RESUMO
Oligosaccharides have myriad functions throughout biological processes1,2. Chemical synthesis of these structurally complex molecules facilitates investigation of their functions. With a dense concentration of stereocentres and hydroxyl groups, oligosaccharide assembly through O-glycosylation requires simultaneous control of site, stereo- and chemoselectivities3,4. Chemists have traditionally relied on protecting group manipulations for this purpose5-8, adding considerable synthetic work. Here we report a glycosylation platform that enables selective coupling between unprotected or minimally protected donor and acceptor sugars, producing 1,2-cis-O-glycosides in a catalyst-controlled, site-selective manner. Radical-based activation9 of allyl glycosyl sulfones forms glycosyl bromides. A designed aminoboronic acid catalyst brings this reactive intermediate close to an acceptor through a network of non-covalent hydrogen bonding and reversible covalent B-O bonding interactions, allowing precise glycosyl transfer. The site of glycosylation can be switched with different aminoboronic acid catalysts by affecting their interaction modes with substrates. The method accommodates a wide range of sugar types, amenable to the preparation of naturally occurring sugar chains and pentasaccharides containing 11 free hydroxyls. Experimental and computational studies provide insights into the origin of selectivity outcomes.
Assuntos
Glicosídeos , Oligossacarídeos , Ácidos Borônicos/química , Brometos/química , Catálise , Glicosídeos/química , Glicosídeos/síntese química , Glicosilação , Ligação de Hidrogênio , Oligossacarídeos/química , Oligossacarídeos/síntese química , Sulfonas/químicaRESUMO
Herein, we disclose a general method for the assembly of C-allyl glycosides containing gem-difluoroalkene groups via a radical-polar crossover strategy. Central to the success of this process is the polarity matching between the benzenesulfinate radical and the glycosyl donor, which facilitates the initiation of the glycosyl radical and the subsequent formation of gem-difluoroalkene sugar derivatives. This method demonstrated good compatibility with various glycosyl donors and functional groups. Furthermore, we showcase the utility of this method in modifying amino acids, potentially paving the way for analogous modifications to peptides.
RESUMO
The alkylation of nucleophiles is among the most fundamental and well-developed transformations in chemistry. However, to achieve selective alkylation of complex substrates remains a nontrivial task. We report herein a general and selective alkylation method without using strong acids, bases, or metals. In this method, the readily available phosphinites/phosphites, in combination with ethyl acrylate, function as effective alkylating agents. Various nucleophilic groups, including alcohols, phenols, carboxylic acids, imides, and thiols can be alkylated. This method can be applied in the late-stage alkylation of natural products and pharmaceutical agents, achieving chemo- and site-selective modification of complex substrates. Experimental studies indicate the relative reactivity of a nucleophile depends on its acidity and its steric environment. Mechanistic studies suggest the reaction pathway resembles that of the Arbuzov-Michalis reaction.
RESUMO
Here we report a simple and general method to achieve fully unprotected, stereoselective glycosylation of carboxylic acids, employing bench-stable allyl glycosyl sulfones as donors. Running the glycosylation reaction under basic conditions was crucial for the efficiencies and selectivities. Both the donor activation stage and the glycosidic bond forming stage of the process are compatible with free hydroxyl groups, thereby allowing for the use of fully unprotected glycosyl donors. This transformation is stereoconvergent, occurs under mild and metal-free conditions at ambient temperature with visible light (455â nm) irradiation, and displays remarkable scope with respect to both reaction partners. Many natural products and commercial drugs, including an acid derived from the complex anticancer agent taxol, were efficiently glycosylated. Experimental studies provide insights into the origin of the stereochemical outcome.
RESUMO
We herein report a method that enables the generation of glycosyl radicals under highly acidic conditions. Key to the success is the design and use of glycosyl sulfinates as radical precursors, which are bench-stable solids and can be readily prepared from commercial starting materials. This development allows the installation of glycosyl units onto pyridine rings directly by the Minisci reaction. We further demonstrate the utility of this method in the late-stage modification of complex drug molecules, including the anticancer agent camptothecin. Experimental studies provide insight into the reaction mechanism.
