Carbocation Intermediates Research Articles

Confinement Effects in Catalysis: Steering the Product Selectivity in Cannabidiol Isomerization by the Resorcinarene Supramolecular Capsule

AbstractThe supramolecular hydrogen‐bonded self‐assembled resorcinarene hexameric capsule promotes the ring closing isomerization of cannabidiol through encapsulation of the intermediate carbocation species formed by protonation with HCl. The confinement effect imparted by the capsule steers product selectivity towards the uncommon products Δ8‐iso‐THC, Δ4(8)‐iso‐THC, together with the hydrated 8‐Hydroxy‐iso‐THC.

Access of arylmethanes via iridium-catalyzed deoxygenative cross-coupling of aryl ketones with anilines/phenols

Construction of arylmethanes is one of the forefronts and significant subjects in the field of organic synthesis due to the prevalence of this motifs in pharmaceuticals and biological compounds. Herein, an iridium-catalyzed deoxygenative cross-coupling of aryl ketones with anilines/phenols was established to synthesize diverse collections of arylmethanes. This process generates benzyl carbocationic intermediates from a wide range of aryl ketones, which were captured with anilines/phenols to access the corresponding arylmethanes under mild conditions. The fluorene compounds were also successfully afforded using ortho-substituted aryl ketones as inputs via intermolecular deoxygenative cross-coupling. This method is viable for applications in cross-coupling of complex bioactive molecules and drugs by this iridium-catalyzed deoxygenative cross-coupling process.

Chemical diversity in angiosperms - monoterpene synthases control complex reactions that provide the precursors for ecologically and commercially important monoterpenoids.

Monoterpene synthases (MTSs) catalyze the first committed step in the biosynthesis of monoterpenoids, a class of specialized metabolites with particularly high chemical diversity in angiosperms. In addition to accomplishing a rate enhancement, these enzymes manage the formation and turnover of highly reactive carbocation intermediates formed from a prenyl diphosphate substrate. At each step along the reaction path, a cationic intermediate can be subject to cyclization, migration of a proton, hydride, or alkyl group, or quenching to terminate the sequence. However, enzymatic control of ligand folding, stabilization of specific intermediates, and defined quenching chemistry can maintain the specificity for forming a signature product. This review article will discuss our current understanding of how angiosperm MTSs control the reaction environment. Such knowledge allows inferences about the origin and regulation of chemical diversity, which is pertinent for appreciating the role of monoterpenoids in plant ecology but also for aiding commercial efforts that harness the accumulation of these specialized metabolites for the food, cosmetic, and pharmaceutical industries.

Development of a Two-Photon-Responsive Chromophore, 2-(p-Aminophenyl)-5,6-dimethoxy-1-(hydroxyinden-3-yl)methyl Derivative, as a Photoremovable Protecting Group.

Photoremovable protecting groups (PPGs) are powerful tools that are widely used to investigate biological events in cells. An important requirement for PPGs is the efficient release of bioactive molecules by using visible to near-infrared light in the biological window (650-1350 nm). In this study, we report a new two-photon (2P)-responsive PPG, 2-(p-aminophenyl)-5,6-dimethoxy-1-(hydroxyinden-3-yl)methyl, with a donor-π-donor cyclic stilbene structure. The 2P cross section was approximately 40-50 GM at ∼700 nm. The quantum yield of the uncaging process of caged benzoate was greater than 0.7, demonstrating that the 2P uncaging efficiency was approximately 30 GM at around 700 nm. This newly developed 2P-responsive chromophore can be used in future biological experiments. The mechanism of the photo-uncaging reaction via the carbocation intermediate was elucidated using transient absorption spectroscopy and product analysis.

Unraveling Spatially Dependent Hydrophilicity and Reactivity of Confined Carbocation Intermediates during Methanol Conversion over ZSM-5 Zeolite.

