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Sulfoximines are increasingly incorporated in agrochemicals and pharmaceuticals, with the two enantiomers of chiral sulfoximines often having profoundly different binding interactions with biomolecules. Therefore, their application to drug discovery and development requires the challenging preparation of single enantiomers rather than racemic mixtures. Here, we report a general and fundamentally new asymmetric synthesis of sulfoximines. The first

To better understand the benzene alkylation with chloroaluminate ionic liquids (ILs) as catalyst, the interfacial properties between the benzene/butene binary reactants and chloroaluminate ILs with varying cation alky chain length and different anions were investigated using molecular dynamics (MD) simulations. The results indicate that ILs can obviously improve the interfacial width, solubility and diffusion of reactants compared to H2SO4. The longer alkyl chains of cations present a density enrichment at the interface and protrude into the binary reactants phase. Furthermore, the ILs consisting of 1-octyl-3-methylimidazolium cations ([Omim]+) and the stronger acidity heptachlorodialuminateanions ([Al2Cl7]–) are more beneficial to promote the interfacial width and facilitate the dissolution and diffusion of benzene in both the IL bulk and the interfacial region in comparison to the ones with shorter alkyl chains cations and weaker acidity anions. The information gives us a better guideline for the design of ILs for benzene alkylation.

Direct reductive amination (DRA) is one of the most efficient methods for amine synthesis. Herein we report a practical homogeneous DRA procedure utilizing iridium catalysis. Applying simple, readily available and inexpensive PPh3 and alike ligands at as low as 0.003 mol%, aldehydes and ketones reductively coupled with primary and secondary amines to efficiently form structurally and functionally diverse amine products, including a set of drugs and their late-stage manipulation. The reaction conditions were exceptionally mild and additive-free, and they tolerated oxygen, moisture, polar protic groups and multiple other functional groups. For targeted products, this methodology is versatile and could offer multiple synthetic routes in regard to the selection of starting materials. The 10 gram-scale synthesis further demonstrated the potential and promise of this procedure in practical amine synthesis.

The zinc (II) and cadmium (II)-salphen catalyzed α-alkylation of ketones with primary alcohols is reported. Various α-alkylated ketones were obtained in good yields through a borrowing hydrogen strategy by using 1 % of catalysts and a catalytic amount of NaOH (10 mol%) as the base under air atmosphere. All synthesized compounds were characteized by 1H and 13C NMR.

We report an efficient alkyl transfer strategy for the direct β-alkylation of chalcones using commercially available alkyl bromides as alkyl reagents. In this transformation, the

Side-chain alkylation of toluene with methanol is a green pathway to realize the one-step production of styrene under mild conditions, but the low selectivity of styrene is difficult to be improved with by-products of ethylbenzene and xylene. In this study, a new way is introduced to improve the catalytic performance by means of assisting basic compounds as co-catalysts during the toluene side-chain alkylation with methanol to styrene. As a result, high activity of side-chain alkylation appears over the basic Cs-modified zeolite catalysts prepared by ion exchange and impregnation methods. This high performance should be mainly attributed to two co-catalysis actions: (1) the promotion of basic compounds for methanol dehydrogenation to formaldehyde as the intermediate for side-chain alkylation; (2) the suppression of the styrene transfer hydrogenation on basic Cs-modified zeolites to avoid the formation of ethylbenzene. Especially for Cs2O/CsX-ex catalyst, the addition of 2 mol% 2-picoline in reaction mixture could achieve both 12.3% toluene conversion and 84.1% styrene selectivity. Whereas the higher concentration of 2-picoline (>6 mol%) caused an inhibition to the catalytic activity because the excessive basic compound poisoned the combined acid-base pathway required for the side-chain alkylation process. In addition, two possible side-chain alkylation reaction routes on Cs-modified zeolite under the different 2-picoline absorption were described.