RESUMO
Here, we describe the unexpected discovery of a Cu-catalyzed condensation polymerization reaction of propargylic electrophiles (CPPE) that transforms simple C3 building blocks into polydiynes of C6 repeating units. This reaction was achieved by a simple system composed of a copper acetylide initiator and an electron-rich phosphine ligand. Alkyne polymers (up to 33.8 kg/mol) were produced in good yields and exclusive regioselectivity with high functional group compatibility. Hydrogenation of the product afforded a new polyolefin-type backbone, while base-mediated isomerization led to a new type of dienyne-based electron-deficient conjugated polymer. Mechanistic studies revealed a new α-α selective Cu-catalyzed dimerization pathway of the C3 unit, followed by in situ organocopper-mediated chain-growth propagation. These insights not only provide an important understanding of the Cu-catalyzed CPPE of C3, C4, and C6 monomers in general but also lead to a significantly improved synthesis of polydiynes from simpler starting materials with handles for the incorporation of an α-end functional group.
Assuntos
Alcinos , Cobre , Catálise , Dimerização , Polimerização , PolímerosRESUMO
We report here the use of simple and readily available alkyl sulfoxides as precursors to radicals and their application in the preparation of pyridine derivatives. We show that alkyl sulfoxides, N-methoxy pyridinium salts and fluoride anions form electron donor-acceptor (EDA) complexes in solution, which, upon visible light irradiation, undergo a radical chain process to afford various pyridine derivatives smoothly. This reaction displays broad scope with respect to both sulfoxides and N-methoxy pyridiniums. The synthetic versatility of sulfoxides as a handle in chemistry adds to their power as radical precursors. Glycosyl sulfoxides are converted to the corresponding pyridyl C-glycosides with high stereoselectivities. Computational and experimental studies provide insights into the reaction mechanism.
Assuntos
Glicosídeos , Sulfóxidos , Glicosídeos/química , Glicosilação , Luz , Piridinas , Sulfóxidos/químicaRESUMO
Here we report a nonenzymatic glycosylation reaction that builds axial S-glycosidic bonds under biorelevant conditions. This strategy is enabled by the design and use of allyl glycosyl sulfones as precursors to glycosyl radicals and exploits the exceptional functional group tolerance of radical processes. Our method introduces a variety of unprotected glycosyl units to the cysteine residues of peptides in a highly selective fashion. Through developing the second-generation protocol, we applied our method in the direct glycosylation of complex polypeptides and proteins. Computational studies were performed to elucidate the reaction mechanism.
Assuntos
Peptídeos/síntese química , Proteínas/síntese química , Glicosilação , Estrutura Molecular , Peptídeos/química , Proteínas/química , EstereoisomerismoRESUMO
Retrograde vesicle trafficking pathways are responsible for returning membrane-associated components from endosomes to the Golgi apparatus and the endoplasmic reticulum (ER), and they are critical for maintaining organelle identity, lipid homeostasis, and many other cellular functions. The retrograde transport pathway has emerged as an important target for intravacuolar bacterial pathogens. The opportunistic pathogen Legionella pneumophila exploits both the secretory and recycling branches of the vesicle transport pathway for intracellular bacterial proliferation. Its Dot/Icm effector RidL inhibits the activity of the retromer by directly engaging retromer components. However, the mechanism underlying such inhibition remains unknown. Here we present the crystal structure of RidL in complex with VPS29, a subunit of the retromer. Our results demonstrate that RidL binds to a highly conserved hydrophobic pocket of VPS29. This interaction is critical for endosomal recruitment of RidL and for its inhibitory effects. RidL inhibits retromer activity by direct competition, in which it occupies the VPS29-binding site of the essential retromer regulator TBC1d5. The mechanism of retromer inhibition by RidL reveals a hotspot on VPS29 critical for recognition by its regulators that is also exploited by pathogens, and provides a structural basis for the development of small molecule inhibitors against the retromer.
