Asymmetric Synthesis of an Atropisomeric ß-Carboline via Regioselective Intermolecular Rh(I)-Catalyzed [2 + 2 + 2] Cyclotrimerization.

The rational design of atropisomeric small molecules is becoming increasingly common in chemical synthesis as a result of the unique advantages this property provides in drug discovery, asymmetric catalysis, and chiroptical activity. In this study, we designed a synthesis of a configurationally stable ß-carboline in six steps. Our synthesis made use of an innovative Grignard addition/elimination reaction that formed an yne-ynamide precursor that then reacted with ethyl cyanoformate in a rhodium(I)-catalyzed [2+2+2] cyclotrimerization reaction to give the atropisomeric ß-carboline in excellent yield, good enantioselectivity, and excellent regioselectivity. Extensive optimization of this transformation is described. Racemization kinetics experiments were also conducted on the individual atropisomers and their absolute configurations were determined by circular dichroism.

Symmetric Anion Mediated Dynamic Kinetic Asymmetric Knoevenagel Reaction for N-C and N-N Atropisomers Synthesis.

A symmetric anion mediated dynamic kinetic asymmetric Knoevenagel reaction was established as a general and efficient method for accessing both N-C and N-N atropisomers. The resulting highly enantio-pure pyridine-2,6(1H,3H)-diones exhibit diverse structures and functional groups. The key to excellent regio- and remote enantiocontrol could be owed to the hydrogen bond between the enolate anion and triflamide block of the organocatalyst. This connected the enolate anion and iminium cation by a chiral backbone. The mechanism investigation via control experiments, correlation analysis, and density functional theory calculations further revealed how the stereochemical information was transferred from the catalyst into the axially chiral pyridine-2,6(1H,3H)-diones. The synthetic applications also demonstrated the reaction's potential.

Synthesis of Alkene Atropisomers with Multiple Stereogenic Elements via Catalytic Asymmetric Rearrangement of 3-Indolylmethanols.

Catalytic enantioselective preparation of alkene atropisomers with multiple stereogenic elements and discovery of their applications have become significant but challenging issues in the scientific community due to the unique structures of this class of atropisomers. We herein report the first catalytic atroposelective preparation of cyclopentenyl[b]indoles, a new kind of alkene atropisomers, with stereogenic point and axial chirality via an unusual rearrangement reaction of 3-indolylmethanols under asymmetric organocatalysis. Notably, this novel type of alkene atropisomers have promising applications in developing chiral ligands or organocatalysts, discovering antitumor drug candidates and fluorescence imaging materials. Moreover, the theoretical calculations have elucidated the possible reaction mechanism and the non-covalent interactions to control the enantioselectivity. This approach offers a new synthetic strategy for alkene atropisomers with multiple stereogenic elements, and represents the first catalytic enantioselective rearrangement reaction of 3-indolylmethanols, which will advance the chemistry of atropisomers and chiral indole chemistry.

Computation-guided scaffold exploration of 2E,6E-1,10-trans/cis-eunicellanes.

Eunicellane diterpenoids are a unique family of natural products containing a foundational 6/10-bicyclic framework and can be divided into two main classes, cis and trans, based on the configurations of their ring fusion at C1 and C10. Previous studies on two bacterial diterpene synthases, Bnd4 and AlbS, revealed that these enzymes form cis- and trans-eunicellane skeletons, respectively. Although the structures of these diterpenes only differed in their configuration at a single position, C1, they displayed distinct chemical and thermal reactivities. Here, we used a combination of quantum chemical calculations and chemical transformations to probe their intrinsic properties, which result in protonation-initiated cyclization, Cope rearrangement, and atropisomerism. Finally, we exploited the reactivity of the trans-eunicellane skeleton to generate a series of 6/6/6 gersemiane-type diterpenes via electrophilic cyclization.

Stereochemical properties of quazepam and its affinity for the GABAA receptor.

