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Abstract Radical substitution is a useful method to functionalize heterocycles, as in the venerable Minisci reaction. Empirically observed regiochemistries indicate that the CF₂H radical has a nucleophilic character similar to alkyl radicals, but the CF₃radical is electrophilic. While the difference between •CH₃and •CF₃is well understood, the reason that one and two Fs make little difference but the third has a large effect is puzzling. DFT calculations with M06-2X both reproduce experimental selectivities and also lead to an explanation of this difference. Theoretical methods reveal how the F inductive withdrawal and conjugative donation alter radical properties, but only CF₃becomes decidedly electrophilic toward heterocycles. Here, we show a simple model to explain the radical orbital energy trends and resulting nucleophilicity or electrophilicity of fluorinated radicals. 

Abstract Nitriles are uncommon in nature and are typically constructed from oximes through the oxidative decarboxylation of amino acid substrates or from the derivatization of carboxylic acids. Here we report a third nitrile biosynthesis strategy featuring the cyanobacterial nitrile synthase AetD. During the biosynthesis of the eagle-killing neurotoxin, aetokthonotoxin, AetD transforms the 2-aminopropionate portion of 5,7-dibromo-l-tryptophan to a nitrile. Employing a combination of structural, biochemical and biophysical techniques, we characterized AetD as a non-haem diiron enzyme that belongs to the emerging haem-oxygenase-like dimetal oxidase superfamily. High-resolution crystal structures of AetD together with the identification of catalytically relevant products provide mechanistic insights into how AetD affords this unique transformation, which we propose proceeds via an aziridine intermediate. Our work presents a unique template for nitrile biogenesis and portrays a substrate binding and metallocofactor assembly mechanism that may be shared among other haem-oxygenase-like dimetal oxidase enzymes. 

Abstract Cyclobutanes are prominent structural components in natural products and drug molecules. With the advent of strain‐release‐driven synthesis, ring‐opening reactions of bicyclo[1.1.0]butanes (BCBs) provide an attractive pathway to construct these three‐dimensional structures. However, the stereoselective difunctionalization of the central C−C σ‐bonds remains challenging. Reported herein is a covalent‐based organocatalytic strategy that exploits radical NHC catalysis to achieve diastereoselective acylfluoroalkylation of BCBs under mild conditions. The Breslow enolate acts as a single electron donor and provides an NHC‐bound ketyl radical with appropriate steric hindrance, which effectively distinguishes between the two faces of transient cyclobutyl radicals. This operationally simple method tolerates various fluoroalkyl reagents and common functional groups, providing a straightforward access to polysubstituted cyclobutanes (75 examples, up to >19 : 1 d.r.). The combined experimental and theoretical investigations of this organocatalytic system confirm the formation of the NHC‐derived radical and provide an understanding of how stereoselective radical‐radical coupling occurs. 

Abstract We describe a full account of our synthetic strategy leading to the first total synthesis of the manzamine alkaloid lissodendoric acid A . These efforts demonstrate that strained cyclic allenes are valuable synthetic building blocks and can be employed efficiently in total synthesis.