Explore the vast range of titles available.

This review discusses recent progress in the most significant synthetic approaches involving transformations under the Mitsunobu reaction. The Mitsunobu reaction entails the \"redox\" condensation of an acidic pronucleophile ‘Nu-H’ and an electrophilic primary or secondary alcohol, facilitated by stoichiometric amounts of phosphines and azodicarboxylate reagents. Widely utilized for dehydrative oxidation–reduction condensation, this reaction shows synthetic utility through its tolerance of a broad range of acidic pronucleophiles, including carboxylic acids, pro-imides, hydroxamates, phenols, thiols, fluorinated alcohols, oximes, thioamides, pyridinium and imidazolium salts, pyrimidine bases, α-ketoesters, and trimethylmethane tricarboxylate, thereby yielding a variety of functional and potentially biologically active compounds. The purpose of this review is to focus on recent advances and applications of Mitsunobu reaction chemistry, particularly from 2010 to 2024. In addition to discussing newer reagents that facilitate purification, we will describe contemporary applications of this chemistry, especially concerning the synthesis of potential biological compounds and their precursors. This focus review of the Mitsunobu reaction summarizes its origins, the current understanding of its mechanism, and recent improvements and applications. We aim for this work to serve as a useful resource for scientists working in this research domain.

The functionalization of carbon-hydrogen (C-H) bonds is one of the most attractive strategies for molecular construction in organic chemistry. The hydrogen atom is considered to be an ideal coupling handle, owing to its relative abundance in organic molecules and its availability for functionalization at almost any stage in a synthetic sequence. Although many C-H functionalization reactions involve C(sp )-C(sp ) coupling, there is a growing demand for C-H alkylation reactions, wherein sp C-H bonds are replaced with sp C-alkyl groups. Here we describe a polarity-match-based selective sp C-H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis. This methodology simultaneously uses three catalytic cycles to achieve hydridic C-H bond abstraction (enabled by polarity matching), alkyl halide oxidative addition, and reductive elimination to enable alkyl-alkyl fragment coupling. The sp C-H alkylation is highly selective for the α-C-H of amines, ethers and sulphides, which are commonly found in pharmaceutically relevant architectures. This cross-coupling protocol should enable broad synthetic applications in de novo synthesis and late-stage functionalization chemistry.

There is evidence to suggest that increasing the level of saturation (that is, the number of sp 3 -hybridized carbon atoms) of small molecules can increase their likelihood of success in the drug discovery pipeline 1 . Owing to their favourable physical properties, alkylamines have become ubiquitous among pharmaceutical agents, small-molecule biological probes and pre-clinical candidates 2 . Despite their importance, the synthesis of amines is still dominated by two methods: N -alkylation and carbonyl reductive amination 3 . Therefore, the increasing demand for saturated polar molecules in drug discovery has continued to drive the development of practical catalytic methods for the synthesis of complex alkylamines 4 – 7 . In particular, processes that transform accessible feedstocks into sp 3 -rich architectures provide a strategic advantage in the synthesis of complex alkylamines. Here we report a multicomponent, reductive photocatalytic technology that combines readily available dialkylamines, carbonyls and alkenes to build architecturally complex and functionally diverse tertiary alkylamines in a single step. This olefin-hydroaminoalkylation process involves a visible-light-mediated reduction of in-situ-generated iminium ions to selectively furnish previously inaccessible alkyl-substituted α-amino radicals, which subsequently react with alkenes to form C( sp 3 )–C( sp 3 ) bonds. The operationally straightforward reaction exhibits broad functional-group tolerance, facilitates the synthesis of drug-like amines that are not readily accessible by other methods and is amenable to late-stage functionalization applications, making it of interest in areas such as pharmaceutical and agrochemical research. Complex tertiary alkylamines are prepared in one step from readily available amines, carbonyls and alkenes, via the visible-light-mediated reduction of in-situ-generated iminium ions to form alkyl-substituted α-amino radicals.

Nitrosamines occur widespread in food, drinking water, cosmetics, as well as tobacco smoke and can arise endogenously. More recently, nitrosamines have been detected as impurities in various drugs. This is of particular concern as nitrosamines are alkylating agents that are genotoxic and carcinogenic. We first summarize the current knowledge on the different sources and chemical nature of alkylating agents with a focus on relevant nitrosamines. Subsequently, we present the major DNA alkylation adducts induced by nitrosamines upon their metabolic activation by CYP450 monooxygenases. We then describe the DNA repair pathways engaged by the various DNA alkylation adducts, which include base excision repair, direct damage reversal by MGMT and ALKBH, as well as nucleotide excision repair. Their roles in the protection against the genotoxic and carcinogenic effects of nitrosamines are highlighted. Finally, we address DNA translesion synthesis as a DNA damage tolerance mechanism relevant to DNA alkylation adducts.

