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We report new pyridine-based donor-acceptor (D-A) molecules that enable the direct reductive transformation of a variety of secondary and tertiary aliphatic bromides. A series of experimental and theoretical results suggested that the D-A molecules promote direct C-Br bond cleavage triggered by the excitation of the complex between the catalyst and the aliphatic bromide and that the alkyl groups significantly contribute to the stabilization of the complex, which improves the efficiency of its excitation.
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In this article, an electron donor-acceptor (EDA) complex between a triarylamine and B(C6F5)3 that catalyzes the dehydrogenative cross-coupling of phenols is described. We demonstrate, for the first time, that the use of both components of the radical ion pairs generated by the photoexcitation of the EDA complex as co-catalysts, and the triarylaminium radical cation (+·NAr3) successfully promotes dehydrogenative cross-coupling between electron-rich phenols and 2-naphthols to provide electron-rich biphenol motifs using molecular oxygen as a terminal oxidant.
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Electrones , Fenoles , Oxidantes , OxígenoRESUMEN
The introduction of a chlorine atom could potentially endow peptide derivatives with notable bioactivity and applicability. However, despite considerable recent progress in C(sp3)-H functionalization chemistry, a general method for the site-selective chlorination of inert aliphatic C-H bonds in peptides still remains elusive. Herein, we report a site-selective C(sp3)-H chlorination of oligopeptides based on an N-chloropeptide strategy. N-chloropeptides, which are easily prepared from the corresponding native oligopeptides, are smoothly degraded in the presence of an appropriate copper catalyst, and a subsequent 1,5-hydrogen atom transfer affords γ- or δ-chlorinated peptides in excellent yield. A wide variety of amino acid residues can thus be site-selectively chlorinated in a predictable manner. This method hence enables the efficient synthesis of otherwise less accessible, chlorine-containing peptide fragments of natural peptides. We moreover demonstrate here the successful estimation of the stereochemistry of the chlorinated carbon atom in aquimarin A. Furthermore, we reveal that side-chain-chlorinated peptides can serve as highly useful substructures with a fine balance between stability and reactivity, which renders them promising targets for synthetic and medicinal applications.
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Cloro , Péptidos Cíclicos , Oligopéptidos , Cloruros , Halógenos , HidrógenoRESUMEN
With the aim of achieving the convergent elongation of peptide chains, an amide bond formation reaction that enables a peptide fragment coupling has long been pursued. The decarboxylative amidation recently reported by our group is a potential solution to this problem. In this article, a mechanistic analysis of the t-butyl hydroperoxide (TBHP) mediated-decarboxylative amidation of α-ketoacids that results in a significant advance in convergent peptide synthesis is described. Despite the observation of epimerization with low bulk substrates in preliminary studies, a systematic examination and understanding of the reaction mechanism enabled the development of a modified epimerization-free reaction whereby peptide fragment couplings using peptide α-ketoacids were successfully achieved.
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Cetoácidos , Péptidos , terc-Butilhidroperóxido , Cetoácidos/química , Oligopéptidos , Fragmentos de PéptidosRESUMEN
The development of chemoselective C(sp3)-H deuteration is of particular interest in synthetic chemistry. We herein report the α-selective, iridium(iii)-bipyridonate-catalyzed hydrogen(H)/deuterium(D) isotope exchange of alcohols using deuterium oxide (D2O) as the primary deuterium source. This method enables the direct, chemoselective deuteration of primary and secondary alcohols under basic or neutral conditions without being affected by coordinative functional groups such as imidazole and tetrazole. Successful substrates for deuterium labelling include the pharmaceuticals losartan potassium, rapidosept, guaifenesin, and diprophylline. The deuterated losartan potassium shows higher stability towards the metabolism by CYP2C9 than the protiated analogue. Kinetic and DFT studies indicate that the direct deuteration proceeds through dehydrogenation of alcohol to the carbonyl intermediate, conversion of [IrIII-H] to [IrIII-D] with D2O, and deuteration of the carbonyl intermediate to give the α-deuterated product.
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An efficient and scalable synthesis of N-perfluoroacylimino-λ3-iodanes was achieved via an unprecedented metathesis between iodosoarenes and perfluoroalkanenitriles. The perfluoroacylamino groups of the iodanes could be introduced to aromatic and heteroaromatic rings using photoirradiation.
