Catalytic Asymmetric Synthesis Research Articles

Catalytic Enantioselective Synthesis of Monosubstituted [n]Paracyclophane using a Desymmetrization/Kinetic Resolution Sequence.

Optically pure monosubstituted [n]paracyclophanes are promising candidates for material synthesis, asymmetric catalysis, and drug discovery. Thus far, only a few catalytic asymmetric synthesis processes have been reported for assessing these stained atropisomers. In this study, we describe a highly enantioselective synthesis of monosubstituted [n]paracyclophanes by combining desymmetrization and kinetic resolution. The proposed protocol involves Pd-catalyzed atroposelective C-H bond olefination enabled by a monoprotected amino acid ligand, which affords a variety of monosubstituted [n]paracyclophanes with excellent enantioselectivity (≥99% ee). Thermodynamic experiments are conducted to investigate the racemization barrier. The synthesized monosubstituted [n]paracyclophanes exhibit vivid fluorescence and impressive circularly polarized luminescence. Further, the emission color and dissymmetry factor can be tuned and controlled by switching the substituent on the benzene ring of the cyclophanes.

Catalytic Asymmetric Total Synthesis of (+)‐Chamaecydin and (+)‐Isochamaecydin and their Stereoisomers

Catalytic Asymmetric Total Synthesis of (+)‐Chamaecydin and (+)‐Isochamaecydin and their Stereoisomers

Catalytic Asymmetric Total Synthesis of (+)-Chamaecydin and (+)-Isochamaecydin and their Stereoisomers.

A modular approach was developed for the first catalytic asymmetric total syntheses of naturally occurring C30 terpene quinone methides and their non-natural stereoisomers, which feature the presence of an unprecedented spiro[4.4]nonane-containing 6-6-6-5-5-3 hexacyclic skeleton. Resting on a chiral phosphinamide-catalyzed enantioselective reduction of 2,2-disubstituted cyclohexane-1,3-dione, a concise route for the synthesis of enantioenriched 6-6 bicyclic fragment was developed. The 6-6 ring fragment and the five-membered ring fragment were unified via a metal-halogen exchange/intermolecular addition reaction. Subsequently, the central 6-5 bicyclic ring system was constructed through a Michael/aldol cascade. The successful establishment of these strategic transformations allowed for an efficient and rapid construction of spiroannulated 6-6-6-5-5 pentacarbocyclic core via a convergent manner. Finally, the total syntheses of naturally occurring (+)-chamaecydin and (+)-isochamaecydin and their corresponding 1',5'-stereoisomers have been achieved divergently by appropriately orchestrating the reaction sequence including isopropyl incorporation, oxidation state adjustment, and carbonyl group-directed regio- and stereoselective cyclopropanation at a late stage.

Catalytic asymmetric synthesis and synthetic application of heteroatom-substituted axially chiral allenes

Heteroatom-substituted axially chiral allenes represent an important subclass of chiral allenes. We summarizes the contributions on heteroatom-substituted axially chiral allenes and their catalytic asymmetric synthesis and synthetic applications.

Biaxially chiral compounds: research and development of synthesis.

With the rapid advancements in asymmetric catalysis, there is a growing need for the asymmetric selective synthesis of complex and diverse molecules with chiral axes. Axially chiral molecules are not only present in natural products and drugs but also in specialized chiral ligands and catalysts. The catalytic asymmetric synthesis of axially chiral molecules has garnered significant attention within the chemical community. To date, two asymmetric catalytic methods have been established for the synthesis of biaxially chiral molecules: transition-metal catalysis and asymmetric organocatalysis. This feature article presents a summary of the research progress made in the field of asymmetric selective synthesis of biaxially chiral molecules. This review focuses on the reaction range, limitations, and reaction mechanism of the biaxially chiral molecular synthesis method, as well as the contribution and advantages of this method in the preparation of various axially chiral compounds.

Catalytic asymmetric synthesis of chiral sulfilimines via S–C bond formation

In this article, recent advances in catalytic asymmetric synthesis of chiral sulfilimines from sulfenamides via S–C bond formation are highlighted.

Catalytic Asymmetric Synthesis and Applications of Stereogenic β'‐Methyl Enones and β,β'‐Dimethyl Ketones