C9-methylated quazepam 1 was prepared, and its physicochemical properties were investigated. The atropisomers of 1 were isolated as (a1R, a2S) and (a1S, a2R) isomers. Their absolute configurations were determined based on ECD spectra in comparison with those calculated using the time-dependent density functional theory. Preliminary examination of affinity for the GABAA receptor revealed that the (a1R, a2S) isomer of 1 possessed higher activity than its antipode (a1S, a2R) isomer. The active configuration of C9-methylated quazepam 1 is the same as that of 1,4-benzodiazepin-2-ones.

Regio- and Atroposelective Ring-Opening of 1H-Benzo[4,5]oxazolopyridinones.

The development of new methods for regio- and stereoselective activation of C-O bonds in ethers holds significant promise for synthetic chemistry, offering advantages in terms of environmental sustainability and economic efficiency. Moreover, the C-N atropisomers represent a fascinating and crucial chiral system, extensively found in natural products, pharmaceutical leads, and the frameworks of advanced materials. In this work, we have introduced a nickel-catalyzed regio- and enantioselective carbon-oxygen arylation reaction for atroposelective synthesis of N-arylisoquinoline-1,3(2H,4H)-diones. The high regioselectivity of C-O cleavage benefits from the high stability of the in situ formed (amido)ethenolate via oxidative addition. Additionally, the self-activation of the aryl C-O bond facilitates the reaction under mild conditions, leading to outstanding enantioselectivities. The diverse post-functionalizations of the axially chiral isoquinoline-1,3(2H,4H)-diones further highlighted the utility of this protocol in preparing valuable C-N atropisomers, including the chiral phosphine ligands.

Atroposelective Synthesis of Planar-Chiral Indoles via Carbene Catalyzed Macrocyclization.

Indole-based planar-chiral macrocycles are widely found in natural products and bioactive molecules. However, in sharp contrast to the preparation of indole-based axially chiral structures, the enantioselective catalysis of indole-based planar-chiral macrocycles is still a formidable task so far. Here we report an N-heterocyclic carbene (NHC)-catalyzed intramolecular atroposelective macrocyclization of 3-carboxaldehyde indole/pyrroles, featuring with broad substrate scope and good functional group tolerance, and allowing for a rapid access to diverse indole/pyrrole-based planar-chiral macrocycles with various tether-lengths (10-16 members) in good yields and with excellent enantioselectivities. Importantly, the indole-based macrocyclic structures with both planar and axial chirality were directly and efficiently obtained through this protocol with excellent enantioselectivities and diastereoselectivities. In addition, these synthesized planar-chiral macrocycles offer many possibilities for chemists to develop new catalysts or ligands, as well as new reactions.

Catalytic Asymmetric Synthesis of Atropisomers Bearing Multiple Chiral Elements: An Emerging Field.

With the rapid development of asymmetric catalysis, the demand for the enantioselective synthesis of complex and diverse molecules with different chiral elements is increasing. Owing to the unique features of atropisomerism, the catalytic asymmetric synthesis of atropisomers has attracted a considerable interest from the chemical science community. In particular, introducing additional chiral elements, such as carbon centered chirality, heteroatomic chirality, planar chirality, and helical chirality, into atropisomers provides an opportunity to incorporate new properties into axially chiral compounds, thus expanding the potential applications of atropisomers. Thus, it is important to perform catalytic asymmetric transformations to synthesize atropisomers bearing multiple chiral elements. In spite of challenges in such transformations, in recent years, chemists have devised powerful strategies under asymmetric organocatalysis or metal catalysis, synthesizing a wide range of enantioenriched atropisomers bearing multiple chiral elements. Therefore, the catalytic asymmetric synthesis of atropisomers bearing multiple chiral elements has become an emerging field. This review summarizes the rapid progress in this field and indicates challenges, thereby promoting this field to a new horizon.

Design and Catalytic Asymmetric Synthesis of Furan-Indole Compounds Bearing both Axial and Central Chirality.