Assuntos
Proteínas de Bactérias/química , Proteínas Ativadoras de GTPase/metabolismo , Legionella pneumophila/fisiologia , Doença dos Legionários/metabolismo , Multimerização Proteica , Proteínas de Transporte Vesicular/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Cristalografia por Raios X , Endossomos/metabolismo , Endossomos/microbiologia , Proteínas Ativadoras de GTPase/genética , Células HeLa , Humanos , Doença dos Legionários/microbiologia , Conformação Proteica , Domínios Proteicos , Transporte Proteico , Proteínas de Transporte Vesicular/químicaRESUMO
Here we report a general approach to make unnatural amino acids from readily available cysteine derivatives. This method capitalizes on an intramolecular radical substitution process that generates alkyl radicals through C-S cleavage. The resulting alkyl radicals partook in diverse C-C bond forming events. These reactions proceed under mild, photocatalytic conditions at room temperature, and can be performed open to air. The utility of these transformations is further demonstrated in the straightforward synthesis of various unnatural amino acids and peptides that are difficult to access previously.
RESUMO
We here report glycosyl sulfoxides appended with an aryl iodide moiety as readily available, air and moisture stable precursors to glycosyl radicals. These glycosyl sulfoxides could be converted to glycosyl radicals by way of a rapid and efficient intramolecular radical substitution event. The use of this type of precursors enabled the synthesis of various complex C-linked glycoconjugates under mild conditions. This reaction could be performed in aqueous media and is amenable to the synthesis of glycopeptidomimetics and carbohydrate-DNA conjugates.
RESUMO
Constitutive activation of signal transducer and activator of transcription 3 (STAT3) occurs in â¼70% of human cancers, and STAT3 is regarded as one of the most promising targets for cancer therapy. However, specific direct STAT3 inhibitors remain to be developed. Oridonin is an ent-kaurane plant-derived diterpenoid with anti-cancer and anti-inflammatory activities. Here, using an array of cell-based and biochemical approaches, including cell proliferation and apoptosis assays, pulldown and reporter gene assays, site-directed mutagenesis, and molecular dynamics analyses, we report that a thiazole-derived oridonin analogue, CYD0618, potently and directly inhibits STAT3. We found that CYD0618 covalently binds to Cys-542 in STAT3 and suppresses its activity through an allosteric effect, effectively reducing STAT3 dimerization and nuclear translocation, as well as decreasing expression of STAT3-targeted oncogenes. Remarkably, CYD0618 not only strongly inhibited growth of multiple cancer cell lines that harbor constitutive STAT3 activation, but it also suppressed in vivo tumor growth via STAT3 inhibition. Taken together, our findings suggest Cys-542 as a druggable site for selectively inhibiting STAT3 and indicate that CYD0618 represents a promising lead compound for developing therapeutic agents against STAT3-driven diseases.
Assuntos
Antineoplásicos/farmacologia , Diterpenos do Tipo Caurano/farmacologia , Neoplasias/tratamento farmacológico , Fator de Transcrição STAT3/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/uso terapêutico , Feminino , Humanos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Neoplasias/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Fator de Transcrição STAT3/metabolismo , Tiazóis/química , Tiazóis/farmacologia , Tiazóis/uso terapêuticoRESUMO
This review covers the use of 2-azaallyl anions, 2-azaallyl cations, and 2-azaallyl radicals in organic synthesis up through June 2018. Particular attention is paid to both foundational studies and recent advances over the past decade involving semistabilized and nonstabilized 2-azaallyl anions as key intermediates in various carbon-carbon and carbon-heteroatom bond-forming processes. Both transition-metal-catalyzed and transition-metal-free transformations are covered. Azomethine ylides, which have received significant attention elsewhere, are discussed briefly with the primary focus on critical comparisons with 2-azaallyl anions in regard to generation and use.
