Just add salt: Vinyl aziridines have been treated with methyl vinyl ketone or ethyl thioacrylate in the presence of Pd0 to give pyrrolidines with moderate to good diastereoselectivity. The presence of nBu4NCl was critical to successful annulation. The synthetic utility of the methodology has been demonstrated in a short (formal) synthesis of (−)‐α‐kainic acid.

Plasmepsin X (PMX) is an essential aspartyl protease controlling malaria parasite egress and invasion of erythrocytes, development of functional liver merozoites (prophylactic activity), and blocking transmission to mosquitoes, making it a potential multistage drug target. We report the optimization of an aspartyl protease binding scaffold and the discovery of potent, orally active PMX inhibitors with in vivo antimalarial efficacy. Incorporation of safety evaluation early in the characterization of PMX inhibitors precluded compounds with a long human half-life (t 1/2 ) to be developed. Optimization focused on improving the off-target safety profile led to the identification of UCB7362 that had an improved in vitro and in vivo safety profile but a shorter predicted human t 1/2 . UCB7362 is estimated to achieve 9 log 10 unit reduction in asexual blood-stage parasites with once-daily dosing of 50 mg for 7 days. This work demonstrates the potential to deliver PMX inhibitors with in vivo efficacy to treat malaria.

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The synthesis of densely functionalized cyclobutanes containing all-carbon quaternary stereocenters in high regio- and diastereoselectivity remains synthetically challenging. Herein, we show that this can be achieved by using a sequential photocatalysis strategy, wherein 3-chloromaleimides undergo triplet sensitized [2 + 2] photocycloadditions with alkynes or alkenes followed by photoredox-catalyzed dechlorinative C–C bond forming reactions to install quaternary stereocenters. This allows the rapid assembly of structurally complex and sterically congested 3-azabicyclo­[3.2.0]­heptane scaffolds from readily available starting materials.

A number of novel fused thiophene derivatives have been prepared and identified as potent inhibitors of MEK. The SAR data of selected examples and the in vivo profiling of compound 13 h demonstrates the functional activity of this class of compounds in HT-29 PK/PD models.