High Rotational Barrier Atropisomers.

Atropisomers have attracted a great deal of attention lately due to their numerous applications in organic synthesis and to their employment in drug discovery. However, the synthetic arsenal at our disposal with which to access them remains limited. The research described herein is two-pronged; we both demonstrate the use of MCR chemistry as a synthetic strategy for the de novo synthesis of a class of atropisomers having high barriers to rotation with the simultaneous insertion of multiple chiral elements and we study these unprecedented molecular systems by employing a combination of crystallography, NMR and DFT calculations. By fully exploiting the synthetic capabilities of our chemistry, we have been able to monitor a range of different types of interaction, i.e. π-π, CH-π, heteroatom-π and CD-π, in order to conduct structure-property studies. The results could be applied both to atroposelective synthesis and in drug discovery.

Atroposelective Arene-Forming Wittig Reaction by Phosphorus PIII/PV=O Redox Catalysis.

The Wittig reaction is renowned as exceptionally versatile method for converting a diversity of aldehydes and ketones into alkenes. Recently, strategies for chiral phosphine catalysis under PIII/PV=O redox cycling emerged to render this venerable transformation stereoselective. Herein, we describe that phosphine redox catalysis enables the enantioselective synthesis of pertinent biaryl atropisomers by means of a stereocontrolled arene-forming Wittig reaction. Key to the process is the release of an endogenous base from readily accessible tert-butyloxycarbonylated Morita-Baylis-Hillman adducts triggered by catalyst intramolecularization, permitting mild phosphine redox catalysis for atroposelective Wittig reactions. By this strategy, a broad diversity of biaryl atropisomers is obtained with up to 94:6 enantioselectivity.

Enantioselective Synthesis of Heteroatom-Linked Non-Biaryl Atropisomers.

Atropisomers hold significant fascination, not only for their prevalence in natural compounds but also for their biological importance and wide-ranging applications as chiral materials, ligands, and organocatalysts. While biaryl and heterobiaryl atropisomers are commonly studied, the enantioselective synthesis of less abundant heteroatom-linked non-biaryl atropisomers presents a formidable challenge in modern organic synthesis. Unlike classical atropisomers, these molecules allow rotation around two bonds, resulting in low barriers to enantiomerization through concerted bond rotations. In recent years the discovery of new configurationally stable rare non-biaryl scaffolds such as aryl amines, aryl ethers and aryl sulfones as well as innovative methodologies to control their configuration have been disclosed in the literature and constitute the topic of this minireview.

Secofumitremorgins C and D, a pair of atropisomers from saltern-derived fungus Aspergillus fumigatus GXIMD00544.

A pair of atropisomers secofumitremorgins C (1a) and D (1b), together with fifteen known alkaloids (2-16), were isolated from a saltern-derived fungus Aspergillus fumigatus GXIMD00544. The structures of atropisomers 1a and 1b were elucidated by the detailed spectroscopic data, chemical reaction and quantum chemical calculations. Compounds 1 and 8 displayed antifungal spore germination effects against plant pathogenic fungus associated with sugarcane Fusarium sp. with inhibitory rates of 53% and 77% at the concentration of 100 µM, repectively. Atropisomers 1 also exhibited antifouling potential against Balanus amphitrite larval settlement with an inhibitory rate of 96% at the concentration of 100 µM.

Cytotoxic indole diterpenoids and rare pyridoxatin atropisomers from the endophytic fungus Tolypocladium sp. SHJJ1.

Phytochemical investigation on the extract of endophytic fungus Tolypocladium sp. SHJJ1 resulted in the identification of a pair of previously undescribed pyridoxatin atropisomers [1 (M/P)] and three new indole diterpenoids (3-5), together with a pair of known pyridoxatin atropisomers [2 (M/P)] and ten known indole diterpenoids (6-15). Their structures, including their absolute configurations were elucidated by extensive spectroscopic analysis, quantum chemical calculations, and X-ray diffraction. Among the undescribed natural products, [1 (M/P)] that two rapidly interconverting atropisomers are the third example to report in the pyridoxatin atropisomers. Except for compounds 1 (M/P) and 2 (M/P), all other compounds were tested for their cytotoxicity using HepG2, A549, and MCF-7 human cell lines. Compound 9 displayed moderate cytotoxicity against the HepG2, A549, and MCF-7 cell lines with IC50 values of 32.39 ± 1.48 µM, 26.06 ± 1.14 µM, and 31.44 ± 1.94 µM, respectively, which was similar to the positive drug cisplatin (with IC50 values of 32.55 ± 1.76 µM, 18.40 ± 1.43 µM, and 27.31 ± 1.22 µM, respectively).

