Synthesis and Langmuir-Blodgett Film Analysis of Atropisomers of “Picket Fence” Porphyrin

Four ＂picket fence＂ porphyrin atropisomers were respectively synthesized from the four corresponding atropisomers of meso-tetra（o-aminophenyl）porphyrin that had been chromatographed on a column eluted with petroleum ether and ethyl acetate. Results show that each atropisomer could be successfully synthesized by controlling the acylation temperature at 0 ℃. They were characterized by 1H NMR, HRMS, IR, UV-Vis and Langmuir-Blodgett（LB） film analyses. Although the results of HRMS, IR, UV-Vis analyses indicate there is no remarkable difference among the atropisomers, the results of the 1H NMR and the mean molecular areas obtained by LB film technique imply that the atropisomers are significantly discrepant. The former shows that the chemical shifts of the methyl and amide protons of each atropisomer are distinct, while the later presents that the different atropisomer molecules can occupy the different surface areas at the air/water interface.

Separation of atropisomers by chiral liquid chromatography and thermodynamic analysis of separation mechanism

In the pharmaceutical industry, the analysis of atropisomers is of considerable interest from both scientific and regulatory perspectives. The compound of interest contains two stereogenic axes due to the hindered rotation around the single bonds connecting the aryl groups, which results in four potential configurational isomers(atropisomers). The separation of the four atropisomers was achieved on a derivatized β-cyclodextrin bonded stationary phase. Further investigation showed that low temperature conditions, including sample preparation(-70 °C), sample storage(-70 °C), and chromatographic separation(6 °C), were critical to preventing interconversion. LC-UV-laser polarimetric analysis identified peaks 1 and 2 as a pair of enantiomers and peaks3 and 4 as another. Thermodynamic analysis of the retention data indicated that the separation of the pairs of enantiomers is primarily enthalpy controlled as indicated by the positive slope of the van't Huff plot. The difference in absolute Δ(Δ H), ranged from 2.20 k J/mol to 2.42 k J/mol.

Catalytic asymmetric synthesis of sulfur-containing atropisomers by C-S bond formations

Chiral organosulfur compounds are not only widely distributed in bioactive natural products and pharmaceuticals,but also play a significant role in chiral ligands/catalysts.Throughout the history of synthetic organic chemistry,chemists have been absorbed in the construction of centrally chiral organosulfur compounds.Nevertheless,there are relatively few reports on installing sulfur functional groups into axially chiral compounds.Atropisomerism is one of the fundamental phenomena in nature,which ubiquitously exists in natural products.After more than a century of development,atropisomers have been designed and extensively applied to pharmaceuticals,functional materials and chiral ligands/catalysts.Due to the importance of chiral sulfurcontaining atropisomers,there is an increasing demand for enantioselective synthesis of them.Recently,a diversity of approaches by C-S bond formations have been established for the construction of enantioenriched sulfur-containing atropisomers,however,there is no comprehensive review to summarize this great progress.In this mini-review,we summarize recent progress in catalytic asymmetric synthesis of sulfur-containing atropisomers by C-S bond formations,which includes sulfur nucleophilic reactions,sulfur electrophilic reactions and sulfur radical reactions.Furthermore,the reaction mechanisms are also discussed.We hope that this mini-review will enable more researchers to further explore this field.

Stereoselective construction of atropisomers featuring a C-N chiral axis

Atropisomeric C-N compounds belong to an important class of axially chiral compounds.However,whereas the asymmetric synthesis of biaryl atropisomers have been well established,general and efficient strategies to access single enantiomers of C-N atropisomers are still rare.Until recently,innovative methods have been developed,providing new opportunities for the highly stereoselective synthesis of this vital class of atropisomers.Herein,we comprehensively summarize the development in this emerging field and give some insights into future advance.Emphasis is placed on the synthetic strategies.

