RESUMEN
A novel reactivity toward C-F bond functionalization has been developed, which could be designated as fluorine atom transfer (FAT). A photoexcited state of an N-heterocyclic carbene-ligated boryl radical exhibits a transcendent reactivity, capable of activating chemically inert carbon-fluorine bonds through homolysis. Combined experimental and computational studies suggest that the ligated boryl radical species directly abstracts a fluorine atom from the organofluoride substrates to provide valuable carbon-centered radicals.
RESUMEN
A practical method for C(sp3)-B bond activation was developed. Using a combination of alkyl trifluoroborates and N-iodosuccinimide (NIS), various C(sp3)-heteroatom bonds were readily generated in an efficient manner. Mechanistic studies revealed the bifunctional ability of NIS: mediating the formation of reactive halogenated intermediates and activating them via halogen bonding. This electrophilic activation of the reaction center enables the utilization of general heteroatom nucleophiles, which are used in a limited capacity in traditional 1,2-metalate rearrangements.
RESUMEN
A novel mechanistic duality has been revealed from the indolyl 1,3-heteroatom transposition (IHT) of N-hydroxyindole derivatives. A series of in-depth mechanistic investigations suggests that two separate mechanisms are operating simultaneously. Moreover, the relative contribution of each mechanistic pathway, the energy barrier for each pathway, and the identity of the primary pathway were shown to be the functions of the electronic properties of the substrate system. Based on the mechanistic understanding obtained, a mechanism-driven strategy for the general and efficient introduction of a heteroatom at the 3-position of indole has been developed. The reaction developed exhibits a broad substrate scope to provide the products in various forms of the functionalised indole. Moreover, the method is applicable to the introduction of both oxygen- and nitrogen-based functional groups.
RESUMEN
A novel strategy for the stereospecific Pd-catalyzed acylative cross-coupling of enantiomerically enriched alkylboron compounds has been developed. The protocol features an extremely high level of enantiospecificity to allow facile access to synthetically challenging and valuable chiral ketones and carboxylic acid derivatives. The use of a sterically encumbered and electron-rich phosphine ligand proved to be crucial for the success of the reaction. Furthermore, on the basis of experimental and computational studies, a unique mechanism for the transmetalation, assisted by the noncovalent interactions of the C(sp3)-based organoboron reagent, has been identified.
RESUMEN
Based on systematic electrochemical analysis, an integrated synthetic platform of C(sp3)-based organoboron compounds was established for the introduction of heteroatoms. The electrochemically mediated bond-forming strategy was shown to be highly effective for the functionalization of sp3-hybridized carbon atoms with significant steric hindrance. Moreover, virtually all the nonmetallic heteroatoms could be utilized as reaction partners using one unified protocol. The observed reactivity stems from the two consecutive single-electron oxidations of the substrate, which eventually generates an extremely reactive carbocation as the key intermediate. The detailed reaction profile could be elucidated through multifaceted electrochemical studies. Ultimately, a new dimension in the activation strategies for organoboron compounds was accomplished through the electrochemically driven reaction development.
Asunto(s)
Carbono , Electrones , Compuestos de Boro , Carbono/química , Catálisis , Indicadores y Reactivos , Oxidación-ReducciónRESUMEN
An unprecedented synthetic strategy is devised to generate ß-aminoboronic acids from aziridines via a sequential process involving 1,2-iodoamine formation and radical borylation under light irradiation. A variety of aziridines including multiply substituted aziridines have been successfully employed as synthetic precursors, expanding their synthetic utility compared to previous methods. Mechanistic studies suggest that the boron source plays a unique role in the borylation step, and in the formation of haloamine intermediates.
Asunto(s)
Aziridinas , BoroRESUMEN
It is important but challenging to elucidate the electrochemical reaction mechanisms of organic compounds using electroanalytical methods. Particularly, a rapid and straightforward method that provides information on reaction intermediates or other key electrochemical parameters may be useful. In this work, we exploited the advantages of classic thin-layer electrochemistry to develop a thin-layer electroanalysis microchip (TEAM). The TEAM provided better-resolved voltammetric peaks than under semi-infinite diffusion conditions owing to its small height. Importantly, rapid and accurate determination of the number of electrons transferred, n, was enabled by mechanically confining the microliter-scale volume analyte at the electrode, while securing ionic conduction using polyelectrolyte gels. The performance of the TEAM was validated using voltammetry and coulometry of standard redox couples. Utilizing the TEAM, a (spectro)electrochemical analysis of FM 1-43, an organic dye widely used in neuroscience, was successfully performed. Moreover, the TEAM was applied to study the electrochemical oxidation mechanism of pivanilides and alkyltrifluoroborate salts with different substituents and solvents. This work suggests that TEAM is a promising tool to provide invaluable mechanistic information and promote the rational design of electrosynthetic strategies.
