Enantioselective Synthesis of Lactone-[2,3-b]piperidines

Significance

Reported is a conceptually inter­esting synthesis of lactolpiperidine derivatives through a tandem Diels-Alder reaction-hemiacetal formation. The enamine dienophile is formed in situ through condensation of an aldehyde and the proline-based catalyst. These lactols are then oxidized to give lactones of high enantiopurity. Although the process can proceed well with reaction times of two to eight hours, there were some cases where it seemed to have problems. For instance, when R^² = 4-BrC₆H₄ the time increased to 36 hours, when R^² = Me the time increased to 230 hours, and when R^¹ = CO₂Et the reaction times increased to around a day, and a stoichiometric quantity of benzoic acid and a shift of solvent to CH₂Cl₂ was required. Although benzoic acid was used as an additive through most of this work, it was shown that acetic acid also led to successful reactions.