Asymmetric Synthesis Research Articles

Pd-Catalyzed Asymmetric Synthesis of Chiral 2-Trifluoromethyl-4-(indol-3-yl)-4H-chromene Derivatives.

This paper presents a new strategy for the construction of the chiral 4H-chromene skeleton. A series of chiral 2-trifluoromethyl-4-(indol-3-yl)-4H-chromenes were synthesized in moderate to good yields (60-92%) with excellent enantioselectivity (up to 97% ee) through the palladium-catalyzed asymmetric condensation of 2H-chromenes and indoles. These trifluoromethylated, stereochemically rich building blocks hold potential value in medicinal chemistry.

Stereoselective Reaction Enabling Simultaneous Analysis of Carbon-Carbon Double-Bond Configuration and the Position of Monounsaturated Fatty Acids through UHPLC-ESI-MRM-MS.

Monounsaturated fatty acids (MUFA) are an important class of nutrients and are involved in lipid metabolism. The positions of the C=C bond and cis-trans isomerism have a significant influence on their physiological activity. However, simultaneously detecting these two structural properties has been challenging due to multiple isomers of MUFA. In this study, we developed a method that involved an N-aminophthalimide (PhthNH2) derivatization of the C=C bond in MUFA, followed by analysis using ultrahigh-performance liquid chromatography-electrospray ionization-multiple reaction monitoring mass spectrometry (UHPLC-ESI-MRM-MS) technology to achieve analysis of cis-trans isomers and positional isomers of the C=C bond. The derivatives of cis-trans isomers of the C=C bond were well separated in UHPLC, and their corresponding C=C bond positions were deduced from characteristic fragment ions in tandem mass spectrometry. With our method, we found MUFA with different double-bond positions and cis-trans isomers in several samples, including mouse kidney, butter, etc., achieving qualitative analysis and relative quantitation. This method is expected to be applied by more researchers in lipidomics studies in the future.

Symmetry Breaking: Case Studies with Organic Cage-Racemates.

ConspectusSymmetry is a pervasive phenomenon spanning diverse fields, from art and architecture to mathematics and science. In the scientific realms, symmetry reveals fundamental laws, while symmetry breaking─the collapse of certain symmetry─is the underlying cause of phenomena. Research on symmetry and symmetry breaking consistently provides valuable insights across disciplines, from parity violation in physics to the origin of homochirality in biology. Chemistry is particularly rich in symmetry breaking studies, encompassing areas such as asymmetric synthesis, chiral resolution, chiral structure assembly, and so on. Across different disciplines, a well-defined methodology is fundamental and necessary to analyze the symmetry or symmetry breaking nature behind the phenomenon, enabling researchers to uncover the underlying principles and mechanisms. Basically, three key points underpin symmetry-related research: the scale-dependency of symmetry/symmetry breaking, the driving force behind symmetry breaking phenomena, and the properties arising from symmetry breaking.This Account will focus on the three aforementioned key points elucidated with organic cages as proof-of-concept models, as organic cages exhibit shape-persistent 3D molecular frameworks, well-defined molecular motion, and a high propensity for crystallization.First, we examine racemization processes of organic cages with dynamic molecular motions to illustrate that symmetry and symmetry breaking are time-scale-dependent. Specifically, the racemization, driven by molecular motion, is influenced by hydrogen bonding and the rigidity of the cage framework, which may or may not be observable within the experimental temporal scale. This determines whether the enantiomeric excess system, namely, the symmetry broken system, can be detected experimentally. We also investigate the hierarchical structures self-assembled by racemic organic cages, demonstrating that symmetry and asymmetry manifest differently across spatial scales, from molecular to supramolecular and macroscopic levels. Second, we discuss the driving force behind spontaneous chiral resolution─a classic symmetry-breaking event during crystallization─from a thermodynamic perspective. We suggest that racemic compounds, compared to conglomerates, are more entropy-favored, explaining their greater prevalence in nature. Spontaneous chiral resolution can take place only when a favorable enthalpy compensates for unfavorable entropy. In conglomerates composed of organic cages, strong intermolecular interactions along the screw axes provide the necessary compensation. Finally, we explore the unique properties that emerge from symmetry-broken molecular packing within crystals of cage racemates, such as second-harmonic generation and piezoelectricity. It turns out that the symmetry operation in molecular packing plays a critical role in determining material properties. By comprehensively analyzing symmetry and symmetry-breaking in organic cage racemates, this Account provides insights into symmetry-related phenomena across scientific disciplines. It also paves the way for designing novel materials with tailored properties for applications in optics, electronics, and beyond.

