An Enantioselective Entry to cis-Perhydroisoquinolines Mercedes Amat,* Maria Pe ´ rez, Annamaria T. Minaglia, Nu ´ ria Casamitjana, and Joan Bosch* Laboratory of Organic Chemistry, Faculty of Pharmacy, UniVersity of Barcelona, 08028-Barcelona, Spain joanbosch@ub.edu; amat@ub.edu Received May 26, 2005 ABSTRACT An enantioselective route to cis-perhydroisoquinolines, involving a cyclocondensation reaction of (R)-phenylglycinol with a racemic oxoester, a stereoselective conjugate addition to an unsaturated bicyclic lactam, and the closure of the carbocyclic ring by a ring-closing metathesis as the key steps is reported. This route allows the preparation of 3-cyano derivatives as well as cis-octahydroisoquinolines bearing a quaternary center at the C4-position. The totally (or partially) reduced cis-isoquinoline ring system is present in a large number of bioactive natural and synthetic products. Among them, of particular interest are the indole alkaloids of the yohimbine-reserpine type, 1 the marine sponge alkaloids of the manzamine 2 and madangamine groups, 3 all of them displaying a variety of notable pharmacological activities, and the HIV protease inhibitors nelfinavir and saquinavir, 4 which are characterized by the presence of a carboxamide function at the C3-position of the isoquinoline ring 5 (Figure 1). This widespread occurrence has stimulated the development of general methodologies and strategies for the enantioselective synthesis of cis-perhydroisoquinoline derivatives. 6 In this context, we have recently reported 7 an enantiodivergent synthesis of cis-hydroisoquinolines, in which the key step was a diastereoselective Diels-Alder reaction of a phenylglycinol-derived unsaturated δ-lactam. (1) (a) Sza ´ntay, C.; Honty, K. In Monoterpenoid Alkaloids. Saxton, J. E., Ed. In The Chemistry of Heterocyclic Compounds; Taylor, E. C., Ed.; Wiley: Chichester, 1994; Supplement to Vol. 25, Part 4, pp 161-216. (b) Creasey, W. A. In Monoterpenoid Alkaloids. Saxton, J. E., Ed. In The Chemistry of Heterocyclic Compounds; Taylor, E. C., Ed.; Wiley: Chich- ester, 1994; Supplement to Vol. 25, Part 4, pp 715-754. (2) (a) For reviews, see: Andersen, R. J.; Van Soest, R. W. M.; Kong, F. In Alkaloids: Chemical and Biogical PerspectiVes; Pelletier, S. W., Ed.; Pergamon: Oxford, 1996; Vol. 10, pp 301-355. (b) Tsuda, M.; Kobayashi, J. Heterocycles 1997, 46, 765-794. (c) Magnier, E.; Langlois, Y. Tetrahedron 1998, 54, 6201-6258. (d) Nakagawa, M. J. Heterocycl. Chem. 2000, 37, 567-581. (3) (a) Kong, F.; Andersen, R. J.; Allen, T. M. J. Am. Chem. Soc. 1994, 116, 6007-6008. (b) Kong, F. Graziani, E. I.; Andersen, R. J. J. Nat. Prod. 1998, 61, 267-271. (4) Kaldor, S. W.; Kalish, V. J.; Davies, J. F., II; Shetty, B. V.; Fritz, J. E.; Appelt, K.; Burgess, J. A.; Campanale, K. M.; Chirgadze, N. Y.; Clawson, D. K.; Dressman, B. A.; Hatch, S. D.; Khalil, D. A.; Kosa, M. B.; Lubbehusen, P. P.; Muesing, M. A.; Patick, A. K.; Reich, S. H.; Su, K. S.; Tatlock, J. H. J. Med. Chem. 1997, 40, 3979-3985. (5) For other bioactive perhydroisoquinoline-3-carboxylic acid derivatives of pharmacological interest, see: (a) Parkes, K. E. B.; Bushnell, D. J.; Crackett, P. H.; Dunsdon, S. J.; Freeman, A. C.; Gunn, M. P.; Hopkins, R. A.; Lambert, R. W.; Martin, J. A.; Merrett, J. H.; Redshaw, S.; Spurden W. C.; Thomas, G. J. J. Org. Chem. 1994, 59, 3656-3664. (b) Filla, S. A.; Winter, M. A.; Johnson, K. W.; Bleakman, D.; Bell, M. G.; Bleisch, T. J.; Castano, A. M.; Clemens-Smith, A.; del Prado, M.; Dieckman, D. K.; Dominguez, E.; Escribano, A.; Ho, K. H.; Hudziak, K. J.; Katofiasc, M. A.; Martinez-Perez, J. A.; Mateo, A.; Mathes, B. M.; Mattiuz, E. L.; Ogden, A. M. L.; Phebus, L. A.; Stack, D. R.; Stratford, R. E.; Ornstein, P. L. J. Med. Chem. 2002, 45, 4383-4386. (6) (a) Houpis, I. N.; Molina, A.; Reamer, R. A.; Lynch, J. E.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1993, 34, 2593-2596. (b) Aube ´, J.; Ghosh, S.; Tanol, M. J. Am. Chem. Soc. 1994, 116, 9009-9018. (c) Kwak, B. S.; Kim, T. J.; Lee, S. I. Catal. Lett. 2002, 83, 93-96. (d) Hattori, K.; Grossman, R. B. J. Org. Chem. 2003, 68, 1409-1417. (e) Vila, X.; Quirante, J.; Paloma, L.; Bonjoch, J. Tetrahedron Lett. 2004, 45, 4661-4664. (7) Casamitjana, N.; Amat, M.; Llor, N.; Carreras, M.; Pujol, X.; Ferna ´ndez, M. M.; Lo ´pez, V.; Molins, E.; Miravitlles, C.; Bosch, J. Tetrahedron: Asymmetry 2003, 14, 2033-2039. ORGANIC LETTERS 2005 Vol. 7, No. 17 3653-3656 10.1021/ol051242c CCC: $30.25 © 2005 American Chemical Society Published on Web 07/27/2005