Carbocations play a pivotal role as reactive intermediates in zeolite-catalyzed methanol-to-hydrocarbon (MTH) transformations. However, the interaction between carbocations and water vapor and its subsequent effects on catalytic performance remain poorly understood. Using micro-magnetic resonance imaging (μMRI) and solid-state NMR techniques, this work investigates the hydrophilic behavior of cyclopentenyl cations within ZSM-5 pores under vapor conditions. We show that the polar cationic center of cyclopentenyl cations readily initiates water nucleus formation through water molecule capture. This leads to an inhomogeneous water adsorption gradient along the axial positions of zeolite, correlating with the spatial distribution of carbocation concentrations. The adsorbed water promotes deprotonation and aromatization of cyclopentenyl cations, significantly enhancing the aromatic product selectivity in MTH catalysis. These results reveal the important influence of adsorbed water in modulating the carbocation reactivity within confined zeolite pores.

Electrophilic Activation of S-Si Reagents by Silylium Ions for Their Regio- and Diastereoselective Addition Across C-C Multiple Bonds.

A regioselective silylium-ion-promoted thiosilylation of internal C-C triple bonds with control over the double bond geometry is described. Both a C(sp2)-S and a C(sp2)-Si bond are formed with a trans relationship in this two-component reaction of an alkyne and a thiosilane. The resulting orthogonally functionalized C-C double bond can be chemoselectively defunctionalized or further processed by cross-coupling reactions with the alkene configuration retained. The procedure is also applicable to the regio- and diastereoselective thiosilylation of terminal allenes to arrive at allylic thioethers containing a vinylsilane unit. These reactions involve the electrophilic activation of the S-Si reagent, both a silylated thiophenol and even alkylthiol derivative, by an in situ-generated carbocation intermediate. The catalytic cycle is maintained by a bissilylated aryl- or alkylsulfonium ion as a shuttle for the cationic silicon electrophile. Its independent preparation and structural characterization by X-ray diffraction are also reported.

Structure-Based Engineering of a Sesquiterpene Cyclase to Generate an Alcohol Product: Conversion of epi-Isozizaene Synthase into α-Bisabolol Synthase.

The sesquiterpene cyclase epi-isozizaene synthase (EIZS) from Streptomyces coelicolor catalyzes the metal-dependent conversion of farnesyl diphosphate (FPP) into the complex tricyclic product epi-isozizaene. This remarkable transformation is governed by an active site contour that serves as a template for catalysis, directing the conformations of multiple carbocation intermediates leading to the final product. Mutagenesis of residues defining the active site contour remolds its three-dimensional shape and reprograms the cyclization cascade to generate alternative cyclization products. In some cases, mutagenesis enables alternative chemistry to quench carbocation intermediates, e.g., through hydroxylation. Here, we combine structural and biochemical data from previously characterized EIZS mutants to design and prepare F95S-F198S EIZS, which converts EIZS into an α-bisabolol synthase with moderate fidelity (65% at 18 °C, 74% at 4 °C). We report the complete biochemical characterization of this double mutant as well as the 1.47 Å resolution X-ray crystal structure of its complex with three Mg2+ ions, inorganic pyrophosphate, and the benzyltriethylammonium cation, which partially mimics a carbocation intermediate. Most notably, the two mutations together create an active site contour that stabilizes the bisabolyl carbocation intermediate and positions a water molecule for the hydroxylation reaction. Structural comparison with a naturally occurring α-bisabolol synthase reveals common active site features that direct α-bisabolol generation. In showing that EIZS can be redesigned to generate a sesquiterpene alcohol product instead of a sesquiterpene hydrocarbon product, we have expanded the potential of EIZS as a platform for the development of designer cyclases that could be utilized in synthetic biology applications.

Iodine‐Catalyzed Cascade Reaction of 2‐Styrylbenzaldehydes with Indoles in the Synthesis of 1H‐Indenes via 4π‐Electrocyclization

AbstractA cascade reaction between 2‐styrylbenzaldehydes and indoles has been developed for the synthesis of 1H‐indenes. An iodine‐catalyzed nucleophilic addition of indoles to an aldehyde group of 2‐styrylbenzaldehydes leads to the formation of carbocation intermediates that undergo 4π‐electrocyclization to give indenes with a trisubstituted double bond. These indenes are transformed into thermodynamically more stable products with a fully substituted double bond under the reaction conditions. Minor quantities of indolylbenzo[b]carbazoles are also produced as by‐products.

