Stereoselective Synthesis of 3-Aryloctahydroindoles and Application in a Formal Synthesis of (-)-Pancracine Sunil V. Pansare,* Rajinikanth Lingampally, and Raie Lene Kirby Department of Chemistry, Memorial UniVersity, St. John’s, Newfoundland, Canada A1B 3X7 spansare@mun.ca Received November 30, 2009 ABSTRACT A stereoselective synthesis of 3-aryloctahydroindoles from enantiomerically enriched γ-nitroketones has been developed. Reduction of imines derived form the nitroketones provides the trans-fused octhaydroindole motif selectively. The cis-octahydroindole skeleton is accessible by an invertive cyclization strategy involving a diastereomerically pure nitromesylate intermediate. This approach was employed in the synthesis of an advanced intermediate to (-)-pancracine. The γ-nitroketone starting materials are readily available via an organocatalytic Michael reaction. The octahydroindole ring system has attracted considerable attention due to its importance in natural product chemistry and medicine. For example, the octahydroindole motif is found in several bioactive natural products such as the Amaryllidaceae 1 and sceletium 1,2 alkaloids and also the aeruginosins. 3 Recently, applications of octahydroindole scaffolds in the diversity-oriented synthesis of Amarylli- daceae alkaloid type structures, 4 glycomimetics, 5 and gly- cosidase inhibitors 6 have been reported. The stereochemistry of the ring junction in the octahydroindole influences its biological profile. Thus, cis-octahydroindoles have been utilized in peptide -turn mimics 7 and also have noradrena- line uptake inhibitor activity, 8 whereas the trans-octahy- droindole motif has been employed in ACE inhibitors. 9 The synthesis of octahydroindoles therefore continues to be actively investigated, 10 and selective access to either the cis- or the trans-octahydroindole motif is of particular interest. Herein, we describe preliminary results on a simple, stereo- selective approach to cis- or trans-3-aryloctahydroindoles from readily available γ-nitroketone precursors. (1) (a) Zhong, J. Nat. Prod. Rep. 2009, 26, 363, and references cited therein. (b) Unver, N. Phytochem. ReV. 2007, 6, 125. (c) Rinner, U.; Hudlicky, T. Synlett 2005, 3, 365. (2) (a) Jeffs, P. W. Alkaloids 1981, 19, 1. (b) Hayashi, M.; Unno, T.; Takahashi, M.; Ogasawara, K. Tetrahedron Lett. 2002, 43, 1462. (3) (a) Bonjoch, J.; Catena, J.; Isabal, E.; Lopez-Canet, M.; Valls, N. Tetrahedron: Asymmetry 1996, 7, 1899. (b) Hoshina, Y.; Doi, T.; Takahashi, T. Tetrahedron 2007, 63, 12740. (c) Hanessian, S.; Ersmark, K.; Wang, X.; Del Valle, J. R.; Blomberg, N.; Xue, Y.; Fjellstrom, O. Biorg. Med. Chem. Lett. 2007, 17, 3480. (d) Hanessian, S.; Wang, X.; Ersmark, K.; Del Valle, J. R.; Klegraf, E. Org. Lett. 2009, 11, 4232. (4) Keaney, G. F.; Johannes, C. W. Tetrahedron Lett. 2007, 48, 5411. (5) Gravier-Pelletier, C.; Le Merrer, Y. Curr. Org. Synth. 2007, 4,1. (6) Gravier-Pelletier, C.; Maton, W.; Bertho, G.; Le Merrer, Y. Tetra- hedron 2003, 59, 8721. (7) Kyle, D. J.; Green, L. M.; Blake, P. R.; Smithwick, D.; Summers, M. F. Peptide Res. 1992, 5, 206. (8) Boes, M.; Burkard, W. P.; Moreau, J. L.; Schoenholzer, P. HelV. Chim. Acta 1990, 73, 932. (9) Brion, F.; Marie, C.; Mackiewicz, P.; Roul, J. M.; Buendia, J. Tetrahedron Lett. 1992, 33, 4889. (10) Recent reports: (a) Cordero-Vargas, A.; Urbaneja, X.; Bonjoch, J. Synlett 2007, 2379. (b) Saito, M.; Matsuo, J.; Ishibashi, H. Tetrahedron 2007, 63, 4865. (c) Reimann, E.; Ettmayr, C.; Polborn, K. Monatsh. Chem. 2004, 135, 557. (d) Hanessian, S.; Tremblay, M.; Petersen, J. F. W. J. Am. Chem. Soc. 2004, 126, 6064. (e) Prevost, N.; Shipman, M. Tetrahedron 2002, 58, 7165. ORGANIC LETTERS 2010 Vol. 12, No. 3 556-559 10.1021/ol902761a  2010 American Chemical Society Published on Web 01/07/2010