Deoxygenative Hetero- and Carbofunctionalizations of Diarylketones.

Direct transformations of diarylketones to hetero- and carbofunctionalized diarylmethanes have been developed. The reactions involve a phospha-Brook rearrangement of diphenylphosphine oxide with diarylketones, followed by substitutions with various nucleophiles such as amides, amines, phenols, thiols, and diborylmethane under palladium catalysis to afford the corresponding functionalized diarylmethanes in a reductive manner.

Palladium-Catalyzed Denitrative Synthesis of Aryl Nitriles from Nitroarenes and Organocyanides.

A denitrative cyanation of nitroarenes using organocyanides and a palladium catalyst was developed. The key for this reaction was the utilization of an aminoacetonitrile as a cyano source to avoid the generation of stoichiometric metal- and halogen-containing chemical waste. A wide range of nitroarenes, including heteroarenes and pharmaceutical molecules, can be converted into aryl nitriles.

A Small-Molecule Modulator Affecting the Clock-Associated PSEUDO-RESPONSE REGULATOR 7 Amount.

Circadian clocks are biological timekeeping systems that coordinate genetic, metabolic and physiological behaviors with the external day-night cycle. The clock in plants relies on the transcriptional-translational feedback loops transcription-translation feedback loop (TTFL), consisting of transcription factors including PSUEDO-RESPONSE REGULATOR (PRR) proteins, plant lineage-specific transcriptional repressors. Here, we report that a novel synthetic small-molecule modulator, 5-(3,4-dichlorophenyl)-1-phenyl-1,7-dihydro-4H-pyrazolo[3,4-d] pyrimidine-4,6(5H)-dione (TU-892), affects the PRR7 protein amount. A clock reporter line of Arabidopsis was screened against the 10,000 small molecules in the Maybridge Hitfinder 10K chemical library. This screening identified TU-892 as a period-lengthening molecule. Gene expression analyses showed that TU-892 treatment upregulates CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1) mRNA expression. TU-892 treatment reduced the amount of PRR7 protein, a transcriptional repressor of CCA1. Other PRR proteins including TIMING OF CAB EXPRESSION 1 were altered less by TU-892 treatment. TU-892-dependent CCA1 upregulation was attenuated in mutants impaired in PRR7. Collectively, TU-892 is a novel type of clock modulator that reduces the levels of PRR7 protein.

Concise Synthesis of (±)-Fortuneicyclidins and (±)-Cephalotine B Enabled by Pd-Catalyzed Dearomative Spirocyclization.

Total syntheses of C11-oxygenated Cephalotaxus alkaloids, fortuneicyclidins A and B, and cephalotine B, were achieved. The key for the synthesis is a Pd-catalyzed dearomative spirocyclization of bromofurans with N-tosylhydrazones, followed by acid-mediated tandem transformation to construct the tetracyclic skeleton with the C11-oxygen functional group. Chemo-selective and catalytic functional group conversions of the tetracyclic intermediate completed the synthesis of fortuneicyclidins and cephalotine B in 8 and 9 steps, respectively.

Chloroacetyl boronate N-tosylhydrazone as a versatile synthetic building block.

Chloroacetyl boronate N-tosylhydrazone (CABT) has been synthesized as a reagent to generate a diverse range of molecular skeletons. CABT can undergo a series of transformations involving nucleophilic substitution of the chloride and coupling of the N-tosylhydrazones, followed by boryl group functionalization. We further demonstrated that this CABT reagent could enable a diversity-oriented synthesis.

Ring-Opening Fluorination of Carbo/Heterocycles and Aromatics: Construction of Complex and Diverse Fluorine-Containing Molecules.

Fluorine-containing molecules have attracted much attention in medicinal, agrochemical, and materials sciences because they offer unique physical and biological properties. Therefore, many efficient fluorination reactions have been developed over the years. Recent advancements in fluorination chemistry have expanded the range of substrates, and regioselectivity/stereoselectivity control has also been achieved. Ring-opening fluorination is an efficient method to construct complex fluorine-containing molecules with diversity, starting from simple cyclic compounds. This review aims to summarize developments in ring-opening fluorination, particularly with larger-sized cyclic compounds. Fluorine introduction and bond cleavage of cyclic compounds such as carbocycles, heterocycles, and aromatics provide efficient access to fluorine-containing compounds that are difficult to be synthesized by conventional methods.

Unified synthesis of multiply arylated alkanes by catalytic deoxygenative transformation of diarylketones.

A deoxygenative transformation of diarylketones leading to multiply arylated alkanes was developed. Diarylketones were reacted with diphenylphosphine oxide resulting in a phospha-Brook rearrangement, followed by palladium-catalyzed cross-couplings or a Friedel-Crafts type alkylation to afford the corresponding multiply arylated alkanes. A variety of diarylketones can be converted to multiply arylated alkanes such as diarylmethanes, tetraarylethanes, and triarylmethanes by reduction, dimerization, and arylation in one pot. Furthermore, a one-pot conversion from arylcarboxylic acids to diarylmethanes and tetraarylethanes, and a synthesis of tetraarylmethane and triphenylethane using sequential coupling reactions are also presented.