We have developed a general process for the formation of α-arylethers via the Pd-catalyzed arylation of secondary α-alkoxytricyclohexylstannanes. Incorporation of cyclohexyl spectator ligands into the alkylstannane and the use of the electron-deficient ligand JackiePhos (1) are critical for achieving selective alkyl transfer in this process. This system circumvents the need for a coordinating/directing oxygen-protecting group to promote selective alkyl transfer and enables α-tetrahydropyran, α-tetrahydrofuran, and open-chain secondary α-alkoxy groups to be employed efficiently in Pd-catalyzed Stille reactions with a broad range of aryl electrophiles. These findings suggest that selective transmetalation of a single marginally activated secondary alkyl unit from Sn to Pd should be broadly achievable provided that unactivated secondary alkyl ligands comprise the other three groups of the tetraalkylstannane.

The first synthetic strategy for nonsymmetrical 3,3″-biflavones is described. To this end, a novel visible-light iridium-catalyzed radical C-3 alkylation of flavones with

The straightforward and rapid incorporation of a thiazolidinedione scaffold into prefunctionalized (hetero)aromatic compounds is in demand for the development of antidiabetic glitazones and other pharmaceuticals. Herein, we report the unprecedented N- and O-directed C-H alkylation of various (hetero)arenes with methylene thiazolidinediones under rhodium(III) catalysis. The applicability of the developed protocol in challenging contexts is exhibited by the late-stage installation of a methylene thiazolidinedione moiety on the C-H bond of commercially available drug molecules. Combined mechanistic investigations aided the elucidation of a plausible reaction mechanism.

A cascade Michael addition/alkylation reaction between 3-chlorooxindoles and α-cyano chalcones catalyzed using a multifunctional quinine-derived aminoindanol-thiourea substance was investigated. A series of spirooxindoles incorporating a densely substituted cyclopropane motif were efficiently obtained with moderate to excellent diastereo- and enantioselectivity and further transformed to products with versatile structural diversity. Density functional theory (DFT) calculations indicated that the tentative intramolecular hydrogen bonds in the chiral catalyst were crucial for the stereocontrol.

Biologically important 4-alkylsyncarpic acids, which resemble the core structure of many natural products, were synthesized in one-pot through the organocatalytic three-component reductive alkylation with excellent yields and

N-alkylation of amines is an important catalytic reaction in synthetic chemistry. Herein, we report a simple strategy for the N-alkylation of 2-aminopyridines with 1,2-diketones using BF

Herein, a novel [Rh]

A chiral phosphine oxide-ligated Ni-Al bimetallic catalyst was used to realize an enantioselective C2-H alkylation of pyridines without the need of a C2-block. A wide range of pyridines, including unsubstituted pyridine, C3, C4, and C2-substituted pyridines, and even complex pyridine-containing bioactive molecules are well compatible with the reaction, providing up to 81% yield and up to 97% ee.

A palladium(phosphinoxazoline) catalyzed method for asymmetric allylic alkylation of α-aryl-α-fluoroacetonitriles is introduced. This reaction achieves C-C bond formation and incorporation of two adjacent chirality centers with moderate to good yields, high enantioselectivities, and up to 15:1

ConspectusCyclometalated π-allyliridium

Chitosan exhibits moderate antimicrobial properties. Here, we enhanced the antimicrobial properties of chitosan through alkylation and chlorination and evaluated the effect of alkylation on chitosan's hydrophobicity, bacterial attachment, chlorination, biocidal property, and stability. First, chitosan films were prepared through casting and were then immersed in a hexanal solution of different concentrations. The aldehyde groups of hexanal reacted with the amino group in chitosan through a Schiff base reaction. Next, the hexanal-modified chitosan films were soaked in 10 % bleach to form N-halamine. The results demonstrated that the surface became more hydrophobic, and chitosan films with increased hexanal-grafting concentrations exhibited less bacterial attachment. However, the degree of chlorination decreased as the degree of alkylation increased, further reducing the diameter of the zone of inhibition. Nevertheless, all chlorinated samples could kill ~5 log of Staphylococcus aureus and Escherichia coli within 30 min. Unlike previous results for chlorinated chitosan, in this study, alkylation before chlorination enhanced antibacterial properties and bactericidal ability and decelerated the degradation of chlorinated samples. The results of a systematic evaluation indicated that a hexanal-grafting concentration of approximately 80 mM maintains the equilibrium of the various properties of chitosan. Alkylated and chlorinated chitosan has considerable potential application as mask filter layers.