RESUMO
We demonstrate that readily available and bench-stable α-oxo-vinylsulfones are competent electrophiles in Ni-catalyzed Suzuki-Miyaura cross-coupling reactions. The C-sulfone bond in the α-oxo-vinylsulfone motif is cleaved chemoselectively in these reactions, furnishing C-aryl glycals or acyclic vinyl ethers in high yields. These reactions proceed under mild conditions and tolerate a remarkable scope of heterocycles and functional groups. Preliminary mechanistic studies revealed the importance of an α-heteroatom in facilitating these transformations.
RESUMO
The removal of two vicinal hydrogen atoms from an alkane to produce an alkene is a challenge for synthetic chemists. In nature, desaturases and acetylenases are adept at achieving this essential oxidative functionalization reaction, for example during the biosynthesis of unsaturated fatty acids, eicosanoids, gibberellins and carotenoids. Alkane-to-alkene conversion almost always involves one or more chemical intermediates in a multistep reaction pathway; these may be either isolable species (such as alcohols or alkyl halides) or reactive intermediates (such as carbocations, alkyl radicals, or σ-alkyl-metal species). Here we report a desaturation reaction of simple, unactivated alkanes that is mechanistically unique. We show that benzynes are capable of the concerted removal of two vicinal hydrogen atoms from a hydrocarbon. The discovery of this exothermic, net redox process was enabled by the simple thermal generation of reactive benzyne intermediates through the hexadehydro-Diels-Alder cycloisomerization reaction of triyne substrates. We are not aware of any single-step, bimolecular reaction in which two hydrogen atoms are simultaneously transferred from a saturated alkane. Computational studies indicate a preferred geometry with eclipsed vicinal C-H bonds in the alkane donor.
Assuntos
Alcanos/química , Alcenos/química , Alcenos/síntese química , Derivados de Benzeno/química , Hidrogênio/química , Ciclização , Ligação de Hidrogênio , Hidrogenação , Isomerismo , OxirreduçãoRESUMO
Arynes (aromatic systems containing, formally, a carbon-carbon triple bond) are among the most versatile of all reactive intermediates in organic chemistry. They can be 'trapped' to give products that are used as pharmaceuticals, agrochemicals, dyes, polymers and other fine chemicals. Here we explore a strategy that unites the de novo generation of benzynes-through a hexadehydro-Diels-Alder reaction-with their in situ elaboration into structurally complex benzenoid products. In the hexadehydro-Diels-Alder reaction, a 1,3-diyne is engaged in a [4+2] cycloisomerization with a 'diynophile' to produce the highly reactive benzyne intermediate. The reaction conditions for this simple, thermal transformation are notable for being free of metals and reagents. The subsequent and highly efficient trapping reactions increase the power of the overall process. Finally, we provide examples of how this de novo benzyne generation approach allows new modes of intrinsic reactivity to be revealed.
RESUMO
Direct and site-selective O-arylation of carbohydrates has been a challenge in synthesis. Herein we report a method based on copper-catalyzed O-arylation to address this challenge. Proper choice of the ancillary ligand on copper is critical for the efficiency and site selectivity of this transformation. This method features mild conditions, tolerates various functional groups, and demonstrates broad substrate scope.
RESUMO
We have found that readily available N-alkyl hydroxylamines are effective reagents for the amination of organoboronic acids in the presence of trichloroacetonitrile. This amination reaction proceeds rapidly at room temperature and in the absence of added metal or base, it tolerates a remarkable range of functional groups, and it can be used in the late-stage assembly of two complex units.
RESUMO
Reported is the asymmetric propargylic substitution (APS) reaction of 5H-thiazol-4-ones using a Cu/Zn dual metal catalytic system and the APS reaction of 5H-oxazol-4-ones using a Cu/Ti catalytic system. These reactions furnish functional-group-rich, terminal-alkyne-containing products with two vicinal stereocenters in high yields and with good to excellent diastereo- and enantioselectivities. This study demonstrates the use of dual metal catalytic systems as a viable approach to improve the selectivity profiles of the copper-catalyzed APS reactions.