Axial Chirality Research Articles

Construction of central and axial chirality via Pd(II)/Bim-catalyzed asymmetric dearomative Michael reaction of polycyclic tropones.

A highly enantioselective Pd/Bim-catalyzed dearomative Michael reaction applying polycyclic tropones as non-benzenoid aromatic Michael acceptors and arylboronic acids as aryl pronucleophiles has been developed. The bridged biaryls bearing central and axial chirality, including pentacyclic cyclohepta[b]indoles and 6,7-dihydrodibenzo[a,c][7]annulen-5-ones, are generally generated in good to high yields and excellent enantioselectivities and can be readily transformed into useful derivatives.

Adaptive Helical Chirality in Supramolecular Microcrystals for Circularly Polarized Lasing

AbstractChiral organic molecules offer a promising platform for exploring circularly polarized lasing, which, however, faces a great challenge that the spatial separation of molecular chiral and luminescent centers limits chiroptical activity. Here we develop a helically chiral supramolecular system with completely overlapped chiral and luminescent units for realizing high‐performance circularly polarized lasing. Adaptive helical chirality is obtained by incorporating chiral agents into organic microcrystals. Benefiting from the efficient coupling of stimulated emission with the adaptive helical chirality, the supramolecular microcrystals enable high‐performance circularly polarized lasing emission with dissymmetry factors up to ~0.7. This work opens up the way to rational design of chiral organic materials for circularly polarized lasing.

Adaptive Helical Chirality in Supramolecular Microcrystals for Circularly Polarized Lasing.

Chiral organic molecules offer a promising platform for exploring circularly polarized lasing, which, however, faces a great challenge that the spatial separation of molecular chiral and luminescent centers limits chiroptical activity. Here we develop a helically chiral supramolecular system with completely overlapped chiral and luminescent units for realizing high-performance circularly polarized lasing. Adaptive helical chirality is obtained by incorporating chiral agents into organic microcrystals. Benefiting from the efficient coupling of stimulated emission with the adaptive helical chirality, the supramolecular microcrystals enable high-performance circularly polarized lasing emission with dissymmetry factors up to ~0.7. This work opens up the way to rational design of chiral organic materials for circularly polarized lasing.

Binaphthalene-Assisted Axial Chirality in Porphyrins: Toward Solid-State Circularly Polarized Luminescence from Self-Assembled Nanostructures.

Circularly polarized luminescence (CPL) is emerging as an effective tool to study the excited-state optical activity in molecules and their self-assembled nanostructures. Chiral porphyrins are a class of optically active molecules wherein the ground-state chirality has been extensively studied in recent times using circular dichroism (CD) spectroscopy. However, obtaining CPL from porphyrin nanostructures, which would have vast implications in biological applications, has remained an uphill task. In this work, we design and synthesize a pair of chiral porphyrin enantiomers functionalized by axially chiral binaphthalene units at the four meso-positions. The molecule undergoes self-assembly following an isodesmic polymerization model, leading to the formation of a spherical nanostructure possessing opposite chirality. Favorable thermodynamic parameters achieved through the controlled experimental conditions helped drive the self-assembly in the forward direction. The limitations imposed by a large nonradiative decay constant arising due to the aggregation-induced quenching could be overcome by fabricating self-standing polymeric films of the nanostructures. The films exhibited relatively high radiative decay and, more interestingly, good CPL activity with clear mirror image spectra for the nanostructures with opposite chirality. The work on CPL-active solid-state materials opens avenue for the design and synthesis of a variety of porphyrin-based chromophoric systems and their nanoaggregates that can find potential application in the field of chiral biosensing and bioimaging, security tags, and display devices.

Iridium-Catalyzed Asymmetric Hydroarylation of Unactivated Alkenes with Heterobiaryls: Simultaneous Construction of Axial and Central Chirality.