Basic amines are key elements of many biologically active natural products and pharmaceuticals. Given their inherent reactivity, it is often necessary to protect basic amines during target-directed synthesis, which results in wasteful protection/deprotection sequences. We report a step-economical approach enabling the protection of secondary amines as carbamates prior to their conversion to tertiary amines via the formal extrusion of CO

The possibility to use glycerol carbonate (GlyC) as an innovative alkylating agent for phenolic compounds in solventless conditions and in the presence of a catalytic amount of both homogeneous and heterogeneous bases is herein described. In particular, the peculiar, polyfunctional structure of GlyC allows one to obtain the formation not only of the mono-phenoxy-1,2-propanediol (MPP) analogue but also of 1,3-diphenoxy-2-propanol (DPP), the latter being elusive using the more traditional, toxic, and carcinogenic reagents such as glycidol and/or 3-chloro-1,2-propandiol. The production of DPP is indeed possible due to the in situ formation of a reactive intermediate, 4-(phenoxy)methyl-1,3-dioxolane-2-one (PhOGlyC), which may undergo a consecutive nucleophilic attack of a phenolate, leading to the selective formation of the disubstituted product. This reaction is nonetheless in competition with PhOGlyC decarboxylation that finally limits DPP yield up to 20%, with an MPP yield up to roughly 60% in the optimized conditions (atmospheric pressure, 140 degrees C, 5 h using Cs2CO3 as the basic catalyst) starting directly from a GlyC/phenolic mixture. For this reason, a multistep synthetic strategy has also been developed, first by obtaining the quantitative formation and isolation of the PhOGlyC intermediate and then by promoting the consecutive reaction with phenol, in this way obtaining a DPP yield of 66% after only 1 h of reaction at 170 degrees C. The obtained phenyl glyceryl ethers are interesting drugs scaffolds (i.e., guaifenesin, mephenesin), intermediates in the preparation of active pharmaceutical ingredients (e.g., chlorphenesin carbamate, methocarbamol), and hydrotropic solvents; preliminary evaluations of MPP and DPP biodegradability and use as alternative surfactants have also been described in this paper.

A Rh-catalyzed weak chelation-guided C4-alkylation of indoles has been accomplished using cyclopropanols as an alkylating agent via the cascade C-H and C-C bond activation. The substrate scope, functional group tolerance, and late-stage mutation of drug molecules are the important practical features.

Fluorinated amino acids play an important role in the field of peptide and protein engineering. Although numerous syntheses have been published in recent decades, strategies that allow routine access to fluorinated amino acids on a gram-scale have been poorly described. Furthermore, the described pathways that gain fluorinated amino acids are based on different synthetic strategies, making a uniform approach that uses similar starting materials highly beneficial. Chiral Ni(II) complexes were introduced as powerful tools in the synthesis of noncanonical amino acids. In this work, we present a strategy for the synthesis of a diverse range of fluorinated amino acids based on the corresponding Ni(II) complex from which the products can be obtained in enantiopure form (99% ee) on a gram-scale. In addition, we describe an optimized procedure for the synthesis of alkyl iodide building blocks that are required for the alkylation reactions with the corresponding Ni(II) complex. Finally, we characterized the synthesized fluorinated amino acids with regard to their hydrophobicity and α-helix propensity.

There are few enantioconvergent reactions in which racemic substrates bearing multiple stereochemical features are converted into products with high levels of diastereo- and enantiocontrol. Here, we disclose a process for the highly enantio- and diastereoselective syntheses of medium ring lactams via an intramolecular counterion-directed C-alkylation reaction. The treatment of racemic biaryl anilides that exist as a complex mixture of enantiomers and diastereoisomeric conformers by virtue of multiple axes of restricted rotation with a quinidine-derived ammonium salt under basic conditions affords medium ring lactams bearing elements of both axial and point chirality via an enolate-driven configurational relaxation process. Thermal equilibration of the syn- and anti-product diasteroisomers has demonstrated that the barriers to bowl inversion are >124 kJ mol-1. We propose that the chiral ammonium salt differentiates between a complex and rapidly equilibrating mixture of enolate and rotational isomers, ultimately leading to highly enantioselective alkylative ring closure. This dynamic and enantioconvergent process offers an operationally simple approach to the synthesis of valuable chiral medium ring lactams for which there are few catalytic and enantioselective approaches.

