A New Asymmetric Synthesis of trans-Hydroisoquinolones Asayuki Kamatani † and Larry E. Overman* Department of Chemistry, 516 Rowland Hall, UniVersity of California, IrVine, California 92697-2025 leoVerma@uci.edu Received February 11, 2001 ABSTRACT A convenient enantioselective synthesis of trans-hydroisoquinolones is described. This synthesis capitalizes on the ready availability of enantioenriched 2-substituted cyclohexenols by exploiting the asymmetry of an allylic carbon-oxygen σ bond to control carbon-carbon bond formation in pinacol-terminated cyclizations of N-acyliminium cations. Decahydroisoquinoline rings are found in structurally diverse isoquinoline alkaloids as well as several important clinical agents. 1,2 Morphine (1) and reserpine (2) are well-known members of these groups. Because of the wide occurrence and pharmacological importance of trans-hydroisoquinolines, the development of new asymmetric routes to this ring system remains an important objective in organic synthesis. In recent years, we have invented a suite of carbon-carbon bond-forming ring constructions that couple pinacol rear- rangements with cationic cyclization reactions. 3,4 The ac- companying communication in this issue details reactions wherein pinacol rearrangement of a ring carbon terminates a cationic cyclization process. 5 Much less developed are cyclization-pinacol reactions concluded by hydride migra- tion. 6 A new sequence of this latter type, which we envisaged † Banyu Pharmaceutical Company, Process Research Division, 3-9-1 Kami-Mutsuna, Okazaki, Aichi 444-0858, Japan. (1) Bentley, K. W. Nat. Prod. Rep. 1999, 16, 367-388 and references therein. (2) Lednicer, D.; Mitscher, L. A. The Organic Chemistry of Drug Synthesis; Wiley: New York, 1997; Vol. 7 and earlier volumes in this series. (3) For brief reviews, see: (a) Overman, L. E. Acc. Chem. Res. 1992, 25, 352-359. (b) Overman, L. E. Aldrichim. Acta 1995, 28, 107-120. (c) Overman, L. E. In SelectiVities in Lewis Acid-Promoted Reactions; NATO ASSI Series 289; Schinzer, D., Ed.; Kluwer Academic: Dordrecht, The Netherlands, 1989; pp 1-20. (4) Recent illustrative examples include (a) MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc. 1995, 117, 10391-10392. (b) Minor, K. P.; Overman, L. E. Tetrahedron 1997, 53, 8927-8940. (c) Hanaki, N.; Link, J. T.; MacMillan, D. W. C.; Overman, L. E.; Trankle, W. G.; Wurster, J. A. Org. Lett. 2000, 2, 223-226. (d) Overman, L. E.; Pennington, L. D. Org. Lett. 2000, 2, 2683-2686. (e) Molina-Ponce, A.; Overman, L. E. J. Am. Chem. Soc. 2000, 122, 8672-8676. (5) Cohen, F.; MacMillan, D. W. C.; Overman, L. E.; Romero, A. Org. Lett. 2001, 3, 1225-1228; accompanying paper in this issue. (6) For other Prins-pinacol reactions that involve hydride migrations, see: (a) Cloninger, M. J.; Overman, L. E. J. Am. Chem. Soc. 1999, 121, 1092-1093. (b) Overman, L. E.; Pennington, L. D. Can. J. Chem. 2000, 78, 732-738. (7) Several catalytic asymmetric reduction procedures would be possible; at the time this work was initiated, oxazaborolidine-catalyzed borane reduction was particularly attractive. 8 (8) (a) Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. J. Chem. Soc., Chem. Commun. 1983, 469-470. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. J. Am. Chem. Soc. 1987, 109, 5551-5553. (c) For a review, see: Itsuno, S. Org. React. 1998, 52, 395-576. (9) Kamatani, A.; Overman, L. E. J. Org. Chem. 1999, 64, 8743-8744. (10) For a review of the Suzuki reaction, see: Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (11) For recent reviews of N-acyliminium ion chemistry, see: (a) Hiemstra, H.; Speckamp, W. N. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2, Chapter 4.5. (b) de Koning, H.; Speckamp, W. N. In Methods of Organic Chemistry (Houben-Weyl); Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart, 1995; Vol. E21b, Chapter D.1.4.5. ORGANIC LETTERS 2001 Vol. 3, No. 8 1229-1232 10.1021/ol015696v CCC: $20.00 © 2001 American Chemical Society Published on Web 03/23/2001