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On the origin of the stereoselectivity in the alkylation of oxazolopiperidone enolates

Posted June 8th, 2010 by pschmidtke
TitleOn the origin of the stereoselectivity in the alkylation of oxazolopiperidone enolates
Publication TypeJournal Article
Year of Publication2006
AuthorsSoteras, I, Lozano O, Gomez-Esque A, Escolano C, Orozco M, Amat M, Bosch J, Luque FJ
JournalJournal of the American Chemical Society
Volume128
Issue20
Pagination6581 - 6588
Date Published2006/05/24/
KeywordsAlkylation;, Computer, Conformation;, Lithium/chemistry;, Molecular, Oxazoles/chemistry;, Piperidones/chemistry;, Simulation;, Stereoisomerism
AbstractThe origin of the diastereoselective alkylation of enolates of oxazolopiperidones is studied by means of theoretical calculations and experimental assays. For the unsubstituted oxazolopiperidone, the alkylation with methyl chloride is predicted to afford mainly the exo product, a finding further corroborated from the analysis of the experimental outcome obtained in the reaction of the racemic oxazolopiperidone. However, such a preference can be drastically altered by the presence of substituents attached to the fused ring. In particular, when the angular carbon adopts an R configuration in a phenylglycinol-derived oxazolopiperidone, the presence of a phenyl ring at position 3 forces the pseudo-planarity of the bicyclic lactam, and the diastereoselectivity is dictated by the internal torsional strain induced in the enolate. However, when the angular carbon adopts an S configuration, the preference for the exo alkylation stems from the intermolecular steric hindrance between the enolate and the alkylating reagent. Interestingly, the intramolecular hydrogen bond formed between the phenyl ring and the carbonyl oxygen in the enolate largely reduces the difference in stability of the two TSs compared to the unsubstituted oxazolopiperidone.