Axial Chirality Research Articles

Asymmetric Total Synthesis of Chaetoglobin A.

An asymmetric total synthesis of chaetoglobin A was achieved. Atroposelective oxidative coupling of a phenol incorporating all but one carbon of the final product was used as a key step to generate axial chirality. The stereochemical outcome of the catalytic oxidative phenolic with the highly substituted phenol used herein was found to be opposite that of the simpler congeners reported previously, providing a cautionary tale about extrapolating asymmetric processes from simple to more complex substrates. Optimization of the postphenolic coupling steps including formylation, oxidative dearomatization, and selective deprotection steps are outlined. The tertiary acetates of chaetoglobin A were exceptionally labile due to activation by the adjacent keto groups, which complicated each of these steps. In contrast, the final oxygen to nitrogen exchange proceeded readily and the spectroscopic data from the synthetic material matches that of the isolated natural product in all respects.

Stereoselective Synthesis Axially Chiral Arylnitriles through Base-Induced Chirality-Relay β-Carbon Elimination of α-Hydroxyl Ketoxime Esters.

We report herein a point-to-axial chirality transfer reaction of α-hydroxyl oxime esters for the synthesis of axially chiral arylnitriles. The reaction proceeds smoothly through a base-promoted retro-benzoin condensation reaction of α-hydroxyl oxime esters, where the axial chirality is created via the C-C bond cleavage based on a proper distorted conformation of the biaryl structure induced by its stereogenic carbon center.

Axial Chirality in Alkylidene‐Cyclic Molecules

AbstractAxial chirality is an interesting stereoisomeric phenomenon in organic chemistry and a key structural feature of several organic compounds. Atropisomers such as biaryls, anilides and diaryl ethers are one type of axially chiral compounds, whose axial chirality is resulted from rotationally blocked single bond. Allenes, spiranes and alkylidenecycloalkanes are another type of axially chiral compounds and their axial chirality come from the perpendicular geometry of two pairs of substituents. The axial chirality in atropisomers, allenes and spiranes has been widely investigated and well developed, while the similar chirality in alkylidene‐cyclic molecules gained very limited attentions. This concept focuses on summarizing recent advances of axial chirality in alkylidene‐cyclic molecules and arouses the research interests to this promising field.

Carbene-Catalyzed Atroposelective Annulation for Quick Access to Axially Chiral Thiazine Derivatives.

An N-heterocyclic carbene (NHC)-catalyzed atroposelective annulation reaction is disclosed for quick and efficient access to thiazine derivatives. A series of axially chiral thiazine derivatives bearing various substituents and substitution patterns were produced in moderate to high yields with moderate to excellent optical purities. Preliminary studies revealed that some of our products exhibit promising antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) that causes rice bacterial blight.

Atroposelective Synthesis of Axially Chiral Styrenes by Nickel Hydride-Catalyzed Hydroarylation of Alkynes

Key words alkynes - atroposelectivity - axial chirality - hydroarylation - nickel catalysis

Organocatalytic Atroposelective Cross-Coupling of 1-Azonaphthalenes and 2-Naphthols.

Atroposelective cross-coupling is one of the most appealing routes to construct axially chiral binaphthyl molecules due to the modular and succinct nature. Although transition-metal-catalyzed cross-couplings offer reliable synthetic means, alternative reaction modes that could be applied to broader substrate range without their pre-functionalization is highly desirable. Herein we show that the application of chiral Brønsted acid catalyst as organocatalyst could accomplish cross-coupling of 1-azonaphthalenes and 2-naphthols with high efficiency, exclusive C4-selectivity as well as excellent enantioselectivity and functional group compatibility. The identification of acylimidazolinone auxiliary for azo activating group, effective remote catalyst control and arene resonance effect synergistically play key roles in the development of this method. The utility is further demonstrated by transformations of the products into other binaphthyl compounds with perfectly retained axial chirality.