In the chemistry community, catalytic asymmetric synthesis of furan-based compounds bearing both axial and central chirality has proven to be a significant but challenging issue owing to the importance and difficulty in constructing such frameworks. In this work, we have realized the first catalytic asymmetric synthesis of five-five-membered furan-based compounds bearing both axial and central chirality via organocatalytic asymmetric (2+4) annulation of achiral furan-indoles with 2,3-indolyldimethanols with uncommon regioselectivity. By this strategy, furan-indole compounds bearing both axial and central chirality were synthesized in high yields with excellent regio-, diastereo-, and enantioselectivities. Moreover, theoretical calculations were conducted to provide an in-depth understanding of the reaction pathway, activation mode, and the origin of the selectivity.

Diaryl-Pyrano-Chromenes Atropisomers: Stereodynamics and Conformational Studies.

The dynamic scenario of di-aryls-pyrano-chromenes was investigated using DFT calculations. The symmetry of the chromene scaffold and the presence of two ortho-substituted aryls substituents can generate two syn/anti diastereoisomers and conformational enantiomers with different rotational barriers. The relative conformations and configurations were derived using NOESY-1D experiments. Depending on the energies related to the conformational exchange, the experimental energy barriers were determined through Dynamic NMR, Dynamic HPLC or kinetic studies. The atropisomeric pairs were resolved in the latter scenario, and their absolute configuration was assigned using the ECD/TD-DFT method.

Stereochemistry of N-Acyl-5H-dibenzo[b,d]azepin-7(6H)-ones.

The stereochemical properties of N-acyl-5H-dibenzo[b,d]azepin-7(6H)-ones (2a-c), which inhibit potassium channels in T cells, were examined by freezing their conformational change due to 4-methyl substitution. N-Acyl-5H-dibenzo[b,d]azepin-7(6H)-ones exist as pairs of enantiomers [(a1R, a2R), (a1S, a2S)], and each atropisomer is separable at room temperature. An alternate procedure for preparing 5H-dibenzo[b,d]azepin-7(6H)-ones involves the intramolecular Friedel-Crafts cyclization of N-benzyloxycarbonylated biaryl amino acids. Consequently, the N-benzyloxy group was removed during the cyclization reaction to produce 5H-dibenzo[b,d]azepin-7(6H)-ones suitable for the subsequent N-acylation reaction.

Asymmetric Synthesis of Axially Chiral Molecules via Organocatalytic Cycloaddition and Cyclization Reactions.

Atropisomeric molecules are present in many natural products, biologically active compounds, chiral ligands and catalysts. Many elegant methodologies have been developed to access axially chiral molecules. Among them, organocatalytic cycloaddition and cyclization have attracted much attention because they have been widely used in the asymmetric synthesis of biaryl/heterobiaryls atropisomers via construction of carbo- and hetero-cycles. This strategy has undoubtedly become and will continue to be a hot topic in the field of asymmetric synthesis and catalysis. This review aims to highlight the recent advancements in this field of atropisomer synthesis by using different organocatalysts in cycloaddition and cyclization strategies. The construction of each atropisomer, its possible mechanism, the role of catalysts, and its potential applications are illustrated.

Enantioselective Synthesis of N-N Biaryl Atropisomers through Iridium(I)-Catalyzed C-H Alkylation with Acrylates.

Enantioselective synthesis of N-N biaryl atropisomers is an emerging area but remains underexplored. The development of efficient synthesis of N-N biaryl atropisomers is in great demand. Herein, the construction of N-N biaryl atropisomers through iridium-catalyzed asymmetric C-H alkylation is reported for the first time. In the presence of readily available Ir precursor and Xyl-BINAP, a variety of axially chiral molecules based on indole-pyrrole skeleton were obtained in good yields (up to 98 %) with excellent enantioselectivity (up to 99 % ee). In addition, N-N bispyrrole atropisomers could also be synthesized in excellent yields and enantioselectivity. This method features perfect atom economy, wide substrate scope, and multifunctionalized products allowing diverse transformations.

Atropostatin: Design and Total Synthesis of an Atropisomeric Lactone-Atorvastatin Prodrug.

