Enantioselective Reaction Research Articles

Enantioselective Intramolecular Oxidative Aminoacetoxylation from Aryl-Substituted Alkene via Chiral Triazole-oxazoline Palladium Complexes.

Here, we describe an enantioselective intramolecular oxidative aminoacetoxylation reaction using a palladium catalyst and an aryl-substituted internal alkene compound as the substrate under mild conditions in several hours. The triazole-oxazoline ligand was selected for the asymmetric catalyst. A range of enantioenriched pyrrolidine-derived vicinal amino acetate compounds were synthesized, showing yields from 47% to 84%, diastereomer ratios from 57:43 to 95:5, and enantiomer excesses from 67% to 92%.

Copper‐Catalyzed Enantioselective Dehydro‐Diels–Alder Reaction: Atom‐Economical Synthesis of Axially Chiral Carbazoles

AbstractThe dehydro‐Diels–Alder (DDA) reaction is a powerful method for the construction of aromatic compounds. However, the enantioselective DDA reaction has been rarely developed, probably due to the competitive thermal reaction. Herein, we report a copper‐catalyzed enantioselective DDA reaction through vinyl cation pathway. The reaction leads to the atom‐economical synthesis of axially chiral phenyl and indolyl carbazoles in generally excellent yields with good to excellent atroposelectivities. This methodology represents the first example of non‐noble metal‐catalyzed enantioselective DDA reaction. Notably, new chiral ligand and organocatalyst derived from the constructed axially chiral carbazole are demonstrated to be useful in asymmetric catalysis.

Highly Enantioselective Construction of Chiral Eight-Membered Cyclic Ethers through Tandem Cyclization of Ynones and Dicarbonyl Compounds.

The enantioselective synthesis of eight-membered cyclic ether has always been a challenge in organic synthesis. Herein, we reported a highly enantioselective tandem cyclization reaction of alkyne ketone and dioxypyridines mediated by chiral bifunctional catalysts. This reaction generates two adjacent stereocenters using an atomeconomic manner, providing a simple and effective method for the one-step synthesis of highly enantioselective eight-membered cyclic ethers.

Enantioselective Cascade Reactions of Aminocatalytic Dienamines and Trienamines Initiated by a Cycloaddition Reaction.

Cycloadditions are widely accepted as a group of reactions that rapidly generate molecular complexity. Being highly atom economic and often predictable, these reactions can generate up to four stereogenic centers and two C-C (or C-X) bonds in one reaction step. During the last two decades, asymmetric aminocatalysis has shown to be a successful strategy for controlling stereoselectivity and enabling reactivity of cycloaddition reactions. By increasing the conjugation of the carbonyl species employed, dienamines and trienamines can be catalytically formed. Not only can these facilitate the cycloaddition, often accompanied by high levels of stereocontrol, but they also leave a residual enamine or carbonyl (by hydrolysis) in the cycloadduct. This residual functionality can engage in further intramolecular reactions generating complex cyclic systems in a one-pot cascade manner. In this regard, asymmetric aminocatalysis can add another layer of complexity to the already complex nature of cycloadditions. In this review, we will present the general concept of such reactivity patterns of dienamines and trienamines, and hereafter showcase examples in the literature. We aspire that the chemical community can use these concepts to design new enantioselective aminocatalytic cascade reactions to access enantioenriched, complex compounds, and perhaps use these in complex molecule synthesis.

Enantioselective Preparation of Cyclopentene-Based Amino Acids with a Quaternary Carbon Center.

Azlactone is an important starting material for synthesizing amino acids containing a quaternary α-carbon. In this study, we have developed a sequential "one-pot" procedure involving an enantioselective spirocyclization reaction followed by acidic azlactone opening, which led to amino acid derivatives. The key step of this procedure is a spirocyclization between propargylated azlactones and enals by using a cooperative catalytic approach that combines chiral secondary amine and achiral Pd(0) complexes. The final acid opening of the azlactone motif allows isolation of the corresponding amino acid derivatives as major diastereoisomers in yields ranging from 37% to 70% with enantioselectivities of 85-97% ee. These synthesized amino acid derivatives hold great potential in the pharmaceutical and bioactive compound industries. Moreover, the final amino acid products with a cyclopentene moiety can be further derivatized, opening up even more possibilities for their application.

Synthesis of Novel Pseudo-Enantiomeric Phase-Transfer Catalysts from Cinchona Alkaloids and Application to the Hydrolytic Dynamic Kinetic Resolution of Racemic 3-Phenyl-2-oxetanone.

