RESUMO
Installing fluorine atoms onto natural products holds great promise for the generation of fluorinated molecules with improved or novel pharmacological properties. The enzymatic oxidative carbon-carbon coupling reaction represents a straightforward strategy for synthesizing biaryl architectures, but the exploration of this method for producing fluorine-substituted derivatives of natural products remains elusive. Here, in this study, we report the protein engineering of cytochrome P450 from Mycobacterium tuberculosis (MtCYP121) for the construction of a series of new-to-nature fluorine-substituted Mycocyclosin derivatives. This protocol takes advantage of a "hybrid" chemoenzymatic procedure consisting of tyrosine phenol lyase-catalyzed fluorotyrosine preparation from commercially available fluorophenols, intermolecular chemical condensation to give cyclodityrosines, and an engineered MtCYP121-catalyzed intramolecular biphenol coupling reaction to complete the strained macrocyclic structure. Computational mechanistic studies reveal that MtCYP121 employs Cpd I to abstract a hydrogen atom from the proximal phenolic hydroxyl group of the substrate to trigger the reaction. Then, conformational change makes the two phenolic hydroxyl groups close enough to undergo intramolecular hydrogen atom transfer with the assistance of a pocket water molecule. The final diradical coupling process completes the intramolecular C-C bond formation. The efficiency of the biaryl coupling reaction was found to be influenced by various fluorine substitutions, primarily due to the presence of distinct binding conformations.
Assuntos
Sistema Enzimático do Citocromo P-450 , Mycobacterium tuberculosis , Engenharia de Proteínas , Sistema Enzimático do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/química , Mycobacterium tuberculosis/enzimologia , Biocatálise , Halogenação , Estrutura MolecularRESUMO
Oxaloacetic acid (OAA) is a ß-ketocarboxylic acid, which plays an important role as an intermediate in some metabolic pathways, including the tricarboxylic acid cycle, gluconeogenesis and fatty acid biosynthesis. Animal studies have indicated that supplementing oxaloacetic acid shows an increase of lifespan and other substantial health benefits including mitochondrial DNA protection, and protection of retinal, neural and pancreatic tissues. Most of the chemical transformations of OAA in the metabolic pathways have been extensively studied; however, the understanding of decarboxylation of OAA at the atomic level is relatively lacking. Here, we carried out MD simulations and combined quantum mechanical/molecular mechanical (QM/MM) calculations as an example to systematically elucidate the binding modes, keto-enol tautomerization and decarboxylation of OAA in the active site of macrophomate synthase (MPS), which is a Mg(II)-dependent bifunctional enzyme that catalyzes both the decarboxylation of OAA and [4+2] cycloaddition of 2-pyrone with the decarboxylated intermediate of OAA (pyruvate enolate). On the basis of our calculations, it was found that the Mg2+-coordinated oxaloacetate may exist in enol forms and keto forms. The four keto forms can be transformed into each other by simply rotating the C2-C3 single bond, nevertheless, the keto-enol tautomerization strictly requires the assistance of pocket water molecules. In addition, the decarboxylation is stereo-electronically controlled, i.e., it is the relative orientation of the terminal carboxyl anion that determines the rate of decarboxylation. As such, the chemistry of oxaloacetate in the active site of MPS is complex. On one hand, the most stable binding mode (K-I) may undergo enol-keto tautomerization to isomerize to the enol form, which may further react with the second substrate; on the other hand, K-I may isomerize to another binding mode K-II to proceed decarboxylation to generate pyruvate enolate and CO2. Starting from K-I, the enol-keto tautomerization corresponds to a barrier of 16.2 kcal mol-1, whereas the decarboxylation is associated with an overall barrier of 19.7 kcal mol-1. These findings may provide useful information for understanding the chemistry of OAA and the catalysis of related enzymes, and they are basically in agreement with the available experimental kinetic data.
Assuntos
Ascomicetos , Complexos Multienzimáticos , Domínio Catalítico , Descarboxilação , Simulação de Dinâmica Molecular , Ácido Oxaloacético/metabolismo , Ácido Oxaloacético/química , Teoria Quântica , Estereoisomerismo , Complexos Multienzimáticos/química , Ascomicetos/enzimologiaRESUMO
An α-diazodifluoroethane sulfonium reagent was developed in this study to undergo [3 + 2] radical cyclization with unactivated alkynes to give the corresponding 3-difluoromethyl pyrazoles under blue light irradiation conditions. The key to the success of this transformation lies in the formation of an electron donor-acceptor (EDA) complex between an electron-deficient α-diazo sulfonium salt and an electron-rich triaryl amine. This study circumvents a major substrate scope limitation in polar cycloaddition reactions of existent diazodifluoroethane reagents.
