Chromoselective Photocatalysis Enables Stereocomplementary Biocatalytic Pathways*.

Controlling the selectivity of a chemical reaction with external stimuli is common in thermal processes, but rare in visible-light photocatalysis. Here we show that the redox potential of a carbon nitride photocatalyst (CN-OA-m) can be tuned by changing the irradiation wavelength to generate electron holes with different oxidation potentials. This tuning was the key to realizing photo-chemo-enzymatic cascades that give either the (S)- or the (R)-enantiomer of phenylethanol. In combination with an unspecific peroxygenase from Agrocybe aegerita, green light irradiation of CN-OA-m led to the enantioselective hydroxylation of ethylbenzene to (R)-1-phenylethanol (99 % ee). In contrast, blue light irradiation triggered the photocatalytic oxidation of ethylbenzene to acetophenone, which in turn was enantioselectively reduced with an alcohol dehydrogenase from Rhodococcus ruber to form (S)-1-phenylethanol (93 % ee).

Photocatalytic α-Tertiary Amine Synthesis via C-H Alkylation of Unmasked Primary Amines.

A practical, catalytic entry to α,α,α-trisubstituted (α-tertiary) primary amines by C-H functionalisation has long been recognised as a critical gap in the synthetic toolbox. We report a simple and scalable solution to this problem that does not require any in situ protection of the amino group and proceeds with 100 % atom-economy. Our strategy, which uses an organic photocatalyst in combination with azide ion as a hydrogen atom transfer (HAT) catalyst, provides a direct synthesis of α-tertiary amines, or their corresponding γ-lactams. We anticipate that this methodology will inspire new retrosynthetic disconnections for substituted amine derivatives in organic synthesis, and particularly for challenging α-tertiary primary amines.

Batch versus flow photochemistry: a revealing comparison of yield and productivity.

The use of flow photochemistry and its apparent superiority over batch has been reported by a number of groups in recent years. To rigorously determine whether flow does indeed have an advantage over batch, a broad range of synthetic photochemical transformations were optimized in both reactor modes and their yields and productivities compared. Surprisingly, yields were essentially identical in all comparative cases. Even more revealing was the observation that the productivity of flow reactors varied very little to that of their batch counterparts when the key reaction parameters were matched. Those with a single layer of fluorinated ethylene propylene (FEP) had an average productivity 20% lower than that of batch, whereas three-layer reactors were 20% more productive. Finally, the utility of flow chemistry was demonstrated in the scale-up of the ring-opening reaction of a potentially explosive [1.1.1] propellane with butane-2,3-dione.

Reactive fragments targeting carboxylate residues employing direct to biology, high-throughput chemistry.

The screening of covalent or 'reactive' fragment libraries against proteins is becoming an integral approach in hit identification, enabling the development of targeted covalent inhibitors and tools. To date, reactive fragment screening has been limited to targeting cysteine residues, thus restricting applicability across the proteome. Carboxylate residues present a unique opportunity to expand the accessible residues due to high proteome occurrence (∼12%). Herein, we present the development of a carboxylate-targeting reactive fragment screening platform utilising 2-aryl-5-carboxytetrazole (ACT) as the photoreactive functionality. The utility of ACT photoreactive fragments (ACT-PhABits) was evaluated by screening a 546-membered library with a small panel of purified proteins. Hits identified for BCL6 and KRASG12D were characterised by LC-MS/MS studies, revealing the selectivity of the ACT group. Finally, a photosensitised approach to ACT activation was developed, obviating the need for high energy UV-B light.

An organophotocatalytic late-stage N-CH3 oxidation of trialkylamines to N-formamides with O2 in continuous flow.

We report an organophotocatalytic, N-CH3-selective oxidation of trialkylamines in continuous flow. Based on the 9,10-dicyanoanthracene (DCA) core, a new catalyst (DCAS) was designed with solubilizing groups for flow processing. This allowed O2 to be harnessed as a sustainable oxidant for late-stage photocatalytic N-CH3 oxidations of complex natural products and active pharmaceutical ingredients bearing functional groups not tolerated by previous methods. The organophotocatalytic gas-liquid flow process affords cleaner reactions than in batch mode, in short residence times of 13.5 min and productivities of up to 0.65 g per day. Spectroscopic and computational mechanistic studies showed that catalyst derivatization not only enhanced solubility of the new catalyst compared to poorly-soluble DCA, but profoundly diverted the photocatalytic mechanism from singlet electron transfer (SET) reductive quenching with amines toward energy transfer (EnT) with O2.

amTCO, a new trans-cyclooctene derivative to study drug-target interactions in cells.

Click chemistry probes have improved the study of drug interactions in live cells and relevant disease models. Proper design of the probes, including the choice of the click moiety coupled to the drug, is crucial to ensure good performance and broad application. A new trans-cyclooctene derivative, amTCO, was synthesised via a novel route using a phthalimide protecting group as a built-in photosensitiser for the cyclooctene isomerization. amTCO improved the physical chemical properties of click chemistry probes compared to standard TCO moieties. An amTCO probe targeting indoleamine 2,3-dioxygenase (IDO1) was a superior tool for visualizing IDO1 and measuring the binding affinities of small molecule inhibitors to IDO1 in cells.

Chromoselective Photocatalysis Enables Stereocomplementary Biocatalytic Pathways.

Controlling the selectivity of a chemical reaction with external stimuli is common in thermal processes, but rare in visible-light photocatalysis. Here we show that the redox potential of a carbon nitride photocatalyst (CN-OA-m) can be tuned by changing the irradiation wavelength to generate electron holes with different oxidation potentials. This tuning was the key to realizing photo-chemo-enzymatic cascades that give either the (S)- or the (R)-enantiomer of phenylethanol. In combination with an unspecific peroxygenase from Agrocybe aegerita, green light irradiation of CN-OA-m led to the enantioselective hydroxylation of ethylbenzene to (R)-1-phenylethanol (99 % ee). In contrast, blue light irradiation triggered the photocatalytic oxidation of ethylbenzene to acetophenone, which in turn was enantioselectively reduced with an alcohol dehydrogenase from Rhodococcus ruber to form (S)-1-phenylethanol (93 % ee).

Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone: a potent, orally bioavailable human CB1/CB2 dual agonist with antihyperalgesic properties and restricted central nervous system penetration.

Selective activation of peripheral cannabinoid CB1 receptors has the potential to become a valuable therapy for chronic pain conditions as long as central nervous system effects are attenuated. A new class of cannabinoid ligands was rationally designed from known aminoalkylindole agonists and showed good binding and functional activities at human CB1 and CB2 receptors. This has led to the discovery of a novel CB1/CB2 dual agonist, naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (13), which displays good oral bioavailability, potent antihyperalgesic activity in animal models, and limited brain penetration.