There are only a few examples being reported for the simultaneous control of central chirality and axial chirality because it is more challenging. Herein, we report an iridium-catalyzed asymmetric hydroarylation of unactivated alkenes with heterobiaryls to simultaneously construct axial and central chirality. The reaction showed a broad substrate scope and delivered the products with satisfactory results. The results of the control experiments demonstrated that the FerroLANE ligand promotes the reaction to proceed along a specific modified Chalk-Harrod mechanism.

Dynamics of side chains in poly(quinoxaline-2,3-diyl)s studied via quasielastic neutron scattering.

The side chain dynamics of poly(quinoxaline-2,3-diyl)s (PQXs) are expected to influence their conformation. To investigate these dynamics experimentally, quasielastic neutron scattering (QENS) was performed for PQXs in deuterated tetrahydrofuran (THF-d8) and deuterated 1,1,2-trichloroethane/THF (1,1,2-TCE-d3/THF-d8), in which they formed right-handed and left-handed helical structures, respectively. The mean-square displacement of the PQX side chains in 1,1,2-TCE-d3/THF-d8 was lower than that in THF-d8. Furthermore, QENS complementary studies and molecular dynamics simulations unraveled a coupling between the main-chain and side chain dynamics of PQXs, suggesting the possibility of controlling the main-chain helical chirality through the dynamics of chiral side chains. These insights present a novel strategy for the design of synthetic helical macromolecules with precise chirality control.

Organocatalytic Atroposelective Synthesis of Axially Chiral Indolyl Ketosulfoxonium Ylides

Despite recent advancements in catalytic synthesis of axial chirality, reports on non‐biaryl atropisomers remain limited because of the stringent steric requirements necessary to establish effective rotational brakes. In this study, we present a novel class of monoaryl atropisomers, indolyl ketosulfoxonium ylides, and describe an organocatalytic protocol for their synthesis. We discovered that a chiral phosphoric acid (CPA) serves as an effective catalyst for the highly enantioselective iodination of ortho‐aminophenylethynyl sulfoxonium ylides. Under the optimized reaction conditions, a strong preference for the intended iodination process over the competing protonation was observed. Subsequently, intramolecular amide cyclization enabled the formation of sterically congested indole fragments. Furthermore, the synthetic utility of the products was demonstrated by showcasing versatile transformations into other chiral scaffolds with complete retention of optical purity.

Organocatalytic Atroposelective Synthesis of Axially Chiral Indolyl Ketosulfoxonium Ylides.

Despite recent advancements in catalytic synthesis of axial chirality, reports on non-biaryl atropisomers remain limited because of the stringent steric requirements necessary to establish effective rotational brakes. In this study, we present a novel class of monoaryl atropisomers, indolyl ketosulfoxonium ylides, and describe an organocatalytic protocol for their synthesis. We discovered that a chiral phosphoric acid (CPA) serves as an effective catalyst for the highly enantioselective iodination of ortho-aminophenylethynyl sulfoxonium ylides. Under the optimized reaction conditions, a strong preference for the intended iodination process over the competing protonation was observed. Subsequently, intramolecular amide cyclization enabled the formation of sterically congested indole fragments. Furthermore, the synthetic utility of the products was demonstrated by showcasing versatile transformations into other chiral scaffolds with complete retention of optical purity.

Modular Synthesis of Tripeptide Analogs with an Aminobitriazole Skeleton Using Diynyl Benziodoxolone as a Trivalent Platform.

A new synthesis method of tripeptide analogs with an aminobitriazole skeleton was proposed. The method involves assembling three amino acid-derived modules at the amino group site and onto a triisopropylsilyl diynyl benziodoxolone by copper-catalyzed electrophilic diynylation of amino acid-derived sulfonamides, chemoselective azide-alkyne cycloadditions with amino acid-derived azides, and deprotection. Various complex aminobitriazoles substituted with pyrene, nucleoside, and N-acetylglucosamine were also synthesized. The produced aminobitriazoles have three sp3 chiral centers and a C-N axial chirality.