The “Magic Methyl” effect has received tremendous interest in medicinal chemistry due to the significant pharmacological and physical modification of properties that have been observed upon introducing a methyl group, especially, a stereogenic methyl group into potential chiral drug candidates. The prevalence of stereogenic β‐methyl ketone structural motifs in bioactive compounds and natural products has long motivated the development of enantioselective strategies toward their synthesis. Herein, we have rationally designed a Rh‐catalyzed asymmetric monohydrogenation of readily‐available β'‐methylene conjugated enones with high efficiency and remarkable site‐selectivity and enantioselectivity control for the practical construction of enantioenriched β'‐methyl unsaturated enones that are difficult to access by other methods. Control experiments revealed that the conjugated C=C bond in β'‐methylene conjugated enones plays a significant role in enhancing the reactivity of monohydrogenation. This methodology is applicable for the preparation of chiral β,β'‐dimethyl ketones through consecutive double asymmetric hydrogenation of β,β'‐dimethylene ketones. Detailed mechanistic investigation and DFT studies further provided strong support for a unique processive catalysis pathway for double asymmetric hydrogenation. The synthetic utilities have been demonstrated in the concise synthesis of several key intermediates for bioactive molecules, asymmetric total synthesis of natural products (S)‐(+)‐ar‐Turmerone and (S)‐(+)‐dihydro‐ar‐Turmerone, and two C2‐symmetric chiral spirocyclic diol frameworks.

Catalytic Asymmetric Synthesis and Applications of Stereogenic β'-Methyl Enones and β,β'-Dimethyl Ketones.

The "Magic Methyl" effect has received tremendous interest in medicinal chemistry due to the significant pharmacological and physical modification of properties that have been observed upon introducing a methyl group, especially, a stereogenic methyl group into potential chiral drug candidates. The prevalence of stereogenic β-methyl ketone structural motifs in bioactive compounds and natural products has long motivated the development of enantioselective strategies toward their synthesis. Herein, we have rationally designed a Rh-catalyzed asymmetric monohydrogenation of readily-available β'-methylene conjugated enones with high efficiency and remarkable site-selectivity and enantioselectivity control for the practical construction of enantioenriched β'-methyl unsaturated enones that are difficult to access by other methods. Control experiments revealed that the conjugated C=C bond in β'-methylene conjugated enones plays a significant role in enhancing the reactivity of monohydrogenation. This methodology is applicable for the preparation of chiral β,β'-dimethyl ketones through consecutive double asymmetric hydrogenation of β,β'-dimethylene ketones. Detailed mechanistic investigation and DFT studies further provided strong support for a unique processive catalysis pathway for double asymmetric hydrogenation. The synthetic utilities have been demonstrated in the concise synthesis of several key intermediates for bioactive molecules, asymmetric total synthesis of natural products (S)-(+)-ar-Turmerone and (S)-(+)-dihydro-ar-Turmerone, and two C2-symmetric chiral spirocyclic diol frameworks.

Atroposelective synthesis of axially chiral imidazo[1,2-a]pyridines via asymmetric multicomponent reaction.

Imidazo[1,2-a]pyridines are privileged heterocycles with diverse applications in medicinal chemistry; however, the catalytic asymmetric synthesis of these heterocyclic structures remains underexplored. Herein, we present an efficient and modular approach for the atroposelective synthesis of axially chiral imidazo[1,2-a]pyridines via an asymmetric multicomponent reaction. By utilizing a chiral phosphoric acid catalyst, the Groebke-Blackburn-Bienaymé reaction involving various 6-aryl-2-aminopyridines, aldehydes, and isocyanides gave access to a wide range of imidazo[1,2-a]pyridine atropoisomers with high to excellent yields and enantioselectivities. Extensive control experiments underscored the pivotal role of the remote hydrogen bonding donor on the substrates in achieving high stereoselectivity for these reactions. The versatile derivatizations of these atropisomeric products, especially their role as an analog of NOBINs and their facile conversion into unique 6,6-spirocyclic products, further emphasize the merits of this methodology.

Catalytic Asymmetric Synthesis of Inherently Chiral Eight‐Membered O‐Heterocycles through Cross‐[4+4] Cycloaddition of Quinone Methides

AbstractInherently chiral eight‐membered rings embedded in tetraphenylene derivatives and hetero‐analogues exhibit unique properties and allow diverse applications. A conceptually viable and straightforward approach to these frameworks is [4+4] cycloaddition, which still remains elusive. Herein, we describe the stereoselective cross‐[4+4] cycloaddition of quinone methides (QMs), leading to the formation of oxa‐analogues of tetraphenylene with exceptional chemo‐, diastereo‐, and enantioselectivity. The structures of these novel rigid eight‐membered O‐heterocycles were explored by single‐crystal X‐ray diffraction, and their stereochemical stability was elaborated through both density functional theory (DFT) calculations and thermal racemization experiments. The developed methodology exhibited broad substrate scope and the resulting cross‐[4+4] cycloadducts could be readily transformed into valuable chiral building blocks. Our findings expand the library of inherently chiral medium‐sized rings and also contribute to the advancement of asymmetric cross‐[4+4] cycloadditions of quinone methides.

Catalytic Asymmetric Synthesis of Inherently Chiral Eight-Membered O-Heterocycles through Cross-[4+4] Cycloaddition of Quinone Methides.

