Dynamic Kinetic Resolution‐Based Asymmetric Hydrogenation of C3 ‐Substituted Isoquinolines

Comprehensive Summary Chiral tetrahydroisoquinolines (THIQs) are common motifs in numerous natural products and bioactive molecules. Direct asymmetric hydrogenation of inactivated isoquinolines represents a straightforward access to them, while current research generally focuses on the construction of THIQs bearing endocyclic stereocenters, prohibiting the exploration of more complex chemical space. Herein, we report an iridium‐catalyzed dynamic kinetic resolution (DKR)‐based asymmetric hydrogenation of C3‐substituted isoquinolines, affording THIQs bearing vicinal endocyclic and exocyclic stereocenters from racemic starting materials. A total of 31 structurally novel THIQs have been obtained with excellent diastereoselectivity (dr > 20 : 1) and good to excellent yields and enantioselectivities (up to 94% ee). The synthetic utility of this method was further demonstrated by a 2.0 mmol‐scale reaction and subsequent transformations of the products. In particular, hydrolysis and cyclization enabled access to vicinal diamine, cyclic urea derivatives and bioactive molecules such as MOR agonist scaffolds. Deuterium‐labeling experiments revealed efficient deuterium incorporation at the α‐position of the THIQ ring and at the C3/C4 positions, supporting a reversible imine‐enamine tautomerization process during the reaction. This work provides a practical approach to stereochemically complex THIQs from simple racemic isoquinolines.