On the Synergism Between H[subscript 2]O and a Tetrahydropyran Template in the Regioselective Cyclization of an Epoxy Alcohol

A regioselective epoxy alcohol cyclization promoted by the combination of neutral water and a tetrahydropyran template was investigated through a series of mechanistic experiments carried out on an epoxy alcohol containing a tetrahydropyran ring (1a) and its carbocyclic congener (1b). In contrast to 1a, cyclizations of 1b were unselective and displayed significantly faster reaction rates suggesting that the tetrahydropyran oxygen in 1a is requisite for regioselective cyclization. Reactions for both substrates were shown to occur in solution and under kinetic control without significant influence from hydrophobic effects. Kinetic measurements carried out in water/dimethyl sulfoxide mixtures suggest that 1b reacts exclusively through an unselective pathway requiring one water molecule more than what is required to solvate the epoxy alcohol. Similar experiments for 1a suggest a competition between an unselective and a selective pathway requiring one and two water molecules in excess of those required to solvate 1a, respectively. The selective pathway observed for 1a but not in 1b is rationalized by electronic and conformational differences between the two compounds. We previously reported1 that the combination of a template2 and water provided a means to conduct highly regioselective epoxide-opening cascades reminiscent of Nakanishi’s proposed biogenesis of the ladder polyether natural products.3 With the aid of mechanistic studies carried out on the original template (tetrahydropyran 1a) and its carbocyclic analog 1b, we now provide a molecular explanation for these phenomena. In short, the data support two competing pathways for 1a: one that is unselective and first order in water and another that is highly