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Identifying the interactome for a protein of interest is challenging due to the large number of possible binders. High-throughput experimental approaches narrow down possible binding partners but often include false positives. Furthermore, they provide no information about what the binding region is (e.g., the binding epitope). We introduce a novel computational pipeline based on an AlphaFold2 (AF) Competitive Binding Assay (AF-CBA) to identify proteins that bind a target of interest from a pull-down experiment and the binding epitope. Our focus is on proteins that bind the Extraterminal (ET) domain of Bromo and Extraterminal domain (BET) proteins, but we also introduce nine additional systems to show transferability to other peptide-protein systems. We describe a series of limitations to the methodology based on intrinsic deficiencies of AF and AF-CBA to help users identify scenarios where the approach will be most useful. Given the method's speed and accuracy, we anticipate its broad applicability to identify binding epitope regions among potential partners, setting the stage for experimental verification., (© 2024 Wiley-VCH GmbH.)

The activation of carbon-hydrogen bonds is considered as one of the most attractive techniques in synthetic organic chemistry because it bears the potential to shorten synthetic routes as well as to produce complementary product scopes compared to traditional synthetic strategies. However, many current methods employ silver salts as additives, leading to stoichiometric metal waste and thereby preventing the full potential of C-H activation to be exploited. Therefore, the development of silver-free protocols has recently received increasing attention. Mechanistically, silver can serve various roles in C-H activation and thus, avoiding the use of silver requires different approaches based on the role it serves in a given process. In this Review, we present the comparison of silver-based and silver-free methods. Focusing on the strategic approaches to develop silver-free C-H activation, we provide the reader with the means to develop sustainable methods for C-H activation., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Alkynes are highly attractive motifs in organic synthesis due to their presence in natural products and bioactive molecules as well as their versatility in a plethora of subsequent transformations. A common procedure to insert alkynes into (hetero)arenes, such as the thiophenes studied herein, consists of a halogenation followed by a Sonogashira cross-coupling. The regioselectivity of this approach depends entirely on the halogenation step. Similarly, direct alkynylations of thiophenes have been described that follow the same regioselectivity patterns. Herein we report the development of a palladium catalyzed C-H activation/alkynylation of thiophenes. The method is applicable to a broad range of thiophene substrates. For 3-substituted substrates where controlling the regioselectivity between the C2 and C5 position is particularly challenging, two sets of reaction conditions enable a regiodivergent reaction, giving access to each regioisomer selectively. Both protocols use the thiophene as limiting reagent and show a broad scope, rendering our method suitable for late-stage modification., (© 2020 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

We report the ligand-enabled C-H activation/olefination of free carboxylic acids in the γ-position. Through an intramolecular Michael addition, δ-lactones are obtained as products. Two distinct ligand classes are identified that enable the challenging palladium-catalyzed activation of free carboxylic acids in the γ-position. The developed protocol features a wide range of acid substrates and olefin reaction partners and is shown to be applicable on a preparatively useful scale. Insights into the underlying reaction mechanism obtained through kinetic studies are reported., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)