Naturally occurring Cinchona alkaloids such as quinidine (QD)/cinchonine (CN) and their diastereomers, quinine (QN)/cinchonidine (CD), have been recognized as pseudo-enantiomeric pairs. Utilizing these pseudo-enantiomeric alkaloids as chiral resources provides complementary enantioselectivity in many asymmetric reactions. During the screening of Cinchona alkaloid phase-transfer catalysts (PTCs) in the hydrolytic dynamic kinetic resolution of racemic 3-phenyl-2-oxetanone (1) to tropic acid (2), we found that the introduction of a 4-trifluoromethylphenyl group at the vinyl terminus of BnQN significantly reduced the enantioselectivity to 41% enantiomeric excess (ee). The optimized structure of tetrahedral intermediates (TI, PTC + 1 + OH-) of hydrolysis obtained by density functional theory (DFT) calculations shows that the orientation of the quinoline and benzene rings of QD class PTC are nearly parallel to each other and to construct a greatly extended π-electron cloud surface, allowing good π-π interaction with the benzene ring of 1.

Organocatalytic Asymmetric [3 + 2] Cyclization: Enantioselective Synthesis of α-Indolyl Pyrrolo[1,2-a]indole Scaffolds.

A novel asymmetric [3 + 2] cyclization of α-indolyl propargylic alcohols with 3-alkyl-1H-indoles via chiral phosphoric acid catalysis has been established. This strategy allowed the synthesis of chiral α-indolyl pyrrolo[1,2-a]indole derivatives with high yields (up to 91%) and excellent enantioselectivities (up to 99% ee), facilitating both the reaction activity and enantioselectivity by using the solvent of CH3CFCl2. Significantly, this protocol will provide an effective synthetic approach for constructing enantioenriched α-indolyl pyrrolo[1,2-a]indole cores of antimalarial natural product isoborreverine analogues.

Asymmetric Counteranion‐Directed Electrocatalysis for Enantioselective Control of Radical Cation

AbstractThe control of enantioselectivity in radical cation reactions presents long‐standing challenges, despite a few successful examples. We introduce a novel strategy of asymmetric counteranion‐directed electrocatalysis to address enantioselectivity in radical cation chemistry. This concept has been successfully demonstrated in two reactions: an asymmetric dehydrogenative indole‐phenol [3+2] coupling and an atroposelective C−H/N−H dehydrogenative coupling. These reactions have enabled the synthesis of benzofuroindolines and C−N axially chiral indoles with high yields and excellent enantiomeric excesses. Detailed mechanistic studies confirmed a radical‐radical coupling mechanism. Moreover, density functional theory (DFT) calculations supported the indole radical cation as the pivotal intermediate, rather than a neutral indolyl radical, shedding new light on the underlying processes driving these reactions.

Structure Revision of Halisphingosine A via Total Synthesis and Bioactivity Studies.

Sphingoid bases are important bioactive lipids found in a variety of organisms, serving as the backbone of sphingolipids, which regulate essential physiological processes. Here we describe the total synthesis and structure revision of halisphingosine A, a sphingoid base initially isolated from marine sponges. To address inconsistencies in the NMR interpretation of this natural product, we developed a synthetic route involving a late-stage enantioselective Henry reaction that allows access to multiple stereoisomers of the proposed halisphingosine core structure. Our library of 32 fully characterized synthetic stereoisomers enabled us to rectify the structure of halisphingosine A as (2R,3R,8R,Z)-2-aminooctadec-9-ene-1,3,8-triol, and to pursue further structure-activity relation (SAR) studies regarding their antimicrobial and cytotoxic potential. In summary, our study offers a yet unreported compound library along with validated analytical datasets of marine sphingoid base derivatives, which significantly affects future ecometabolomic marine research and will facilitate the identification of inhibitors of sphingolipid metabolism or antagonists of sphingolipid base-sensing receptors.

