The interaction between an electronically excited photocatalyst and an organic molecule can result in the genertion of a diverse array of reactive intermediates that can be manipulated in a variety of ways to result in synthetically useful bond constructions. This Review summarizes dual-catalyst strategies that have been applied to synthetic photochemistry. Mechanistically distinct modes of photocatalysis are discussed, including photoinduced electron transfer, hydrogen atom transfer, and energy transfer. We focus upon the cooperative interactions of photocatalysts with redox mediators, Lewis and Brønsted acids, organocatalysts, enzymes, and transition metal complexes.

Relatively few catalytic systems are able to control the stereochemistry of electronically excited organic intermediates. Here we report the discovery that a chiral Lewis acid complex can catalyze triplet energy transfer from an electronically excited photosensitizer. This strategy is applied to asymmetric [2+2] photocycloadditions of 2′-hydroxychalcones using tris(bipyridyl) ruthenium(II) as a sensitizer. A variety of electrochemical, computational, and spectroscopic data rule out substrate activation via photoinduced electron transfer and instead support a mechanism in which Lewis acid coordination dramatically lowers the triplet energy of the chalcone substrate. We expect that this approach will enable chemists to more broadly apply their detailed understanding of chiral Lewis acid catalysis to stereocontrol in reactions of electronically excited states.

We report a protocol for oxidative [3+2] cycloadditions of phenols and alkenes applicable to the modular synthesis of a large family of dihydrobenzofuran natural products. Visible light-activated transition metal photocatalysis enables the use of ammonium persulfate as an easily handled, benign terminal oxidant. The broad range of organic substrates that are readily oxidized by photoredox catalysis suggests that this strategy may be applicable to a variety of useful oxidative transformations.

Although bespoke, sequence-specific proteases have the potential to advance biotechnology and medicine, generation of proteases with tailor-made cleavage specificities remains a major challenge. We developed a phage-assisted protease evolution system with simultaneous positive and negative selection and applied it to three botulinum neurotoxin (BoNT) light-chain proteases. We evolved BoNT/X protease into separate variants that preferentially cleave vesicle-associated membrane protein 4 (VAMP4) and Ykt6, evolved BoNT/F protease to selectively cleave the non-native substrate VAMP7, and evolved BoNT/E protease to cleave phosphatase and tensin homolog (PTEN) but not any natural BoNT protease substrate in neurons. The evolved proteases display large changes in specificity (218- to >11,000,000-fold) and can retain their ability to form holotoxins that self-deliver into primary neurons. These findings establish a versatile platform for reprogramming proteases to selectively cleave new targets of therapeutic interest.

We report a protocol for oxidative [3+2] cycloadditions of phenols and alkenes applicable to the modular synthesis of a large family of dihydrobenzofuran natural products. Visible light-activated transition metal photocatalysis enables the use of ammonium persulfate as an easily handled, benign terminal oxidant. The broad range of organic substrates that are readily oxidized by photoredox catalysis suggests that this strategy may be applicable to a variety of useful oxidative transformations. Keywords cycloaddition; heterocycles; phenols; photocatalysis; photooxidationThe choice of terminal oxidant is important in the design of oxidative reactions. 1 Many of the most commonly used oxidants produce stoichiometric byproducts that can be practically or environmentally problematic. Our laboratory has a long-standing interest in the propensity of photoexcited Ru*(bpy) 3 2+ to undergo redox reactions with a diverse range of quenchers, 2 a feature that has been increasingly exploited in the design of synthetic reactions. 3 We wondered if photoredox catalysis might offer a general strategy to employ benign, kinetically inert oxidants in oxidative transformations. Recent interest in photoredox catalysis has largely been focused on redox-neutral and net reductive reactions; the examples of net oxidative transformations published to date have generally utilized either stoichiometric halocarbon oxidants, 4 which are not ideal from an environmental standpoint, or molecular oxygen, 5 which is a triplet quencher of many photoexcited molecules 6 that can negatively impact the overall efficiency of photocatalytic reactions. Thus, there exists a need for a more practical, general approach to the design of oxidative photoredox reactions.We became interested in studying phenol oxidation as a starting point to explore this challenge. Phenols participate in a rich variety of oxidatively induced transformations, 7

We describe the synthesis of Xyzidepsin, a depsipeptidic analogue of HDAC inhibitor Romidepsin (FK228), using a solid-phase strategy. Our latent thioester solid-phase linker was synthesized in 92% yield (three steps). Chemoselective conditions unmasked the thioester functionality and cyclized the depsipeptidic macrocycle. An IC50 value of 0.50 μM ± 0.05 was obtained for U937 cells. This synthetic route, well-suited to SAR, represents a generalizable route toward all manner of analogues, including structures with acidic and basic amino acids.

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