Hydrogen-bonding catalysis and inhibition by simple solvents in the stereoselective kinetic epoxide-opening spirocyclization of glycal epoxides to form spiroketals Journal Article
| Authors: | Wurst, J. M.; Liu, G.; Tan, D. S. |
| Article Title: | 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 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. © 2011 American Chemical Society. |
| Keywords: | oxygen; kinetics; inhibition kinetics; hydrogen bond; hydrogen bonding; sugars; chemical structure; catalysis; cyclization; natural product; concentration (parameters); reaction analysis; stereochemistry; stereoisomerism; spiro compound; solvent; solvents; transition state; nucleophile; stereo-selective; epoxy compounds; hydrogen; hydrogen bonds; electrophile; spirocyclization; side reactions; natural products; stereoselectivity; chemical reaction kinetics; second orders; epoxide; side-chains; experimental data; anomeric carbon; cosolvents; differential reaction; electrophiles; first-order; hammett analysis; hydrogen bondings; inversion of configuration; methyl glycosides; spiroketals; structural motifs; acetone; reaction rates; acetal; methylglycoside; sulfur; epoxide opening spirocyclization; ring opening; temperature dependence |
| Journal Title: | Journal of the American Chemical Society |
| Volume: | 133 |
| Issue: | 20 |
| ISSN: | 0002-7863 |
| Publisher: | American Chemical Society |
| Date Published: | 2011-05-25 |
| Start Page: | 7916 |
| End Page: | 7925 |
| Language: | English |
| DOI: | 10.1021/ja201249c |
| PUBMED: | 21539313 |
| PROVIDER: | scopus |
| PMCID: | PMC3113711 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 3 October 2011" - "CODEN: JACSA" - "Source: Scopus" |
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