Direct Radiofluorination of Arene C-H Bonds via Photoredox Catalysis Using a Peroxide as the Terminal Oxidant.

Herein, we describe an organic photoredox system for direct arene C-H radiofluorination, using a peroxide oxidizing agent and LEDs as the light source. In conjunction with an optimized photocatalyst and a microtubing reactor, this system is applicable to a range of electron-rich aromatics and heteroaromatics. We also demonstrate the feasibility of C-H radiofluorination without an azeotropic drying step, which greatly simplifies the workflow of the labeling process.

Homobenzylic Oxygenation Enabled by Dual Organic Photoredox and Cobalt Catalysis.

Activation of aliphatic C(sp3)-H bonds in the presence of more activated benzylic C(sp3)-H bonds is often a nontrivial, if not impossible task. Herein we show that leveraging the reactivity of benzylic C(sp3)-H bonds to achieve reactivity at the homobenzylic position can be accomplished using dual organic photoredox/cobalt catalysis. Through a two-part catalytic system, alkyl arenes undergo dehydrogenation followed by an anti-Markovnikov Wacker-type oxidation to grant benzyl ketone products. This formal homobenzylic oxidation is accomplished with high atom economy without the use of directing groups, achieving valuable reactivity that traditionally would require multiple chemical transformations.

Synthesis and Characterization of Acridinium Dyes for Photoredox Catalysis.

Photoredox catalysis is a rapidly evolving platform for synthetic methods development. The prominent use of acridinium salts as a sustainable option for photoredox catalysts has driven the development of more robust and synthetically useful versions based on this scaffold. However, more complicated syntheses, increased cost, and limited commercial availability have hindered the adoption of these catalysts by the greater synthetic community. By utilizing the direct conversion of a xanthylium salt into the corresponding acridinium as the key transformation, we present an efficient and scalable preparation of the most synthetically useful acridinium reported to date. This divergent strategy also enabled the preparation of a suite of novel acridinium dyes, allowing for a systematic investigation of substitution effects on their photophysical properties.

An Oxetane-Based Polyketide Surrogate To Probe Substrate Binding in a Polyketide Synthase.

Polyketides are a large class of bioactive natural products with a wide range of structures and functions. Polyketides are biosynthesized by large, multidomain enzyme complexes termed polyketide synthases (PKSs). One of the primary challenges when studying PKSs is the high reactivity of their poly-ß-ketone substrates. This has hampered structural and mechanistic characterization of PKS-polyketide complexes, and, as a result, little is known about how PKSs position the unstable substrates for proper catalysis while displaying high levels of regio- and stereospecificity. As a first step toward a general plan to use oxetanes as carbonyl isosteres to broadly interrogate PKS chemistry, we describe the development and application of an oxetane-based PKS substrate mimic. This enabled the first structural determination of the acyl-enzyme intermediate of a ketosynthase (KS) in complex with an inert extender unit mimic. The crystal structure, in combination with molecular dynamics simulations, led to a proposed mechanism for the unique activity of DpsC, the priming ketosynthase for daunorubicin biosynthesis. The successful application of an oxetane-based polyketide mimic suggests that this novel class of probes could have wide-ranging applications to the greater biosynthetic community interested in the mechanistic enzymology of iterative PKSs.

A Direct Synthesis of Highly Substituted π-Rich Aromatic Heterocycles from Oxetanes.

The ubiquitous use of π-rich five-membered heterocycles has driven the development of new methods for their synthesis for more than a century. Here, we disclose a general and reliable reaction manifold for the construction of highly substituted heterocycles through a facile Lewis-acid-catalyzed oxetane rearrangement. Notably, this methodology employs a keto-oxetane motif as a 1,4-dicarbonyl surrogate, which can be synthesized using robust alkylation or alkenylation reactions, and thus obviates the need to access 1,4-dicarbonyl compounds via umpoled starting materials. We harnessed this reactivity to generate a broad range of substituted furans and pyrroles, and extended this methodology to produce benzo-fused versions thereof.

The Alga Ochromonas danica Produces Bromosulfolipids.

Many halogenases interchangeably incorporate chlorine and bromine into organic molecules. On the basis of an unsubstantiated report that the alga Ochromonas danica, a prodigious producer of chlorosulfolipids, was able to produce bromosulfolipids, we have investigated the promiscuity of its halogenases toward bromine incorporation. We have found that bromosulfolipids are produced with the exact positional and stereochemical selectivity as in the chlorosulfolipid danicalipin A when this alga is grown under modified conditions containing excess bromide ion.

Modeling linear and cyclic PKS intermediates through atom replacement.

The mechanistic details of many polyketide synthases (PKSs) remain elusive due to the instability of transient intermediates that are not accessible via conventional methods. Here we report an atom replacement strategy that enables the rapid preparation of polyketone surrogates by selective atom replacement, thereby providing key substrate mimetics for detailed mechanistic evaluations. Polyketone mimetics are positioned on the actinorhodin acyl carrier protein (actACP) to probe the underpinnings of substrate association upon nascent chain elongation and processivity. Protein NMR is used to visualize substrate interaction with the actACP, where a tetraketide substrate is shown not to bind within the protein, while heptaketide and octaketide substrates show strong association between helix II and IV. To examine the later cyclization stages, we extended this strategy to prepare stabilized cyclic intermediates and evaluate their binding by the actACP. Elongated monocyclic mimics show much longer residence time within actACP than shortened analogs. Taken together, these observations suggest ACP-substrate association occurs both before and after ketoreductase action upon the fully elongated polyketone, indicating a key role played by the ACP within PKS timing and processivity. These atom replacement mimetics offer new tools to study protein and substrate interactions and are applicable to a wide variety of PKSs.