In the present study, a series of ordered nanostructured KIT-6 silica, functionalized with different numbers of sulfonic groups (–SO3H) introduced by grafting or co-condensation, were synthesized. The obtained samples were subjected to thorough physicochemical characterization using X-ray diffraction, transmission electron microscopy, low temperature nitrogen sorption, infrared spectroscopy and elemental analysis. It has been observed that the amount of the used functional group precursor clearly affects the structural and textural parameters of the studied materials synthesized by co-condensation. On the other hand, the samples modified by grafting, irrespective of the number of the introduced –SO3H groups, exhibit a stable mesoporous structure with Ia3d symmetry, characteristic of KIT-6 materials. The developed synthesis procedures yielded potential solid acid catalysts, which were used in the test catalytic reactions: Friedel-Crafts alkylation, fatty acid esterification and Pechmann condensation. Both the developed synthesis algorithm and the catalytic reaction procedures comprised elements of "green chemistry", as the transformation of the functional groups precursor (–SH to –SO3H) took place in the presence of H2O2, an oxidant considered to be environmentally friendly, while the catalytic reactions were carried out without solvents and under microwave-assisted conditions, which allowed a significant shortening of the reaction time.

The structure determination of the 30-membered cyclodepsipeptide decatransin was demonstrated on the basis of total synthesis. Both (

A Ru(II)-catalyzed decarbonylative alkylation and annulation of salicylaldehydes and 2-aminobenzaldehydes with iodonium ylides has been developed for the synthesis of dibenzo[

Histone deacetylases (HDACs) play an essential role in the transcriptional regulation of cells through the deacetylation of nuclear histone and non-histone proteins and are promising therapeutic targets for the treatment of various diseases. Here, the synthesis of new compounds in which a hydroxamic acid residue is attached to differently substituted pyrimidine rings via a methylene group bridge of varying length as potential HDAC inhibitors is described. The target compounds were obtained by alkylation of 2-(alkylthio)pyrimidin-4(3H)-ones with ethyl 2-bromoethanoate, ethyl 4-bromobutanoate, or methyl 6-bromohexanoate followed by aminolysis of the obtained esters with hydroxylamine. Oxidation of the 2-methylthio group to the methylsulfonyl group and following treatment with amines resulted in the formation of the corresponding 2-amino-substituted derivatives, the ester group of which reacted with hydroxylamine to give the corresponding hydroxamic acids. The synthesized hydroxamic acids were tested as inhibitors of the HDAC4 and HDAC8 isoforms. Among the synthesized pyrimidine-based hydroxamic acids N-hydroxy-6-[6-methyl-2-(methylthio)-5-propylpyrimidin-4-yloxy]hexanamide was found to be the most potent inhibitor of both the HDAC4 and HDAC8 isoforms, with an IC50 of 16.6 µM and 1.2 µM, respectively.

As saturated heterocyclic building blocks become increasingly popular in medicinal chemistry and drug discovery programs, expansion of the synthetic toolkit to novel stereofunctionalized heterocycles is a priority. Herein, we report the development of a palladium-catalyzed decarboxylative asymmetric allylic alkylation reaction to access a broad range of enantioenriched α-difunctionalized 5- and 6-membered sulfones from easily accessible racemic starting materials. The allylic alkylation step was found to occur with high levels of enantioselectivity as a result of a palladium-mediated dynamic kinetic resolution of

Background: Bifunctional ionic liquid [BIL] was found to be a highly effective catalyst for ether synthesis without any inorganic base or solvent. Using this protocol, different aryl substitutions were reacted with different phenols in good to excellent yields. The BIL is reusable without any loss in catalytic activity for nine consecutive cycles. The Williamson reaction is a convenient renovation in fine chemical synthesis since the ethers are important in both bulk and fine industrial chemicals preparation and academic applications. Method: The mixture of the phenol (1mmol), alcohol (1.2 mmol), and BIL ionic liquid (0.3 mol%) was added to a round-bottomed flask (100 mL) with continuous stirring for 1 hour. Objective: The aim of this study is to highlight the use of BIL to synthesize mixed ethers using substituted phenols and to study the reusability in the next cycle. Results: The products obtained were phenol and substituted phenols containing withdrawing substituents in respectable yields. However, the reactions involving substituted phenols containing electron-donating groups often afford the corresponding products in low yields. Conclusion: BIL is found to be an effective catalyst in the etherification of various unsymmetrical ethers under mild conditions. Bifunctional ionic liquid as a solvent and catalyst will show real rewards by providing a ‘green’ method with the safer procedure, less reaction time periods, mild conditions, easy separation, and ionic liquid recycle.

