b Tehrani KA, D’hooghe M, De Kimpe N. Tetrahedron 2003; 59: 3099
• 15c Leonard NJ, Hay AS, Fulmer RW, Gash VW. J. Am. Chem. Soc. 1955; 77: 439
• 16 Schmidt HJ. R, Schäfer HJ. Angew. Chem., Int. Ed. Engl. 1981; 20: 109
• 17 For selected natural products, see: Agatsuma T, Akama T, Nara S, Matsumiya S, Nakai R, Ogawa H, Otaki S, Ikeda S.-I, Saitoh Y, Kanda Y. Org. Lett. 2002; 4: 4387
• 18 Kim KH, Lee KH, Choi SU, Kim KR, Lee KR. Heterocycles 2010; 81: 1493
• 19 Binet J, Thomas D, Benmbarek A, de Fornel D, Renaut P. Chem. Pharm. Bull. 2002; 50: 316
• 20a Ehmke A, Witte L, Biller A, Hartmann T. Z. Naturforsch. 1990; 45c: 1185
• 20b Biller A, Boppré M, Witte L, Hartmann T. Phytochemistry 1994; 35: 615
• 21 Suzuki T, Oka M, Maeda K, Furusawa K, Uesaka H, Kataoka T. Chem. Pharm. Bull. 1999; 47: 28