Organocatalytic Atroposelective Cross‐Coupling of 1‐Azonaphthalenes and 2‐Naphthols

AbstractAtroposelective cross‐coupling is one of the most appealing routes to construct axially chiral binaphthyl molecules due to the modular and succinct nature. Although transition‐metal‐catalyzed cross‐couplings offer reliable synthetic means, alternative reaction modes that could be applied to broader substrate range without their pre‐functionalization is highly desirable. Herein we show that the application of chiral Brønsted acid catalyst as organocatalyst could accomplish cross‐coupling of 1‐azonaphthalenes and 2‐naphthols with high efficiency, exclusive C4‐selectivity as well as excellent enantioselectivity and functional group compatibility. The identification of acylimidazolinone auxiliary for azo activating group, effective remote catalyst control and arene resonance effect synergistically play key roles in the development of this method. The utility is further demonstrated by transformations of the products into other binaphthyl compounds with perfectly retained axial chirality.

Vibrational Circular Dichroism Studies on Axially Chiral Carbodiimides and Allenes

AbstractThe axial chirality of molecules with two consecutive double bonds (X=Y=Z) has not been well studied because of a lack of analytical methods and because of difficulties in their preparation in enantiomerically pure forms. This Synpacts article describes the use of vibrational circular dichroism spectroscopy to study the stereochemistry of carbodiimides and allenes. A strategy to obtain carbodiimides with one-handed chirality by using conformationally restrained frameworks is also discussed.1 Introduction2 Carbodiimides with Partially Biased Axial Chirality and One-Handed Axial Chirality3 Axially Chiral Allenes4 Conclusions

Korupensamine A, but not its atropisomer, korupensamine B, inhibits SARS-CoV-2 in vitro by targeting its main protease (Mpro).

By combining docking and molecular dynamics simulations, we explored a library of 65 mostly axially chiral naphthylisoquinoline alkaloids and their analogues, with most different molecular architectures and structural analogues, for their activity against SARS-CoV-2. Although natural biaryls are often regarded without consideration of their axial chirality, they can bind to protein targets in an atroposelective manner. By combining docking results with steered molecular dynamics simulations, we identified one alkaloid, korupensamine A, that atropisomer-specifically inhibited the main protease (Mpro) activity of SARS-CoV-2 significantly in comparison to the reference covalent inhibitor GC376 (IC50=2.52±0.14 and 0.88±0.15μM, respectively) and reduced viral growth by five orders of magnitude in vitro (EC50=4.23±1.31μM). To investigate the binding pathway and mode of interaction of korupensamine A within the active site of the protease, we utilized Gaussian accelerated molecular dynamics simulations, which reproduced the docking pose of korupensamine A inside the active site of the enzyme. The study presents naphthylisoquinoline alkaloids as a new class of potential anti-COVID-19 agents.

Dynamic Covalent Reactions and Chirality Sensing with Diphenylethene Derived Hemiaminals.

The differentiation of enantiomers is of significance in synthetic chemistry and pharmaceutical chemistry. Herein, we report a facile method for chirality sensing of monoalcohols, a challenging target due to the poor reactivity, by combining dynamic covalent chemistry with helical chirality. Four diphenylethene (DPE) derived cyclic hemiaminals were constructed, and the incorporation of a broad range of alcohols and thiols with high efficiency was achieved. The reversibility was further verified by dynamic component exchange. The helical chirality of the DPE motif was induced through chirality transfer by the central chirality of the analytes, resulting in circular dichroism responses. The chirality differentiation of seven chiral secondary alcohols including both alkyl and aryl alcohols was realized, further allowing the quantification of enantiomeric excess with high accuracy. The results described should lay a foundation for future endeavors in chemical sensing, asymmetric synthesis, and chiroptical materials.

Enantioseparation of new axially chiral carboxylic acids on polysaccharide-based chiral stationary phases under normal phase elution conditions

In the last decade, the availability of new and versatile synthetic strategies for the preparation of substituted 4,4’-bipyridyl derivatives based on chemo- and regioselective functionalization of the 4,4’-bipyridine core has encouraged studies for exploring the bioactivity of these compounds in the fields of drug discovery and medicinal chemistry. In substituted 4,4’-bipyridines, chirality may emerge from restricted rotation induced by sterically hindered atoms or functional groups located around the 4,4’-biaryl bond (chiral axis). The first atropisomeric substituted 4,4’-bipyridine was prepared in 2008, and no asymmetric synthesis to produce pure atropisomers of chiral 4,4’-bipyridine derivatives has been available so far. Thus, in the last few years, our groups developed methods to separate atropisomers of a wide series of 4,4’-derivatives by high-performance liquid chromatography (HPLC) using polysaccharide-based chiral stationary phases (CSPs). In the frame of our interest in this field, we reported herein the synthesis of two new chiral carboxylic acids containing an axially chiral 4,4’-bipyridyl unit as source of chirality, and their HPLC enantioseparation on polysaccharide-based CSPs. In particular, the impact of analyte and CSP structures on the enantioseparation outcomes as well as mechanisms and noncovalent interactions underlying the enantioseparation were explored by using electrostatic potential analysis and molecular dynamics (MD) simulations.

