Direct methods for stereoselective functionalization of C(sp3)–H bonds in complex organic molecules could facilitate much more efficient preparation of therapeutics and agrochemicals. Here, we report a copper-catalyzed radical relay pathway for enantioselective conversion of benzylic C–H bonds into benzylic nitriles. Hydrogen-atom abstraction affords an achiral benzylic radical that undergoes asymmetric C(sp3)–CN bond upon reaction with a chiral copper catalyst. The reactions proceed efficiently at room temperature with the benzylic substrate as limiting reagent, exhibit broad substrate scope with high enantioselectivity (typically 90-99% enantiomeric excess), and afford products that are key precursors to important bioactive molecules. Mechanistic studies provide evidence for diffusible organic radicals and highlight the difference between these reactions and C–H oxidations mediated by enzymes and other catalysts that operate via radical rebound pathways.

The direct transformation of C-H bonds into diverse functional groups represents one of the most atom- and step-economical strategies for organic synthesis and has received substantial attention over the last few decades. Despite recent advances, asymmetric C-H bond functionalizations are less developed, especially asymmetric oxidations of sp C-H bonds. Inspired by enzyme (e.g., P450) catalysis, chemists have made great efforts to develop non-enzymatic systems for enantioselective oxidations of sp C-H bonds. However, the involvement of highly reactive radical intermediates makes enantioselective transformations extremely challenging. In this Account, we present our recent studies on the enantioselective induction of prochiral benzylic radicals using a chiral bisoxazoline (Box)/Cu catalytic system. This reaction system was developed on the basis of our extensive studies of copper-catalyzed intermolecular alkene difunctionalizations, such as azidotrifluoromethylations, trifluoromethylcyanations, and trifluoromethylarylations. In these reactions, the proposed catalytic cycle starts from the oxidation of the Cu(I) species by the activated Togni-I reagent (via a Lewis acid/base interaction with a silyl reagent or arylboronic acid) through a single electron transfer process. The generated CF radical can efficiently add to the alkene, and the resultant carbon-centered radical is subsequently trapped by an active Cu(II) species bearing a nucleophile (e.g., an N, CN, or Ar moiety) to form a new C-heteroatom or C-C bond and regenerate the Cu(I) catalyst. Kinetic studies of the trifluoromethylarylation of alkenes support a Cu(I/II/III) catalytic cycle in which the carbon radical reacts with the Cu(II) species to form a highly reactive Cu(III) intermediate and its reductive elimination contributes to the final bond formation. This assumption inspired us to explore asymmetric radical transformations by introducing chiral ligands. Enantioselective cyanations and arylations of benzylic radicals have been demonstrated in the presence of chiral Box/Cu(I) catalysts, and a series of asymmetric difunctionalizations of styrenes have been successfully achieved. In addition, by means of the same benzylic radical trapping process, enantioselective decarboxylative cyanations have been demonstrated using a cooperative photocatalysis and copper catalysis system. Compared with radical addition and decarboxylative processes, hydrogen atom abstraction (HAA) provides direct and facile access to benzylic radicals. By using bisbenzenesulfonimidyl radical for HAA, our group has developed an enantioselective cyanation of benzylic C-H bonds via a copper-catalyzed radical relay, and excellent reactivity and enantioselectivity were achieved in the presence of chiral Box/Cu(I) catalysts. In addition, a regioselective benzylic C-H bond arylation proceeding through a similar process was also developed, providing simple access to 1,1-diarylalkanes. Notably, alkyl arenes were used as the limiting reagent in these reactions, which allowed the late-stage fu...

Histone H3-lysine79 (H3K79) methyl transferase DOT1L plays critical roles in normal cell differentiation as well as initiation of acute leukemia. We used structure and mechanism based design to discover several potent inhibitors of DOT1L with IC50 values as low as 38 nM. These inhibitors exhibit only weak or no activities against four other representative histone lysine and arginine methyltransferases, G9a, SUV39H1, PRMT1 and CARM1. The x-ray crystal structure of a DOT1L:inhibitor complex reveals that N6-methyl group of the inhibitor, located favorably in a predominantly hydrophobic cavity of DOT1L, provides the observed high selectivity. Structural analysis shows that it will disrupt at least one H-bond and/or have steric repulsion for other histone methyltransferases. These compounds represent novel chemical probes for biological function studies of DOT1L in health and disease.