Entropic factors provide unusual reactivity and selectivity in epoxide-opening reactions promoted by water

Abstract

Despite the myriad of selective enzymatic reactions that occur in water, chemists have rarely capitalized on the unique properties of this medium to govern selectivity in reactions. Here we report detailed mechanistic investigations of a water-promoted reaction that displays high selectivity for what is generally a disfavored product. A combination of structural and kinetic data indicates not only that synergy between substrate and water suppresses undesired pathways but also that water promotes the desired pathway by stabilizing charge in the transition state, facilitating proton transfer, doubly activating the substrate for reaction, and perhaps most remarkably, reorganizing the substrate into a reactive conformation that leads to the observed product. This approach serves as an outline for a general strategy of exploiting solvent-solute interactions to achieve unusual reactivity in chemical reactions. These findings may also have implications in the biosynthesis of the ladder polyether natural products, such as the brevetoxins and ciguatoxins.entropic control | biomimetic G iven its simple structure and low molecular weight, water is a remarkably complex substance. Several landmark investigations (1) have revealed the ability of water to self-assemble to form sophisticated dynamic hydrogen bond networks, which accounts for its unusual properties, such as its high boiling point and high surface tension (2). Despite the unique properties that it offers and that nature has exploited, water is generally eschewed in synthetic chemistry largely because of chemical incompatibility with many commonly used reagents and the low aqueous solubility of many organic molecules coupled with the attendant assumption that homogeneity is required for reactivity. Although several important examples of remarkable reactivity have been documented for reactions carried out in water (3-5), on the surface of water (6, 7), or in micelles suspended in water (8, 9), utilization of the "biological solvent" in organic reactions remains uncommon.We became acutely aware of the remarkable properties of water when we discovered that neutral aqueous solutions of epoxy alcohol 1a underwent a spontaneous and selective "endo" cyclization reaction to form 6,6-fused bicyclic product 2a (Fig. 1) (10-12). Exceptional reactivity and selectivity were observed only when two criteria were satisfied: The substrate contained a sixmembered tetrahydropyran ring, and the solvent used was water at pH 7.0. These surprising results were counter to a set of general empirical rules put forth by Baldwin for cyclization reactions, which state that the smaller ring product resulting from what is commonly called an exo cyclization is favored for similar reactions (13). The tetrahydropyranol ring, therefore, appeared to "template" the endo cyclization pathway to form the larger ring product with water playing a critical yet heretofore unknown role.Moreover, 2a is a substructure found in a large family of natural products commonly referred to as the ladder polyethers (e....

Studies toward brevisulcenal F via convergent strategies for marine ladder polyether synthesis

“…We hypothesize that this cation may coordinate to the substrate in different ways to cause conformational changes, which have previously been shown to affect the rate and selectivity of epoxy alcohol cyclizations. 34 Murai and co-workers have also shown that coordination of a Lewis acid to the substrate can influence the regioselectivity of epoxide-opening cascades. 5a In our case, coordination of the cation with the MOM ether and its neighboring epoxide may be responsible for the undesired exo cyclization.…”

Stereocontrolled Synthesis of Spiroketals: An Engine for Chemical and Biological Discovery

“…Indeed, Jamison and coworkers have reported related catalytic functions of water in their epoxide-opening cascades to form ladder polyethers, with differential kinetic orders of hydrogen-bonding catalysis proposed to provide selectivity for competing endo and exo reaction manifolds. 27 Taken together, these studies reveal the dramatic and specific roles that simple solvents can play in hydrogen-bonding catalysis of epoxide-opening reactions and raise the possibility that specific solvent catalysis may play as yet unappreciated roles in other reactions as well.…”

Synthesis of the ABC framework of tamulamides A and B

“…Among our efforts is the development of directing-group free cascades that use THP or 1,3-dioxane templates. 11,12 The latter, in particular, can provide greatly-enhanced endo selectivity, with the 6-membered THP product favored under basic, acidic or neutral water conditions.…”