Enantioselective Synthesis of N-Benzylic Heterocycles by Ni/Photoredox Dual Catalysis.

An asymmetric cross-coupling of α-N-heterocyclic trifluoroborates with aryl bromides using Ni/photoredox dual catalysis has been developed. This C(sp2)-C(sp3) cross-coupling provides access to pharmaceutically relevant chiral N-benzylic heterocycles in good to excellent enantioselectivity when bioxazolines (BiOX) are used as the chiral ligand. High-throughput experimentation significantly streamlined reaction development by identifying BiOX ligands for further investigation and by allowing for rapid optimization of conditions for new trifluoroborate salts.

Multilabel Classification Models for the Prediction of Cross-Coupling Reaction Conditions.

Machine-learned ranking models have been developed for the prediction of substrate-specific cross-coupling reaction conditions. Data sets 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 data set, 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.

Application of the Photoredox Coupling of Trifluoroborates and Aryl Bromides to Analog Generation Using Continuous Flow.

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 Csp3-Csp2 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.

Nickel-catalyzed asymmetric reductive cross-coupling of α-chloroesters with (hetero)aryl iodides.

An asymmetric reductive cross-coupling of α-chloroesters and (hetero)aryl iodides is reported. This nickel-catalyzed reaction proceeds with a chiral BiOX ligand under mild conditions, affording α-arylesters in good yields and enantioselectivities. The reaction is tolerant of a variety of functional groups, and the resulting products can be converted to pharmaceutically-relevant chiral building blocks. A multivariate linear regression model was developed to quantitatively relate the influence of the α-chloroester substrate and ligand on enantioselectivity.

Structure-property studies of an imidazoquinoline chemotype with antitrypanosomal activity.

Human African trypanosomiasis is a neglected tropical disease (NTD) that is fatal if left untreated. Although approximately 13 million people live in moderate- to high-risk areas for infection, current treatments are plagued by problems with safety, efficacy, and emerging resistance. In an effort to fill the drug development pipeline for HAT, we have expanded previous work exploring the chemotype represented by the compound NEU-1090, with a particular focus on improvement of absorption, distribution, metabolism and elimination (ADME) properties. These efforts resulted in several compounds with substantially improved aqueous solubility, although these modifications typically resulted in a loss of trypanosomal activity. We herein report the results of our investigation into the antiparasitic activity, toxicity, and ADME properties of this class of compounds in the interest of informing the NTD drug discovery community and avoiding duplication of effort.

Enantioselective Electroreductive Coupling of Alkenyl and Benzyl Halides via Nickel Catalysis.

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.

Calcium-Dependent Protein Kinase 5 Is Required for Release of Egress-Specific Organelles in Plasmodium falciparum.

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 Pfalciparum 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 Pfalciparum 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.IMPORTANCE The signs and symptoms of clinical malaria result from the replication of parasites in human blood. Efficient egress of the malaria parasite Plasmodium falciparum out of an infected red blood cell is critical for pathogenesis. The Pfalciparum calcium-dependent protein kinase 5 (PfCDPK5) is essential for parasite egress. Following PfCDPK5 knockdown, parasites remain trapped inside their host cell and do not egress, but the mechanism for this block remains unknown. We show that PfCDPK5 colocalizes with parasite organelles known as micronemes. We demonstrate that PfCDPK5 is critical for the discharge of these micronemes and that failure of this step is the molecular mechanism of the parasite egress arrest. We also show that hyperactivation of the cGMP-dependent kinase PKG can overcome this arrest. Our data suggest that small molecules that inhibit the egress signaling pathway could be effective antimalarial therapeutics.

Synthesis of Cycloalkyl Substituted 7-Azaindoles via Photoredox Nickel Dual Catalytic Cross-Coupling in Batch and Continuous Flow.

An efficient photoredox/Ni dual catalytic Csp2-Csp3 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.