RESUMO
The introduction of difluoromethylene moieties into organic molecules has garnered significant attention due to their profound influence on the physicochemical and biological properties of compounds. Nonetheless, the existing approaches for accessing difluoroalkanes from readily available feedstock chemicals remain limited. In this study, we present an efficient and modular protocol for the synthesis of difluorinated compounds from alkenes, employing the readily accessible reagent, ClCF2SO2Na, as a versatile "difluoromethylene" linchpin. By means of an organophotoredox-catalysed hydrochlorodifluoromethylation of alkenes, followed by a ligated boryl radical-facilitated halogen atom transfer (XAT) process, we have successfully obtained various difluorinated compounds, including gem-difluoroalkanes, gem-difluoroalkenes, difluoromethyl alkanes, and difluoromethyl alkenes, with satisfactory yields. The practical utility of this linchpin strategy has been demonstrated through the successful preparation of CF2-linked derivatives of complex drugs and natural products. This method opens up new avenues for the synthesis of structurally diverse difluorinated hydrocarbons and highlights the utility of ligated boryl radicals in organofluorine chemistry.
RESUMO
Catalytic asymmetric hydroboration of fluoroalkyl-substituted alkenes is a straightforward approach to access chiral small molecules possessing both fluorine and boron atoms. However, enantioselective hydroboration of fluoroalkyl-substituted alkenes without fluorine elimination has been a long-standing challenge in this field. Herein, a copper-catalyzed hydroboration of difluoroalkyl-substituted internal alkenes with high levels of regio- and enantioselectivities is reported. The native carbonyl directing group, copper hydride system, and bisphosphine ligand play crucial roles in suppressing the undesired fluoride elimination. This atom-economic protocol provides a practical synthetic platform to obtain a wide scope of enantioenriched secondary boronates bearing the difluoromethylene moieties under mild conditions. Synthetic applications including functionalization of biorelevant molecules, versatile functional group interconversions, and preparation of difluoroalkylated Terfenadine derivative are also demonstrated.
RESUMO
Herein, we describe a [2+1] annulation reaction of di/trifluorodiazoethane with (alkylidene)malononitriles. This protocol offers a streamlined synthesis of a wide range of stereospecific and densely functionalized difluoromethyl and trifluoromethyl cyclopropane-1,1-dicarbonitriles. Further functional group interconversions or skeletal elaborations afford structurally distinct cyclopropyl variants.
RESUMO
Herein we describe the base-mediated [3 + 2] cycloaddition reaction of di/trifluoromethylated hydrazonoyl chlorides with fluorinated nitroalkenes. The reaction protocol provides a direct and facile strategy for the dual incorporation of a fluorine atom and fluoroalkyl group into pyrazole cores, thus allowing rapid access to a wide variety of densely functionalized 3-di/trifluoroalkyl-5-fluoropyrazoles in generally high yields with excellent regioselectivities. Furthermore, several drug-like 3-di/trifluoroalkyl-5-fluoropyrazoles have been synthesized, demonstrating potent inhibitory activities against cyclooxygenase 2 (COX-2).
RESUMO
Selective structural modification of amino acids and peptides is a central strategy in organic chemistry, chemical biology but also in pharmacology and material science. In this context, the formation of tetrazole rings, known to possess significant therapeutic properties, would expand the chemical space of unnatural amino acids but has received less attention. In this study, we demonstrated that the classic unimolecular Wolff rearrangement of α-amino acid-derived diazoketones could be replaced by a faster intermolecular cycloaddition reaction with aryldiazonium salts under identical practical conditions. This strategy provides an efficient synthetic platform that could transform proteinogenic α-amino acids into a plethora of unprecedented tetrazole-decorated amino acid derivatives with preservation of the stereocenters. Density functional theory studies shed some light on the reaction mechanism and provided information regarding the origins of the chemo- and regioselectivity. Furthermore, this diazo-cycloaddition protocol was applied to construct tetrazole-modified peptidomimetics and drug-like amino acid derivatives.