Design of Stable Chiral Aminosulfonium Ylides and Their Catalytic Asymmetric Synthesis

AbstractThe isolation and catalytic enantioselective synthesis of configurationally stable S‐stereogenic sulfonium ylides have been significant challenges in the field of asymmetric synthesis. These reactive intermediates are crucial for a variety of synthetic transformations, yet their inherent tendency towards rapid inversion at the sulfur stereocenter has hindered their practical utilization. Conventional approaches have focused on strategies that incorporate a C=S bond‐containing cyclic framework to help mitigate this stereochemical lability. In this work, we present an alternative tactic that leverages the stabilizing influence of an adjacent N‐atom and cyclic sulfide moiety. Exploiting a copper catalyzed enantioselective intermolecular carbene transfer reaction, structurally diverse S‐stereogenic aminosulfonium ylides have been achieved in excellent yields and enantioselectivities. Experimental results indicate that the careful selection of 2‐diazo‐1,3‐diketone precursors is crucial for achieving optimal stereoinduction in this transformation. The resulting highly enantioenriched aminosulfonium ylides allow for further stereospecific elaborations to furnish aminosulfonium ylide oxides and sulfinamide. This work expands the boundaries of chiral sulfonium ylide chemistry, providing access to a broad range of previously elusive S‐stereogenic aminosulfonium ylide scaffolds.

Catalytic Enantioselective Aldol Reactions of Pyruvates as Nucleophiles with Chlorinated and Fluorinated Aldehydes and Ketones.

Reactions of pyruvates as nucleophiles under catalytic conditions are difficult to control without the use of enzymes as catalysts. Here, enantioselective aldol reactions of pyruvates with chlorinated and fluorinated aldehydes and ketones under organocatalytic conditions, in which pyruvates act as nucleophiles, are reported. Based on analyses of self-aldol reactions of pyruvates in the presence of model catalysts, catalysts of the desired cross aldol reactions were developed. Using the primary amine-derived catalyst, the desired aldol products, i.e., γ-chlorinated alkyl or γ-fluorinated alkyl group-substituted γ-hydroxy α-ketoesters, were obtained in good to high yields with high enantioselectivities.

Organocatalytic Strategy for a Formal 1,6-Conjugate Hydroxylation.

Thanks to the versatile vinylogous hexafluoro iso-propyl acrylate molecular platforms, a regio- and enantioselective sulfa-Michael reaction was achieved upon organocatalytic conditions, allowing the subsequent amidation, one-pot oxidation, and Mislow-Bravermann-Evans [2,3]-sigmatropic rearrangement along with a 1,3-chirality transfer, leading eventually to a formal asymmetric 1,6-hydroxylation sequence.

Enantioselective photochemical reactions within the confined cavities of supramolecular assemblies

Compared to bulk solvents, reactions in the confined spaces of supramolecular self-assemblies feature rate acceleration, high efficiency and substrate selectivity. These advantages lead to efficient catalytic efficiency and excellent selectivity in enantioselective supramolecular photochemical transformations. During the last few years, enantioselective supramolecular photocatalysis has developed into one of the most powerful strategies to construct enantioenriched chiral compounds. In this review, the recent advances of enantioselective photochemical reactions taking place within the confined spaces of supramolecular assemblies are summarized, with an emphasis on the specific catalytic modes and chemical transformations. Organization of the data follows a subdivision according to supramolecular host and reaction type. At last, the current limitations and the future research orientation of this research field are discussed.

Asymmetric one-carbon ring expansion of diverse N-heterocycles via copper-catalyzed diyne cyclization.

One-carbon ring expansion reaction of N-heterocycles has gained particular attention in the past decade because this method allows for the conversion of readily available N-heterocycles into potentially useful complex ring-expanded N-heterocycles, which are inaccessible by traditional methods. However, the catalytic asymmetric variant of this reaction has been rarely reported to date. Herein, we disclose an enantioselective one-carbon ring expansion reaction through chiral copper-catalyzed diyne cyclization, leading to the practical, atom-economic and divergent assembly of an array of valuable chiral N-heterocycles bearing a quaternary stereocenter in generally good to excellent yields with excellent enantioselectivities (up to >99% ee). This protocol represents the first example of asymmetric one-carbon ring expansion reaction of N-heterocycles based on alkynes.

An Enantioselective Decarboxylative Glycolate Aldol Reaction.

Herein, we report the application of a benzyloxy-functionalized malonic acid half thioester as an activated ester equivalent in a highly enantioselective decarboxylative glycolate aldol reaction. This robust method operates at ambient temperature, tolerates air and moisture, and generates CO2 as the only byproduct. The synthetic applicability of the method is demonstrated by the large-scale enantiodivergent synthesis of α-benzyloxy-β-hydroxybutyric acid thioester and its subsequent conversion to diverse polyoxygenated building blocks, deoxy-sugars, and (-)-angiopterlactone B.