Accessing Medium-Sized Rings via Vinyl Carbocation Intermediates.

Medium-sized rings (8-11-membered cycles) are often more challenging to synthesize than smaller rings (5-7-membered cycles) due to ring strain. Herein, we report a catalytic method for forming 8- and 9-membered rings that proceeds via the intramolecular Friedel-Crafts reactions of vinyl carbocation intermediates. These reactive species are generated catalytically through the ionization of vinyl toluenesulfonates by a Lewis acidic lithium cation-weakly coordinating anion salt.

Synthesis of dioxapropellanes using Mn(III)-based oxidative tandem cyclization of tetracarbonyl compounds with diarylethenes

Abstract The Mn(III)-based oxidation of tetracarbonyl compounds with 1,1-diarylethenes formed dioxapropellanes. The use of methylenebis(3-hydroxycyclohex-2-en-1-one)s as a tetracarbonyl compound led to the production of 3,4,5,6,7,9-hexahydro-8H-4a,9a-(epoxyethano)xanthene-1,8(2H)-diones in good yields. Although the reaction competed with self-cyclization to form 3,5,6,7-tetrahydro-4H-spiro[benzofuran-2,1′-cyclohexane]-2′,4,6′-triones, it could be controlled by adding the co-solvent formic acid at room temperature. The reactions of alkyl- and aryl-substituted methylenebis(3-hydroxycyclohex-2-en-1-one)s resulted in the corresponding dioxapropellanes as a diastereomixture. The formation of diastereomers is explained by the steric hindrance of the intermediate carbocations during tandem cyclization. The reactions using 2-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)butane-1,4-diones and 2,2′-methylenebis(3-hydroxycyclopent-2-en-1-one)s also produced the corresponding dioxapropellanes. The structure determination of the products and the reaction pathway for the formation of dioxapropellanes are discussed.

Reactivity of Frustrated Lewis Pair: Carbocation versus Radical Intermediates.

Recent reports of radical formation within frustrated Lewis pairs (FLPs) suggested that single-electron transfer (SET) could play an important role in their chemistry especially for C-C coupling. In sharp contrast, our extensive dispersion-corrected DFT calculations show that although reactive benzhydryl radical along with phosphine radical cation species can be kinetically generated from bulky phosphines and benzhydryl cation, direct P-C hetero-coupling may lead to bulky phosphonium cation as reactive carbocation transfer reagents to styrene substrates, which is kinetically much more favorable than the recently proposed radical C-C coupling between benzhydryl radical and styrene. Similarly, meta-stable radical cation Mes3 P+ ⋅ salt is also kinetically accessible via SET reactions of Mes3 P and B(C6 F5 )3 with 0.5 equivalent of p-O2 C6 Cl4 .

Crosslinking Mechanism of Tannin-Based Adhesives Based on Model Compounds: Copolycondensation of Resorcinol with Dimethylol Urea

This study focuses on the competition reaction rules of a system containing resorcinol (as a tannin model compound) and dimethylol urea (as a urea–formaldehyde resin model compound) under various alkaline and acidic environments. The aim is to investigate the crosslinked modification mechanism of urea–formaldehyde resin with tannin adhesive. The study delves into the competitive relationship between self-condensation polymerization reactions and co-condensation polymerization reactions. It specifically highlights the conditions for the copolycondensation reaction of dimethylolurea and resorcinol and validates its rationality through an examination of the resorcinol–urea–formaldehyde system’s reaction rules. The results show that (1) under strongly acidic conditions, the activity of carbocation intermediates produced by hydroxymethyl resorcinol for the resorcinol phenol ring is higher than the electrophilic reactivity of nitrogen atoms on hydroxymethyl urea, which is more beneficial for the resorcinol–formaldehyde self-polycondensation reaction, and the co-polycondensation structures do not play a dominant role. (2) Under weakly acidic conditions, the co-polycondensation structures are evidently advantageous over self-polycondensation structures, and the degree of the co-polycondensation reaction is positively correlated with pH below the neutral point of resorcinol. (3) Under alkaline conditions, the self-polycondensation between resorcinol and formaldehyde is dominant in the system. (4) The concentration of hydroxymethyl urea carbocation is the key factor to determine the degree of the co-polycondensation reaction.