Inherently chiral eight-membered rings embedded in tetraphenylene derivatives and hetero-analogues exhibit unique properties and allow diverse applications. A conceptually viable and straightforward approach to these frameworks is [4+4] cycloaddition, which still remains elusive. Herein, we describe the stereoselective cross-[4+4] cycloaddition of quinone methides (QMs), leading to the formation of oxa-analogues of tetraphenylene with exceptional chemo-, diastereo-, and enantioselectivity. The structures of these novel rigid eight-membered O-heterocycles were explored by single-crystal X-ray diffraction, and their stereochemical stability was elaborated through both density functional theory (DFT) calculations and thermal racemization experiments. The developed methodology exhibited broad substrate scope and the resulting cross-[4+4] cycloadducts could be readily transformed into valuable chiral building blocks. Our findings expand the library of inherently chiral medium-sized rings and also contribute to the advancement of asymmetric cross-[4+4] cycloadditions of quinone methides.

Enantioselective construction of C-B axially chiral alkenylborons by nickel-catalyzed radical relayed reductive coupling

The catalytic asymmetric synthesis of axially chiral alkenes remains a daunting challenge due to the lower rotational barrier, especially for longer stereogenic axis (e.g. C-B axis). The asymmetric radical difunctionalization of alkynes represents an efficient strategy for these targets. Key to the success of such transformations lies in aryl-stabilized highly reactive alkenyl radical intermediates, however, it remains an elusive whether a boryl group could play a similar role. Here we report a nickel-catalyzed atroposelective radical relayed reductive coupling reaction of our designed ethynyl-azaborines with simple alkyl and aryl halides through a boron-stabilized vinyl radical intermediate. This transformation enables a straightforward access to the challenging axially chiral alkenylborons bearing a C-B axis in generally high enantioselectivity and excellent stereoselectivity.

Construction of Sulfur(IV)‐Chiral Six‐Membered Heterocycles by Pd‐Catalyzed Asymmetric (4+2) Dipolar Cyclization

AbstractChiral sulfur‐containing compounds play an important role in asymmetric catalysis and synthesis, chiral pharmaceuticals, and chiral materials. While great progress has been made in the synthesis of these compounds, the asymmetric catalytic synthesis of chiral sulfur‐containing heterocycles remains relatively limited compared to acyclic ones. In this study, we successfully report an efficient and highly selective synthesis of structurally diverse chirality‐at‐sulfur(IV) six‐membered heterocycles under mild conditions via a Pd‐catalyzed asymmetric (4+2) dipolar cyclization. More importantly, these products enable the enantioselective preparation of a variety of other S‐stereogenic derivatives.

Catalytic kinetic resolution of helical polycyclic phenols via an organocatalyzed enantioselective dearomative amination reaction.

Despite the considerable potential applications for helically chiral molecules across various sectors, their catalytic asymmetric synthesis remains nascent and has seen very limited advancement compared to that of central and axial chiral compounds, primarily owing to the scarcity of available starting materials and the immense challenges associated with achieving stereochemical control. Herein, we report an innovative approach to the facile synthesis and catalytic kinetic resolution of uniquely structured and stereochemically complex helical polycyclic phenols by using a steric hindrance-regulated enantioselective dearomative amination reaction. The distinguished aspects of this method include the exceptional stability of the dearomatized products and impressive versatility of the recovered substrates in the construction of enantioenriched helical frameworks. This work showcases that the strategic incorporation of appropriate steric groups near the reaction site of an electron-rich aromatic compound can indeed enable an interrupted Friedel-Crafts reaction, thus opening an alternate avenue for the study of dearomatization in nonfunctionalized arenes.

Enantioselective Synthesis of Axially Chiral Tetrasubstituted Alkenes by Copper‐Catalyzed C(sp2)–H Functionalization of Arenes with Vinyl Cations

Axially chiral tetrasubstituted alkenes are of increasing value and interest in chemistry‐related areas. However, their catalytic asymmetric synthesis remains elusive, due to the high steric repulsion and relatively low conformational stability. Herein, we disclose the straightforward construction of atropisomeric tetrasubstituted alkenes via an effective enantiocontrol of vinyl cations. This copper‐catalyzed enantioselective C(sp2)–H functionalization of sterically hindered (hetero)arenes with vinyl cations enables the efficient and atom‐economical preparation of axially chiral acyclic tetrasubstituted styrenes and pyrrolyl ethylenes with high atroposelectivities. Importantly, this reaction represents the first example for the assembly of axially chiral alkenes through vinyl cation approach. Computational mechanistic studies reveal the reaction mechanism, origin of regioselectivity, Z/E selectivity and enantioselectivity. The synthetic utility has been demonstrated by diverse product derivatizations, chiral organocatalyst synthesis, as well as further applications in asymmetric catalysis.

Enantioselective Synthesis of Axially Chiral Tetrasubstituted Alkenes by Copper-Catalyzed C(sp2)-H Functionalization of Arenes with Vinyl Cations.

