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We previously reported that the combination of a template and water provided a means to conduct highly regioselective epoxide-opening cascades reminiscent of Nakanishi's proposed biogenesis of the ladder polyether natural products. We have also previously proposed a molecular explanation for these phenomena. A regioselective epoxy alcohol cyclization promoted by the combination of neutral water and a tetrahydropyan template was investigated through a series of mechanistic experiments carried out on an epoxy alcohol containing a tetrahydropyran ring and its carbocyclic congener. In contrast to the tetrahydropyran case, cyclizations of the cyclohexyl case 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 the cyclohexyl case reacts exclusively through an unselective pathway requiring one water molecule more than what is required to solvate the epoxy alcohol. Similar experiments for the tetrahydropyran case suggest a competition between an unselective and a selective pathway requiring one and two water molecules in excess of those required to solvate the starting material, respectively. The selective pathway observed for the tetrahydropyran-containing system (but not the cyclohexyl) is rationalized by a twist-intermediate that is stabilized by hydrogen bonding between the tetrahydropyran oxygen and exogeneous water molecules. This study exemplifies the intimate connection between the identity of the epoxy alcohol template and the special properties of water; variation of either leads to an unselective reaction. We are currently elucidating the details of this interplay further and hope that the lessons learned from these studies will not only provide clues for the development of new templates and catalysts for regioselective cyclizations of epoxy alcohols, but also augment our understanding of related, consecutive epoxide openings (“Nakanishi cascade” reactions).

We are now investigating the mechanisms of these cascades, and these studies are reinforcing our viewpoint that the unique features are critical for the success of Nakanishi cascades. In particular, the mode of activation (water) dictates the _direction_ of the cascade, and this directionality affords the maximum desired selectivity. Moreover, the templating effect that we described previously (one ring) appears to be reinforced with each ring formation. That is, the two-ring template formed after the first cyclization engenders a higher desired selectivity than the first ring does by itself.