Nonalternant B,N-Embedded Helical Nanographenes Containing Azepines: Programmable Synthesis, Responsive Chiroptical Properties and Spontaneous Resolution into a Single-Handed Helix.

Heteroatom-embedded helical nanographenes (NGs) constitute an important and appealing class of intrinsically chiral materials. In this work, a series of B,N-embedded helical NGs (BN-HNGs) bearing azepines was synthesized via stepwise regioselective cyclodehydrogenation. First, the phenyl- or nitrogen-bridged dimers were efficiently clipped into highly congested model compounds 1 and 2. Later, the controllable Scholl reactions of the tetraphenyl-tethered precursor generated 1, 7 or 8 new C-C bonds, thereby establishing a robust method for the preparation of nonalternant BN-HNGs with up to 31 fused rings. The helical bilayer nature was unambiguously verified by X-ray diffraction analysis. The helical chirality was transferred to the stereogenic boron centers upon fluoride coordination, with a concave-concave structure to comply with the bilayer skeleton. Notably, the largest nonalternant BN-HNG (6) spontaneously resolved into a homochiral 41 helix structure as a molecular spiral staircase during crystallization via conglomerate formation at the single-crystal scale. The large twisted C2-symmetric π-surface and the dynamic chiral skeleton induced by curved azepines might have synergistic effects on self-recognition of enantiomers of 6 to achieve the intriguing spontaneous resolution behavior. The chiroptical properties of the enantiomer of 6 were further investigated, revealing that 6 had a strong chiroptical response in the visible range (400-700 nm).

Synthesis of N-N Axially Chiral Pyrrolyl-oxoisoindolin via Isothiourea-Catalyzed Acylative Dynamic Kinetic Resolution.

The development of methods for the asymmetric synthesis of N-N axial chirality remains elusive and challenging. Here, we disclose a method for the construction of N-N axially chiral pyrrolyl-oxoisoindolins along with central chirality via the isothiourea (ITU)-catalyzed acylative dynamic kinetic resolution (DKR). Axial chirality was introduced into the acylative DKR of hemiaminals for the first time. This protocol features mild conditions with excellent yields and enantioselectivities.

Atroposelective Synthesis of Axial Biaryls by Dynamic Kinetic Resolution Using Engineered Imine Reductases.

Axially chiral biaryl compounds are ubiquitous scaffolds in natural products, bioactive molecules, chiral ligands and catalysts, but biocatalytic methods for their asymmetric synthesis are limited. Herein, we report a highly efficient biocatalytic route for the atroposelective synthesis of biaryls by dynamic kinetic resolution (DKR). This DKR approach features a transient six-membered aza-acetal-bridge-promoted racemization followed by an imine reductase (IRED)-catalyzed stereoselective reduction to construct the axial chirality under ambient conditions. Directed evolution of an IRED from Streptomyces sp. GF3546 provided a variant (S-IRED-Ss-M11) capable of catalyzing the DKR process to access a variety of biaryl aminoalcohols in high yields and excellent enantioselectivities (up to 98 % yield and >99 : 1 enantiomeric ratio). Molecular dynamics simulation studies on the S-IRED-Ss-M11 variant revealed the origin of its improved activity and atroposelectivity. By exploiting the substrate promiscuity of IREDs and the power of directed evolution, our work further extends the biocatalysts' toolbox to construct challenging axially chiral molecules.

Switching of Circularly Polarized Luminescence via Dynamic Axial Chirality Control of Chiral Bis(Boron Difluoride) Complexes with Salen Ligands

AbstractThe intensity and handedness of circularly polarized luminescence (CPL) were successfully controlled by dynamic molecular motion in solutions. Bis(boron difluoride) complexes with chiral salen ligands were synthesized and their photophysical properties were investigated. Although these complexes showed rapid molecular rotation about the C−N bond axis in solution at room temperature, two conformers assigned as atropisomers were observed in the NMR spectra at low temperature. Furthermore, the equilibrium of these atropisomers was found to change depending on the external environment, such as the solvent and temperature, allowing precise control of the intensity and handedness of CPL without luminescence color shifts. Theoretical calculations based on density functional theory (DFT) revealed that intramolecular chiral exciton coupling is the key to changes in CPL properties.

