Access to Complex Scaffolds Through [2 + 2] Cycloadditions of Strained Cyclic Allenes.

We report the strain-induced [2 + 2] cycloadditions of cyclic allenes for the assembly of highly substituted cyclobutanes. By judicious choice of trapping agent, complex scaffolds bearing heteroatoms, fused rings, contiguous stereocenters, spirocycles, and quaternary centers are ultimately accessible. Moreover, we show that the resulting cycloadducts can undergo thermal isomerization. This study provides an alternative strategy to photochemical [2 + 2] cycloadditions for accessing highly functionalized cyclobutanes, while validating the use of underexplored strained intermediates for the assembly of complex architectures.

Small molecule inhibition of RNA binding proteins in haematologic cancer.

In recent years, advances in biomedicine have revealed an important role for post-transcriptional mechanisms of gene expression regulation in pathologic conditions. In cancer in general and leukaemia specifically, RNA binding proteins have emerged as important regulator of RNA homoeostasis that are often dysregulated in the disease state. Having established the importance of these pathogenetic mechanisms, there have been a number of efforts to target RNA binding proteins using oligonucleotide-based strategies, as well as with small organic molecules. The field is at an exciting inflection point with the convergence of biomedical knowledge, small molecule screening strategies and improved chemical methods for synthesis and construction of sophisticated small molecules. Here, we review the mechanisms of post-transcriptional gene regulation, specifically in leukaemia, current small-molecule based efforts to target RNA binding proteins, and future prospects.

General Co-catalytic Hydrothiolation of gem-Difluoroalkenes.

Regioselective functionalization of gem-difluoroalkenes enables convergent late-stage access to fluorinated functional groups, though most functionalization reactions proceed through defluorinative functionalization processes that deliver mono-fluorovinyl products. In contrast, fewer reactions undergo net hydrofunctionalization to generate difluorinated products. Herein, we report a photocatalytic hydrothiolation of gem-difluoroalkenes that enables access to a broad spectrum of α,α-difluoroalkylthioethers. Notably, the reaction successfully couples nonactivated substrates, which expands the scope of accessible molecules relative to previously reported reactions involving organo- or photocatalytic strategies. Further, this reaction successfully couples biologically relevant molecules under aqueous conditions, highlighting potential applications in both late-stage and biorthogonal functionalizations.

Acid-Catalyzed Hydrothiolation of gem-Difluorostyrenes to Access α,α-Difluoroalkylthioethers.

The substitution of hydrogen atoms with fluorine in bioactive molecules can greatly impact physicochemical, pharmacokinetic, and pharmacodynamic properties. However, current synthetic methods cannot readily access many fluorinated motifs, which impedes utilization of these groups. Thus, the development of new methods to introduce fluorinated functional groups is critical for developing the next generation of biological probes and therapeutic agents. The synthesis of one such substructure, the α,α-difluoroalkylthioether, typically requires specialized conditions that necessitate early-stage installation. A late-stage and convergent approach to access α,α-difluoroalkylthioethers could involve nucleophilic addition of thiols across gem-difluorostyrenes. Unfortunately, under basic conditions, nucleophilic addition to gem-difluorostyrenes generates an anionic intermediate that can undergo facile elimination of fluoride to generate α-fluorovinylthioethers. To overcome this decomposition, we herein exploit an acid-based catalyst system to facilitate simultaneous nucleophilic addition and protonation of the unstable intermediate. Ultimately, the optimized mild conditions afford the desired α,α-difluoroalkylthioethers in high selectivity and moderate to excellent yields. These α,α-difluoroalkylthioethers are less nucleophilic and more oxidatively stable relative to nonfluorinated thioethers, suggesting the potential application of this unexplored functional group in biological probes and therapeutic agents.

Late-Stage Conversion of a Metabolically Labile Aryl Methyl Ether-Containing Natural Product to Fluoroalkyl Analogues.

We report the conversion of aryl methyl ethers and phenols into six fluoroalkyl analogues through late-stage functionalization of a natural product-derived FDA-approved therapeutic. This series of short synthetic sequences exploits a combination of both modern and traditional methods and demonstrates that some recently reported methods do not always work as well as desired on a natural product-like scaffold. Nonetheless, reaction optimization can deliver sufficient quantities of each target analogue for medicinal chemistry purposes. In some cases, classical reactions and synthetic sequences still outcompete modern organofluorine transformations, which should encourage the continued search for improved reactions. Overall, the project provides a valuable synthetic roadmap for medicinal chemists to access a range of fluorinated therapeutic candidates with distinct physicochemical properties relative to the original O-based analogue.