Catalytic Asymmetric Synthesis of N-N Biaryl Atropisomers.

Atropisomers have emerged as important structural scaffolds in natural products, drug design, and asymmetric synthesis. Recently, N-N biaryl atropisomers have drawn increasing interest due to their unique structure and relatively stable axes. However, its asymmetric synthesis remains scarce compared to its well-developed C-C biaryl analogs. In this concept, we summarize the asymmetric synthesis of N-N biaryl atropisomers including N-N pyrrole-pyrrole, N-N pyrrole-indole, N-N indole-indole, and N-N indole-carbazole, during which a series synthetic strategies are highlighted. Also, a synthetic evolution is briefly reviewed and an outlook of N-N biaryl atropisomers synthesis is offered.

Enantioselective Synthesis of Axially Chiral Diaryl Ethers via NHC Catalyzed Desymmetrization and Following Resolution.

Axially chiral diaryl ethers are present in numerous natural products and bioactive molecules. However, only few catalytic enantioselective approaches have been established to access diaryl ether atropisomers. Herein, we report the N-heterocyclic carbene-catalyzed enantioselective synthesis of axially chiral diaryl ethers via desymmetrization of prochiral 2-aryloxyisophthalaldehydes with aliphatic alcohols, phenol derivatives, and heteroaromatic amines. This reaction features mild reaction conditions, good functional group tolerance, broad substrate scope and excellent enantioselectivity. The utility of this methodology is illustrated by late-stage functionalization, gram-scale synthesis, and diverse enantioretentive transformations. Control experiments and DFT calculations support the association of NHC-catalyzed desymmetrization with following kinetic resolution to enhance the enantioselectivity.

Catalytic Atroposelective Synthesis of Axially Chiral Azomethine Imines and Neuroprotective Activity Evaluation.

Azomethine imines, as a prominent class of 1,3-dipolar species, hold great significance and potential in organic and medicinal chemistry. However, the reported synthesis of centrally chiral azomethine imines relies on kinetic resolution, and the construction of axially chiral azomethine imines remains unexplored. Herein, we present the synthesis of axially chiral azomethine imines through copper- or chiral phosphoric acid catalyzed ring-closure reactions of N'-(2-alkynylbenzylidene)hydrazides, showcasing high efficiency, mild conditions, broad substrate scope, and excellent enantioselectivity. Furthermore, the biological evaluation revealed that the synthesized axially chiral azomethine imines effectively protect dorsal root ganglia (DRG) neurons by inhibiting apoptosis induced by oxaliplatin, offering a promising therapeutic approach for chemotherapy-induced peripheral neuropathy (CIPN). Remarkably, the (S)- and (R)-atropisomers displayed distinct neuroprotective activities, underscoring the significance of axial stereochemistry.

On the Nature of the Rotational Energy Barrier of Atropisomeric Hydrazides.

N-N atropisomers represent a useful class of compounds that has recently received important attention from many research groups. This article presents an in-depth analysis of the energy barrier needed for the racemization process of atropoisomeric hydrazides, combining an experimental and computational approach. The focus is on examining how electronic and steric factors impact the racemization process. The results obtained indicate that the barrier observed during the racemization process mainly arises from an increase in the p-orbital character of the nitrogen atoms.

The Effect of Intramolecular Hydrogen Bonds on the Rotational Barriers of the Biaryl C-C Axis.

Axially chiral compounds are attracting more attention recently. Although hydrogen bonds are reported as a vital weak force that influences the properties of compounds, the effect of intramolecular hydrogen bonds on the atropisomerization of the Caryl -Caryl single bonds has not yet been well quantitatively investigated. Here, a series of axially chiral biaryl compounds were synthesized to study the effect of hydrogen bonds on the rotational barriers of the biaryl C-C axis. Experimental studies demonstrated that the rotational barrier of hydrogen bonding biaryl 9 was significantly lower (46.7 kJ mol-1 ) than biaryl 10 without hydrogen bonds. Furthermore, theoretical studies revealed that the intramolecular hydrogen bond stabilized the transition state (TS) of tri-ortho-substituted biaryl 9, relieving the steric repulsion in the TS. We believe that this study will provide chemists with a deeper understanding of the atropisomerization process of axially chiral biaryl compounds.