Aryl Dance Reaction of Arylbenzoheteroles.

We report a 1,2-migration (aryl dance reaction) of the aryl group on heteroles. AlCl3 can efficiently convert C3-arylheteroles to C2-arylheteroles. Depending on the electron density of the substrate, conversion from C2- to C3-arylheteroles was also possible with catalytic Zn(OTf)2. A one-pot aryl dance/acylation or bromination and arylation/aryl dance cascade was also demonstrated.

Identification of α-Synuclein Proaggregator: Rapid Synthesis and Streamlining RT-QuIC Assays in Parkinson's Disease.

We report the discovery of two compounds, TKD150 and TKD152, that promote the aggregation of α-synuclein (aSN) using a real-time quaking-induced conversion (RT-QuIC) assay to detect abnormal aSN. By utilizing a Pd-catalyzed C-H arylation of benzoxazole with iodoarenes and implementing a planar conformation to the design, we successfully identified TKD150 and TKD152 as proaggregators for aSN. In comparison to a previously reported proaggregator, PA86, the two identified compounds were able to promote aggregation of aSN at twice the rate. Application of TKD150 and TKD152 to the RT-QuIC assay will shorten the inherent lag time and may allow wider use of this assay in clinical settings for the diagnosis of α-synucleinopathy-related diseases.

Synthesis and Properties of Pyridine-Fused Triazolylidene-Palladium: Catalyst for Cross-Coupling Using Chloroarenes and Nitroarenes.

The synthesis and catalytic activity of pyridine-fused triazolylidene as a novel abnormal N-heterocyclic carbene (aNHC) ligand is described. The evaluation of physical properties using X-ray crystallographic analysis and infrared spectroscopy revealed that these triazolylidenes have a high electron-donating ability toward the metal center. The application of this triazolylidene to the palladium-catalyzed cross-coupling of chloroarenes and nitroarenes with arylboronic acids showcased its ability to activate C-Cl and C-NO2 bonds.

Structure-Function Study of a Novel Inhibitor of Cyclin-Dependent Kinase C in Arabidopsis.

The circadian clock, an internal time-keeping system with a period of about 24 h, coordinates many physiological processes with the day-night cycle. We previously demonstrated that BML-259 [N-(5-isopropyl-2-thiazolyl) phenylacetamide], a small molecule with mammal CYCLIN DEPENDENT KINASE 5 (CDK5)/CDK2 inhibition activity, lengthens Arabidopsis thaliana (Arabidopsis) circadian clock periods. BML-259 inhibits Arabidopsis CDKC kinase, which phosphorylates RNA polymerase II in the general transcriptional machinery. To accelerate our understanding of the inhibitory mechanism of BML-259 on CDKC, we performed structure-function studies of BML-259 using circadian period-lengthening activity as an estimation of CDKC inhibitor activity in vivo. The presence of a thiazole ring is essential for period-lengthening activity, whereas acetamide, isopropyl and phenyl groups can be modified without effect. BML-259 analog TT-539, a known mammal CDK5 inhibitor, did not lengthen the period nor did it inhibit Pol II phosphorylation. TT-361, an analog having a thiophenyl ring instead of a phenyl ring, possesses stronger period-lengthening activity and CDKC;2 inhibitory activity than BML-259. In silico ensemble docking calculations using Arabidopsis CDKC;2 obtained by a homology modeling indicated that the different binding conformations between these molecules and CDKC;2 explain the divergent activities of TT539 and TT361.

Chemical biology to dissect molecular mechanisms underlying plant circadian clocks.

Circadian clocks regulate the diel rhythmic physiological activities of plants, enabling them to anticipate and adapt to day-night and seasonal changes. Genetic and biochemical approaches have suggested that transcription-translation feedback loops (TTFL) are crucial for Arabidopsis clock function. Recently, the study of chemical chronobiology has emerged as a discipline within the circadian clock field, with important and complementary discoveries from both plant and animal research. In this review, we introduce recent advances in chemical biology using small molecules to perturb plant circadian clock function through TTFL components. Studies using small molecule clock modulators have been instrumental for revealing the role of post-translational modification in the clock, or the metabolite-dependent clock input pathway, as well as for controlling clock-dependent flowering time.

Pd-Catalyzed 1,4-Carboamination of Bicyclic Bromoarenes with Diazo Compounds and Amines.

A palladium-catalyzed 1,4-carboamination of bromoarenes with diazo compounds and amines was developed. This reaction proceeds through a palladium-carbene that then generates a π-benzylpalladium intermediate, forming ipso C-C and para C-N bonds on bromoarenes in a regioselective manner. The successful application of this transformation to the rapid synthesis of an antitumor agent demonstrates its synthetic utility.

Palladium-Catalyzed Tandem Ester Dance/Decarbonylative Coupling Reactions.

