Copper-catalyzed atroposelective synthesis of C-O axially chiral compounds enabled by chiral 1,8-naphthyridine based ligands.

Axially chiral molecular scaffolds are widely present in therapeutic agents, natural products, catalysts, and advanced materials. The construction of such molecules has garnered significant attention from academia and industry. The catalytic asymmetric synthesis of axially chiral biaryls, along with other non-biaryl axially chiral molecules, has been extensively explored in the past decade. However, the atroposelective synthesis of C-O axial chirality remains largely underdeveloped. Herein, we document a copper-catalyzed atroposelective construction of C-O axially chiral compounds using novel 1,8-naphthyridine-based chiral ligands. Mechanistic investigations have provided good evidence in support of a mechanism involving synergistic interplay between a desymmetrization reaction and kinetic resolution process. The method described in this study holds great significance for the atroposelective synthesis of C-O axially chiral compounds, with promising applications in organic chemistry. The utilization of 1,8-naphthyridine-based ligands in copper catalysis is anticipated to find broad applications in asymmetric copper(i)-catalyzed azide-alkyne cycloadditions (CuAACs) and beyond.

Catalytic Asymmetric Construction of α,α-Diaryl Aldehydes via Oxo-Hydroarylation of Terminal Alkynes.

Chiral aldehydes containing a tertiary stereogenic center are versatile building blocks in organic chemistry. In particular, such structural motifs bearing an α,α-diaryl moiety are very challenging scaffolds and their efficient asymmetric synthesis is not reported. In this work, a phosphoric acid-catalyzed enantioselective synthesis of α,α-diaryl aldehydes from simple terminal alkynes is presented. This approach yields a wide range of highly enolizable α,α-diaryl aldehydes in good yields with excellent enantioselectivities. Facile transformations of the products, as well as an efficient synthesis of bioactive molecules, including an effective anti-smallpox agent and an FDA-approved antidepressant drug (+)-sertraline, are demonstrated.

Development of Recyclable Polystyrene-Supported Phosphonic Acid Resins for Carbohydrate Immobilization and Glycosylation.

This article describes the development of a recyclable polystyrene-based phosphonic acid resin and its use for the synthesis of immobilized glycosyl phosphonate donors and subsequent glycosylation reaction. This solid support was generated on a decagram scale from the commercially available Merrifield resin and subsequently functionalized via two different methods into eight different glycosylphosphonates. The resultant glycosylphosphonate-containing resins were obtained in 59-96% yields and were found to be bench-stable at room temperature. These donors could be activated using trifluoroborane etherate at 80 °C to react with various alcohol- and thiol-based acceptors to provide 17 different glycosides in good-to-excellent yields (53-98%). In addition, it was demonstrated that glycosylated resin could be recovered and recycled multiple times to regenerate immobilized glycosylphosphonate donors and could be subjected to on-resin glycan elongation.

Molecular Editing of Pyrroles via a Skeletal Recasting Strategy.

Heterocyclic scaffolds are commonly found in numerous biologically active molecules, therapeutic agents, and agrochemicals. To probe chemical space around heterocycles, many powerful molecular editing strategies have been devised. Versatile C-H functionalization strategies allow for peripheral modifications of heterocyclic motifs, often being specific and taking place at multiple sites. The past few years have seen the quick emergence of exciting "single-atom skeletal editing" strategies, through one-atom deletion or addition, enabling ring contraction/expansion and structural diversification, as well as scaffold hopping. The construction of heterocycles via deconstruction of simple heterocycles is unknown. Herein, we disclose a new molecular editing method which we name the skeletal recasting strategy. Specifically, by tapping on the 1,3-dipolar property of azoalkenes, we recast simple pyrroles to fully substituted pyrroles, through a simple phosphoric acid-promoted one-pot reaction consisting of dearomative deconstruction and rearomative reconstruction steps. The reaction allows for easy access to synthetically challenging tetra-substituted pyrroles which are otherwise difficult to synthesize. Furthermore, we construct N-N axial chirality on our pyrrole products, as well as accomplish a facile synthesis of the anticancer drug, Sutent. The potential application of this method to other heterocycles has also been demonstrated.

Enantioselective De Novo Synthesis of α,α-Diaryl Ketones from Alkynes.

Chiral α,α-diaryl ketones are structural motifs commonly present in bioactive molecules, and they are also valuable building blocks in synthetic organic chemistry. However, catalytic asymmetric synthesis of α,α-diaryl ketones bearing a tertiary stereogenic center remains largely unsolved. Herein, we report a catalytic de novo enantioselective synthesis of α,α-diaryl ketones from simple alkynes via chiral phosphoric acid (CPA) catalysis. A broad range of enolizable α,α-diaryl ketones are prepared in good yields and with excellent enantioselectivities. The described protocol also serves as an efficient deuteration method for the preparation of enantiomerically enriched deuterated α,α-diaryl ketones. Using the methodology reported, bioactive molecules, including one of the best-selling anti-breast cancer drugs, tamoxifen, are readily synthesized.

Honokiol induces apoptosis-like death in Cryptocaryon irritans Tomont.

