The protein–protein interaction (PPI) between menin and mixed lineage leukemia (MLL) plays a critical role in acute leukemias, and inhibition of this interaction represents a new potential therapeutic strategy for MLL leukemias. We report development of a novel class of small-molecule inhibitors of the menin–MLL interaction, the hydroxy- and aminomethylpiperidine compounds, which originated from HTS of ∼288000 small molecules. We determined menin–inhibitor co-crystal structures and found that these compounds closely mimic all key interactions of MLL with menin. Extensive crystallography studies combined with structure-based design were applied for optimization of these compounds, resulting in MIV-6R, which inhibits the menin–MLL interaction with IC50 = 56 nM. Treatment with MIV-6 demonstrated strong and selective effects in MLL leukemia cells, validating specific mechanism of action. Our studies provide novel and attractive scaffold as a new potential therapeutic approach for MLL leukemias and demonstrate an example of PPI amenable to inhibition by small molecules.

The Chan–Lam reaction remains a highly utilized transformation for C–N bond formation. However, anilines remain problematic substrates due to their lower nucleophilicity. To address this problem, we developed an electrochemically mediated Chan–Lam coupling of aryl boronic acids and amines utilizing a dual copper anode/cathode system. The mild conditions identified have enabled the preparation of a wide range of functionalized biarylanilines in good yields and chemoselectivities.

Closing in on azacines: We have developed a new six step approach for the rapid and enantioselective synthesis of indolizidine, pyrrolo[1,2‐a]azepine, and pyrrolo[1,2‐a]azocine azabicyclic systems and their respective lactam congeners, which are found in a host of natural products as well as pharmaceutical preparations. This protocol enables a concise enantioselective total synthesis of (+)‐grandisine D in 16.4 % overall yield from commercial materials (see scheme).

The Balz-Schiemann reaction remains a highly utilized means for preparing aryl fluorides from anilines. However, the limitations associated with handling aryl diazonium salts often hinder both the substrate scope and scalability of this reaction. To address this, a new continuous flow protocol was developed that eliminates the need to isolate the aryl diazonium salts. The new process has enabled the fluorination of an array of aryl and heteroaryl amines.