One major focus of our research is the catalytic asymmetric [2,3]-rearrangements of reactive zwitterions, which are synthetically versatile molecules implicated in a diverse range of chemical transformations. These reactive substrates were traditionally thought to be incompatible with enantioselective catalysis because of their propensity to undergo facile thermal [2,3]-rearrangements in the absence of a catalyst. Our group has challenged this assumption held widely in our field for decades.
We have developed a series of first-in-class metal-catalyzed stereoselective [2,3]-rearrangements of zwitterionic reactive intermediates, including ammonium ylides formed through a palladium-catalyzed amine allylic alkylation, allylic amine N-oxides with palladium, and a full program of rearrangements of allylic iodonium ylides.
Similar to allylic ammonium ylides and allylic amine N-oxides, allylic iodonium ylides can undergo thermal [2,3]-rearrangements with the added possibility of a [1,2]-rearrangement, giving rise to sixteen possible products. Utilizing copper catalysis, we can transform iodonium ylides formed from their corresponding diazoesters and allylic iodides with copper into the [2,3]- and [1,2]-rearrangement products with high regioselectivity and diastereoselectivity. Our first investigation found that sterically hindered, electron withdrawing ligands on copper favored the [2,3]-rearrangement product, and electron donating phosphines furnished the [1,2]-rearrangement product.
Phosphoric Acid Catalyzed Rearrangements
Stereoselective Functionalization of Hydrocarbons
Our group has explored enantioselective rearrangements for the stereoselective functionalization of hydrocarbons found in inexpensive and abundant components of petrochemical feedstock. Terminal alkenes react with sulfur-based oxidants developed in our laboratory to generate a zwitterionic species, which we have then engaged in variety of processes. This zwitterionic species can undergo a [2,3]-rearrangement to access the allylic amination product or nucleophilic displacement for formal alkylation of an allylic C-H bond with Grignard reagents.
As an extension of our approach to the catalytic allylic functionalization of unactivated terminal olefins, we have recently solved the more challenging problem of catalytic asymmetric allylic functionalization of internal olefins. While most strategies for allylic oxidation of olefins are based on metal-catalyzed C–H activations and C–H insertions, these processes are inherently non-regioselective for the oxidation of unactivated internal olefins in the absence of directing groups.
We hypothesized that if the hetero-ene reaction could be rendered stereoselective by a chiral catalyst, this reaction manifold may provide the ideal platform to develop a highly enantioselective, E/Z selective, and regioselective allylic oxidation of unactivated internal olefins. This approach was successfully realized with a SbCl5-BINOL catalyst system. This method represents the first example of selectively converting unsymmetrical internal olefins into allylic functionalized products with high stereoselectivity and regioselectivity. Stereospecific transformations of the multifunctional allylic oxidation products highlight the potential for rapidly converting internal olefins into a broad range of enantioenriched structures that can be utilized in the synthesis of complex target molecules.
Current efforts in catalysis in our laboratory include the development of rearrangements of a variety of in-situ generated ylides, selective allylic functionalizations, and further uses of sulfur-based oxidants.