Evidence That Epoxide-Opening Cascades Promoted by Water Are Stepwise and Become Faster and More Selective After the First Cyclization

Morten, Christopher J.; Byers, Jeffery A.; Jamison, Timothy F.

doi:10.1021/ja1088748

Cited by 44 publications

(23 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…9,10 In particular, the observed stereoselectivity for inversion of configuration at the anomeric carbon may be attributed to either of two possible reaction mechanisms (Figure 2). An S N 2 reaction manifold (pathway A) would require sufficient hydrogen-bonding activation of the epoxide electrophile to induce nucleophilic substitution by the sidechain hydroxyl group without formation of a discrete oxocarbenium intermediate, which might lead to reduced stereoselectivity.…”

Section: Resultsmentioning

confidence: 99%

“…Jamison and coworkers have reported second-order catalysis by water in their landmark studies of regioselective epoxide-opening cascades to form ladder polyethers. 9 Williams and coworkers have provided computational support for hydrogen-bonding catalysis at the distal epoxide in their intriguing work on spirodiepoxide-opening reactions. 10 To date, however, the role of hydrogen-bonding catalysis in epoxide-opening spirocyclizations of glycal epoxides, and the critical and distinctive impact upon stereoselectivity in this reaction, has not been studied in detail.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hydrogen-Bonding Catalysis and Inhibition by Simple Solvents in the Stereoselective Kinetic Epoxide-Opening Spirocyclization of Glycal Epoxides to Form Spiroketals

2011

View full text Add to dashboard Cite

Mechanistic investigations of a MeOH-induced kinetic epoxide-opening spirocyclization of glycal epoxides have revealed dramatic, specific roles for simple solvents in hydrogen-bonding catalysis of this reaction to form spiroketal products stereoselectively with inversion of configuration at the anomeric carbon. A series of electronically-tuned C1-aryl glycal epoxides was used to study the mechanism of this reaction based on differential reaction rates and inherent preferences for SN2 versus SN1 reaction manifolds. Hammett analysis of reaction kinetics with these substrates is consistent with an SN2 or SN2-like mechanism (ρ = −1.3 vs. ρ = −5.1 for corresponding SN1 reactions of these substrates). Notably, the spirocyclization reaction is second-order dependent on MeOH and the glycal ring oxygen is required for second-order MeOH catalysis. However, acetone cosolvent is a first-order inhibitor of the reaction. A transition state consistent with the experimental data is proposed in which one equivalent of MeOH activates the epoxide electrophile via a hydrogen bond while a second equivalent of MeOH chelates the sidechain nucleophile and glycal ring oxygen. A paradoxical previous observation that decreased MeOH concentration leads to increased competing intermolecular methyl glycoside formation is resolved by the finding that this side reaction is only first-order dependent on MeOH. This study highlights the unusual abilities of simple solvents to act as hydrogen-bonding catalysts and inhibitors in epoxide-opening reactions, providing both stereoselectivity and discrimination between competing reaction manifolds. This spirocyclization reaction provides efficient, stereocontrolled access to spiroketals that are key structural motifs in natural products.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hydrogen-Bonding Catalysis and Inhibition by Simple Solvents in the Stereoselective Kinetic Epoxide-Opening Spirocyclization of Glycal Epoxides to Form Spiroketals

2011

View full text Add to dashboard Cite

show abstract

“…9,10 The presence of the oxygen in the heterocyclic ring was vital for the desired selectivity. It has also been suggested that enzymes may catalyze the formation of an initial THP ring, and that this THP then “templates” the cascade favoring an all endo ring closure sequence.…”

Section: Introductionmentioning

confidence: 99%

A Dioxane Template for Highly Selective Epoxy Alcohol Cyclizations

Mousseau

Morten

Jamison

2013

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

Ladder polyether natural products are a class of natural products denoted by their high functional group density and large number of well-defined stereocenters. They comprise the toxic component of harmful algal blooms (HABs), having significant negative economic and environmental ramifications. However, their mode of action, namely blocking various cellular ion channels, also denotes their promise as potential anticancer agents. Understanding their potential mode of biosynthesis will not only help with developing ways to limit the damage of HABs, but would also facilitate the synthesis of a range of analogues with interesting biological activity. 1,3-Dioxan-5-ol substrates display remarkable ‘enhanced template effects’ in water-promoted epoxide cyclization processes en route to the synthesis of these ladder polyether natural products. In many cases they provide near complete endo to exo selectivity in the cyclization of epoxy alcohols, thereby strongly favouring the formation of tetrahydropyran (THP) over tetrahydrofuran (THF) rings. The effects of various Brønsted and Lewis acidic and basic conditions are explored to demonstrate the superior selectivity of the template over the previously reported THP-based epoxy alcohols. In addition, the consideration of other synthetic routes are also considered with the goal of gaining rapid access to a plethora of potential starting materials applicable towards the synthesis of ladder polyethers. Finally, cascade sequences with polyepoxides are investigated, further demonstrating the versatility of this new reaction template.

show abstract

“…In addition to uncovering the specific details about epoxy alcohol cyclization reactions, these mechanistic studies are relevant to the biosynthetic proposal (18) for the formation of the ladder polyether natural products. The very slow reaction rates observed for 1a and even slower rates for cascade reactions of multiple epoxides, such as 4 and 6 (12,24), are problematic for a biosynthetic proposal involving consecutive or concurrent epoxy alcohol cyclizations promoted by neutral water. The data presented above suggest rate constants for endo cyclizations to be on the order of 10 −5 ·s −1 at 300 K, which translates to a half-life of 16.6 h. These rates seem unlikely under physiological conditions where metabolism or extrusion of intermediates during a cascade reaction would compete.…”

Section: Implications For the Biogenisis Of The Ladder Polyether Naturalmentioning

confidence: 99%

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

Byers

Jamison

2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

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....

show abstract

Evidence That Epoxide-Opening Cascades Promoted by Water Are Stepwise and Become Faster and More Selective After the First Cyclization

Cited by 44 publications

References 49 publications

Hydrogen-Bonding Catalysis and Inhibition by Simple Solvents in the Stereoselective Kinetic Epoxide-Opening Spirocyclization of Glycal Epoxides to Form Spiroketals

Hydrogen-Bonding Catalysis and Inhibition by Simple Solvents in the Stereoselective Kinetic Epoxide-Opening Spirocyclization of Glycal Epoxides to Form Spiroketals

A Dioxane Template for Highly Selective Epoxy Alcohol Cyclizations

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

Contact Info

Product

Resources

About