Enantioselective Catalytic Synthesis of Inherently Chiral Calixarenes.

Since the introduction of the concept of inherent chirality by Böhmer, an important part of research focused on the asymmetric synthesis of calixarene macrocycles. However, long synthetic procedures and tedious separation strategies hampered the application of this technology in many topics of organic chemistry, including enantioselective molecular recognition and catalysis. Very recently, a new generation of enantioselective catalytic methodologies has been reported, able to provide highly functionalized, inherently chiral calixarenes in a straightforward manner. In this review, we will discuss these new catalytic methods and the versatile properties of such macrocycles that call for potential applications in many areas of science.

Total Synthesis of (+)-7,7'-Bistaxodione via Late-Stage Electrochemical Dimerization.

The first asymmetric total synthesis of the tetraterpenoid (+)-7,7'-bistaxodione (4a) via a unique late-stage electrochemical oxidative dimerization of a diterpenoid quinone methide tumor Inhibitor (+)-taxodione (3a) has been described. The naturally occurring monomer 3a was synthesized from aromatic abietane diterpenoid, ferruginol (1e) . Further, an efficient convergent synthetic route toward the naturally occurring aromatic abietane terpenoids has been shown via a Lewis acid-mediated diastereoselective cationic epoxy-ene cyclization. This synthetic method directly allows for the formation of a functionalized aromatic abietane scaffold with four contiguous stereogenic centers (two of which are all-carbon quaternary centers).

Preparation of Mesoporous Cu2O Nanospheres for Green Synthesis in the Enantioselective Boron Conjugate Addition of α,β‐Unsaturated Chiral Compounds in Aqueous Phase

AbstractChiral organoboron compounds are essential intermediates in various significant reactions. However, there are still few efficient catalysts for their synthesis. This paper reports a novel catalytic material for chiral asymmetric boron conjugate addition reactions: mesoporous Cu2O nanospheres (M−Cu2O). M−Cu2O is approximately 0.55 μm, exhibiting dense and uniformly distributed worm‐like pores. It features a specific surface area of 15.7 m2/g and an average pore size of 14.3 nm. Under the conditions of Toluene:H2O=9:1, with a chiral ligand amount of 3.6 mol% and no additional base, it achieves a high yield (98% yield) and impressive enantioselectivity (99% ee) for the template substrate chalcone using only 3.0 mol% of the catalyst. Notably, the catalyst can be easily recovered and maintains robust catalytic performance after seven cycles, yielding 92% and an ee value of 90%. This work presents a mild and effective method for synthesizing chiral boron compounds in an aqueous phase, significantly enhancing the application potential of mesoporous copper oxide nanospheres.

Stereoselective Synthesis of Amino Esters via 1,5-Conjugate Addition Using Pd/Cu Dual Catalysis

Stereoselective Synthesis of Amino Esters via 1,5-Conjugate Addition Using Pd/Cu Dual Catalysis

Cu(II)-NHC Catalyzed Insertion of Quinoid Carbenes into cis-Epoxides: Stereoselective Synthesis of trans-Dihydronaphthodioxine.