Visible Light Accelerated Vinyl C-H Arylation in Pd-Catalysis：＂ Application in the Synthesis of ortho Tetra-substituted Vinylarene Atropisomers

A visible light accelerated C-H functionalization reaction in palladium-catalyzed arylation of vinyl arenes with diaryliodonium salts is reported in the absence of additional photosensitizer. The kinetic isotope effect （kH/kD） was changed from 3.6 （under darkness） to 1.1 when irradiated by visible light, which indicated that the C-H functionalization step was the rate determining step under darkness and significantly accelerated by the irradia- tion of visible light. Finally the synthesis of ortho tetra-substituted vinylarene atropisomers with high enantiospecificity was realized via this protocol.

“Atropisomeric” Drugs: Basic Concept and Example of Application to Drug Development

Many therapeutic drugs are racemates;i.e. they are chiral molecules consisting of “left”- and “right-handed” enantiomers (stereoisomers that are mirror images of each other, and are non-superimposable). In some cases, both enantiomers of the drug contribute to some extent (or equally) to the therapeutic effect;in other cases they contribute not at all. The same is true for the adverse effects of racemate drugs: the adverse effects of a racemate drug can be greater-than, less-than, or equal to one or the other enantiomer. An unusual situation arises when a drug consists of “atropisomers”, stereoisomers arising because of hindered rotation about a single chemical bond. We summarize the concept of atropisomerism, and give examples.

Recent advances in the construction of axially chiral arylpyrroles

Catalytic enantioselective preparation of axially chiral molecules has gained considerable interest over the past decades, due to their numerous applications in bioactive molecules, natural products, pharmaceuticals, materials, ligands, and catalysts. Compared with the well-established synthetic approaches for six-membered axially chiral skeletons, methodologies directed towards five-membered axially chiral compounds are relatively rare. Among these, axially chiral arylpyrroles are especially important structural motifs with wide utility, and the atroposelective synthesis of them is highly desirable. In recent years, novel strategies have been developed based on transition-metal catalysis and organocatalysis. This review summarizes the recent achievements in atroposelective preparation of arylpyrroles, by emphasizing the synthetic methods for each axially chiral framework, reaction mechanisms, and applications.

Chiral discrimination of small substituents in biaryl atropisomer construction:enantioselective synthesis of axially chiral 1-azafluorene via Ni-catalyzed[2+2+2]cycloaddition

Construction of axially chiral 1-azafluorenes via nickel-catalyzed[2+2+2]cycloaddition of alkynes and(o-alkynyl)benzyl nitriles is described.This strategy enables enantioselective discrimination of two sterically similar ortho substituents,such as H and F,during the construction of tri-ortho-substituted biaryl atropisomers.Mechanistic studies including the stereochemistry model and the stability of the atropenantiomers toward racemization are provided.The unique steric hindrance provided by 1-azafluorene skeleton and the fine chiral cavity of the nickel catalyst are key to achieving high enantioselectivity.

Construction of axially chiral compounds via catalytic asymmetric radical reaction

The chemistry of axially chiral compounds has emerged as a subject of increasing interest due to their widespread presence in natural products,bioactive molecules,advanced materials,and chiral ligands/catalysts.On the other hand,catalytic asymmetric radical-based transformations provide a complementary platform for the construction of enantiomerically enriched molecules that are in growing demand in the chemical and pharmaceutical in-dustries.In recent years,considerable research efforts have been devoted to the development of catalytic asymmetric radical reactions for the construction of axially chiral compounds based on the unique reactivity modes of diverse radicals.In this review,we critically illustrate these recent achievements according to different radical precursors and catalytic activation modes.Wherever possible,special emphasis is also placed on the discussion of mechanistic features underlying these works and substrate scopes.This review should be of great interest to the experts in this area,but also serve as a helpful starting point for new researchers in this field.

Atropisomer-based construction of a new perylene diimide macrocycle as visible-light photocatalyst for selective sulfide oxidation

By using a perylene diimine(PDI)syn-atropisomer as highly preorganized precursor,we successfully constructed a visible-light-active organic macrocycle PDI-M.The formation of macrocyclic structure effectively avoids self-aggregation of PDI cores and enhances the absorption in visible region.As a photocatalyst,PDI-M exhibits excellent activity on aerobic selective oxidation of sulfide into sulfoxide under visible light irradiation at room temperature.Mechanism studies show that both superoxide and singlet oxygen act as reactive oxygen species.This work provides a typical case toward the maximum utilization of photosensitive groups under mild conditions.