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The controlled synthesis of biphenyls, which play a prominent role in pharmaceuticals, agrochemicals, and liquid crystals, typically requires hazardous organometallic reagents, aryl halides, and heavy metal catalysts. We recently reported a metal-free, photochemical alternative ("photosplicing") for the selective preparation of a wide range of pharmaceutically important biphenyls. Whereas the traceless sulfonamide linker enables and controls the aryl coupling, unwanted toxic byproducts are released. Therefore, we designed over 25 different temporary linkers and tested them for their suitability for the photosplicing reaction in a flow reactor. We found that a surprisingly high number of functional groups enable light-induced aryl fusion and identified a number of linkers for environmentally friendly procedures. We also report that a thiol-ene (click) - photosplicing sequence enables a convenient route to biaryls such as liquid crystals. This work sheds light on thus far neglected photochemistry of temporary linkers, reduces toxic byproducts, and expands the available starting materials for metal-free biphenyl synthesis.

The intricate frameworks of paracyclophanes are an important target for synthesis since they are found in various chiral auxiliaries, solar cells, high-performance plastics, pharmaceuticals, and molecular machines. Whereas numerous methods exist for the preparation of symmetric paracyclophanes, protocols for the efficient synthesis of strained asymmetric scaffolds are limited. Here we report a remarkably simple photochemical route to strained [3.2]paracyclophanes starting from readily available educts. By way of NMR and X-ray analyses, we discovered that UV-irradiation of an aromatic carboxylic ester tethered to a toluene moiety leads to the intramolecular formation of a new C-C bond, with loss of an alcohol. A systematic evaluation of the reaction conditions and substituents, as well as radical starter and triplet quenching experiments, point to a reaction mechanism involving an excited triplet state and hydrogen atom transfer. The new method proved to be robust and versatile enabling the synthesis of a range of cyclophanes with different substitutions, including an unusual diastereoisomer with two planar chiral centers, and thus proved to be a valuable addition to the synthetic toolbox.

Clostridia coordinate many important processes such as toxin production, infection, and survival by density‐dependent communication (quorum sensing) using autoinducing peptides (AIPs). Although clostridial AIPs have been proposed to be (thio)lactone‐containing peptides, their true structures remain elusive. Here, we report the genome‐guided discovery of an AIP that controls endospore formation in Ruminiclostridium cellulolyticum. Through a combination of chemical synthesis and chemical complementation assays with a mutant strain, we reveal that the genuine chemical mediator is a homodetic cyclopeptide (cAIP). Kinetic analyses indicate that the mature cAIP is produced via a cryptic thiolactone intermediate that undergoes a rapid S→N acyl shift, in a manner similar to intramolecular native chemical ligation (NCL). Finally, by implementing a chemical probe in a targeted screen, we show that this novel enzyme‐primed, intramolecular NCL is a widespread feature of clostridial AIP biosynthesis., The genome‐guided discovery of an autoinducing peptide (AIP) that controls endospore formation in Ruminiclostridium cellulolyticum is reported. A combination of chemical synthesis and chemical complementation assays with a mutant strain reveals that the genuine chemical mediator is a homodetic cyclopeptide (cAIP).

Benzoxazole scaffolds feature prominently in diverse synthetic and natural product-derived pharmaceuticals. Our understanding of their bacterial biosynthesis is, however, limited to ortho-substituted heterocycles from actinomycetes. We report an overlooked biosynthetic pathway in anaerobic bacteria (typified in Clostridium cavendishii) that expands the benzoxazole chemical space to meta-substituted heterocycles and heralds a distribution beyond Actinobacteria. The first benzoxazoles from the anaerobic realm (closoxazole A and B) were elucidated by NMR and chemical synthesis. By genome editing in the native producer, heterologous expression in Escherichia coli, and systematic pathway dissection we show that closoxazole biosynthesis invokes an unprecedented precursor usage (3-amino-4-hydroxybenzoate) and manner of assembly. Synthetic utility was demonstrated by the precursor-directed biosynthesis of a tafamidis analogue. A bioinformatic survey reveals the pervasiveness of related gene clusters in diverse bacterial phyla.

Many pharmaceuticals feature biaryl motifs that are crucial for their binding to the target. Yet, benchmark methods for selective cross-couplings rely on highly toxic heavy metal catalysts, which are unfavorable in the synthesis of pharmaceuticals. Metal-free coupling reactions, on the other hand, may require harsh conditions and lack selectivity. We report a novel, metal-free cross-coupling reaction that involves the tethering of two phenyl groups by a temporary, traceless sulfonamide linker that directs a photochemical aryl fusion into a single coupling product. The perfect regio- and chemoselectivity of the reaction could be rationalized by a cyclic intermediate, which fragments into the biaryl and volatile side products. Using a flow reactor, we synthesized numerous substituted biaryl building blocks for important therapeutics in high yields, such as antibiotics, antitumor, neuroprotective and cholesterol-lowering agents as well as antiarthritic non-steroidal antiinflammatory drugs (NSAIDs). The new method was successfully employed in a total synthesis of cannabinol, an important analgesic and antiemetic therapeutic. We also report a metal-free synthesis of key building blocks used for the preparation of sartans, antihypertensive agents that rank among the top blockbuster drugs worldwide. This safe and convenient protocol is a valuable alternative for the widely used metal-dependent aryl cross-coupling methods.

The number of isolable compounds which contain different noble-gas–element bonds is limited for xenon and even more so for krypton. Examples of Xe–Cl bonds are rare, and prior to this work, no Xe–Br bonded compound had been isolated in macroscopic quantities. The syntheses, isolation, and characterization of the first compounds to contain Xe–Br bonds and their chlorine analogues are described in the present work. The reactions of XeO3 with [N(CH3)4]Br and [N(C2H5)4]Br have provided two bromoxenate salts, [N(C2H5)4]3[Br3(XeO3)3] and [N(CH3)4]4[Br4(XeO3)4], in which the cage anions have Xe–Br bond lengths that range from 3.0838(3) to 3.3181(8) A. The isostructural chloroxenate anions (Xe–Cl bond lengths, 2.9316(2) to 3.101(4) A) were synthesized by analogy with their bromine analogues. The bromo- and chloroxenate salts are stable in the atmosphere at room temperature and were characterized in the solid state by Raman spectroscopy and low-temperature single-crystal X-ray diffraction, and in the gas phase by ...

The metal‐free, highly selective synthesis of biaryls poses a major challenge in organic synthesis. The scope and mechanism of a promising new approach to (hetero)biaryls by the photochemical fusion of aryl substituents tethered to a traceless sulfonamide linker (photosplicing) are reported. Interrogating photosplicing with varying reaction conditions and comparison of diverse synthetic probes (40 examples, including a suite of heterocycles) showed that the reaction has a surprisingly broad scope and involves neither metals nor radicals. Quantum chemical calculations revealed that the C−C bond is formed by an intramolecular photochemical process that involves an excited singlet state and traversal of a five‐membered transition state, and thus consistent ipso–ipso coupling results. These results demonstrate that photosplicing is a unique aryl cross‐coupling method in the excited state that can be applied to synthesize a broad range of biaryls., Without a trace: The scope and mechanism of (hetero)biaryl synthesis by photochemical fusion of aryl substituents tethered to a traceless sulfonamide linker (photosplicing) are reported. The reaction has a broad scope and involves neither metals nor radicals. Theoretical calculations revealed that the C−C bond is formed by an intramolecular photochemical process that is initiated by formation of a U‐shaped conformation, involves an excited singlet state and traversal of a five‐membered transition state, and thus consistently results in ipso–ipso coupling.