Assuntos
Aminoácidos , Prata , Aminoácidos/química , Reação de Cicloadição , Sais , Peptídeos , Tetrazóis/química , CatáliseRESUMO
Catalytic asymmetric hydrogenation of enamido phosphorus derivatives is one of the most efficient methods for the construction of chiral amino phosphorus products, among which the congested tetra-substituted substrates remains an unaddressed challenge. In this study, we utilize a commercially available Rh-Josiphos system for the efficient and stereoselective hydrogenation of a wide set of tetra-substituted cyclic ß-enamido phosphonates/phosphine oxides, thus enabling access to chiral ß-amino phosphorus compounds featuring two vicinal stereocenters. This protocol was broadly applicable to different ring systems possessing various phosphonate/phosphine oxide groups and further applied in the preparation of amino-phosphine ligands. DFT mechanistic explorations indicate that the C=C migratory insertion into RhIII -H bond could be the rate- and stereo-determining step. The origins of stereoselectivity are revealed through distortion/interaction analysis, which is primarily regulated by distinguished dispersion interactions and steric repulsions.
RESUMO
We report a photoredox platform for constructing styrenyl polyfluoro (hetero)arenes with branch selectivity by taking advantage of sulfinate as both a radical-relay precursor and a sacrificial nucleofuge. This protocol merges photoredox catalysis with radical-radical coupling and an elimination process in a one-pot operation and features good functional group tolerance, mild conditions, and a facile method to access polyfluoro (hetero)aryl derivatives of natural products and drugs.
RESUMO
Chiral heterocyclic compounds are needed for important medicinal applications. We report an in silico strategy for the biocatalytic synthesis of chiral N- and O-heterocycles via Baldwin cyclization modes of hydroxy- and amino-substituted epoxides and oxetanes using the limonene epoxide hydrolase from Rhodococcus erythropolis. This enzyme normally catalyzes hydrolysis with formation of vicinal diols. Firstly, the required shutdown of the undesired natural water-mediated ring-opening is achieved by rational mutagenesis of the active site. In silico enzyme design is then continued with generation of the improved mutants. These variants prove to be versatile catalysts for preparing chiral N- and O-heterocycles with up to 99% conversion, and enantiomeric ratios up to 99:1. Crystal structural data and computational modeling reveal that Baldwin-type cyclizations, catalyzed by the reprogrammed enzyme, are enabled by reshaping the active-site environment that directs the distal RHN and HO-substituents to be intramolecular nucleophiles.
Assuntos
Epóxido Hidrolases , Ciclização , Biocatálise , Epóxido Hidrolases/metabolismo , Limoneno , Catálise , EstereoisomerismoRESUMO
The application of abundant and inexpensive fluorine feedstock sources to synthesize fluorinated compounds is an appealing yet underexplored strategy. Here, we report a photocatalytic radical hydrodifluoromethylation of unactivated alkenes with an inexpensive industrial chemical, chlorodifluoromethane (ClCF2H, Freon-22). This protocol is realized by merging tertiary amine-ligated boryl radical-induced halogen atom transfer (XAT) with organophotoredox catalysis under blue light irradiation. A broad scope of readily accessible alkenes featuring a variety of functional groups and drug and natural product moieties could be selectively difluoromethylated with good efficiency in a metal-free manner. Combined experimental and computational studies suggest that the key XAT process of ClCF2H is both thermodynamically and kinetically favored over the hydrogen atom transfer pathway owing to the formation of a strong boron-chlorine (B-Cl) bond and the low-lying antibonding orbital of the carbon-chlorine (C-Cl) bond.
Assuntos
Alcenos , Boranos , Alcenos/química , Aminas , Cloro , Clorofluorcarbonetos , Clorofluorcarbonetos de Metano , HalogêniosRESUMO
Here we present a quadruple functionalization approach for the modular construction of fully substituted N1 -aryl 3-di/trifluoro-methyl-4/5-cyanopyrazole pharmacophores from readily available hydrazonyl chlorides and dicyanoalkenes. The realization of this [3+2] cycloaddition reaction hinges upon the employment of N-aryl di/trifluoromethyl nitrile imines as the 1,3-dipoles to bypass external synthetic steps and dicyanoalkenes as the dipolarophiles to tune the regioselectivity. This one-pot strategy offers access to a divergent library of cyano analogues of prevalent 3-di/trifluoromethyl pyrazole pharmacophores, among which several compounds have shown potent inhibitory activity towards cyclooxygenase 2 (COX-2) compared with marketed drug Celecoxib.