Asunto(s)
Electroquímica/métodos , Análisis por Micromatrices/métodos , Difusión , Electrodos , Electrones , Oxidación-ReducciónRESUMEN
A synthetic strategy for the formation of C(sp3)-N bonds, particularly through a copper-catalyzed oxidative cross-coupling, is rare. Herein, we report a novel synthetic approach for the preparation of tertiary sulfonamides via copper-catalyzed intra- and intermolecular oxidative C(sp3)-N cross-coupling reactions. This method allows the utilization of the readily available C(sp3)-based pinacol boronate as a substrate and the tolerance of a wide range of functional groups under mild reaction conditions. The success of this strategy relies on the unprecedented additive effects of silanol and NaIO4.
RESUMEN
Graspetides, also known as ω-ester-containing peptides (OEPs), are a family of ribosomally synthesized and post-translationally modified peptides (RiPPs) bearing side chain-to-side chain macrolactone or macrolactam linkages. Here, we present the molecular details of precursor peptide recognition by the macrocyclase enzyme PsnB in the biosynthesis of plesiocin, a group 2 graspetide. Biochemical analysis revealed that, in contrast to other RiPPs, the core region of the plesiocin precursor peptide noticeably enhanced the enzyme-precursor interaction via the conserved glutamate residues. We obtained four crystal structures of symmetric or asymmetric PsnB dimers, including those with a bound core peptide and a nucleotide, and suggest that the highly conserved Arg213 at the enzyme active site specifically recognizes a ring-forming acidic residue before phosphorylation. Collectively, this study provides insights into the mechanism underlying substrate recognition in graspetide biosynthesis and lays a foundation for engineering new variants.
Asunto(s)
Ligasas/metabolismo , Péptidos/metabolismo , Ligasas/química , Estructura Molecular , Péptidos/química , Procesamiento Proteico-Postraduccional , Especificidad por SustratoRESUMEN
Reported herein is a novel reaction engineering protocol to enhance the efficiency of a transition metal-catalysed process by strategically preventing ligand degradation. Based on spectroscopic investigations, a decomposition pathway of a chiral phosphoramidite ligand during a Cu-catalysed reaction was identified. The involvement of the destructive process could be minimized under the modified reaction conditions that control the amount of nucleophilic alkoxide base, which is the origin of ligand decomposition. Overall, the strategy has been successfully applied to a new class of asymmetric conjugate addition reactions with bis[(pinacolato)boryl]methane, in which α,ß-unsaturated enones are utilised as substrates.
RESUMEN
A mechanistically unique functionalization strategy for a benzylic C(sp3)-H bond has been developed based on the facile oxidation event of indole substrates. This novel pathway was initiated by efficient radical generation at the benzylic position of the substrate, with subsequent transition metal catalysis to complete the overall transformation. Ultimately, an aryl or an acyl group could be effectively delivered from an aryl (pseudo)halide or an acid anhydride coupling partner, respectively. The developed method utilizes mild conditions and exhibits a wide substrate scope for both substituted indoles and C(sp2)-based reaction counterparts. Mechanistic studies have shown that competitive hydrogen atom transfer (HAT) processes, which are frequently encountered in conventional methods, are not involved in the product formation process of the developed strategy.
RESUMEN
A single-electron transfer mediated modular indole formation reaction from a 2-iodoaniline derivative and a ketone has been developed. This transition-metal-free reaction shows a broad substrate scope and unconventional regioselectivity trends. Moreover, important functional groups for further transformation are tolerated under the reaction conditions. Density functional theory studies reveal that the reaction proceeds by metal coordination, which converts a disfavored 5-endo-trig cyclization to an accessible 7-endo-trig process.
RESUMEN
A practical procedure for 11CN-labeling of unprotected peptides has been developed. The method was shown to be highly chemoselective for cysteine over other potentially nucleophilic residues, and the radiolabeled products were synthesized and purified in less than 15 min. Appropriate for biomedical applications, the method could be used on an extremely small scale (20 nmol) with a high radiochemical yield. The success of the protocol stems from the use of a Pd-reagent based on a dihaloarene, which enables direct "nucleophile-nucleophile" coupling of the peptide and [11C]cyanide by temporal separation of nucleophile addition.
Asunto(s)
Cianuros/química , Marcaje Isotópico , Paladio/química , Péptidos/química , Radioisótopos de Carbono , Estructura Molecular , Péptidos/síntesis químicaRESUMEN
A mild method for the arylation of lysine in an unprotected peptide is presented. In the presence of a preformed biarylphosphine-supported palladium(II)-aryl complex and a weak base, lysine amino groups underwent C-N bond formation at room temperature. The process generally exhibited high selectivity for lysine over other amino acids containing nucleophilic side chains and was applicable to the conjugation of a variety of organic compounds, including complex drug molecules, with an array of peptides. Finally, this method was also successfully applied to the formation of cyclic peptides by macrocyclization.