A straightforward synthesis of trans-dihydronaphthodioxine has been efficiently accomplished through Cu(II)-NHC catalysis, involving the stereoselective ring opening of cis-epoxides with quinoid-carbene. Intramolecular SN2-like substitution facilitates the inversion of stereochemistry during cis-epoxide ring opening. This reaction has been developed under simple conditions, demonstrating a broad substrate scope with a wide chemoselective profile. Additionally, late-stage functionalization of complex bioactive molecules has been successfully achieved.

Stereoselective Synthesis of C-Glycosides Enabled by Iridium Photocatalysis

Stereoselective Synthesis of C-Glycosides Enabled by Iridium Photocatalysis

Enantioselective Borylcupration/Cyclization of Alkene-Tethered Oxime Esters.

A copper-catalyzed enantioselective synthesis of borylated 1-pyrrolines from γ,δ-unsaturated oxime esters is reported. Twenty-four novel 1-pyrroline derivatives are reported in yields ranging from 26% to 96% and enantioselectivities from 74.5:25.5 er to 99:1 er. Examples derived from α-unsubstituted, non-fluorinated oxime esters are reported. The hydroxyl group following oxidation of the Bpin moiety acts as a directing group in highly diastereoselective reductions of the pyrrolines to the corresponding prolinol derivatives. Additionally, the Bpin group can be retained in the products following a simplified, chromatography-free workup procedure. DFT supports a reaction mechanism which proceeds through the formation of an (R)-benzylic copper intermediate, followed by stereoretentive cyclization with respect to the configuration at the metalated carbon. The conclusions of the computational data are corroborated through control experiments and deuterium-labelling studies.

Enantioselective Synthesis of Tetrahydro-β-Carbolines via Copper/Iridium Dual Catalysis

Enantioselective Synthesis of Tetrahydro-β-Carbolines via Copper/Iridium Dual Catalysis

Enantioselective Synthesis of Axially Chiral Macrocycles

Enantioselective Synthesis of Axially Chiral Macrocycles

Enantioselective Synthesis of Tetrahydro-1H-1,3-methanocarbazoles by Formal (3 + 3)-Cycloaddition Using Bicyclo[1.1.0]butanes.

Asymmetric synthesis presents many challenges, with the selective formation of chiral bridged polyheterocycles being a notable example. Cycloadditions using bicyclo[1.1.0]butanes (BCB) offer a promising solution along those lines, yet, despite significant advances in that emerging area, asymmetric control has remained limited thus far. Here, we describe an organocatalytic, enantioselective formal (3 + 3)-cycloaddition of BCBs with 1H-indol-3-yl((hetero)aryl)methanol derivatives. This approach enables the rapid and efficient synthesis of chiral tetrahydro-1H-1,3-methanocarbazole derivatives (34 examples) from readily available starting materials, with very good stereochemical control (up to 98:2 er). Successful scale-up experiments and product modification demonstrated the potential of this methodology. Control experiments and DFT calculations provide insights into the mechanistic pathway.

PIFA-Mediated Enantioselective Synthesis of Azatricycles

PIFA-Mediated Enantioselective Synthesis of Azatricycles

Enantioselective Synthesis of Chiral Benzocyclobutanes via Palladium Catalysis

Enantioselective Synthesis of Chiral Benzocyclobutanes via Palladium Catalysis

Enantioselective synthesis of 2-substituted bicyclo[1.1.1]pentanes via sequential asymmetric imine addition of bicyclo[1.1.0]butanes and skeletal editing.

