title: On the origin of the stereoselectivity in the alkylation of oxazolopiperidone enolates.
abstract: The 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.
authors.affiliation: Department of Physical Chemistry, Faculty of Pharmacy, University of Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Soteras
authors.forename: Oscar
authors.initials: O
authors.lastname: Lozano
authors.forename: Arantxa
authors.initials: A
authors.lastname: Gómez-Esqué
authors.forename: Carmen
authors.initials: C
authors.lastname: Escolano
authors.forename: Modesto
authors.initials: M
authors.lastname: Orozco
authors.forename: Mercedes
authors.initials: M
authors.lastname: Amat
authors.forename: Joan
authors.initials: J
authors.lastname: Bosch
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Luque
mesh_terms: D000478:Alkylation; D003198:Computer Simulation; D008094:Lithium / Q000737:chemistry; D008968:Molecular Conformation; D010080:Oxazoles / Q000737:chemistry*; D010881:Piperidones / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D010080:Oxazoles; D010881:Piperidones; D008094:Lithium