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Lisina/química , Compuestos Organometálicos/química , Paladio/química , Péptidos Cíclicos/síntesis química , Ciclización , Estructura Molecular , Péptidos Cíclicos/químicaRESUMEN
We describe an efficient and mild method for the synthesis of macrocyclic peptides via nitrogen arylation from unprotected precursors. Various electrophiles and lysine-based nucleophiles were investigated and showed high-yielding product formation, even for a macrocyclization scan with 14 variants. We found that nitrogen-linked aryl products were more stable to base and oxidation when compared to thiol arylated species, thereby highlighting the utility of this methodology. Finally, N-aryl macrocyclization was performed on a p53 peptide inhibitor of MDM2 and resulted in identification of a nanomolar binder with improved proteolytic stability and cell permeability.
Asunto(s)
Hidrocarburos Aromáticos/química , Nitrógeno/química , Péptidos/química , Secuencia de Aminoácidos , Ciclización , Lisina/químicaRESUMEN
A new biaryl monophosphine ligand (AlPhos, L1) allows for the room-temperature Pd-catalyzed fluorination of a variety of activated (hetero)aryl triflates. Furthermore, aryl triflates and bromides that are prone to give mixtures of regioisomeric aryl fluorides with Pd-catalysis can now be converted to the desired aryl fluorides with high regioselectivity. Analysis of the solid-state structures of several Pd(II) complexes, as well as density functional theory (DFT) calculations, shed light on the origin of the enhanced reactivity observed with L1.
Asunto(s)
Bromuros/química , Flúor/química , Paladio/química , Temperatura , Catálisis , Cristalografía por Rayos X , Ligandos , Modelos MolecularesRESUMEN
Contemporary organic chemists employ a broad range of catalytic and stoichiometric methods to construct molecules for applications in the material sciences, and as pharmaceuticals, agrochemicals, and sensors. The utility of a synthetic method may be greatly reduced if it relies on a glove box to enable the use of air- and moisture-sensitive reagents or catalysts. Furthermore, many synthetic chemistry laboratories have numerous containers of partially used reagents that have been spoiled by exposure to the ambient atmosphere. This is exceptionally wasteful from both an environmental and a cost perspective. Here we report an encapsulation method for stabilizing and storing air- and moisture-sensitive compounds. We demonstrate this approach in three contexts, by describing single-use capsules that contain all of the reagents (catalysts, ligands, and bases) necessary for the glove-box-free palladium-catalysed carbon-fluorine, carbon-nitrogen, and carbon-carbon bond-forming reactions. This strategy should reduce the number of error-prone, tedious and time-consuming weighing procedures required for such syntheses and should be applicable to a wide range of reagents, catalysts, and substrate combinations.
Asunto(s)
Técnicas de Química Sintética/métodos , Aminas/química , Bromuros/química , Carbono/química , Catálisis , Flúor/química , Indicadores y Reactivos , Ligandos , Nitrógeno/química , Compuestos Organometálicos/química , Paladio/química , Ceras/químicaRESUMEN
A new radiosynthetic protocol for the preparation of [(11)C]aryl nitriles has been developed. This process is based on the direct reaction of in situ prepared L·Pd(Ar)X complexes (L = biaryl phosphine) with [(11)C]HCN. The strategy is operationally simple, exhibits a remarkably wide substrate scope with short reaction times, and demonstrates superior reactivity compared to previously reported systems. With this procedure, a variety of [(11)C]nitrile-containing pharmaceuticals were prepared with high radiochemical efficiency.
Asunto(s)
Nitrilos/química , Compuestos Organometálicos/química , Paladio/química , Fosfinas/química , Temperatura , Radioisótopos de Carbono/química , CinéticaRESUMEN
The structure of the stable Pd(0) precatalyst [(1,5-cyclooctadiene)(Lâ¢Pd)2] (L = AdBrettPhos) for the Pd-catalyzed fluorination of aryl triflates has been further studied by solid state NMR and X-ray cystrallography of the analogous N-phenylmaleimide complex. The reactivity of this complex with CDCl3 to form a dearomatized complex is also presented. In addition, studies suggest that related bulky biaryl phosphine ligands form similar complexes, although the smaller ligand BrettPhos forms a monomeric [(1,5-cyclooctadiene)(Lâ¢Pd)] species instead.
RESUMEN
4-Methylphenol (4-MP), a putative bisphenol A (BPA) degradation intermediate, was detected at concentrations reaching 2.1 mg L(-1) in anoxic microcosms containing 10 mg L(-1) BPA and 5 g of freshwater sediment material collected from four geographically distinct locations and amended with nitrate, nitrite, ferric iron, or bicarbonate as electron acceptors. 4-MP accumulation was transient, and 4-MP degradation was observed under all redox conditions tested. 4-MP was not detected in microcosms not amended with BPA. Unexpectedly, incubations with (13)C-labeled BPA failed to produce (13)C-labeled 4-MP suggesting that 4-MP was not derived from BPA. The detection of 4-MP in live microcosms amended with lactate, but not containing BPA corroborated that BPA was not the source of 4-MP. These findings demonstrate that the transient formation of 4-MP as a possible BPA degradation intermediate must be interpreted cautiously, as microbial activity in streambed microcosms may generate 4-MP from sediment-associated organic material.