Photocatalyzed Enantioselective Functionalization of C(sp3)-H Bonds.

Owing to its diverse activation processes including single-electron transfer (SET) and hydrogen-atom transfer (HAT), visible-light photocatalysis has emerged as a sustainable and efficient platform for organic synthesis. These processes provide a powerful avenue for the direct functionalization of C(sp3)-H bonds under mild conditions. Over the past decade, there have been remarkable advances in the enantioselective functionalization of the C(sp3)-H bond via photocatalysis combined with conventional asymmetric catalysis. Herein, we summarize the advances in asymmetric C(sp3)-H functionalization involving visible-light photocatalysis and discuss two main pathways in this emerging field: (a) SET-driven carbocation intermediates are followed by stereospecific nucleophile attacks; and (b) photodriven alkyl radical intermediates are further enantioselectively captured by (i) chiral π-SOMOphile reagents, (ii) stereoselective transition-metal complexes, and (iii) another distinct stereoscopic radical species. We aim to summarize key advances in reaction design, catalyst development, and mechanistic understanding, to provide new insights into this rapidly evolving area of research.

Class II terpene cyclases: structures, mechanisms, and engineering.

Covering: up to July 2023Terpene cyclases (TCs) catalyze some of the most complicated reactions in nature and are responsible for creating the skeletons of more than 95 000 terpenoid natural products. The canonical TCs are divided into two classes according to their structures, functions, and mechanisms. The class II TCs mediate acid-base-initiated cyclization reactions of isoprenoid diphosphates, terpenes without diphosphates (e.g., squalene or oxidosqualene), and prenyl moieties on meroterpenes. The past twenty years witnessed the emergence of many class II TCs, their reactions and their roles in biosynthesis. Class II TCs often act as one of the first steps in the biosynthesis of biologically active natural products including the gibberellin family of phytohormones and fungal meroterpenoids. Due to their mechanisms and biocatalytic potential, TCs elicit fervent attention in the biosynthetic and organic communities and provide great enthusiasm for enzyme engineering to construct novel and bioactive molecules. To engineer and expand the structural diversities of terpenoids, it is imperative to fully understand how these enzymes generate, precisely control, and quench the reactive carbocation intermediates. In this review, we summarize class II TCs from nature, including sesquiterpene, diterpene, triterpene, and meroterpenoid cyclases as well as noncanonical class II TCs and inspect their sequences, structures, mechanisms, and structure-guided engineering studies.

Mechanistic docking in terpene synthases using EnzyDock.

Terpene Synthases (TPS) catalyze the formation of multicyclic, complex terpenes and terpenoids from linear substrates. Molecular docking is an important research tool that can further our understanding of TPS multistep mechanisms and guide enzyme design. Standard docking programs are not well suited to tackle the unique challenges of TPS, like the many chemical steps which form multiple stereo-centers, the weak dispersion interactions between the isoprenoid chain and the hydrophobic region of the active site, description of carbocation intermediates, and finding mechanistically meaningful sets of docked poses. To address these and other unique challenges, we developed the multistate, multiscale docking program EnzyDock and used it to study many TPS and other enzymes. In this review we discuss the unique challenges of TPS, the special features of EnzyDock developed to address these challenges and demonstrate its successful use in ongoing research on the bacterial TPS CotB2.

(Invited) Electrocatalytic Radical-Polar Crossover Hydrofunctionalization of Alkenes

Due to the unique reactivity of open-shell intermediates, the development of catalytic transformations driven by single-electron transfer (SET) has been an area of intense research in organic chemistry. In particular, the employment of unconventional means of activation, including photoredox catalysis and electrocatalysis, has provided unique entry to single-electron reactivities and led to new solutions to challenging synthetic problems that are not readily addressed using existing tools.We disclose a general electrocatalytic hydrofunctionalization by utilizing a wide range of alkenes. The integration of the two involves an electrochemically instigated cobalt-hydride-catalyzed radical-polar crossover of alkenes that enable the generation of key cationic intermediates, which could readily be entrapped by challenging nucleophiles. We highlight the importance of precise control of the reaction potential by electrochemistry in conjunction with the decisive role of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as the co-solvent to obtain optimal and exclusive chemoselectivity.In addition, we develope an electrocatalytic method for intramolecular hydroamination of allylic sulfonamides to access azetidines. The merger of cobalt catalysis and electricity enables regioselective generation of key carbocationic intermediates, which could directly undergo intramolecular C-N bond formation. The mechanistic investigations including electrochemical kinetic analysis suggest that the catalyst regeneration by nucleophilic cyclization is involved in the rate-determining step (RDS) of our electrochemical protocol and highlight the ability of electrochemistry in providing ideal means to mediate catalyst oxidation.