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Nitrilos , Estructura MolecularRESUMEN
Conventional methods for the construction of dehydroamino acids (ΔAAs), which are a unique class of non-proteinogenic amino acids, require the pre-installation of special amino acids. Herein, we report and demonstrate the practical utility of an N-chloropeptide strategy for the rapid construction of ΔAA-containing peptides. The electrophilic N-chlorination of peptide bonds is drastically accelerated by a catalytic amount of quinuclidine (ABCO), and the subsequent ß-elimination of N-chloroamide efficiently provides ΔAA-containing peptides in high yield. The strategy enables, for the first time, the construction of a wide variety of ΔAA residues in peptides without any pre-functionalized side chains and facilitates the late-stage installation of ΔAA motifs into already-constructed oligopeptides, including a medicinally important macrocyclic peptide.
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Aminoácidos , Péptidos , Aminoácidos/química , Oligopéptidos , Péptidos/química , Péptidos CíclicosRESUMEN
The homolytic cleavage of C-O bonds to afford alkyl radicals is an attractive yet challenging transformation in organic synthesis. Herein we describe a photocatalyzed deoxygenative C-C coupling reaction of xanthate salts, which can be easily prepared from the corresponding alcohols. The key to the success of this strategy is the low oxidation potential of the xanthate salt and the use of an appropriate phosphine to accelerate the desulfurative release of carbonyl sulfide.
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Novel innovative catalytic systems such as hydrogen-bond donors and thiourea hybrid catalysts have been developed for the asymmetric synthesis of biologically important pharmaceuticals and natural products. Benzothiadiazines possess a stronger hydrogen-bond donor ability compared to thioureas and exhibit remarkable catalytic performance for the activation of α,ß-unsaturated amides. Hybrid thioureas (bearing an arylboronic acid and an ammonium salt) efficiently promote the hetero-Michael addition to α,ß-unsaturated carboxylic acids and the O-alkylation of keto enols with 5-chlorofuran-2(5H)-one. These hybrid catalysts enable the first total synthesis of non-racemic avenaol, a noncanonical strigolactone, as well as the asymmetric synthesis of several pharmaceuticals. In addition, this study discovers unique chemical phenomena (i.e., the dual role of benzoic acid as a boron ligand and a proton shuttle, the chirality switch of products by solvent used, and the dynamic kinetic resolution of a racemic electrophile in an SN2-type reaction).
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Compuestos Bicíclicos con Puentes/síntesis química , Ciclopropanos/síntesis química , Tiourea/química , Ácido Benzoico/química , Boro/química , Compuestos Bicíclicos con Puentes/química , Catálisis , Ciclopropanos/química , Enlace de Hidrógeno , Cinética , Ligandos , Estructura MolecularRESUMEN
A mild and chemoselective three-component thioesterification using olefins, α-ketoacids, and elemental sulfur has been developed. The photocatalytic activation of elemental sulfur, a cheap and abundant sulfur source, enables the rapid installation of a sulfur atom into molecules, reactions that ordinarily would require the use of reactive and malodorous sulfur-containing compounds such as thiols and thioacids. This novel reaction is characterized by high yields and a broad substrate scope, which enables the introduction of thioester moieties into complex molecules including a steroid, a peptide, and a nonprotected glycoside. Mechanistic studies indicated that the success of this transformation depends on the multiple roles played by the elemental sulfur, including those of a sulfurizing agent, a terminal oxidant, and a HAT mediator.
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We report the first total synthesis of shagenesâ A and B, which are tricyclic terpenoids containing a cis-substituted cyclopropane, via ring-closing metathesis of an enamide and Ir-catalyzed double-bond isomerization of an alkylidenecyclopropane. Chemo- and diastereoselectivity in the distorted cis-substituted structures were controlled by the alkylidenecyclopropane reactivity and using the ketone functionality as a remote directing group for the Ir catalyst, respectively. The total synthesis suggested the absolute configuration of shagenes.
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ortho-Nitro-substituted N-trifluoroacetyl imino-λ3-iodane is a bench-stable trifluoroacetyl nitrene precursor, in which intra- and intermolecular halogen bonding (XB) plays an important role. Potential synthetic applications of this novel precursor were explored.
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This report describes the total synthesis of the complex, oxygenated tetracyclic alkaloid, lyconesidine B. The key synthetic challenge involves diastereoselective generation of a decahydroquinoline ring with a quaternary carbon at the angular position via domino cyclopropanation, ring-opening, and reduction. Another crucial step is the domino ene-yne metathesis involving a quaternary ammonium ion, leading to the construction of a decahydroazaazulen framework.
