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. 2010 Feb 19;75(4):1107-18.
doi: 10.1021/jo902222a.

Erosion of stereochemical control with increasing nucleophilicity: O-glycosylation at the diffusion limit

Matthew G Beaver  1 , K A Woerpel
Affiliations

Erosion of stereochemical control with increasing nucleophilicity: O-glycosylation at the diffusion limit

Matthew G Beaver et al. J Org Chem. .

Abstract

Nucleophilic substitution reactions of 2-deoxyglycosyl donors indicated that the reactivity of the oxygen nucleophile has a significant impact on stereoselectivity. Employing ethanol as the nucleophile resulted in a 1:1 (alpha:beta) ratio of diastereomers under S(N)1-like reaction conditions. Stereoselective formation of the 2-deoxy-alpha-O-glycoside was only observed when weaker nucleophiles, such as trifluoroethanol, were employed. The lack of stereoselectivity observed in reactions of common oxygen nucleophiles can be attributed to reaction rates of the stereochemistry-determining step that approach the diffusion limit. In this scenario, both faces of the prochiral oxocarbenium ion are subject to nucleophilic addition to afford a statistical mixture of diastereomeric products. Control experiments confirmed that all nucleophilic substitution reactions were performed under kinetic control.

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Figures

Figure 1
Figure 1
Stereoselectivity (d.r.) vs. Nucleophilicity (F) in Pyran Systems
Scheme 1
Scheme 1
Nucleophilic Substitutions of 2-Deoxyglycoside 1
Scheme 2
Scheme 2
Modes of Addition to the 2-Deoxyglucose-Derived Oxocarbenium Ion 5
Scheme 3
Scheme 3
Reactive Intermediates Involved in Nucleophilic Substitutions
Scheme 4
Scheme 4
Modes of Addition to the 5-CH2OBn-Substituted Oxocarbenium Ions 27 and 28
Scheme 5
Scheme 5
Modes of Addition to the 4-OBn-Substituted Oxocarbenium Ions 36 and 37
Scheme 6
Scheme 6
Modes of Addition to the 3-OBn-Substituted Oxocarbenium Ion
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