Atroposelective PIII /PV =O Redox Catalysis for the Isoquinoline-Forming Staudinger-aza-Wittig Reaction.

Herein, we describe the feasibility of atroposelective PIII /PV =O redox organocatalysis by the Staudinger-aza-Wittig reaction. The formation of isoquinoline heterocycles thereby enables the synthesis of a broad range of valuable atropisomers under mild conditions with enantioselectivities of up to 98 : 2 e.r. Readily prepared azido cinnamate substrates convert in high yield with stereocontrol by a chiral phosphine catalyst, which is regenerated using a silane reductant under Brønsted acid co-catalysis. The reaction provides access to diversified aryl isoquinolines, as well as benzoisoquinoline and naphthyridine atropisomers. The products are expeditiously transformed into N-oxides, naphthol and triaryl phosphine variants of prevalent catalysts and ligands. With dinitrogen release and aromatization as ideal driving forces, it is anticipated that atroposelective redox organocatalysis provides access to a multitude of aromatic heterocycles with precise control over their configuration.

Parity Violation Energy Difference Calculation of Atropisomers.

Enantiomers have a different energy due to the parity violation effects. Up to now, these effects are difficult to calculate and their final effect on the choice of one enantiomer in the homochirality issue is still a matter of debate. Nevertheless, many scientists support the role of this tiny energy difference in the triggering of homochirality. In this work, we studied the energy difference in atropisomers, a class of stereoisomers in which the chirality is given by the block of rotation around one bond. Atropisomers might have a low energy barrier for the interconversion and this is interesting for the equilibration of the two enantiomers and the choice of the most stable enantiomer. Moreover, structures might be extended like in the case of polymers or crystals having helical framework and thus giving an additive effect on the parity violation energy of the whole structure. The parity violation energy difference here is discussed with the correlation on the general structure of the final molecule giving a qualitative model to predict the sign of local contributions of atoms.

Enantioselective Synthesis of Atropisomers by Oxidative Aromatization with Central-to-Axial Conversion of Chirality.

Atropisomers are fascinating objects of study by themselves for chemists but also find applications in various sub-fields of applied chemistry. Obtaining them in enantiopure form is far from being a solved challenge, and the past decades has seen a surge of methodological developments in that direction. Among these strategies, oxidative aromatization with central-to-axial conversion of chirality has gained increasing popularity. It consists of the oxidation of a cyclic non-aromatic precursors into the corresponding aromatic atropisomers. This review proposes a critical analysis of this research field by delineating it and discussing its historical background and its present state of the art to draw potential future development directions.

Enantioselective Strategies for The Synthesis of N-N Atropisomers.

Axially chiral compounds have been always considered a laboratory curiosity with rare prospects of being applied in asymmetric synthesis. Things have changed very quickly in the last twenty years when it was understood the important role and the enormous impact that these compounds have in medicinal, biological and material chemistry. The asymmetric synthesis of atropisomers became a rapidly expanding field and recent reports on the development of N-N atropisomers strongly prove how this research field is a hot topic open to new challenges and frontiers of asymmetric synthesis. This review focuses on the recent advances in the enantioselective synthesis of N-N atropisomers highlighting the strategies and breakthroughs to obtain this novel and stimulating atropisomeric framework.

Catalyst Control over Threefold Stereogenicity: Selective Synthesis of Atropisomeric Sulfones with Stereogenic C-S Axes.

Catalyst control over higher-order stereogenicity addresses significantly extended stereochemical space, but selective methods to govern threefold stereogenic units remained elusive. Herein, we report the stereoselective synthesis of threefold stereogenic triptycyl sulfones with atropisomerism arising from a C(sp3 )-S bond. An oxidation of a stereodynamic thioether controlled by a chiral phosphoric acid catalyst allowed selective access to enantioenriched triptycyl sulfoxides. The ensuing enantiospecific and diastereoselective catalytic oxidation to a threefold stereogenic sulfone provided overall control over the stereogenic C-S axis. All three stereoisomers were addressable with enantio- and diastereodivergence and a stereoselectivity of up to (-sc): (+sc) : (ap)=94 : 6 :<1.