Atorvastatins play an important role in the inhibition of HMG-CoA reductase, an enzyme present in the liver that takes part in the biosynthesis of cholesterol. In this article, we report the total synthesis of a lactone-atorvastatin prodrug with additional atropisomeric features. Conformational and experimental studies of model compounds were designed to test the stability of the chiral axis. Docking calculations were performed to evaluate the constant inhibition of a library of atorvastatins. Full synthesis of the best candidate was achieved and thermally stable atropisomeric lactone-atorvastatin was obtained. The absolute configuration of the chiral axis of the atropisomers was assigned by means of chiroptical ECD spectroscopy coupled with TD-DFT calculations.

Syntheses and crystal structure of a (2,6-diiso-propyldi-naphtho-[2,1-d:1',2'-f][1,3]dithiepin-4-yl)(phen-yl)methanol atropisomer.

The racemic title compound, C34H32OS2, comprises an atropisomeric binaphthyl di-thio-acetal substituted at the methyl-ene carbon atom with a chiral benzyl alcohol. The two naphthalene ring systems are additionally substituted at the 3,3'-position with isopropyl groups. The overall stereochemistry is defined as aS,R and aR,S. The hydroxyl group forms an intra-molecular O-H⋯S hydrogen bond to one of the sulfur atoms. The crystal structure contains weak C-H⋯π inter-actions that link the mol-ecules into extended arrays.

Development of axially chiral urazole scaffolds for antiplant virus applications against potato virus Y.

BACKGROUND: Potato virus Y (PVY) was first discovered by Smith in 1931 and is currently ranked as the fifth most significant plant virus. It can cause severe damage to plants from the family Solanaceae, which results in billions of dollars of economic loss worldwide every year. To discover new antiviral drugs, a class of multifunctional urazole derivatives bearing a stereogenic CN axis were synthesized with excellent optical purities for antiviral evaluations against PVY. RESULTS: The absolute configurations of the axially chiral compounds exhibited obvious distinctions in antiviral bioactivities, with several of these enantio-enriched axially chiral molecules showing excellent anti-PVY activities. In particular, compound (R)-9f exhibited remarkable curative activities against PVY with a 50% maximal effective concentration (EC50 ) of 224.9 µg mL-1 , which was better than that of ningnanmycin (NNM), which had an EC50 of 234.0 µg mL-1 . And the EC50 value of the protective activities of compound (R)-9f was 462.2 µg mL-1 , which was comparable to that of NNM (442.0 µg mL-1 ). The mechanisms of two enantiomer of the axially chiral compounds 9f were studied by both molecule docking and defensive enzyme activity tests. CONCLUSION: Mechanistic studies demonstrated that the axially chiral configurations of the compounds played significant roles in the molecule PVY-CP (PVY Coat Protein) interactions and could enhance the activities of the defense enzymes. The (S)-9f showed only one carbon-hydrogen bond and one π-cation interaction between the chiral molecule and the PVY-CP amino acid sites. In contrast, the (R)-enantiomer of 9f exhibited three hydrogen bonding interactions between the carbonyl groups and the PVY-CP active sites of ARG157 and GLN158. The current study provides significant information on the roles that axial chiralities play in plant protection against viruses, which will facilitate the development of novel green pesticides bearing axial chiralities with excellent optical purities. © 2023 Society of Chemical Industry.

Synthesis and stereodynamics of intramolecular hemiacetals in biaryl aldehyde-alcohols.

Soai's asymmetric autocatalysis represents a highly remarkable example for spontaneous symmetry breaking and enantioselective amplification in the enantioselective alkylation of pyrimidine-5-carbaldehydes to the corresponding chiral pyrimidine alcohols. Recently, zinc hemiacetalate complexes, formed from pyrimidine-5-carbaldehydes and the chiral product alcohol, were identified by in situ high-resolution mass spectrometric measurements as highly active transient asymmetric catalysts in this autocatalytic transformation. To study the formation of such hemiacetals and their stereodynamic properties, we focused on the synthesis of coumarin homolog biaryl systems with carbaldehyde and alcohol substituents. Such systems are able to form hemiacetals by intramolecular cyclization. An interesting feature of the substituted biaryl backbone is that tropos and atropos systems can be obtained, enabling or disabling the intramolecular cyclization to hemiacetals. Biaryl structures with various functional groups were synthesized, and the equilibrium and stereodynamics between the closed and open structures were investigated by dynamic enantioselective HPLC (DHPLC). The enantiomerization barriers ΔGǂ and activation parameters ΔHǂ and ΔSǂ were determined from temperature dependent kinetic measurements.

