An electrochemically driven enantioselective nickel-catalyzed reductive cross-coupling of alkenyl bromides and benzyl chlorides is reported. The reaction forms products bearing allylic stereogenic centers with good enantioselectivity under mild conditions in an undivided cell. Electrochemical activation and turnover of the catalyst mitigate issues posed by metal powder reductants. This report demonstrates that enantioselective Ni-catalyzed cross-electrophile couplings can be driven electrochemically.

The human malaria parasite Plasmodium falciparum requires efficient egress out of an infected red blood cell for pathogenesis. This egress event is highly coordinated and is mediated by several signaling proteins, including the plant-like P. falciparum calcium-dependent protein kinase 5 (PfCDPK5). Knockdown of PfCDPK5 results in an egress block where parasites are trapped inside their host cells. The mechanism of this PfCDPK5-dependent block, however, remains unknown. Here, we show that PfCDPK5 colocalizes with a specialized set of parasite organelles known as micronemes and is required for their discharge, implicating failure of this step as the cause of the egress defect in PfCDPK5-deficient parasites. Furthermore, we show that PfCDPK5 cooperates with the P. falciparum cGMP-dependent kinase (PfPKG) to fully activate the protease cascade critical for parasite egress. The PfCDPK5-dependent arrest can be overcome by hyperactivation of PfPKG or by physical disruption of the arrested parasite, and we show that both treatments facilitate the release of the micronemes required for egress. Our results define the molecular mechanism of PfCDPK5 function and elucidate the complex signaling pathway of parasite egress.

Machine-learned ranking models have been developed for the prediction of substrate-specific cross-coupling reaction conditions. Datasets of published reactions were curated for Suzuki, Negishi, and C-N couplings, as well as Pauson-Khand reactions. String, descriptor, and graph encodings were tested as input representations, and models were trained to predict the set of conditions used in a reaction as a binary vector.Unique reagent dictionaries categorized by expert-crafted reaction roles were constructed for each dataset, leading to context-aware predictions. We find that relational graph convolutional networks and gradient-boosting machines are very effective for this learning task, and we disclose a novel reaction-level graph-attention operation in the top-performing model. File list (2)download file view on ChemRxiv 2020-10-13_ChemRxiv.pdf (2.25 MiB) download file view on ChemRxiv 2020-10-13_ChemRxiv_SI.pdf (3.28 MiB)

A method for the coupling of aryl bromides with potassium alkyl trifluoroborates, via nickel/photoredox dual catalysis, has been developed for use in continuous flow. This operationally simple protocol is able to form Csp-Csp bonds with significantly reduced reaction times and a broader substrate scope than when conducted in batch. The utility of this method for rapid analog synthesis has been demonstrated by the synthesis of a small library of alkyl-substituted quinazolines.

An efficient photoredox/Ni dual catalytic C-C cross-coupling protocol in a continuous-flow regime to synthesize a variety of regioisomeric cycloalkyl substituted 7-azaindoles has been developed. These transformations proceed efficiently under mild conditions (blue LED light irradiation at 30 °C over 40 min residence time in mixed solvent systems). Reactions are easy to perform and afford most of the desired 2-, 3-, 4-, 5-, and 6-cycloalkyl substituted 7-azaindoles in moderate-to-good yield.