posted on 2006-05-24, 00:00authored byIgnacio Soteras, Oscar Lozano, Arantxa Gómez-Esqué, Carmen Escolano, Modesto Orozco, Mercedes Amat, Joan Bosch, F. Javier Luque
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.