A systematic study on the use of noble metals (Pd, Pt, Au) supported on titanate nanotubes (NT-Ti) for selectively producing BTX and p-cymene from waste tire pyrolysis is provided here. All the materials were characterized for chemical, textural and structural properties using a range of analytical techniques. The M/NT-Ti (M: Pd, Pt, or Au) catalysts exhibit low nanoparticle sizes (1.8 Pt ≈ Au > support > non-catalyst. The Py-GC/MS suggest that the catalysts participate in the secondary reactions of dealkylation, dehydrogenation, isomerization, aromatization, and cyclization leading to a higher formation of BTX than the uncatalyzed reaction. Finally, a comprehensive reaction pathway describing the catalytic pyrolysis of WT over Pd/NT-Ti was proposed by studying the catalytic pyrolysis of individual polymers constituting the waste tires, and D, L -Limonene.

Hydroaminoalkylation is a powerful, atom-economic catalytic reaction for the reaction of amines with alkenes and alkynes. This C-H functionalization reaction allows for the atom-economic alkylation of amines using simple alkenes or alkynes as the alkylating agents. This transformation has significant potential for transformative approaches in the pharmaceutical, agrochemical, and fine chemical industries in the preparation of selectively substituted amines and

Herein, we report the first total synthesis of pentaketide ansamycin microansamycin H. Key to our success was the

We report herein an asymmetric C-H dehydrogenative allylic alkylation by a synergistic catalytic system involving a chiral primary amine, a photoredox catalyst, and a cobaloxime cocatalyst. The ternary catalytic system enables the coupling of β-ketocarbonyls and olefins with good yields and high enantioselectivities. Mechanism studies disclosed a cooperative radical addition process with a chiral α-imino radical and Co(II)-metalloradical wherein the chiral primary aminocatalyst and the cobaloxime catalyst work in concert to control the stereoinduction.

"Click" reactions have revolutionized research in many areas of science. However, a disadvantage of the high stability of the Click product is that identifying simple treatments for cleanly dissociating the latter under the same guiding principles, i.e., a "Clip" reaction, remains a challenge. This study demonstrates that electron-deficient alkynes, conveniently installed on methionine residues, can participate in well-known Click (nucleophilic thiol-allene addition) and subsequent Clip reactions (radical thiol-ene addition). To illustrate this concept, a variety of bioconjugates (peptide-peptide; peptide-fluorophore; peptide-polymer; and peptide-protein) were prepared. Interestingly, the Clip reaction of these bioconjugates releases the original peptides concurrent with regeneration of their unmodified methionine residue, in minutes. Moreover, the conjugates demonstrate substantial stability toward endogenous levels of reactive species in bacteria, illustrating the potential for this chemistry in the biosciences. The reaction conditions employed in the Click and Clip steps are compatible with the preservation of the integrity of biomolecules/fluorophores and involve readily accessible reagents and the natural functional groups on peptides/proteins.

Lanthanum-containing (LaX) and cerium-containing X zeolites (CeX) were prepared by a double-exchange, double-calcination method. By changing the calcination atmospheres between nitrogen and air, the CeIV contents in CeX zeolites were adjusted and their impacts on physicochemical properties and catalytic performance in isobutane alkylation were established. The crystallinity of CeX zeolite was found to be negative correlated with the CeIV content. This is believed to be due to the water formed during the oxidation of CeIII, which facilitates the framework dealumination. As a consequence, calcining in air results in a great elimination of strong Bronsted acid sites while under nitrogen protection, this phenomenon was mostly hindered and the sample's acidity was preserved. When tested in a continuously flowed slurry reactor, the catalyst lifetime for isobutane alkylation was found to be linearly related with the strong Bronsted acid concentration. In addition, Ce3+ was found more benefit for the hydride transfer compared with La3+, which is ascribed to the stronger polarization effect on the C-H bond of isobutane. Moreover, the decline of hydride transfer activity can be slowed down by the catalytic cracking of the bulky molecules. Based on the product distribution, a new catalytic cycle of dimethylhexanes (DMHs) involving a direct formation of isobutene rather than tert-butyl carbocation was proposed in isobutane alkylation.