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Alcaloides/síntesis química , Lycopodium/química , Oxígeno/química , Alcaloides/química , Aminas/química , Estructura MolecularRESUMEN
Organo-radical catalysts have recently attracted great interest, and the development of this field can be expected to broaden the applications of organocatalysis. Herein, the first example of a radical-generating system is reported that does not require any photoirradiation, radical initiators, or preactivated substrates. The oxidative C-C-bond cleavage of 2-substituted cyclohexanones was achieved using an azolium salt and a hydroquinone as co-catalysts. A catalytic mechanism was proposed based on the results of diffusion-ordered spectroscopy and cyclic voltammetry measurements, as well as computational studies.
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An asymmetric thia-Michael addition of arylthiols to α,ß-unsaturated carboxylic acids using a thiourea catalyst that bears arylboronic acid and tertiary amine moieties is reported. Both enantiomers of the Michael adducts can be obtained in high enantioselectivity and good yield merely by changing the solvent. The origin of the chirality switch in the products was examined in each solvent via spectroscopic analyses.
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The highly stereoselective synthesis of 1,1'-disaccharides was achieved by using 1,2-dihydroxyglycosyl acceptors and glycosyl donors in the presence of a tricyclic borinic acid catalyst. In this reaction, the complexation of the diols and the catalyst is crucial for the activation of glycosyl donors, as well as for the 1,2-cis-configuration of the products. The anomeric stereochemistry of the glycosyl donor depends on the employed glycosyl donor. Applications of the produced 1,1'-disaccharides are also described.
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A mild and chemoselective method for the thioacylation of amines using α-keto acids and elemental sulfur has been developed. The key to the success of this transformation is the nucleophilic activation of elemental sulfur by thiols such as 1-dodecanethiol. A variety of functional groups, including unprotected hydroxyl, carboxyl, amide, sulfide, and tertiary amine moieties, are tolerated under the applied reaction conditions. To demonstrate the advantages of this method compared with conventional O-S exchange reactions using Lawesson's reagent or P2S5, thioamide moieties were introduced site-specifically into biologically active compounds.
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Although acetalization is a fundamental transformation in organic synthesis, intermolecular asymmetric acetalization remains an unsolved problem. In this study, a thiourea-ammonium hybrid catalyst was shown to promote the O-alkylation of enols with a racemic γ-chlorobutenolide through dynamic kinetic resolution to give chiral acetals with good enantioselectivity. The catalyst simultaneously activates both the nucleophile and electrophile in a multifunctional manner. This method was applied to the asymmetric synthesis of several strigolactones. DFT calculations suggest that hydrogen-bonding interactions between the chlorine atom of the γ-chlorobutenolide and the tosylamide hydrogen atom of the catalyst, as well as other types of noncovalent catalyst-substrate interactions, are crucial for achieving high stereoselectivity.
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Strategies for the formation of amide bonds, that is, one of the most basic and important transformations in organic synthesis, have so far focused predominantly on dehydration reactions. Herein, we report and demonstrate the practical utility of a novel decarboxylative amidation of α-ketoacids by using inexpensive tert-butyl hydroperoxide (TBHP), which is characterized by high yields, a broad substrate scope, mild reaction conditions, and a unique chemoselectivity. These features enable the synthesis of peptides from amino acid derived α-ketoacids under preservation of the stereochemical information.
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In Chinese medicine, herbal medicine is commonly used to treat individuals suffering from many types of diseases. We thus expected that some herbal medicines would contain promising compounds for cancer chemotherapy. Indeed, we found that Sanguisorba officinalis extracts strongly inhibit the growth of B16F10 melanoma cells, and we identified ellagic acid (EA) as the responsible ingredient. B16F10 cells treated with EA exhibited strong G1 arrest accompanied by accumulation of p53, followed by inactivation of AKT. Addition of a PTEN inhibitor, but not a p53 inhibitor, abrogated the EA-induced AKT inactivation and G1 arrest. The PTEN inhibitor also diminished EA-induced p53 accumulation. Furthermore, EA apparently increased the protein phosphatase activity of PTEN, as demonstrated by the reduced phosphorylation level of FAK, a protein substrate of PTEN. Furthermore, an in vitro PTEN phosphatase assay on PIP3 showed the direct modulation of PTEN activity by EA. These results suggest that EA functions as an allosteric modulator of PTEN, enhancing its protein phosphatase activity while inhibiting its lipid phosphatase activity. It is notable that a combination of EA and cisplatin, a widely used chemotherapy agent, dramatically enhanced cell death in B16F10 cells, suggesting a promising strategy in chemotherapy.