Tandem cycloisomerization reactions of functionalized 1,6-enynes under indium(III) catalysis are described. This atom-economic transformation proceeds smoothly with 5-exo-dig regioselectivity using commercial In(III) halides and 1,6-enynes furnished with alcohol, carboxylic acid or amine functional groups to give bicyclic structures in good yields and diastereoselectivities. The reaction with enynals involves a three–step mechanism to give an oxatricycle and a conjugated 1,3-diene. In the absence of the internal nucleophile the enyne cycloisomerization evolves through a skeletal rearrangement or a cyclopropanation reaction after the regioselective 5-exo-dig cyclization. The 1,6-enyne cycloisomerization is stereospecific and the stereoselectivity appears to be independent of the internal nucleophile. Experimental data support a common reaction mechanism involving an initial alkyne electrophilic p-coordination of In(III) followed by Markovnikov electrophilic alkene addition and ring-closure by nucleophilic attack. DFT studies hold up a stepwise mechanism involving the formation of a chiral non-classical carbocation intermediate that determines the diastereoselectivity of this tandem cycloisomerization reaction.
