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

Abstract

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.

Chiral Phosphoric Acid Catalyzed Stereoselective Spiroketalizations

“…Assuming that the reaction of oxocarbenium ion and tethered hydroxyl nucleophile should be very fast in solvents like pentane, an alternative concerted mechanism proceeding through transition state 29 could be proposed. 7,14 In this case, the phosphoric acid acts as a bifunctional catalyst that protonates the enol ether and deprotonates the hydroxyl group at the same time. Although the properties of oxocarbenium/phosphate ion pairs are relatively unexplored, the computational and mechanistic studies conducted with iminium/phosphate ion pairs suggest that CPAs could serve as bifunctional catalysts that facilitate proton transfer.…”

“…3c,6 Among such general strategies is the reductive cyclization developed by the Rychnovsky group (Scheme 2). 6g,i This strategy relies on selective reductive lithiation of 2-cyano tetrahydropyrans (5) that results in axial alkyllithium intermediates (6) that undergo intramolecular alkylation resulting in non-thermodynamic spiroketals (7). This approach was applied to the synthesis of various nonanomeric spiroketals including the pectenotoxin 2 AB spiroketal system 7.…”

Synthesis of 5,6- and 6,6-Spirocyclic Compounds

“…The effect of substitution on the aryl ring in this system was also studied by the same authors [140] (Scheme 67). The retention spiroacetals 268 were obtained under spontaneous cyclization conditions with good selectivity across most ring sizes, except for the electron-poor NO 2 -substituted analogue.…”

“…Scheme 64 Ring opening of epoxides in the synthesis of spiroacetals This method has also been extended to the synthesis of mono(benzannulated) spiroacetals [139,140] (Scheme 66). For both the threo and erythro glycal-derived epoxides, the retention spiroacetals 265a and 266b could be obtained selectively using the Ti(Oi-Pr) 4 protocol.…”

“…The spiroacetals were obtained as mixtures of anomers, but treatment with catalytic acid induced complete epimerization to the desired anomeric spiroacetal 275. Scheme 66 Tan et al's selective syntheses of mono(benzannulated) spiroacetals via intramolecular epoxide ring opening [139,140] Tan et al [78] have also applied an intramolecular epoxide ring-opening in their synthesis of acortatarin B (Scheme 70).…”