The new homogeneous catalysts that are required to tame the reactivity of single-carbon reagents, and particularly the need to assemble these catalysts in a fast and modular fashion have inspired the discovery of a new class of organometallic amide reagents (Angew. Chem. Int. Ed. 2017, 12962; Angew. Chem. Int. Ed. 2017, 16042; Synlett 2018, 1329). These have demonstrated to enable new Pummerer (Angew. Chem. Int. Ed. 2017, 16042) and carboxylate addition reactions (Org. Lett. 2019, 7908; Chem. Eur. J. 2022, e202104053) without a precedent in organic chemistry. These reagents are advantageous because their reactivity and selectivity are clearly superior to current carbon nucleophiles, and they are conveniently prepared in situ from commercial components. We have also explained the exotic mechanism of action of these reagents (Chem. Eur. J. 2020, 2767).
After initial scouting of iterative coupling on sulphides (Angew. Chem. Int. Ed. 2017, 16042; Synlett 2018, 1329), we have identified redox-active carbenes as ideal single-carbon precursors due to the superior reactivity of carbene intermediates and the versatility of the redox-active ester manifold. In fact, we have found that the presence of the latter enhances the reactivity and selectivity of geminal carbene intermediates (Angew. Chem. Int. Ed. 2019, 5930 - journal cover). We have illustrated these findings in the context of cyclopropanation reactions due to their challenging synthesis and their importance in medicinal chemistry. Redox-active carbenes have demonstrated to be instrumental in the enantioselective cyclopropanation of aliphatic olefins, which are traditionally unreactive and poorly selective in this context. We have developed several adapted methods to transform the resulting enantiopure redox-active cyclopropanes into various classes of compounds through stereoselective decarboxylative coupling reactions. Further, we have proven that the same carbene precursor can also lead to more congested quaternary stereocenters with high enantioselectivity using simple rhodium catalysts (ACS Catal. 2019, 7870) and explored the mechanistic details behind the unusual performance of redox-active carbenes through high level calculations and kinetic studies (ACS Catalysis 2021, 10950).
These results have inspired unforeseen breakthroughs discovered during the diversification of the redox-active carbene insertion products, including a photo ligation using visible light and NADH (J. Am. Chem. Soc. 2020, 20143), a stereoselective decarboxylative reduction mediated by visible light and benzothiazolines (ACS Catalysis 2021, 13312), and a new scalable decarboxylative borylation that will be published soon.