Optical properties of chiral three-dimensional photonic crystals

We perform a theoretical and numerical study of the optical properties of both direct and inverse three-dimensional (3D) chiral woodpile structures and a corresponding chiral Bragg stack, also known as a Reusch pile. We compute transmission spectra in the helical direction for finite crystals and photonic band structures, where we ensure the effective index of all structures to be the same. We find that both 3D structures show dual-band circular dichroism, where light with a particular circular polarization state---either left- or right-handed---reveals a broad stop band with major attenuation, whereas the other polarization state is transmitted nearly unimpeded. We observe such gaps in different frequency ranges with alternating handedness. The appearance of the circular-polarized gaps is successfully interpreted with a physical model wherein the circular polarization either corotates or counterrotates with the chiral structure, thereby effectively leading to a spatially dependent or a constant refractive index, and thus to the presence or absence of a gap. We find that the presence or absence of circularly polarized gaps is tuned by the transverse periods perpendicular to the chiral axis in both the 3D direct and inverse chiral woodpile crystal structures. The tunability of circular dichroism may find applications as on-chip sensors for circularly polarized light and in the on-chip detection of chiral molecules.

Copper-catalyzed asymmetric C(sp2)–H arylation for the synthesis of P- and axially chiral phosphorus compounds

Transition metal-catalyzed C–H bond functionalization is an important method in organic synthesis, but the development of methods that are lower cost and have a less environmental impact is desirable. Here, a Cu-catalyzed asymmetric C(sp2)–H arylation is reported. With diaryliodonium salts as arylating reagents, a range of ortho-arylated P-chiral phosphonic diamides were obtained in moderate to excellent yields with high enantioselectivities (up to 92% ee). Meanwhile, enantioselective C-3 arylation of diarylphosphine oxide indoles was also realized under similar conditions to construct axial chirality.

Synthesis of Pure Supramolecular Polymers from Poly(substituted Phenylacetylene)s by Highly Selective Photocyclic Aromatization and Their Characterization: Effect of the Structures and Properties of Precursor Covalent Polymers on those of the Resulting Pure Supramolecular Polymers

Several pure supramolecular polymers (SPs) were quantitatively synthesized by highly selective photocyclic aromatization (SCAT reaction) of poly(substituted phenylacetylene)s (CPs). The structures such as the degree of polymerization (DPn) and the one-handed helicities (chiralities) of the main chains of these precursor covalent polymers (CPs) were well-controlled by living or helix-sense-selective polymerizations. We found that the structures and properties of the resulting SPs were strongly influenced by those of the precursor CPs. In other words, some of the structures and properties of CPs were transferred to those of SPs. For example, the CPs with higher DPns yielded the corresponding SPs with higher DPns and strengths, and the CPs with one-handed helical chirality produced the corresponding SPs with enantioselective permeability in the membrane and supramolecular chirality in solution. In addition, since the shapes of solid materials from these CPs were transferred to the resulting SPs with some mechanical strength, they are promising for many practical applications such as membrane permeations.

The Role of Counteranion in Rhodium Catalysis

Key words Satoh–Miura reaction - axial chirality - counteranion-directed pathway switching - rhodium-catalyzed C–H activation

Organocatalytic Asymmetric Dearomatization Reaction for the Construction of Axially Chiral Urazole Embedded Naphthalenones

AbstractHerein we disclose a catalytic asymmetric dearomatization reaction of β‐naphthols with 4‐aryl‐1,2,4‐triazole‐3,5‐diones. A chiral phosphoric acid with spiro motif was found to be effective for this reaction. The chiral urazole embedded naphthalenones having both axial and central chirality were obtained in good to high yields (70–85%) with high diastereo‐ and enantioselectivities (>20:1, 8–96% ees), having C−N rotational energy barrier 31.54 K.Cal.mol−1 and t1/225 °C=589.8 years. The scope of the reaction was broad and few applications including a bromo‐amination reaction have been demonstrated.magnified image

