10.1021/ol3019677 r 2012 American Chemical Society Published on Web 08/14/2012 ORGANIC LETTERS 2012 Vol. 14, No. 17 4466–4469 Intramolecular Direct Dehydrohalide Coupling Promoted by KO t Bu: Total Synthesis of Amaryllidaceae Alkaloids Anhydrolycorinone and Oxoassoanine Subhadip De, Santanu Ghosh, Subhajit Bhunia, Javeed Ahmad Sheikh, and Alakesh Bisai* Department of Chemistry, Indian Institute of Science Education and Research (IISER) Bhopal, MP-462023, India alakesh@iiserb.ac.in Received July 16, 2012 ABSTRACT A transition-metal-free intramolecular dehydrohalide coupling via intramolecular homolytic aromatic substitution (HAS) with aryl radicals has been developed in the presence of potassium tert-butoxide and an organic molecule as the catalyst. The methodology has been applied to a concise synthesis of Amaryllidaceae alkaloids viz. oxoassoanine (1b), anhydrolycorinone (1d), and other related structures. Interestingly, the method also works only in the presence of potassium tert-butoxide. In contemporary organic synthesis, CÀC bond-forming reactions 1 through selective functionalization of aromatic compounds via CÀH bond activation have emerged as an extremely useful exploratory synthetic strategy. 2 Thus, the challenge to devise newer, efficient methods to directly transform CÀH bonds to other functional groups moti- vates synthetic chemists to develop an ‘ideal synthetic procedure’, 3 which could eventually be applied to natural product synthesis and drug discovery. 4 Significant effort has already been made in direct CÀH bond transformation through traditional demetalhalide cross-coupling utilizing transition metal catalysts. 4 Direct cross-coupling methods, such as demetal hydride, 5 demetal hydroxide, 6 dehydrative, 7 dehydrohalide, 8 and dehydro- genative 9 cross-couplings, have received considerable (1) (a) Smit, W. A.; Bochkov, A. F.; Caple, R. Organic Synthesis: The Science behind the Art; Royal Society of Chemistry: Cambridge, 1998. (b) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; John Wiley & Sons: New York, 1995. (c) For numerous examples, see: Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; Wiley-VCH: New York, 1996. (d) Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis II; Wiley- VCH: Weinheim, 2003. (2) For excellent reviews, see: (a) Shilov, A. E.; Shul’pin, G. B. Chem. Rev. 1997, 97, 2879. (b) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861. (c) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (d) Diaz-Requejo, M. M.; Perez, P. J. Chem. Rev. 2008, 108, 3379. (3) (a) Wender, P. A. Chem. Rev. 1996, 96, 1. (b) Gaich, T.; Baran, P. S. J. Org. Chem. 2010, 75, 4657. (c) Burns, N. Z.; Baran, P. S.; Hoffman, R. W. Angew. Chem., Int. Ed. 2009, 48, 2854. (d) Br€ uckl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Acc. Chem. Res. 2012, 45, 826 and references cited. (4) For reviews, see: (a) Li, C.-J.; Trost, B. M. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 13197. (b) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press: New York, 1998. (c) McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38, 2447. (d) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (e) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704. (5) (a) Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai, S. J. Am. Chem. Soc. 2003, 125, 1698. (b) Chen, X.; Goodhue, C. E.; Yu, J. J. Am. Chem. Soc. 2006, 128, 12634. (c) Pastine, S. J.; Gribkov, D. V.; Sames, D. J. Am. Chem. Soc. 2006, 128, 14220. (d) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1473. (6) Kang, F.-A.; Sui, Z.; Murray, W. V. J. Am. Chem. Soc. 2008, 130, 11300 and references cited therein. (7) Kang, F.-A.; Lanter, J. C.; Cai, C.; Sui, Z.; Murray, W. V. Chem. Commun. 2010, 1347. (8) For a review, see: Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (9) (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (b) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1115. (c) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (10) (a) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (b) Campeau, L.-C.; Stuart, D. R.; Fagnou, K. Aldrichimica Acta 2007, 40, 7.