7128 J. Am. Chem. Soc. zyxwvu 1988, 110, 7128-7135 Stereoselective Cyclization of Enynes Mediated by Metallocene Reagentst T. V. RajanBabu,* William A. Nugent,* Douglass F. Taber,' and Paul J. Fagan Contribution from the Central Research and Development Department, E. I. du Pont de Nemours and Company, Experimental Station, Wilmington. Delaware 19898. Received March 15, 1988 Abstract: 1,6- and 1,7-enynes are efficiently cyclized to bicyclic metallacyclopenteneswith titanocene or zirconocene reagents which are easily generated in situ. The metallacycles can be hydrolyzed to release the alkylidenecycloalkane or can be metathesized with main group halides such as SzCl2, SeZCl2, or Ph2SnCI2 to give heterocycles. The zirconium-mediated reaction is more effective for sterically demanding cases. The alkylidene moiety is introduced with zyxwv 100% stereoselectivity for the &diastereomer; this provides an excellent starting place for the elaboration of chiral side chains as illustrated by a formal synthesis of the ant pheromone invictolide. The cyclization is compatible with alkyl and silyl ether functionality. Sugar enynes, efficiently synthesized from readily available sugar lactones, undergo stereospecific cyclization to highly functional, enantiomerically pure carbocycles. Transition-metal-mediated synthetic methods are bringing about a revolution in the manufacture of fine chemicals.2 As a part of Du Pont's research effort in this area we have developed the stereoselective cyclization of diacetylenes mediated by titanocene and zirconocene reagents (eq I). This reaction provides an efficient route to reactive E,E-exocyclic dienes zyxwvuts (eq la)3 and to a variety of heterocycles (eq lb).4 R' M =TI, Zi: n = 2-5 QCI, SCI,. SOCI,. PhSbCb, PhBCI,, GeCL, eIc Several years ago we also communicated the first example of the cyclization of an enyne by using a group 4 metallocene reagentS (eq 2). Three features of this reaction appeared to be of special CH, = CH (CH,),C =CCH, - 'cp2Ti" dTiCP2 H'_ (2) 1 interest: (1) Metallacycles 1 should be useful nucleophiles com- parable in reactivity to Grignard reagents6 We envisioned, for example, extending eq 1 b to the synthesis of unusual heterocycles such as dihydroselenophenes. (2) Equation 2 proceeds with 100% control of the stereochemistry of the alkylidene moiety. This should provide an excellent starting place for the construction of carbocyclic targets with control of side-chain stereochemistry. (3) On the basis of our experience with the diyne cyclization, we expected eq 2 to be compatible with a range of functional groups. A particularly intriguing possibility was the use of eq 2 to directly convert carbohydrates to highly functional, enantiomerically pure carbocycles. We have investigated each of these possibilities and report our initial results. An important development in the period since our initial report has been provided by Negishi and co-workers. These researchers have shown' that the combination of zirconocene dichloride with 2 molar equivalents of butyllithium provides a clean and convenient method for generating a "zirconocene" equivalent in situ. In our more recent studies we have frequently utilized this reagent combination in place of the older procedureS~* based on CpzZrC1, 'Contribution No. 4698. Table I. GLC Yield (%) of Cycloalkanes from Enynes (eq 3)' reagent/enyne 1-octen-6-yne (%) 1-nonen-7-yne (%) Cp2TiClz/PMePhz/Na( Hg) 80 91 Cp2ZrClz/Mg(Hg) 60 51 Cp2ZrCI2/2BuLi 82 89 ' See Experimental Section for detailed reaction conditions. and amalgamated magnesium metal. Of particular interest is the use of this reagent by Negishi et al. to effect the Pauson-Khand type carbonylation of C-silylated enynes to cyclopenten~nes.~~~~ Results and Discussion Comparison of Reagents. Initial studies on the cyclization of the simple enynes 1-octen-6-yne and 1-nonen-7-yne (eq 3) are summarized in Table I. Metallocenes were generated in situ by using the optimized reagent systems developed in our studies on diyne cy~lization.~ Cyclization of either substrate in eq 3 with 1) "Cp2M" CH, = CH (CH,),C=CCH, -F (CH,), n=3,4 the reagent system Cp2TiC12/PMePhz/sodium amalgam followed by hydrolysis afforded the corresponding ethylidene cycloalkane in 80-90% yield by GLC analysis. Zirconocene generated in situ from CpZrCl,/Mg/HgCI, also effected this cyclization but in somewhat lower yield. However, with the Cp2ZrCI2/2BuLi (1) Du Pont Visiting Research Scientist, summer 1986; permanent address: Department of Chemistry, University of Delaware, DE 19716. (2) For a series of reviews documenting the impact of this revolution on the manufacture of pharmaceuticals,agrichemicals, and other fine chemicals see: Parshall, G. W.; Nugent, W. A. Chemtech 1988, 28, 184-190; 314-320, (3) Nugent, W. A,; Thorn, D. L.; Harlow, R. L. J. Am. Chem. SOC. 1987, (4) Fagan, P. J.; Nugent, W. A. J. Am. Chem. zyxw Soc. 1988,110,2310-2312. (5) Nugent, W. A,; Calabrese, J. C. J. Am. Chem. SOC. 1984, 106, 6422-6424. Nugent, W. A.; RajanBabu, T. V.; Thorn, D. L. Abstract of Papers, 190th National Meeting of the American Chemical Society, Anaheim, CA; American Chemical Society, Washington, DC, 1986; ORGN 78. (6) Bertelo, C. A,; Schwartz, J. J. Am. Chem. SOC. 1975, 97, 228-230. Schwartz, J.; Loots, M. J.; Kosugi, H. J. Am. Chem. SOC. 1980, 102, (7) Negishi, E.-i.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Letf. (8) Famili, A.; Farona, M. F.; Thanedar, S. J. Chem. Soc., Chem. Com- (9) Negishi, E.-i.; Holmes, S. J.; Tour, J. M.; Miller, J. A. J. Am. Chem. (10) Negishi, E.-i.; Swanson, D. R.; Cederbaum, F. E.; Takahashi, T. 376-38 3. 109, 2788-2796. 1 3 3 3- 1 340. 1986, 27, 2829-2832. mun. 1983, 435-436. SOC. 1985, 107, 2568-2569. Tetrahedron zyxwvuts Lett. 1987, 28, 917-920. 0002-7863/88/1510-7128$01.50/0 0 1988 American Chemical Society