Stereochemical investigation on the construction of poly-functionalized bicyclo[3.3.1]nonenones by successive Michael reactions of 2-cyclohexenones.

A method for the practical construction of poly-functionalized bicyclo[3.3.1]nonenones by successive Michael reactions of cyclohexenones with acrylates using K2CO3 and TBAB (n-Bu4N+ Br-) was developed. The construction could be carried out in both stepwise and one-pot reactions with similar tendencies in regioselectivity. The alpha-regioselectivity in the intramolecular Michael reaction agreed with that stereoelectronically expected in intermolecular reactions based upon consideration of the HOMO orbital profile of the enolate I, the precursor to ring-closure, although the reaction site was trisubstituted and prone to steric hindrance in most of the examples presented. For the acetoxymethylacrylates substituted at either the alpha or gamma position, steric hindrance of the substituents (R2 and R3) served as a controlling factor to induce high regiocontrol. Facial selection in the protonation of enolate II, formed upon ring-closure, was also affected by these substituents. In both the intramolecular Michael reaction and the protonation of enolate II, the ammonium counter cation played an important role.