Chiral Atropisomeric-NHC Catechodithiolate Ruthenium Complexes for Z-Selective Asymmetric Ring-Opening Cross Metathesis of Exo-Norbornenes.

A set of 16 chiral ruthenium complexes containing atropisomerically stable N-Heterocyclic Carbene (NHC) ligands was synthesized from prochiral NHC precursors. After a rapid screening in asymmetric ring-opening-cross metathesis (AROCM), the most effective chiral atrop BIAN-NHC Ru-catalyst (up to 97 : 3 er) was then converted to a Z-selective catechodithiolate complex. The latter proved to be highly efficient in Z-selective AROCM of exo-norbornenes affording valuable trans-cyclopentanes with excellent Z-selectivity (>98 %) and high enantioselectivity (up to 96.5 : 3.5 er).

Organocatalytic Enantioselective Synthesis of Axially Chiral N,N'-Bisindoles.

This study establishes the first organocatalytic enantioselective synthesis of axially chiral N,N'-bisindoles via chiral phosphoric acid-catalyzed formal (3+2) cycloadditions of indole-based enaminones as novel platform molecules with 2,3-diketoesters, where de novo indole-ring formation is involved. Using this new strategy, various axially chiral N,N'-bisindoles were synthesized in good yields and with excellent enantioselectivities (up to 87 % yield and 96 % ee). More importantly, this class of axially chiral N,N'-bisindoles exhibited some degree of cytotoxicity toward cancer cells and was derived into axially chiral phosphine ligands with high catalytic activity. This study provides a new strategy for enantioselective synthesis of axially chiral N,N'-bisindoles using asymmetric organocatalysis and is the first to realize the applications of such scaffolds in medicinal chemistry and asymmetric catalysis.

A Dynamic Thermodynamic Resolution Strategy for the Stereocontrolled Synthesis of Streptonigrin.

We report that axially chiral biaryl boronic esters can be generated with control of atroposelectivity by a Binol-mediated dynamic thermodynamic resolution process. These intermediates can be progressed to enantioenriched products through stereoretentive functionalization of the carbon-boron bond. Finally, we have exploited this method in the first highly stereoselective total synthesis of P-streptonigrin.

Atroposelective Amination of Indoles via Chiral Center Induced Chiral Axis Formation.

The construction of an N-C chiral axis for N-aryl indole derivatives is meaningful as they widely exist in functionalized molecules. This work provides a novel method for this purpose via amination of amino acid derivatives at the C2 position of the indole and chiral center induced chiral axis formation. The protocol of this transformation is easily accessible, not requiring metal or an organic chiral catalyst, endowing this method with great potential in the construction of axis chiral N-aryl indoles.

Trans enantiomeric separation of MESA and MOXA, two environmentally important metabolites of the herbicide, metolachlor.

Complete separation of the trans-enantiomers of the two most abundant, persistent polar metabolites of metolachlor, metolachlor ethane sulfonic acid (MESA) and metolachlor oxanilic acid (MOXA), was achieved using UPLC equipped with a reverse phase chiral column and trace detection with an electrospray triple quadrupole mass spectrometer. Various conditions that influenced the separation and instrumental signal were investigated to achieve the optimum separation and instrument response within an analysis time of less than 30 minutes. Different eluting solvent compositions for each metabolite were required for optimized separation of of the 4 enantiomers. Standard curves were responsive to less than 13 ng/mL and 8 ng/mL for the least plentiful MOXA and MESA enantiomers, respectively with a linear coefficient of determination greater than 0.998. Suitability of the method for quantification of the 4 mixed enantiomers of each was demonstrated using natural surface water samples collected from the Choptank River watershed in Eastern Maryland.•LC chiral separation parameters were varied to achieve optimal separation of the major enantiomers of the two metolachlor metabolites.•LC/MS-MS parameters were adjusted to maximize response and minimize analysis time.•Finished methods were used to quantitate enantiomers in archived stream water extracts from agricultural watersheds with corn/soybean production.