Cobalt-Catalyzed Selective Unsymmetrical Dioxidation of gem-Difluoroalkenes.

gem-Difluoroalkenes represent valuable synthetic handles for organofluorine chemistry; however, most reactions of this substructure proceed through reactive intermediates prone to eliminate a fluorine atom and generate monofluorinated products. Taking advantage of the distinct reactivity of gem-difluoroalkenes, we present a cobalt-catalyzed regioselective unsymmetrical dioxygenation of gem-difluoroalkenes using phenols and molecular oxygen, which retains both fluorine atoms and provides ß-phenoxy-ß,ß-difluorobenzyl alcohols. Mechanistic studies suggest that the reaction operates through a radical chain process initiated by Co(II)/O2/phenol and quenched by the Co-based catalyst. This mechanism enables the retention of both fluorine atoms, which contrasts most transition-metal-catalyzed reactions of gem-difluoroalkenes that typically involve defluorination.

Fluoroalkylation of Dextromethorphan Improves CNS Exposure and Metabolic Stability.

Aryl-methyl ethers, while present in many bioactive compounds, are subject to rapid O-dealkylation, which can generate bioinactive or toxic metabolites. Such is the case for dextromethorphan, which readily undergoes P450 mediated O-dealkylation to provide the psychoactive phenolic metabolite dextrorphan, an N-methyl-d-aspartate (NMDA) receptor antagonist that causes hallucinations and encourages recreational abuse. As a general strategy to minimize this undesired degradation, both deuteration and fluorination strategies might be exploited, though such strategies have rarely been compared in matched series. In this manuscript, we designed, synthesized, and evaluated in vitro and in vivo new fluoroalkyl analogs of dextromethorphan and D3-dextromethorphan that minimize metabolic degradation and increased CNS exposure relative to dextromethorphan and related deuterated analogs currently in clinical trials.

Fluorine-Retentive Strategies for the Functionalization of gem-Difluoroalkenes.

gem-Difluoroalkenes are readily available fluorinated building blocks, and the fluorine-induced electronic perturbations of the alkenes enables a wide array of selective functionalization reactions. However, many reactions of gem-difluoroalkenes result in a net C─F functionalization to generate monofluorovinyl products or addition of F to generate trifluoromethyl-containing products. In contrast, fluorine-retentive strategies for the functionalization of gem-difluoroalkenes remain less generally developed, and is now becoming a rapidly developing area. This review will present the development of fluorine-retentive strategies including electrophilic, nucleophilic, radical, and transition metal catalytic strategies with an emphasis on key physical organic and mechanistic aspects that enable reactivities.

Diflunisal Derivatives as Modulators of ACMS Decarboxylase Targeting the Tryptophan-Kynurenine Pathway.

In the kynurenine pathway for tryptophan degradation, an unstable metabolic intermediate, α-amino-ß-carboxymuconate-ε-semialdehyde (ACMS), can nonenzymatically cyclize to form quinolinic acid, the precursor for de novo biosynthesis of nicotinamide adenine dinucleotide (NAD+). In a competing reaction, ACMS is decarboxylated by ACMS decarboxylase (ACMSD) for further metabolism and energy production. Therefore, the inhibition of ACMSD increases NAD+ levels. In this study, an Food and Drug Administration (FDA)-approved drug, diflunisal, was found to competitively inhibit ACMSD. The complex structure of ACMSD with diflunisal revealed a previously unknown ligand-binding mode and was consistent with the results of inhibition assays, as well as a structure-activity relationship (SAR) study. Moreover, two synthesized diflunisal derivatives showed half-maximal inhibitory concentration (IC50) values 1 order of magnitude better than diflunisal at 1.32 ± 0.07 µM (22) and 3.10 ± 0.11 µM (20), respectively. The results suggest that diflunisal derivatives have the potential to modulate NAD+ levels. The ligand-binding mode revealed here provides a new direction for developing inhibitors of ACMSD.