Assuntos
Iminas , Nitrilas , Reação de Cicloadição , PirazóisRESUMO
Here we report the design and synthesis of two new difluoro-diazoketone reagents (difluorophenylthiol diazoketone and difluorophenoxyl diazoketone) and their [3+2] cycloaddition reactions with aryldiazonium salts under silver catalysis conditions. This protocol enables regioselective access to a broad scope of difluorophenylthiol- and difluorophenoxyl-substituted tetrazole-carbinols in a one-pot operation. Further synthetic derivatizations including dephenylthiolation and unexpected phenylthiol group migration/fluorination allow the efficient preparation of α-difluoromethyl tetrazole-carbinols and α-trifluoromethyl tetrazole-thioethers.
RESUMO
A N-iodosuccinimide (NIS)-promoted [3 + 2] annulation reaction of aryldiazonium salts with guanidines has been developed for the construction of previously elusive 2-aryl-5-amino-2H-tetrazoles. This transformation takes advantage of readily available starting materials, proceeds under metal-free, mild, and robust conditions, and holds broad functional group compatibility. The utility of this protocol is further manifested via coupling, annulation, deamination, and denitrogenation derivatizations.
RESUMO
Triazines are an important class of six-membered aromatic heterocycles possessing three nitrogen atoms, resulting in three types of regio-isomers: 1,2,4-triazines (a-triazines), 1,2,3-triazines (v-triazines), and 1,3,5-triazines (s-triazines). Notably, the application of triazines as cyclic aza-dienes in inverse electron-demand Diels-Alder (IEDDA) cycloaddition reactions has been established as a unique and powerful method in N-heterocycle synthesis, natural product preparation, and bioorthogonal chemistry. In this review, we comprehensively summarize the advances in the construction of these triazines via annulation and ring-expansion reactions, especially emphasizing recent developments and challenges. The synthetic transformations of triazines are focused on IEDDA cycloaddition reactions, which have allowed access to a wide scope of heterocycles, including pyridines, carbolines, azepines, pyridazines, pyrazines, and pyrimidines. The utilization of triazine IEDDA reactions as key steps in natural product synthesis is also discussed. More importantly, a particular attention is paid on the bioorthogonal application of triazines in fast click ligation with various strained alkenes and alkynes, which opens a new opportunity for studying biomolecules in chemical biology.
Assuntos
Produtos Biológicos , Triazinas , Produtos Biológicos/química , Ciclização , Reação de Cicloadição , Elétrons , Triazinas/químicaRESUMO
A diethylzinc-promoted unconventional annulation reaction of 2,2,2-trifluorodiazoethane with 2H-azirines is described. This transformation involves two [3 + 2] cycloaddition steps and one dinitrogen extrusion process in one pot, thus giving a broad array of 3-trifluoromethyl pyrazolines in good yields with excellent diastereoselectivities. Further transformations provide facile access to 3-trifluoromethyl pyrazoles and 3,5-ditrifluoromethyl pyridazines with good efficiency.
RESUMO
A Et3N-triggered regioselective [3 + 2] cycloaddition reaction of 3-alkynoates with Seyferth-Gilbert reagent has been developed to furnish a series of trisubstituted pyrazole-3-phosphonates. A one-pot cycloaddition/alkylation sequence further offered access to the corresponding fully substituted pyrazoles.
Assuntos
Reação de Cicloadição , Alquilação , Indicadores e ReagentesRESUMO
The development of new synthetic strategies for the efficient construction of versatile pyrrole pharmacores, especially in an operationally simple and environmentally benign fashion, still remains a momentous yet challenging goal. Here, we report a KOAc-catalyzed double decarboxylative transannulation between readily accessible oxazolones and isoxazolidinediones. This transformation represents a new way for skeletal remodeling by utilizing CO2 moiety as traceless activating and directing groups in both reaction partners. The synthetic value is evidenced by the rapid preparation of a broad spectrum of highly functionalized 3-carbamoyl-4-aryl pyrroles in good to excellent yields with exclusive regio-control, including the important Atorvastatin core.