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The diarylation and skeletal diversification of unstrained cyclic amines was exploited to expand and modify the favorable properties of this important substrate class with pivotal roles in drug discovery. Cyclic amines were employed in the synthesis of a novel class of amino-substituted diaryliodonium salts, which were converted to highly functionalized diarylamines through an atom-efficient one-pot N-arylation/ ring opening reaction with external nucleophiles. The reaction proceeds through the in situ formation of a diarylammonium intermediate that undergoes a nucleophilic ring opening by cleavage of the strong C-N bond. A wide variety of diarylamines was obtained through introduction of two different aryl groups of varied electronics, and the retained iodo-substituent enables downfield diversifications of the products. More than 20 nucleophiles, including amines, phenols, carboxylic acids, thiols and halides, were alkylated with high functional group tolerance, and the strategy could be utilized in late-stage functionalization of natural products and pharmaceuticals.

Our group has reported several one-pot protocols for the synthesis of diaryliodonium salts, which have been recognized as attractive multi-purpose reagents in areas ranging from organic synthesis to materials chemistry. Over the years, we have identified limitations in the published protocols concerning synthesis of mixed electron-rich and electron-poor, as well as highly electron-poor diaryliodonium salts, as the corresponding starting materials are either too reactive or too unreactive. In this update, we discuss the underlying limitations concerning the stability and reactivity of the involved reagents and provide strategies to overcome these challenges through updated synthetic protocols.

Sterile alpha motif and histidine-aspartic acid domain containing protein-1 (SAMHD1) is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase central to cellular nucleotide pool homeostasis. Recent literature has also demonstrated how SAMHD1 can detoxify chemotherapy metabolites thereby controlling their clinical responses. To further understand SAMHD1 biology and to investigate the potential of targeting this enzyme as a neoadjuvant to existing chemotherapies we set out to discover selective small molecule-based inhibitors of SAMHD1. Here we report a discovery pipeline encompassing a biochemical screening campaign and a set of complementary biochemical, biophysical, and cell-based readouts for further characterisation of the screen output. The identified hit compound TH6342 and its analogues, accompanied by their inactive negative control analogue TH7126, demonstrated specific, low μM potency in inhibiting the hydrolysis of both natural substrates and nucleotide analogue therapeutics, shown using complementary enzyme-coupled and direct enzymatic activity assays. Their mode of inhibition was subsequently detailed by coupling kinetic studies with thermal shift assays, where TH6342 and analogues were shown to engage with pre-tetrameric SAMHD1 and deter the oligomerisation and allosteric activation of SAMHD1 without occupying nucleotide binding pockets. We further outline the development and application of multiple cellular assays for assessing cellular target engagement and associated functional effects, including CETSA and an in-cell dNTP hydrolase activity assay, which highlighted future optimisation strategies of this chemotype. In summary, with a novel mode of inhibition, TH6342 and analogues broaden the set of tool compounds available in deciphering SAMHD1 enzymology and functions, and furthermore, the discovery pipeline reported herein represents a thorough framework for future SAMHD1 inhibitor development.Abstract Figure

Two regioselective, high-yielding one-pot routes to oxygen-bridged cyclic diaryliodonium salts and ortho-aryloxy-substituted acyclic diaryliodonium salts are presented. Starting from easily available ortho-iodo diaryl ethers, complete selectivity in formation of either the cyclic or acyclic product could be achieved by varying the reaction conditions. The complimentary reactivities of these novel ortho-oxygenated iodonium salts were demonstrated through a series of chemoselective arylations under metal-catalyzed and metal-free conditions, to deliver a range of novel, ortho-functionalized diaryl ether derivatives.

The arylation of heteroatom nucleophiles is a central strategy to reach diarylated compounds that are key building blocks in agrochemicals, materials and pharmaceuticals. Nucleophilic aromatic substitution is a classical tool for such arylations, and hypervalent iodine-mediated arylations are modern alternatives to achieve a wider scope of products. Herein, we combine the benefits of those strategies to enable an atom-efficient and transition metal-free functionalization of N- and O- nucleophiles with two structurally different aryl groups, to provide di- and triarylamines and diaryl ethers in one single step (> 100 examples). The core of this strategy is the unique reactivity discovered with certain fluorinated diaryliodonium salts, which unveils novel reaction pathways in hypervalent iodine chemistry. The method is suitable for aliphatic amines, anilines, ammonia and even water and tolerates a wide variety of functional and protecting groups. Furthermore, the retained iodine substituent is easily accessible for derivatization of the products.

A transition metal‐free N‐arylation of primary and secondary amines with diaryliodonium salts is presented. Both acyclic and cyclic amines are well tolerated, providing a large set of N‐alkyl anilines. The methodology is unprecedented among metal‐free methods in terms of amine scope, the ability to transfer both electron‐withdrawing and electron‐donating aryl groups, and efficient use of resources, as excess substrate or reagents are not required.