Defense: Xiaoxiao Ma- The Development of Palladium-Catalyzed Regio- and Enantioselective Difunctionalizations of Conjugated Dienes and Enynes

Conjugated dienes and enynes serve as important building blocks for constructing molecules with high complexity, yet achieving regio- and stereocontrol in their difunctionalization remains a persistent challenge. To address these problems, we develop difunctionalization utilizing a palladium catalyst, enabling regioselective and enantioselective reactions. For 1,3-dienes, regioselectivity can be controlled by different catalytic systems, and thermally disfavored 4,1-selective alkenylamination for aryl dienes can be achieved by using indole-derived phosphoramidite ligand, while Xantphos ligand favors classic 4,3-addition. This protocol demonstrated great functional group tolerance, delivering allylic amines with an extra alkene functionality for further functionalization. For internal 1,3-enynes, the diastereoselectivity can be controlled by the conformation of the enynes, while the enantioselectivity is determined by the catalyst, thus affording the trisubstituted allenes bearing axial and central chirality in one single step. Different functional groups, including OTBS and NBoc groups, can be tolerated with high efficiency. Both methods are compatible under one mmol scale, demonstrating their practicality in synthesis. Coordinating counteranion is detrimental to both reactions, diminishing selectivity and the yield. Mechanistic studies reveal that the 4,1-selectivity for the aryl dienes is likely accomplished via π-stacking-stabilized transition states, whereas the enantioselectivity for the enyne difunctionalization is achieved by the substituent on the enyne distinguishing the key intermediates. This work establishes general methods for palladium-catalyzed difunctionalization over conjugated π systems, realizing rapid access to pharmaceutically relevant complex structures while providing mechanistic insight for future research.