Progress toward an asymmetric synthesis of euphanes is described. A C14-desmethyl euphane system possessing five differentially substituted and electronically distinct alkenes has been prepared. The route employed is based on sequential metallacycle-mediated annulative cross-coupling, double asymmetric Brønsted acid mediated intramolecular Friedel-Crafts alkylation, and an oxidative rearrangement to establish the requisite C10 quaternary center. These studies have also led to the discovery of a novel euphane-based modulator of the Liver X Receptor.

Molecular electrophotocatalysis has emerged as a powerful strategy for the development of sustainable synthetic protocols. With the proof-of-concept, we exploited a versatile electrophotocatalytic deaminative alkylation approach. Mechanistic investigation indicated that in situ recycling of the alkyl radicals was the key point. Notably, ligand modification and late-stage functionalization of pharmaceuticals were also established, highlighting its feasibility in practical utilization.

A stereodivergent Pd/Cu catalyst system for asymmetric desymmetric alkylation of allylic geminal dicarboxylates has been developed, which was successfully applied to the asymmetric synthesis of β-h...

Cyclohexylphenol (CHP) is a high added-value chemical, extensively used for the preparation of dyes, resins and biocides. This molecule is currently synthetized by phenol alkylation with cyclohexene/cyclohexanol using highly polluting mineral Bronsted acids as catalysts. The present contribution reports the one-pot production of cyclohexylphenol via hydroalkylation, using phenol as the only organic reactant, over a number of bifunctional catalysts consisting of Co2P (5 wt.% Co) supported over different zeolites (ferrierite, mordenite, beta and MCM-22). Phenol conversion increased in the order: Co2P/Mordenite (30%)

A method for the preparation of 3-alkylated spiro[4.5]trienones

Compounds rich in sp(3)-hybridized carbons are desirable in drug discovery. Nickel-catalyzed hydrocarbonation of alkenes is a potentially efficient method to synthesize these compounds. By using abundant, readily available, and stable alkenes as pro-nucleophiles, these reactions can have broad scope and high functional group tolerance. However, this methodology is still in an early stage of development, as the first efficient examples were reported only in 2016. Herein, we summarize the progress of this emerging field, with an emphasis on enantioselective reactions. We highlight major developments, critically discuss a wide range of possible mechanisms, and offer our perspective of the state and challenges of the field. We hope this Perspective will stimulate future works in this area, making the methodology widely applicable in organic synthesis.

3-Alkyl-3-hydroxyoxindoles, a subclass of oxindole products, have antioxidant, neuroprotective, anticancer, and anti-HIV activities. In this study, a green and economical protocol for the synthesis of 3-alkyl-3-hydroxyoxindoles is developed for the first time via α-alkylation-α-hydroxylation of oxindole with benzyl alcohols without using any transition-metal catalysts in yields of 29-93%.

Herein, we report an on-DNA photoredox-mediated deaminative alkylation method for diversifying DNA-tagged acrylamide substrate with amine-derived radicals. The radicals can be conveniently generated from sterically hindered primary amines, and the deaminative alkylation can tolerate a broad array of radical precursors. Furthermore, the methodology is applicable to Boc-protected diamines, free amino acids, and aryl halides, which bear functional groups enabling additional rounds of diversification. The method is believed to offer a high potential for constructing DNA-encoded libraries, as was demonstrated by the production of a mock library in a 2 × 3 matrix format and confirmation of DNA stability by UPLC-MS and qPCR experiments.

An efficient photocatalytic alkylation/cyclization of allylic amide with N-hydroxyphthalimide ester has been developed. The transformation is taken advantage of alkyl radicals to attack allylic amide with the assist of inexpensive rose bengal as photocatalyst to prepare a series of alkyl substituted oxazolines in moderate to excellent yields. High regioselectivity, operational safety, mild conditions and excellent substrate generality give this protocol broad application prospects.