Axially chiral tetrasubstituted alkenes are of increasing value and interest in chemistry-related areas. However, their catalytic asymmetric synthesis remains elusive, owing to the high steric repulsion and relatively low conformational stability. Herein, we disclose the straightforward construction of atropisomeric tetrasubstituted alkenes by effective enantiocontrol in a reaction with vinyl cation intermediates. This copper-catalyzed enantioselective C(sp2)-H functionalization of sterically hindered (hetero)arenes with vinyl cations enables the efficient and atom-economical preparation of axially chiral acyclic tetrasubstituted styrenes and pyrrolyl ethylenes with high atroposelectivities. Importantly, this reaction represents the first example of the assembly of axially chiral alkenes via vinyl cations. Computational mechanistic studies reveal the reaction mechanism, origin of regioselectivity, Z/E selectivity and enantioselectivity. The synthetic utility has been demonstrated by diverse product derivatizations, chiral organocatalyst synthesis, as well as further applications in asymmetric catalysis.

Enantioselective synthesis of inherently chiral sulfur-containing calix[4]arenes via chiral sulfide catalyzed desymmetrizing aromatic sulfenylation

Inherently chiral calixarenes hold great potential for applications in chiral recognition, sensing, and asymmetric catalysis due to their unique structures. However, due to their special structures and relatively large sizes, the catalytic asymmetric synthesis of inherently chiral calixarenes is challenging with very limited examples available. Here, we present an efficient method for the enantioselective synthesis of inherently chiral sulfur-containing calix[4]arenes through the desymmetrizing electrophilic sulfenylation of calix[4]arenes. This catalytic asymmetric reaction is enabled by a chiral 1,1’-binaphthyl-2,2’-diamine-derived sulfide catalyst and hexafluoroisopropanol. Various inherently chiral sulfur-containing calix[4]arenes are obtained in moderate to excellent yields with high enantioselectivities. Control experiments indicate that the thermodynamically favored C-SAr product is formed from the kinetically favored N-SAr product and the combination of the chiral sulfide catalyst and hexafluoroisopropanol is crucially important for both enantioselectivity and reactivity.

Asymmetric Synthesis of Chiral Calix[4]arenes with Both Inherent and Axial Chirality via Cobalt-Catalyzed Enantioselective Intermolecular C-H Annulation.

Inherently chiral calixarenes have garnered significant attention due to their distinctive properties, yet the development of efficient catalytic asymmetric synthesis methods remains a critical challenge. Herein, we report the asymmetric synthesis of calix[4]arenes featuring inherent or both inherent and axial chirality via a cobalt-catalyzed C-H activation/annulation strategy in high yield with excellent enantio- and diastereoselectivity (up to >99 % ee and >20 : 1 dr). Electrooxidation was also suitable for this transformation to obviate the sacrificial metal oxidants, underscoring the environmentally friendly potential of this approach. A key octahedral cobaltacycle intermediate was synthesized and characterized, providing valuable insights into the mode of enantio- and diastereocontrol of this protocol. Noteworthy photoluminescence quantum yields of up to 0.94 were measured, underscoring the potential of these compounds in the domain of organic fluorescent materials.

Asymmetric Synthesis of Chiral Calix[4]arenes with Both Inherent and Axial Chirality via Cobalt‐Catalyzed Enantioselective Intermolecular C−H Annulation

AbstractInherently chiral calixarenes have garnered significant attention due to their distinctive properties, yet the development of efficient catalytic asymmetric synthesis methods remains a critical challenge. Herein, we report the asymmetric synthesis of calix[4]arenes featuring inherent or both inherent and axial chirality via a cobalt‐catalyzed C−H activation/annulation strategy in high yield with excellent enantio‐ and diastereoselectivity (up to >99 % ee and >20 : 1 dr). Electrooxidation was also suitable for this transformation to obviate the sacrificial metal oxidants, underscoring the environmentally friendly potential of this approach. A key octahedral cobaltacycle intermediate was synthesized and characterized, providing valuable insights into the mode of enantio‐ and diastereocontrol of this protocol. Noteworthy photoluminescence quantum yields of up to 0.94 were measured, underscoring the potential of these compounds in the domain of organic fluorescent materials.

Catalytic Asymmetric Synthesis of Bicyclic Isothioureas from a Common Enolizable Template.

While bicyclic isothiourea (ITU) moieties are found in biologically active molecules and organocatalysts, a catalytic asymmetric synthesis of ITUs is pending. Here, we report the catalytic, enantioselective functionalization of enolizable template II with a variety of electrophiles, including unsaturated ketones, esters, sulfones, nitro compounds, and thiolating reagents, as an entry to enantioenriched bicyclic ITUs III. Scope and limitations are shown, as well as examples of product derivatization.