Direct Catalytic Asymmetric and Regiodivergent N1‐ and C3‐Allenylic Alkylation of Indoles

AbstractHerein we report a Pd‐catalyzed asymmetric allenylic alkylation strategy for the direct functionalization of 1H‐indoles by employing P‐chiral BIBOP‐type ligands. The regioselectivity (N1/C3) of this process can be switched efficiently. Using Cs2CO3 at elevated temperatures in MeCN, N1‐alkylated indoles bearing axial chirality with a stereocenter non‐adjacent (β) to the nitrogen are produced in good yields with high enantioselectivity and complete N1‐regioselectivity regardless of the electronic properties and substitution patterns of diverse indoles. Using K2CO3 at room temperature in CH2Cl2, chiral C3‐alkylated indoles can also be obtained. Notably, we introduce a new class of tri‐substituted allenylic electrophiles that proceeded through different pathways from di‐substituted allenylic electrophiles.

Direct Catalytic Asymmetric and Regiodivergent N1- and C3-Allenylic Alkylation of Indoles.

Herein we report a Pd-catalyzed asymmetric allenylic alkylation strategy for the direct functionalization of 1H-indoles by employing P-chiral BIBOP-type ligands. The regioselectivity (N1/C3) of this process can be switched efficiently. Using Cs2 CO3 at elevated temperatures in MeCN, N1-alkylated indoles bearing axial chirality with a stereocenter non-adjacent (β) to the nitrogen are produced in good yields with high enantioselectivity and complete N1-regioselectivity regardless of the electronic properties and substitution patterns of diverse indoles. Using K2 CO3 at room temperature in CH2 Cl2 , chiral C3-alkylated indoles can also be obtained. Notably, we introduce a new class of tri-substituted allenylic electrophiles that proceeded through different pathways from di-substituted allenylic electrophiles.

Construction of Acyclic All‐Carbon Quaternary Stereocenters and 1,3‐Nonadjacent Stereoelements via Organo/Metal Dual Catalyzed Asymmetric Allenylic Substitution of Aldehydes

AbstractA method for the asymmetric construction of functionalized acyclic all‐carbon quaternary stereocenters and 1,3‐nonadjacent stereoelements has been developed via organo/metal dual catalyzed asymmetric allenylic substitution of branched and linear aldehydes, by developing an unknown acyclic secondary‐secondary diamine as the enabling organocatalyst. Although it is believed that secondary‐secondary diamines are difficult to be used as the organocatalysts in organo/metal dual catalysis, this study demonstrates that such diamines can be successfully combined with a metal catalyst in organo/metal dual catalysis. Our study enables the asymmetric construction of two important classes of motifs which were previously difficult to access, axially chiral allene‐containing acyclic all‐carbon quaternary stereocenters and 1,3‐nonadjacent stereoelements bearing allenyl axial chirality and central chirality, in good yields with high enantio‐ and diastereoselectivity.

Construction of Acyclic All-Carbon Quaternary Stereocenters and 1,3-Nonadjacent Stereoelements via Organo/Metal Dual Catalyzed Asymmetric Allenylic Substitution of Aldehydes.

A method for the asymmetric construction of functionalized acyclic all-carbon quaternary stereocenters and 1,3-nonadjacent stereoelements has been developed via organo/metal dual catalyzed asymmetric allenylic substitution of branched and linear aldehydes, by developing an unknown acyclic secondary-secondary diamine as the enabling organocatalyst. Although it is believed that secondary-secondary diamines are difficult to be used as the organocatalysts in organo/metal dual catalysis, this study demonstrates that such diamines can be successfully combined with a metal catalyst in organo/metal dual catalysis. Our study enables the asymmetric construction of two important classes of motifs which were previously difficult to access, axially chiral allene-containing acyclic all-carbon quaternary stereocenters and 1,3-nonadjacent stereoelements bearing allenyl axial chirality and central chirality, in good yields with high enantio- and diastereoselectivity.