Development of New Carbene Catalysts and Design of Organocatalytic Reactions

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Due to their unique properties, N-heterocyclic carbenes (NHCs) have attracted a lot of attention from the synthetic community. In addition to their widespread use as ligands for transition metals, they have been shown to act as catalysts in their own right. A remarkable feature of NHC catalysts is their ability to effect a reversal of reactivity (umpolung) for aldehydes. Whereas aldehydes normally react as electrophiles, they can behave as acyl anion equivalents in the presence of NHCs. The NHC-catalyzed benzoin reaction was discovered several decades ago but applications in synthetic endeavours remain scarce despite its ability to form carbon-carbon bonds. The main limitation comes from the difficulty to achieve the cross-coupling of two different aldehydes. Recent developments by our group and others have made certain types of cross-benzoin reactions possible. Nevertheless, the range of reaction partners that can be coupled together chemoselectively remains quite limited. Building on our success with alpha-amino aldehydes, we propose to design new catalysts and substrates that will make a wider variety of cross-benzoin reactions possible. In addition to issues of chemoselectivity, diastereo- and enantioselectivity need to be addressed in order for these reactions to achieve their full potential. One very powerful, albeit challenging, area of investigation will consist in the dynamic kinetic asymmetric transformation of chiral aldehydes via cross-benzoin, Stetter, and aza-benzoin reactions to deliver products in a chemo-, diastereo- and enantioselective fashion. Despite the astounding number of new carbenes that have been developed for use in organometallic complexes, NHC catalysts currently in use belong to only four closely related families. As even minor modifications of the catalyst structure can lead to dramatically divergent outcomes, we propose to conduct a rational catalyst discovery program. Our recent discovery that oxazolium salts can catalyze the benzoin, Stetter, and other reactions supports the notion that many more heterocyclic carbenes can play complementary roles in organocatalysis. A systematic survey of heterocycles and substituents will uncover new and interesting reactivities. Alongside this survey of new catalyst families, more conventional heterocycles will be explored in a new light. Specifically, thiazolylidenes and bis(amino)carbenes (BACs) will be revisited as we believe interesting new reactivity can be uncovered using these frameworks.