Gold-Catalyzed Cycloisomerization of 1,6-Cyclohexenylalkyne: An Efficient Entry to Bicyclo[3.2.1]oct-2-ene and Bicyclo[3.3.1]nonadiene.

An efficient and mild synthetic route for the preparation of functionalized bicyclo[3.2.1]oct-2-ene and bicyclo[3.3.1]nonadiene via gold-mediated cycloisomerization of 1,6-enynes has been developed. This atom-economical catalytic process was optimized and relied on the efficiency of IPrAuNTf2 allowing the formation of functionalized bicyclic adducts in 55-91% isolated yields (18 products). The reliable access to bicyclic derivatives was demonstrated on a 3 g scale with a low catalyst loading. The process occurred on a 5-exo versus 6-endo pathway depending on the substitution of the alkynyl moiety. Density functional theory (DFT) calculations were performed on the stability of intermediates, and this study corroborated the endo/exo ratio and the mechanistic pathway with key intermediates. Reduction of the ester moiety and hydrogenation of the exo-methylene double bond of the bicyclo[3.2.1]oct-2-ene adduct illustrated the potential postfunctionalization of bicyclic derivatives.