N 6 -Methyladenosine (m 6 A) is the most common posttranscriptional modification of RNA and plays critical roles in cancer pathogenesis. However, the biological function of long noncoding RNA (lncRNA) methylation remains unclear. As a demethylase, ALKBH5 (alkylation repair homolog protein 5) is involved in mediating methylation reversal. The purpose of this study was to investigate lncRNA m 6 A modification and its role in gastric cancer (GC). Bioinformatics predicted interactions of ALKBH5 with lncRNAs. Five methods were employed to assess the function of nuclear paraspeckle assembly transcript 1 (NEAT1), including gene silencing, RT-PCR, separation of nuclear and cytoplasmic fractions, scrape motility assays, and transwell migration assays. Then, m 6 A RNA immunoprecipitation and immunofluorescence were used to detect methylated NEAT1 in GC cells. Rescue assays were performed to define the relationship between NEAT1 and ALKBH5. NEAT1 is a potential binding lncRNA of ALKBH5. NEAT1 was overexpressed in GC cells and tissue. Additional experiments confirmed that knockdown of NEAT1 significantly repressed invasion and metastasis of GC cells. ALKBH5 affected the m 6 A level of NEAT1. The binding of ALKBH5 and NEAT1 influences the expression of EZH2 (a subunit of the polycomb repressive complex) and thus affects GC invasion and metastasis. Our findings indicate a novel mechanism by which ALKBH5 promotes GC invasion and metastasis by demethylating the lncRNA NEAT1. They may be potential therapeutic targets for GC.

Organic halides are important building blocks in synthesis, but their use in (photo)redox chemistry is limited by their low reduction potentials. Halogen-atom transfer remains the most reliable approach to exploit these substrates in radical processes despite its requirement for hazardous reagents and initiators such as tributyltin hydride. In this study, we demonstrate that α-aminoalkyl radicals, easily accessible from simple amines, promote the homolytic activation of carbon-halogen bonds with a reactivity profile mirroring that of classical tin radicals. This strategy conveniently engages alkyl and aryl halides in a wide range of redox transformations to construct sp³-sp³, sp³-sp², and sp²-sp² carbon-carbon bonds under mild conditions with high chemoselectivity.

Cheminformatics-based machine learning (ML) has been employed to determine optimal reaction conditions, including catalyst structures, in the field of synthetic chemistry. However, such ML-focused strategies have remained largely unexplored in the context of catalytic molecular transformations using Lewis-acidic main-group elements, probably due to the absence of a candidate library and effective guidelines (parameters) for the prediction of the activity of main-group elements. Here, the construction of a triarylborane library and its application to an ML-assisted approach for the catalytic reductive alkylation of aniline-derived amino acids and C-terminal-protected peptides with aldehydes and H 2 is reported. A combined theoretical and experimental approach identified the optimal borane, i.e., B(2,3,5,6-Cl 4 -C 6 H)(2,6-F 2 -3,5-(CF 3 ) 2 -C 6 H) 2 , which exhibits remarkable functional-group compatibility toward aniline derivatives in the presence of 4-methyltetrahydropyran. The present catalytic system generates H 2 O as the sole byproduct. Machine learning has not been strategically applied to design main-group catalysts. Here, the authors built an in-silico library of triarylboranes, which was used to identify reactive catalysts for functionalizing amino acids and peptides with H 2 .

A simple ammonium iodide salt in amide solvent catalyzes regioselective decarboxylative alkylation of C(sp 3 )-H bonds of N-aryl glycine derivatives, of C(sp 2 )-H bond of heteroarenes, and cascade radical addition to unsaturated bond followed by intramolecular addition to arene, with a broad scope of N-hydroxyphthalimide derived redox active esters under visible light irradiation. The reactions are suggested to proceed through photoactivation of a transiently assembled chromophore from electron-deficient phthalimide moiety and iodide anion through an anion- π interaction in solvent cage followed by diffusion to generate solvated free radical species to react with C-H substrates The simplicity, practicality, and broad substrate scope of this method highlight the synthetic power of photocatalysis through transiently assembled chromophore, and will hopefully inspire further developments of low cost photocatalysis based on various non-covalent interactions, which are prevalent in supramolecular chemistry and biosystems, for sustainable organic synthesis.