The substitution of an aromatic ring with a C(sp3)-rich bicyclic hydrocarbon, known as bioisosteric replacement, plays a crucial role in modern drug discovery. Substituted bicyclo[1.1.1]pentanes (BCPs) are particularly noteworthy owing to their uniquely three-dimensional stereochemical complexity. 1,3-Difunctionalized BCPs have been widely used as bioisosteres for para-substituted phenyl rings, and they have been incorporated into numerous lead pharmaceutical candidates. 2-Substituted BCPs (substituted at the bridge position) can function as alternatives to ortho- or meta-substituted arene rings; however, the general and efficient construction of these scaffolds remains challenging, particularly if performed in an enantioselective manner. Here we present an approach for synthesizing enantioenriched 2-substituted BCPs by a nitrogen-atom insertion-and-deletion strategy, involving a chiral Brønsted acid-catalytic enantioselective cycloaddition of bicyclo[1.1.0]butanes with imines and nitrogen deletion of resulting aza-bicyclo[2.1.1]hexanes (aza-BCHs) with generally good enantiopurity retention. Mechanistic experiments verify the radical pathway. Chiral BCPs have been readily incorporated into medicinally relevant molecules, and a drug analogue has been successfully prepared enantioselectively.

Photoinduced stereoselective reactions using pyridinium salts as radical precursors.

Pyridinium salts are amine surrogates that are abundant in nature and the redox active nature of the pyridinium salts allows them to serve as precursors for generating radical species under mild conditions that can be initiated by light, heat or metal catalysis. The stereoselective formation of products has always been a topic of interest for synthetic chemists worldwide. In this context, pyridinium salts can readily undergo single electron reduction to form a neutral radical, and the N-X bond's subsequent fragmentation furnishes the X radical without any harsh reaction conditions. As a consequence, the past decade has witnessed an increased effort in utilizing pyridinium salts to photocatalytically generate radicals for the regioselective, diastereoselective as well as enantioselective formation of products that have been summarised in this review.

Enantioselective Synthesis of αα‐Trifluoromethyl tert‐Alcohols and Amines via Organocatalyst‐Mediated Aldol and Mannich Reactions

The asymmetric aldol reaction of ethyl trifluoropyruvate with aldehydes was developed using diarylprolinol as a catalyst, affording α‐trifluoromethyl‐substituted tertiary alcohols with high enantioselectivity. Similarly, the asymmetric Mannich reaction of aldehydes with an imine derived from ethyl trifluoropyruvate was developed using diphenylprolinol silyl ether in combination with an acid, yielding α‐trifluoromethyl‐substituted tertiary amines. The absolute and relative configurations of the products were determined by vibrational circular dichroism (VCD).

Enantioselective Total Syntheses of Vallesamidine and Schizozygane Alkaloids.

A general streamlined strategy for the enantioselective total syntheses of the schizozygane family of natural products and related alkaloid vallesamidine is described. Specifically, a catalytic enantioconvergent cross-coupling sets the quaternary stereogenic center in a pluripotent intermediate adorned with an olefin and three orthogonal carboxylate groups, upon which the modularity of the synthesis relies. A late-stage catalytic oxidative lactamization of an alkyne is instrumental in the first-generation synthesis of the schizozygane alkaloids. In the second-generation approach, a novel application of the van Leusen reaction for the generation of lactams is pivotal to accessing the schizozygane alkaloids from a common intermediate. The strategies outlined here are expected to enable detailed biological investigations as well as facilitate access to and provide solutions for the late-stage modification of bioactive alkaloids.

Asymmetric Functionalization Harnessing Radical-Mediated Functional-Group Migration.

Along with the renaissance of radical chemistry, the past decade has witnessed rapid development in radical-mediated rearrangement reactions. A wide diversity of radical approaches harnessing functional-group migration (FGM) have been devised to enhance both synthetic efficiency and molecular complexity. However, the application of FGM reactions to construct stereogenic centers remains underexplored owing to the inherent challenges of asymmetric radical reactions. In this Minireview, we summarize the emerging area of asymmetric functionalization involving radical-mediated FGM reactions. Enantioselectivity can be regulated by chiral substrates, auxiliaries or reagents, or achieved through asymmetric transition-metal catalysis. This synthetic strategy demonstrates its superiority in the production of valuable complex molecules that are otherwise difficult to obtain by conventional methods.