"Dance reaction" on the aromatic ring is a powerful method in organic chemistry to translocate functional groups on arene scaffolds. Notably, dance reactions of halides and pseudohalides offer a unique platform for the divergent synthesis of substituted (hetero)aromatic compounds when combined with transition-metal-catalyzed coupling reactions. Herein, we report a tandem reaction of ester dance and decarbonylative coupling enabled by palladium catalysis. In this reaction, 1,2-translocation of the ester moiety on the aromatic ring is followed by decarbonylative coupling with nucleophiles to enable the installation of a variety of nucleophiles at the position adjacent to the ester in the starting material.

Ring-Opening Fluorination of Isoxazoles.

A ring-opening fluorination of isoxazoles has been developed. Upon treatment of isoxazoles with an electrophilic fluorinating agent (Selectfluor), fluorination followed by deprotonation leads to tertiary fluorinated carbonyl compounds. This method features mild reaction conditions, good functional group tolerance, and a simple experimental procedure. Diverse transformations of the resulting α-fluorocyanoketones were also demonstrated, furnishing a variety of fluorinated compounds.

Pd-Catalyzed Asymmetric Dearomative Arylation of Indoles via a Desymmetrization Strategy.

Pd-catalyzed asymmetric dearomative arylation of C3-substituted indoles is realized via a desymmetrization strategy. A BINOL-derived chiral phosphoramidite ligand is found to be highly efficient for the stereoselective control in this reaction. This method provides a convenient synthesis of spiroindolenines bearing two stereogenic centers in good yields (up to 98%) with excellent diastereo- and enantioselectivities (up to >20:1 dr and 97% ee), which could also be applied in asymmetric dearomative arylation of the simple C3-tethered indoles.

Ring-opening fluorination of bicyclic azaarenes.

We have discovered a ring-opening fluorination of bicyclic azaarenes. Upon treatment of bicyclic azaarenes such as pyrazolo[1,5-a]pyridines with electrophilic fluorinating agents, fluorination of the aromatic ring is followed by a ring-opening reaction. Although this overall transformation can be classified as an electrophilic fluorination of an aromatic ring, it is a novel type of fluorination that results in construction of tertiary carbon-fluorine bonds. The present protocol can be applied to a range of bicyclic azaarenes, tolerating azines and a variety of functional groups. Additionally, mechanistic studies and enantioselective fluorination have been examined.

Phosphorylation of RNA Polymerase II by CDKC;2 Maintains the Arabidopsis Circadian Clock Period.

The circadian clock is an internal timekeeping system that governs about 24 h biological rhythms of a broad range of developmental and metabolic activities. The clocks in eukaryotes are thought to rely on lineage-specific transcriptional-translational feedback loops. However, the mechanisms underlying the basic transcriptional regulation events for clock function have not yet been fully explored. Here, through a combination of chemical biology and genetic approaches, we demonstrate that phosphorylation of RNA polymerase II by CYCLIN DEPENDENT KINASE C; 2 (CDKC;2) is required for maintaining the circadian period in Arabidopsis. Chemical screening identified BML-259, the inhibitor of mammalian CDK2/CDK5, as a compound lengthening the circadian period of Arabidopsis. Short-term BML-259 treatment resulted in decreased expression of most clock-associated genes. Development of a chemical probe followed by affinity proteomics revealed that BML-259 binds to CDKC;2. Loss-of-function mutations of cdkc;2 caused a long period phenotype. In vitro experiments demonstrated that the CDKC;2 immunocomplex phosphorylates the C-terminal domain of RNA polymerase II, and BML-259 inhibits this phosphorylation. Collectively, this study suggests that transcriptional activity maintained by CDKC;2 is required for proper period length, which is an essential feature of the circadian clock in Arabidopsis.

Ni-Catalyzed Aryl Sulfide Synthesis through an Aryl Exchange Reaction.

A Ni-catalyzed aryl sulfide synthesis through an aryl exchange reaction between aryl sulfides and a variety of aryl electrophiles was developed. By using 2-pyridyl sulfide as a sulfide donor, this reaction achieved the synthesis of aryl sulfides without using odorous and toxic thiols. The use of a Ni/dcypt catalyst capable of cleaving and forming aryl-S bonds was important for the aryl exchange reaction between 2-pyridyl sulfides and aryl electrophiles, which include aromatic esters, arenol derivatives, and aryl halides. Mechanistic studies revealed that Ni/dcypt can simultaneously undergo oxidative additions of aryl sulfides and aromatic esters, followed by ligand exchange between the generated aryl-Ni-SR and aryl-Ni-OAr species to furnish aryl exchanged compounds.

Synthesis of Decaarylanthracene with Nine Different Substituents.

A synthesis of decaarylanthracene with nine different substituents has been accomplished by a coupling/ring-transformation strategy. The oxidation of tetraarylthiophenes with four different substituents to the corresponding thiophene S-oxides and a [4 + 2] cycloaddition with a double benzyne precursor afforded a multiply arylated naphthalene derivative. Subsequently, the naphthalene derivative was converted into a naphthalyne, and then a [4 + 2] cycloaddition of another thiophene S-oxide provided decaarylanthracenes with nine different aryl groups.