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 S(N)2 versus S(N)1 reaction manifolds. Hammett analysis of reaction kinetics with these substrates is consistent with an S(N)2 or S(N)2-like mechanism (ρ = -1.3 vs ρ = -5.1 for corresponding S(N)1 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 side-chain 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.

Figure 1

Stereoselective spirocyclization of glycal epoxides (2) with inversion (3) or retention (4) of configuration at the anomeric carbon. DMDO = dimethyldioxirane; TIPS = triisopropylsilyl.

Figure 2

Possible S_N2 and S_N1 mechanisms for MeOH-induced epoxide-opening spirocyclization of glycal epoxides with inversion of configuration at the anomeric carbon.

Figure 3

Hammett analysis of acid-catalyzed spiroketal epimerization via an S_N1 mechanism. a) S_N1 mechanism for acid-catalyzed epimerization of contrathermodynamic (inversion) spiroketals 8a–f to thermodynamic (retention) spiroketals 11a–f. R = CH₂CH₂OTBDPS. b) Rates of conversion with 10 mol% TsOH in CDCl₃ at rt. The p-nitro-substituted substrate 8f does not react within 72 h under these conditions. Pseudo-first-order rate differences among the six substrates 8a–f illustrate the electronic requirements for the formation of oxocarbenium intermediates 21a–f. Representative data from one of two replicate experiments shown. c) Hammett plot exhibits a linear correlation for the electronically varied substrates 8a–e with a steep negative slope indicative of an S_N1 transition state (ρ = −5.1).

Figure 4

Hammett analysis of methanol-catalyzed epoxide-opening spirocyclization via a proposed S_N2 mechanism. a) Methanol-catalyzed epoxide-opening spirocyclization of glycal epoxides 22a–f with inversion of configuration to afford spiroketals 8a–f. R = CH₂CH₂OTBDPS. b) Rates of inversion product formation with 11.9 M CD₃OD (4:3:1.3 CD₃OD/CDCl₃/acetone) at −35 °C. The p-methoxy-substituted substrate 5a also forms the corresponding retention product 11a, but the diagnostic NMR peaks are resolved. The linear fit for the p-CF₃-substituted substrate 5e is based upon a total of seven datapoints out to 52 min, although only the first three datapoints are shown for clarity. The p-nitro-substituted glycal epoxide intermediate 22f does not react at this temperature. Representative data from one of three replicate experiments shown. c) Hammett plot exhibits a linear correlation for the electronically varied substrates 22a–e with a shallow negative slope indicative of an S_N2 transition state (ρ = −1.3).

Figure 5

Second-order catalysis by methanol in the epoxide-opening spirocyclization of glycal epoxide 22c (R = H). a) Plot of k_obs (min⁻¹) for inversion product formation at varying [CD₃OD] yields a polynomial curve. Mean values over two replicate experiments shown. b) Plot of k_obs (min⁻¹) versus [CD₃OD] yields a linear correlation, consistent with second-order dependence on methanol. Mean values over two replicate experiments shown.

Figure 6

Three possible S_N2 transition states for MeOH-catalyzed epoxide-opening spirocyclization with inversion of configuration under MeOH hydrogen-bonding catalysis. In transition state 23, both the epoxide leaving group and alcohol nucleophile are activated with separate MeOH hydrogen bonds. Transition state 24 is similar, but the upper MeOH also engages in a second hydrogen bond to the tetrahydropyran ring oxygen that may disfavor competing S_N1 mechanisms involving oxocarbenium formation. In transition state 25, the epoxide electrophile is activated by two MeOH hydrogen bonds, as seen in epoxide hydrolase enzymes.

Figure 7

Epoxide-opening spirocyclizations of a cyclohexene oxide substrate lacking the glycal ring oxygen. The thermal spirocyclization in toluene-d₈ proceeds to only 85% conversion even after 72 h. Stereochemical assignments were determined by ¹H-NMR and NOESY analysis of the spiroether product.

Figure 8

Fractional-order catalysis by methanol in the epoxide-opening spirocyclization a substrate lacking the glycal ring oxygen. a) Methanol-catalyzed epoxide-opening spirocyclization of cyclohexene oxide 27 with inversion of configuration to afford spiroether 28. b) Plot of k_obs (min⁻¹) for spiroether formation at varying [CD₃OD] yields a fractional-order curve. Mean values over two replicate experiments shown. c) Plot of k_obs (min⁻¹) versus [CD₃OD]^0.59 yields a linear correlation, consistent with the fractional-order dependence on methanol. Mean values over two replicate experiments shown.

Figure 9

First-order inhibition by acetone in the epoxide-opening spirocyclization of glycal epoxide 22c (R = H). a) Plot of k_obs (min⁻¹) for inversion product formation at varying [acetone] yields an inhibitory curve. Mean values over two replicate experiments shown. b) Plot of k_obs (min⁻¹) versus [acetone]⁻¹ yields a linear correlation, consistent with negative first-order dependence on acetone. Mean values over two replicate experiments shown.

Figure 10

First-order dependence on methanol in the intermolecular methyl glycoside formation side reaction. a) Methanolysis of the glycal epoxide generated in situ from protected glycal 29 to afford methyl glycoside 30. b) Plot of k_obs (min⁻¹) versus [CD₃OD] yields a linear correlation, consistent with first-order dependence on methanol. Mean values over two replicate experiments shown.

Figure 11

Proposed S_N1 mechanism for competing intermolecular methyl glycoside-forming side reaction.