Enantioselective β‑Protonation of Enals via a Shuttling Strategy

Remote asymmetric protonation is a longstanding challenge due to the small size of protons. Reactions involving electron-deficient olefins pose a further difficulty due to the electrophilic nature of these substrates. We report a shuttling system that delivers a proton in a highly enantioselective manner to the β-carbon of enals using a chiral N-heterocyclic carbene (NHC) catalyst. Choices of a Brønsted base shuttle and a Brønsted acid cocatalyst are critical for highly stereoselective β-protonation of the homoenolate intermediate and regeneration of the NHC catalyst results in functionalization of the carbonyl group. Thioesters with a β-chiral center were prepared in a redox-neutral transformation with an excellent yield and ee

Annihilation of Nanoscale Inversion Domains in Nitrogen-Polar AlN under High-Temperature Annealing

Inversion domains (IDs) are common defects in N-polar III-nitride thin films grown on sapphire substrates. In this work, the atomic structure and lateral migration of the randomly distributed Al-polar nanoscale IDs in N-polar AlN films subjected to high-temperature thermal annealing are investigated. With the increasing annealing temperature and time, Al-polar AlN IDs gradually shrunk in sizes. The vertical stripes transformed into cone-shaped caps on top of the AlN columns and were completely removed at last. The annihilation of the IDs was explained in terms of the lateral migration of the inversion domain boundary (IDB) induced by the imbalance of the strain state on two sides of the IDB. This work clarifies the evolution mechanism of AlN IDs during high-temperature annealing, providing a promising approach in the realization of uniform-polar AlN template for the development of high-efficiency optoelectronic and electronic devices

Combating Drug-Resistant Mutants of Anaplastic Lymphoma Kinase with Potent and Selective Type‑I^1/2 Inhibitors by Stabilizing Unique DFG-Shifted Loop Conformation

Targeted inhibition of anaplastic lymphoma kinase (ALK) dramatically improved therapeutic outcomes in the treatment of ALK-positive cancers, but unfortunately patients invariably progressed due to acquired resistance mutations in ALK. Currently available drugs are all type-I inhibitors bound to the ATP-binding pocket and are most likely to be resistant in patients harboring genetic mutations surrounding the ATP pocket. To overcome drug resistance, we rationally designed a novel kind of “bridge” inhibitor, which specially bind into an extended hydrophobic back pocket adjacent to the ATP-binding site of ALK. The novel type-I^1/2 inhibitors display excellent antiproliferation activity against ALK-positive cancer cells and appear superior to two clinically used drugs, crizotinib and ceritinib. Structural and molecular modeling analyses indicate that the inhibitor induces dramatic conformational transition and stabilizes unique DFG-shifted loop conformation, enabling persistent sensitivity to different genetic mutations in ALK. These data highlight a rationale for further development of next-generation ALK inhibitors to combat drug resistance