A Formal γ-C-H Functionalization of Carboxylic Acids Guided by Metal-Nitrenoids as an Unprecedented Mechanistic Motif.

Harnessing the key intermediates in metal-catalyzed reactions is one of the most essential strategies in the development of selective organic transformations. The nitrogen group transfer reactivity of metal-nitrenoids to ubiquitous C-H bonds allows for diverse C-N bond formation to furnish synthetically valuable aminated products. In this study, we present an unprecedented reactivity of iridium and ruthenium nitrenoids to generate remote carbocation intermediates, which subsequently undergo nucleophile incorporation, thus developing a formal γ-C-H functionalization of carboxylic acids. Mechanistic investigations elucidated a unique singlet metal-nitrenoid reactivity to initiate an abstraction of γ-hydride to form the carbocation intermediate that eventually reacts with a broad range of carbon, nitrogen, and oxygen nucleophiles, as well as biorelevant molecules. Alternatively, the same intermediate can lead to deprotonation to afford β,γ-unsaturated amides in a less nucleophilic solvent.

Bicyclopentylation of Alcohols with Thianthrenium Reagents.

Herein we present the first method for the synthesis of bicyclo[1.1.1]pentyl (BCP) alkyl ethers from alcohols. The reaction uses BCP-thianthrenium reagents and is catalyzed by a dual copper/photoredox catalyst system. Unlike known alkylations of tertiary alcohols via carbocation intermediates, our Cu-mediated radical process circumvents the labile BCP carbocations. The approach demonstrates a broad tolerance for functional groups when applied to primary, secondary, and even tertiary alcohols. In addition, we highlight the utility of this method in late-stage functionalizations of both natural products and pharmaceuticals as well as in the rapid construction of BCP analogs of known pharmaceuticals that would otherwise be difficult to access.

Catalytic, dearomative 2,3-difluorination of indoles

Indolines, characterized by their diverse biological activities and structural significance, have garnered considerable attention in the realms of natural product synthesis and drug discovery. Concurrently, the incorporation of fluorine atoms into organic molecules has emerged as a powerful strategy to enhance their pharmacological properties. Herein, we report a robust and diastereoselective approach for the synthesis of 2,3-difluorinated indolines through the iodine(I/III)-catalyzed dearomatization of readily available indoles. The protocol operates under mild conditions, displaying excellent functional group tolerance and remarkable diastereoselectivity. By employing this developed protocol, vicinal-difluorinated analogues of indole-containing drugs can be efficiently accessed. Theoretical calculations have shed light on the underlying reaction mechanism, proposing the formation of a β-fluorine-substituted carbocation intermediate. It is postulated that the observed high diastereoselectivity can be attributed to the dipole-dipole interactions facilitated by the C–F bond. Crystallographic analysis has revealed the profound impact of fluorine atom introduction on the conformational preferences of the indoline core. Given the unique structural characteristics and pharmacological significance of 2,3-difluorinated indolines, we anticipate their widespread application in medicinal chemistry and drug discovery endeavors.

Diastereoselective Cross-Dehydrogenative Coupling Reactions of Amides with Diarylmethanes Using DDQ through Oxidative C–H Benzylic Activation

AbstractThis study reports the chiral-auxiliary-controlled diastereoselective dehydrogenative coupling of diarylmethanes with amides by using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone as the oxidant. The scope of the proposed reaction is very broad, with a wide variety of substrates and nucleophiles being applicable. The chiral induction can be attributed to the coordination of the oxygen atom on the chiral auxiliary with the carbocation intermediates.