Catalytic desymmetrization reactions to synthesize all-carbon quaternary stereocentres

The term all-carbon quaternary stereocentre refers to a chiral carbon atom featuring four different carbon substituents. Such structural motifs are prominent in natural products, drugs and bioactive compounds. Incorporating such conformationally constrained stereocentres into molecules allows the exploration of chemical spaces with enhanced potency, selectivity and other drug-related properties. Exploiting efficient catalytic enantioselective methods to construct all-carbon quaternary stereocentres is highly desirable for drug discovery, but constitutes a long-term challenge in organic synthesis. The desymmetrization strategy has been established as a powerful approach to this end and has found wide application in the total synthesis of natural products and bioactive compounds. The attractive features of this approach include its use of symmetric substrates that can be relatively easily prepared and that endow the products with a synthetic handle for further diversification, alleviating the steric repulsion that needs to be overcome to construct quaternary carbons, creating multiple stereocentres via one manipulation, and putting a wide range of catalytic reactions to use. This Review highlights the key advances in this area during the period 2016-2022, points out the challenges to be overcome, and outlines the synthetic opportunities still to be explored. Catalytic enantioselective synthesis of all-carbon quaternary stereocentres is a long-term challenge in organic synthesis because of substantial steric repulsion and dissimilarities between the substituents around the stereocentre. This Review presents how the desymmetrization strategy plays an important role in constructing these types of motifs.