Polarizing the Nazarov Cyclization: The Impact of Dienone Substitution Pattern on Reactivity and Selectivity Wei He, Ildiko R. Herrick, Tulay A. Atesin, Patrick A. Caruana, Colleen A. Kellenberger, and Alison J. Frontier* Department of Chemistry, UniVersity of Rochester, Rochester, New York 14627 Received September 15, 2007; E-mail: frontier@chem.rochester.edu Abstract: The impact of dienone substitution on the Nazarov cyclization has been examined in detail. Substrates bearing different substituents at each of four positions on the dienone backbone were systematically probed in order to identify trends leading to higher reactivity and better selectivity. Desymmetrization of the pentadienyl cation and oxyallyl cation intermediates through placement of polarizing groups at both the C-2 and C-4 positions was found to be particularly effective. These modifications allowed cyclizations to occur in the presence of catalytic amounts of mild Lewis acids. It was also found that stereoconvergent cyclization of mixtures of E and Z isomers of alkylidene -ketoesters occurred via an efficient isomerization process that occurred under the reaction conditions. Introduction Electrocyclic reactions are powerful synthetic transformations with the ability to create new carbon-carbon bonds stereospe- cifically by simple orbital reorganization. One type of electro- cyclic reaction is a 4π-electron process known as the Nazarov cyclization, involving the conversion of divinyl ketones 1 to cyclopentenones 5 by activation with a Lewis acid (eq 1). 1 Cyclization of pentadienyl cation 2 must proceed with conservation of orbital symmetry, dictating conrotatory ring closure to give a product with an anti relationship between R 1 and R 2 (see 3, eq 1). Since disrotatory closure is electronically forbidden in the thermal reaction, stereospecificity is ensured for the bond formation. 2 Experimental data is consistent with this prediction: thermal cyclization under acidic conditions gives the product expected from a conrotatory ring closure, 3 and the photochemical reaction gives the opposite diastereomer, as expected from disrotatory ring closure. 2,4 In some cases, however, isomerization of the dienone complicates analysis. 5 The Nazarov reaction should be recognized as a valuable synthetic transformation, since the stereospecific electrocycliza- tion can convert achiral molecules into single stereoisomeric products. However, the cyclization of simple dienones like those depicted in eq 1 is often plagued with reactivity and selectivity problems that seriously compromise synthetic utility. Specifi- cally, (1) strong Lewis acids are often necessary to promote cyclization; (2) one or more equivalents of promoter are required in most cases; (3) regioselectivity of the elimination step can be unselective (see 3 f 4); (4) elimination of the proton often leads to loss of a stereocenter (see 4); and (5) the final enolate protonation is often unselective (see 4 f 5). Two strategies addressing some of the problems associated with synthetic utility in Nazarov cyclization have been disclosed, and both involved modification of the substitution pattern of the substrates 1. Regioselective elimination became possible with the develop- ment of Denmark’s silicon-directed Nazarov cyclization pro- tocol, in which -silyl divinyl ketones are employed in the cyclization. 6 West found that the intermediate cation (see 3, eq (1) (a) Habermas, K. L.; Denmark, S. E.; Jones, T. K. Org. React. (N.Y.) 1994, 45, 1. (b) Santelli-Rouvier, C.; Santelli, M. Synthesis 1983, 429. (c) Denmark, S. E. In ComprehensiVe Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, p 751. (d) Pellissier, H. Tetrahedron 2005, 61, 6479. (e) Frontier, A. J.; Collison, C. Tetrahedron 2005, 6, 7577. (f) Harmata, M. Chemtracts: Org. Chem. 2004, 17, 416. (g) Tius, M. A. Eur. J. Org. Chem. 2005, 11, 2193. (2) (a) Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. Engl. 1969, 8, 781. (b) Woodward, R. B.; Hoffmann, R. The ConserVation of Orbital Symmetry; Verlag Chemie: Weinheim, 1970. (3) Shoppee, C. W.; Cooke, B. J. A. J. Chem. Soc., Perkin Trans. 1 1972, 2271. (4) Visser, C. P.; Cerfontain, H. Recl. TraV. Chim. Pays-Bas 1983, 102, 307. (5) (a) Noyori, R.; Ohnishi, Y.; Kato, M. Tetrahedron Lett. 1971, 19, 1515. (b) Noyori, R.; Ohnishi, Y.; Kato, M. Bull. Chem. Soc. Jpn. 1975, 48, 2881. (c) Noyori, R.; Ohnishi, Y.; Kato, M. J. Am. Chem. Soc. 1975, 97, 928. (6) (a) Denmark, S. E.; Jones, T. K. J. Am. Chem. Soc. 1982, 104, 2642. (b) Jones, T. K.; Denmark, S. E. HelV. Chim. Acta 1983, 66, 2377. (c) Jones, T. K.; Denmark, S. E. HelV. Chim. Acta 1983, 66, 2397. (d) Denmark, S. E.; Habermas, K. L.; Hite, G. A.; Jones, T. K. Tetrahedron 1986, 42, 2821. (e) Denmark, S. E.; Klix, R. C. Tetrahedron 1988, 44, 4043. (f) Denmark, S. E.; Habermas, K. L.; Hite, G. A. HelV. Chim. Acta 1988, 71, 168. (g) Denmark, S. E.; Hite, G. A. HelV. Chim. Acta 1988, 71, 195. (h) Denmark, S. E.; Wallace, M. A.; Walker, C. B. J. Org. Chem. 1990, 55, 5543. Published on Web 12/28/2007 10.1021/ja077162g CCC: $40.75 © 2008 American Chemical Society J. AM. CHEM. SOC. 2008, 130, 1003-1011 9 1003