Herein, an efficient molecular oxygen-mediated method for the selective hydroxyalkylation and alkylation of quinoxalin-2(1H)-ones with alkylboronic acids under transition-metal free conditions has been developed. This strategy demonstrates a broad scope of quinoxalin-2(1H)-ones and alkylboronic acids, giving 3-hydroxyalkylquinoxalin-2(1H)-ones and 3-alkylquinoxalin-2(1H)-ones in moderate-to-good yield. Control experiments reveal that a radical pathway is involved.

The development of innovative strategies and methods to provide natural product-like macrocycles not accessible by biosynthesis, but endowed with novel bioactivities and simplified structure, is highly desirable. Inspired by the key scaffolds of rapamycin and FR252921, herein, we report a Rh(III)-catalyzed C–H alkylation macrocyclization, which enables access to CF3-substituted macrolides. DFT calculations reveal that the chemoselectivity between C–H alkylation and olefination macrocyclization was highly controllable. Moreover, the unique CF3-substituted macrolides showed potent anti-inflammation activities against TNF-α, IL-6 and CCL2 mRNA expression.

Alcohols and carboxylic acids are among the most commercially abundant, synthetically versatile, and operationally convenient functional groups in organic chemistry. Under visible light photoredox catalysis, these native synthetic handles readily undergo radical activation, and the resulting open-shell intermediates can subsequently participate in transition metal catalysis. In this report, we describe the C(sp(3))–C(sp(3)) cross-coupling of alcohols and carboxylic acids through the dual combination of N-heterocyclic carbene (NHC)-mediated deoxygenation and hypervalent iodine-mediated decarboxylation. This mild and practical Nicatalyzed radical-coupling protocol was employed to prepare a wide array of alkyl–alkyl cross-coupled products, including highly congested quaternary carbon centers from the corresponding tertiary alcohols or tertiary carboxylic acids. We demonstrate the synthetic applications of this methodology to alcohol C(1)-alkylation and formal homologation, as well as to the late-stage functionalization of drugs, natural products, and biomolecules.

Reported herein is a sustainable approach for a regioselective, Rh(III)-catalyzed C(7)-H alkylation of 8-aminoquinolines via metal carbene migratory insertion. This transformation displays a high functional group tolerance and exquisite site selectivity to afford the C-7 alkylated products. These products are derivatized to afford π-extended angular pyrroloquinolines, one of which (

N6-methyl adenosine (m6A) is an eminent epigenetic mark in mRNAs that affects a broad range of biological functions in diverse species. However, the chemically inert methyl group prevents a direct labeling of this modification for subsequent detection and sequencing. Therefore, most current approaches for the labeling of m6A still have limitations of relying on the utilization of corresponding methyltransferases, which resulted in the lacking of efficiency. Here we present an approach which selectively alkylated the N6-formyl adenosine (f6A), the key intermediate during chemical oxidation of m6A, with an alkyne functionality that can be further labeled with click reactions. This covalent labeling approach will be able to facilitate in the affinity purification, detection and genome-wide profiling studies.

The ability to differentiate and selectively activate remote C–H bonds represents a perennial challenge in the field of C–H activation. Since its first report in 2012, a now-established “directing template” (DT) approach remains demonstrably effective for the functionalization of remote C–H bonds. As selectivity is hypothesized to be principally determined by the optimal positioning of the reactive catalyst to a target C–H bond, a DT’s spatial factors are particularly important towards achieving high selectivity, though a systematic study on its requisite factors remain unelucidated. Through an in-depth analysis of 119 structurally unique published remote-DTs, this report summarizes the key factors that are central towards achieving high selectivity at defined aryl positions, which are experimentally corroborated through the development of new aliphatic meta and para-selective DTs for electronically unbiased arenes. These empirical rules—which summarize key distance and geometric factors—are expected to be useful tools for the future development of site-selective arene C–H activation, as well as other reactions that rely on covalent/non-covalent DT-mediated remote regioselection.

ispartof: JOURNAL OF CATALYSIS vol:406 pages:206-212 status: published