An Atropisomerism Study of Large Cycloarylenes: [n]Cyclo-4,10-Pyrenylenes' Case.

An atropisomerism of large cycloarylenes was studied using [n]cyclo-4,10-pyrenylenes (n=6-21) as an illustrative example with two simple assumptions: (1) alternating configurations (R,S,R,S,…) are thermodynamically most stable, and (2) three consecutive identical configurations (R,R,R or S,S,S) are prevented. Ni-mediated coupling of a 5,9-diiodopyrene gave a series of directly-linked cyclic pyrene oligomers in one-pot reaction. As-synthesized cyclic hexamer was assigned as an (R,S,S,R,R,S) structure, converted into an (R,S,R,S,R,S)-form upon heating. Cyclic heptamer consists of two types of C2 symmetric structures predicted from assumption (2), one of which was convergent to one another by heating. Three atropisomers of cyclic octamer were analyzed from the possible five candidates by means of 1 H nuclear magnetic resonance (NMR) spectroscopy, and the conversion process to (R,S,R,S,R,S,R,S) configurations upon heating was investigated. In total, according to two simple rules, the analysis of atropisomerism could be performed smoothly.

Syntheses and crystal structures of two di-naph-tho[2,1-d:1',2'-f][1,3]dithiepine atropisomers.

The closely related title compounds, 1-(di-naphtho-[2,1-d:1',2'-f][1,3]dithiepin-4-yl)-2,2-di-methyl-propan-1-ol, C26H24OS2, 1 and 2-(di-naphtho-[2,1-d:1',2'-f][1,3]dithiepin-4-yl)-3,3-di-methyl-butan-2-ol, C27H26OS2, 2, both comprise an atrop-isomeric binaphthyl di-thio-acetal unit substituted at the methyl-ene carbon atom with a chiral neopentyl alcohol grouping. The overall stereochemistry of the racemate in each case is defined as aS,R and aR,S. In 1, the hydroxyl group generates inversion dimers via pairwise inter-molecular O-H⋯S hydrogen bonds whereas in 2, the O-H⋯S link is intra-molecular. Weak C-H⋯π inter-actions link the mol-ecules into extended arrays in both structures.

Novel 1,2,4-triazoles derived from Ibuprofen: synthesis and in vitro evaluation of their mPGES-1 inhibitory and antiproliferative activity.

Some novel triazole-bearing ketone and oxime derivatives were synthesized from Ibuprofen. In vitro cytotoxic activities of all synthesized molecules against five cancer lines (human breast cancer MCF-7, human lung cancer A549, human prostate cancer PC-3, human cervix cancer HeLa, and human chronic myelogenous leukemia K562 cell lines) were evaluated by MTT assay. In addition, mouse embryonic fibroblast cells (NIH/3T3) were also evaluated to determine the selectivity. Compounds 18, 36, and 45 were found to be the most cytotoxic, and their IC50 values were in the range of 17.46-68.76 µM, against the tested cancer cells. According to the results, compounds 7 and 13 demonstrated good anti-inflammatory activity against the microsomal enzyme prostaglandin E2 synthase-1 (mPGES-1) enzyme at IC50 values of 13.6 and 4.95 µM. The low cytotoxicity and non-mutagenity of these compounds were found interesting. Also, these compounds significantly prevented tube formation in angiogenesis studies. In conclusion, the anti-inflammatory and angiogenesis inhibitory activities of these compounds without toxicity suggested that they may be promising agents in anti-inflammatory treatment and they may be supportive agents for the cancer treatment.