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Enyne ring-closing metathesis (RCM) has recently emerged as a powerful tool for the formation of 1,3conjugated dienes. Under the influence of its efficacy and reliability, the enyne RCM reaction with ruthenium (Ru)based catalysts has been elegantly applied toward the total synthesis of bioactive compounds or natural products. In spite of its usefulness, the enyne RCM has yet a problem which remains to be solved: endo/exo mode selectivity. The exo/endo-selectivity in the enyne RCM has been studied and the reported results have varied. Mori reported that RCM of enyne having an monoor di-substituted alkene and a terminal alkyne gave only the exo product, while that of enyne having a disubstituted alkene and an internal alkyne gave a mixture of both endo and exo products. Lee reported that a competitive cross metathesis (CM) of the alkyne moiety in enyne substrate with ethylene led to a triene, which then underwent ring closure offering selectively endo product in 9-11 membered macrocycles. In the investigation on the reactivity profile of catalysts, Grela observed that the use of Grubbs’ first-generation complexes containing PCy3 ligand such as A and C led to only an exo product, while the use of second-generation complexes containing N-heterocyclic carbene (NHC) ligand led to a mixture of endo and exo products in the RCM of enyne having a disubstituted alkene and a terminal alkyne. Schrock and Hoveyda reported their elegant results on endoselective enyne RCM reactions promoted by use of in situ generated molybdenum (Mo)-based complexes containing pyrrole ligand and later by both tungsten (W)and Mobased mono-aryloxide pyrrolide (MAP) imido alkylidene complexes. Therefore, we envisioned that the endo/exo selectivity of terminal enyne RCM with Ru carbene catalysts could lead us to the selective synthesis of medium-sized N-containing heterocycles as shown in Scheme 1. We examined the well-known Ru-based complexes A-D as well as pyridine-chelating Ru complex E (Fig. 1). It was expected that the NHC ligand along with pyridine moiety in complex E would have an effect on the endo/exo selectivity in enyne RCM reactions. Our study started from a simple representative substrate 1 bearing a terminal alkyne at one end and a terminal olefin at the other. Each of five catalysts (A-E, 5 mol %) was added to the solution of 1 in benzene and the solution was refluxed for 2 h under an atmosphere of Ar. RCM of enyne 1 mediated by catalysts A-D gave only the 5-membered exocyclized compound 3 (Entry 1-4, Table 1). On the other hand, pyridine chelating catalyst E produced a small but significant amount of 6-membered endo-cyclized product 2 with the endo: exo ratio of 27:73 (45% conversion, 6% isolated yield of combined exo/endo) (Entry 5, Table 1). It is the first example of the endo-cyclized product being formed in the terminal enyne RCM using Ru-based catalyst. Since we were interested in the determination of endo/exo selectivity in terminal enyne RCM with Ru carbene catalysts under various reaction conditions, the task of improving isolated yield in each reaction was beyond the scope of the work described in this paper. Subsequently, we tested enyne RCM of 1 using the catalyst E in several representative solvents (Table 2). Among suitable organic solvents, toluene, benzene, tetrahydrofuran (THF), 1,2-dimethoxyethane (DME) and 1,2-dichloroethane (DCE) were carefully selected and examined because catalyst E showed the activating This paper is dedicated to Professor Eun Lee on the occasion of his honourable retirement. Scheme 1. Terminal enyne RCM with ruthenium carbene catalysts.

Terminal Enyne Ring-Closing Metathesis Catalyzed by Ruthenium Carbene Catalysts