Decarboxylative Intramolecular Arene Alkylation Using N-(Acyloxy)phthalimides, an Organic Photocatalyst, and Visible Light.

An intramolecular arene alkylation reaction has been developed using the organic photocatalyst 4CzIPN, visible light, and N-(acyloxy)phthalimides as radical precursors. Reaction conditions were optimized via high-throughput experimentation, and electron-rich and electron-deficient arenes and heteroarenes are viable reaction substrates. This reaction enables access to a diverse set of fused, partially saturated cores which are of high interest in synthetic and medicinal chemistry.

Applications and Prospects for Triplet-Triplet Annihilation Photon Upconversion.

Triplet-triplet annihilation photon upconversion (TTA-UC) is a photophysical process in which the energy of two photons are combined into a single photon of higher energy. While this strategy has been recognized in applications ranging from bioimaging to solar energy conversion, its uses in synthetic organic chemistry have not been extensively developed. Here, we present a short tutorial on the theoretical underpinnings and the design principles of TTA-UC systems. Selected applications are then discussed to highlight key features of the TTA mechanism, along with a prospective discussion of the potential of these mechanisms to enable innovation in photocatalysis, methods development, and synthetic organic chemistry.

Utilization of High-Throughput Experimentation (HTE) and ChemBeads Toward the Development of an Aryl Bromide and Benzyl Bromide Photoredox Cross-Electrophile Coupling.

The discussion herein describes a metallaphotoredox reaction that allows for efficient exploration of benzyl structure-activity relationships in medicinal chemistry. The use of HTE (high-throughput experimentation) and ChemBeads allows for rapid reaction optimization. The formation of di(hetero)arylmethanes via cross-electrophile coupling between aryl bromides and benzyl bromides provides access to diverse chemical space. The breadth of the substrate scope will be discussed, along with the utilization of batch photochemistry for the preparation of this di(hetero)arylmethane motif on a larger scale.

Discovery and SAR Study of Boronic Acid-Based Selective PDE3B Inhibitors from a Novel DNA-Encoded Library.

Human genetic evidence shows that PDE3B is associated with metabolic and dyslipidemia phenotypes. A number of PDE3 family selective inhibitors have been approved by the FDA for various indications; however, given the undesirable proarrhythmic effects in the heart, selectivity for PDE3B inhibition over closely related family members (such as PDE3A; 48% identity) is a critical consideration for development of PDE3B therapeutics. Selectivity for PDE3B over PDE3A may be achieved in a variety of ways, including properties intrinsic to the compound or tissue-selective targeting. The high (>95%) active site homology between PDE3A and B represents a massive obstacle for obtaining selectivity at the active site; however, utilization of libraries with high molecular diversity in high throughput screens may uncover selective chemical matter. Herein, we employed a DNA-encoded library screen to identify PDE3B-selective inhibitors and identified potent and selective boronic acid compounds bound at the active site.