BACKGROUND: Cryptocaryon irritans, a common parasite in tropical and subtropical marine teleost fish, has caused serious harm to the marine aquaculture industry. Honokiol was proven to induce C. irritans tomont cytoplasm shrinkage and death in our previous study, but the mechanism by which it works remains unknown. METHODS: In this study, the changes of apoptotic morphology and apoptotic ratio were detected by microscopic observation and AnnexinV-FITC/PI staining. The effects of honokiol on intracellular calcium ([Ca2+]i) concentration, mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS), quantity of DNA fragmentations (QDF) and caspase activities were detected by Fluo-3 staining, JC-1 staining, DCFH-DA staining, Tunel method and caspase activity assay kit. The effects of honokiol on mRNA expression levels of 61 apoptosis-related genes in tomonts of C. irritans were detected by real-time PCR. RESULTS: The results of the study on the effects of honokiol concentration on C. irritans tomont apoptosis-like death showed that the highest levels of prophase apoptosis-like death rate (PADR), [Ca2+]i concentration, ROS, the activities of caspase-3/9 and the lowest necrosis ratio (NER) were obtained at a concentration of 1 µg/ml, which was considered the most suitable for inducing C. irritans tomont apoptosis-like death. When C. irritans tomonts were treated with 1 µg/ml honokiol, the [Ca2+]i concentration began to increase significantly at 1 h. Following this, the ROS, QDF and activities of caspase-3/9 began to increase significantly, and the ΔΨm began to decrease significantly at 2 h; the highest PADR was obtained at 4 h. The mRNA expression of 14 genes was significantly upregulated during honokiol treatment. Of these genes, itpr2, capn1, mc, actg1, actb, parp2, traf2 and fos were enriched in the pathway related to apoptosis induced by endoplasmic reticulum (ER) stress. CONCLUSIONS: This article shows that honokiol can induce C. irritans tomont apoptosis-like death. These results suggest that honokiol may disrupt [Ca2+]i homeostasis in ER and then induce C. irritans tomont apoptosis-like death by caspase cascade or mitochondrial pathway, which might represent a novel therapeutic intervention for C. irritans infection.

Diastereo- and atroposelective synthesis of N-arylpyrroles enabled by light-induced phosphoric acid catalysis.

The C-N axially chiral N-arylpyrrole motifs are privileged scaffolds in numerous biologically active molecules and natural products, as well as in chiral ligands/catalysts. Asymmetric synthesis of N-arylpyrroles, however, is still challenging, and the simultaneous creation of contiguous C-N axial and central chirality remains unknown. Herein, a diastereo- and atroposelective synthesis of N-arylpyrroles enabled by light-induced phosphoric acid catalysis has been developed. The key transformation is a one-pot, three-component oxo-diarylation reaction, which simultaneously creates a C-N axial chirality and a central quaternary stereogenic center. A broad range of unactivated alkynes were readily employed as a reaction partner in this transformation, and the N-arylpyrrole products are obtained in good yields, with excellent enantioselectivities and very good diastereoselectivities. Notably, the N-arylpyrrole skeletons represent interesting structural motifs that could be used as chiral ligands and catalysts in asymmetric catalysis.

Asymmetric multifunctionalization of alkynes via photo-irradiated organocatalysis.

Alkynes represent a family of pivotal and sustainable feedstocks for various industries such as pharmaceuticals, agrochemicals, and materials, and they are widely used as important starting materials for the production of a broad range of chemical entities. Nevertheless, efficient structural elaborations of alkynes in chemical synthesis, especially asymmetric multifunctionalization of alkynes, remain largely unexplored. It is thus imperative to develop new asymmetric synthetic approaches, making use of these richly available chemical feedstocks, and enabling their conversion to value-added chiral molecules. Here, we disclose our findings on highly enantioselective multifunctionalization of alkynes by merging photochemistry and chiral phosphoric acid catalysis. Our reported one-pot synthetic protocol is applicable to all types of alkyne substrates, incorporating all three reactants in a fully atom-economic fashion to produce optically enriched tetrasubstituted triaryl- and diarylmethanes, important structural scaffolds in medicinal chemistry and biological sciences.

Nickel-Hydride-Catalyzed Diastereo- and Enantioselective Hydroalkylation of Cyclopropenes.

Cyclopropanes are structural motifs that are widely present in natural products and bioactive molecules, and they are also tremendously useful building blocks in synthetic organic chemistry. Asymmetric synthesis of cyclopropane derivatives has been an intensively researched area over the years, but efficient asymmetric preparation of alkylcyclopropane scaffolds remains a challenging topic. Herein, we report a nickel-hydride-catalyzed enantioselective and diastereoselective hydroalkylation of cyclopropenes for facile synthesis of chiral alkylcyclopropane motifs. The reported method is efficient and versatile, taking place under mild reaction conditions, and having broad applicability and excellent functional group tolerance.

Regiodivergent sulfonylarylation of 1,3-enynes via nickel/photoredox dual catalysis.

Catalytic difunctionalization of 1,3-enynes represents an efficient and versatile approach to rapidly assemble multifunctional propargylic compounds, allenes and 1,3-dienes. Controlling selectivity in such addition reactions has been a long-standing challenging task due to multiple reactive centers resulting from the conjugated structure of 1,3-enynes. Herein, we present a straightforward method for regiodivergent sulfonylarylation of 1,3-enynes via dual nickel and photoredox catalysis. Hinging on the nature of 1,3-enynes, diverse reaction pathways are feasible: synthesis of α-allenyl sulfones via 1,4-sulfonylarylation, or preparation of (E)-1,3-dienyl sulfones with high chemo-, regio- and stereoselectivity through 3,4-sulfonylarylation. Notably, this is the first example that nickel and photoredox catalysis are merged to achieve efficient and versatile difunctionalization of 1,3-enynes.