Asymmetric Cascade Dearomatization-Cyclization Reaction of Tryptamines with β,γ-Alkynyl-α-imino Esters: Access to Hexahydropyrrolo[2,3-b]indole-Containing Tetrasubstituted α-Amino Allenoates.

An organocatalytic enantio- and diastereoselective synthesis of hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted α-amino allenoates, exhibiting both axial and central chirality, has been accomplished via cascade dearomatization-cyclization reaction. The γ-addition to β,γ-alkynyl-α-imino esters provides a library of densely substituted highly enantioenriched allenes in high yields and excellent stereoselectivities. In addition, the scope of this methodology has been extended to tryptophol as well. A scale-up reaction and synthetic transformations of the products were performed to demonstrate the practical usefulness of this approach.

Enantioselective Construction of Anthracenylidene-Based Axial Chirality by Asymmetric Heck Reaction.

Anthracenylidene is an intriguing structural unit with potential in various fields. The study presents a novel approach to introducing axial chirality into this all-carbon core skeleton through a remotely controlled desymmetrization strategy. A palladium-catalyzed enantioselective Heck arylation of exocyclic double bond of anthracene with two distinct substituents at the C10 position is harnessed to realize such a transformation. The judicious identification of the P-centrally chiral ligand is pivotal to ensure the competitive competence in reactivity and stereocontrol when the heteroatom handle is absent from the anthracenylidene skeleton. Both C10 mono- and disubstituted substrates were compatible for the established catalytic system, and structurally diverse anthracenylidene-based frameworks were forged with good-to-high enantiocontrol. The subsequent derivatization of the obtained products yielded a valuable array of centrally and axially chiral molecules, thus emphasizing the practicality of this chemistry. DFT calculations shed light on the catalytic mechanism and provided insights into the origin of the experimentally observed enantioselectivity for this reaction.

Fentanyl-Type Antagonist of the μ-Opioid Receptor: Important Role of Axial Chirality in the Active Conformation.

In recent years, synthetic opioids have emerged as a predominant cause of drug-overdose-related fatalities, causing the "opioid crisis." To design safer therapeutic agents, we accidentally discovered μ-opioid receptor (MOR) antagonists based on fentanyl with a relatively uncomplicated chemical composition that potentiates structural modifications. Here, we showed the development of novel atropisomeric fentanyl analogues that exhibit more potent antagonistic activity against MOR than naloxone, a morphinan MOR antagonist. Derivatives displaying stable axial chirality were synthesized based on the amide structure of fentanyl. The aS- and aR-enantiomers exerted antagonistic and agonistic effects on the MOR, respectively, and each atropisomer interacted with the MOR by assuming a distinct binding mode through molecular docking. These findings suggest that introducing atropisomerism into fentanyl may serve as a key feature in the molecular design of future MOR antagonists to help mitigate the opioid crisis.

Cobaltaelektro‐katalysierte C−H‐Aktivierung für zentrale und axiale doppelte Enantioinduktion

