Enantioselective Reactions of Palladium Enolate Intermediates: Beyond Allylic Alkylation

The enantioselective Pd-catalyzed allylic alkylation reaction has proven to be an incredibly powerful and versatile methodology for the construction of stereoenriched building blocks bearing all-carbon quaternary centers. We have contributed to this field by investigating the application of chiral phosphinooxazoline (PHOX) palladium catalysts in the context of asymmetric alkylations of unstabilized nucleophiles toward a diverse array of products. In the course of our computational and mechanistic investigations, we have uncovered an oxygen-bound Pd enolate intermediate that is proposed to undergo an inner-sphere pericyclic reductive elimination. This mechanistic hypothesis stands in contrast to the outer-sphere and charge-separated mechanisms proposed for many other Pd-catalyzed allylic alkylation reactions. Intercepting this chiral enolate with other electrophiles beyond an allyl group would allow more diverse chemical space to be accessible using this platform. This Account describes several distinct approaches toward this end that are enabled by joint computational and experimental mechanistic studies. To begin, we discuss our early efforts to intercept Pd enolates using exogeneous electrophiles such as acidic protons and benzylidene malononitriles. Through these approaches, we discovered that strongly activated and polarized external electrophiles were the most successful substrates in the context of selective asymmetric transformations. We have expanded this scope to weaker carbon electrophiles by intramolecularly tethering these groups to our Pd enolate precursors alongside the application of exogeneous allyl scavengers. These strategies allow the formation of products that do not bear an allyl substituent. This development enabled construction of a library of chiral spirocycles, motifs that are prevalent in bioactive molecules. In order to extend the range of electrophiles compatible with this chemistry, we have identified the use of terminally substituted allyl groups to be important for the formation of stereotriads and -tetrads. Exploring these reactions experimentally and computationally has suggested new possible turnover mechanisms and stereochemical considerations that have informed further design iterations.