AbstractIn den letzten Jahren hat sich die enantioselektive Elektrokatalyse zunehmend als eine effektive Methode für die nachhaltige molekulare Synthese herausgestellt. Trotz unbestreitbarer Fortschritte bleiben Strategien zur Kontrolle über zwei unterschiedliche stereogene Elemente mit hoher Selektivität schwer fassbar. Im Gegensatz dazu beschreiben wir hier elektrochemische Cobalt‐katalysierte C−H‐Aktivierungen, welche die Installation chiraler stereogener Zentren zusammen mit einer chiralen Achse mit hoher Enantio‐ und Diastereoselektivität ermöglichen. Die entwickelte elektrokatalytische Strategie erlaubte C−H/N−H‐Aktivierungen/Anellierungen mit cyclischen und acyclischen Alkenen und gewährte einen direkten Zugang zu vielseitigen sowohl zentralen als auch atropo‐chiralen Dihydroisochinolinonen gepaart mit der wertvollen Wasserstoffbildungsreaktion. Studien zur Atropo‐Stabilität der erhaltenen Verbindungen demonstrierten, dass die äußerst milden Bedingungen, gewährleistet durch den elektrokatalytischen Prozess, entscheidend für die hohen erzielten Stereoselektivitäten waren.

Cobaltaelectro-Catalyzed C-H Activation for Central and Axial Double Enantio-Induction.

In recent years, enantioselective electrocatalysis has surfaced as an increasingly-effective platform for sustainable molecular synthesis. Despite indisputable progress, strategies that allow the control of two distinct stereogenic elements with high selectivity remain elusive. In contrast, we, herein, describe electrochemical cobalt-catalyzed C-H activations that enable the installation of chiral stereogenic centers along with a chiral axis with high levels of enantio- and diastereoselectivities. The developed electrocatalysis strategy allowed for C-H/N-H activations/annulations with cyclic and non-cyclic alkenes providing expedient access to various central as well as atropo-chiral dihydroisoquinolinones paired to the valuable hydrogen evolution reaction. Studies on the atropo-stability of the obtained compounds demonstrated that the exceedingly mild conditions ensured by the electrocatalytic process were key for the achieved high stereoselectivities.

Unusually Short H⋅⋅⋅H Contacts in Intramolecularly Cyclized Helically Fused Anthracenes.

The intramolecular coupling of dichloro-substituted helically fused anthracenes using the Yamamoto coupling yielded cyclized products with sterically congested molecular structures. The X-ray analysis and DFT calculations showed that the aromatic framework adopted a nonplanar structure with a twisted conformation about the newly formed single bond, which acts as a chiral axis. Interestingly, the X-ray structure obtained through the Hirshfeld atom refinement revealed short interatomic distances between the inner hydrogen atoms (1.648-1.692 Å), much shorter than the sum of their van der Waals radii. Owing to these unusually short contacts, the 1H NMR spectrum exhibited a significant deshielding (12.5 ppm) and a large nuclear Overhauser effect (44 %). Additionally, the IR spectrum displayed a high-frequency shift of the C-H stretching vibration. These observations, along with the noncovalent interaction plot indicative of a characteristic steric environment, strongly support the presence of steric hindrance. Moreover, dynamic NMR measurement of the mesityl-substituted derivative yielded a barrier to helical inversion of 84 kJ mol-1. The optical properties and crystal packing of the cyclized products are also reported.

Design, Preparation, and Implementation of Axially Chiral Benzotetramisoles as Lewis Base Catalysts for Asymmetric Cycloadditions

AbstractDeveloping novel catalysts with potent activity is of great importance in organocatalysis. In this study, we designed and prepared a new class of benzotetramisole Lewis base catalysts (AxBTM) that have both central and axial chirality. This unique feature of these catalysts results in a three‐dimensional microenvironment with multi‐layers of chirality. The performance of the developed catalysts was tested in a series of cycloaddition reactions. These included the AxBTM‐catalyzed (2+2) cycloaddition between α‐fluoro‐α‐aryl anhydride with imines or oxindoles, and the sequential gold/AxBTM‐catalyzed (4+2) cycloaddition of enynamides with pentafluorophenyl esters. The interplay between axial and central chirality had a collaborative effect in regulating the stereochemistry in these cycloadditions, leading to high levels of stereoselectivity that would otherwise be challenging to achieve using conventional BTM catalysts. However, the (2+2) and (4+2) cycloadditions have different predilections for axial and central chirality combinations.