Preparation of two new chiral metal-organic frameworks for lipase immobilization and their use as biocatalysis in the enantioselective hydrolysis of racemic naproxen methyl ester

Considering the selective pharmacological activity of chiral drugs, it is important to develop new chiral materials to synthesize them. In this work, two new chiral MOFs (UiO-66@Np and UiO-66@Ib) were prepared by the covalent attachment of the chiral compounds (S-naproxen and S-ibuprofen) to the amine-functionalized Zr-MOF (UiO-66-NH2). Then, Candida rugosa lipase (CRL) was immobilized on these chiral MOFs to fabricate two new biocomposites (UiO-66@Np@CRL and UiO-66@Ib@CRL) as effective biocatalysts, which enable significant enhancement in the catalytic activity and enantioselectivity of lipase. The FTIR, SEM, EDX, TGA, and PXRD analyses were carried out to confirm the formation of the biocomposites. The catalytic performances of the biocomposites (UiO-66@Np@CRL and UiO-66@Ib@CRL) were evaluated in the typical hydrolysis of p-nitro-phenyl palmitate (p-NPP) and the catalytic enantioselective hydrolysis of (R,S)-naproxen methyl ester. Under optimal conditions, UiO-66@Np@CRL showed a higher enantiomeric excess of the substrate (ees) value and a 98 % and 50 % conversion rate, respectively, than that of UiO-66@Ib@CRL. Besides, an excellent enantioselectivity (E) value of 458 was obtained in the presence of the biocomposite (UiO-66@Np@CRL). In addition, it was observed that the catalytic activity, conversion rate and ees value of this composite (UiO-66@Np@CRL) remained almost unchanged in reuse after 6 months. The results showed that in enantioselective reactions, the highest conversion and enantioselectivity could be achieved when the chiral compound bound to the MOF and the model compound used are the same.

Unveiling the Loss Mode Enabled Tunable Plasmonic Chirality at Flat Metal Surface.

Plasmonic chirality has garnered significant interest in the past decade due to its enhanced chiral light-matter interactions. Current methods for achieving plasmonic chirality often rely on complex nanostructures or metamaterials, which are hampered by intricate fabrication processes. In this work, we present an approach to generate plasmonic chiral structured surface plasmon polariton (s-SPP) fields on a single, flat metal surface, bypassing elaborate fabrication techniques. The plasmonic chiral s-SPP fields are excited by the superposition of multiple differently oriented transverse magnetic polarized plane waves. We demonstrate, both theoretically and experimentally, the flexible tuning of chiral plasmonic patterns by adjusting the symmetry and phase differences of the incident waves. This method provides a facile mean to optically tailor plasmonic chiral properties on a subwavelength scale, offering potential applications in sensing, enantioselective reactions, imaging, and reconfigurable chiral switches.

Copper-Catalyzed Enantioselective [4π + 2σ] Cycloaddition of Bicyclobutanes with Nitrones.

The selective construction of bridged bicyclic scaffolds has garnered increasing attention because of their extensive use as saturated bioisosteres of arene in pharmaceutical industry. However, in sharp contrast to their racemic counterparts, assembling chiral bridged bicyclic structures in an enantioselective and regioselective manner remains challenging. Herein, we describe our protocol for constructing chiral 2-oxa-3-azabicyclo[3.1.1]heptanes (BCHeps) by enantioselective [4π + 2σ] cycloadditions of bicyclo[1.1.0]butanes (BCBs) and nitrones taking advantage of a chiral copper(II) complex as a Lewis acid catalyst. This method features mild conditions, good functional group tolerance, high yield (up to 99%), and excellent enantioselectivity (up to 99% ee). Density functional theory (DFT) calculation elucidates the origin of the reaction's enantioselectivity and the mechanism of BCB activation by Cu(II) complex.

Investigating Competing Inner‐ and Outer‐Sphere Electron‐Transfer Pathways in Copper Photoredox‐Catalyzed Atom‐Transfer Radical Additions: Closing the Cycle

This integrated computational and experimental study comprehensively examines the viability of competing inner‐sphere electron transfer (ISET) and outer‐sphere electron transfer (OSET) processes in [Cu(dap)2]+‐mediated atom‐transfer radical additions (ATRA) of olefins and CF3SO2Cl that can deliver both R–SO2Cl and R–Cl products. Five sterically‐ and electronically‐varied representative alkenes were selected from which to explore and reconcile the range of experimentally observed outcomes. Findings are consistent with photoexcited [Cu(dap)2]+ initiating photoelectron transfer via ISET and the subsequent regeneration of the oxidized catalyst via single‐electron transfer in the ground state via ISET to close the catalytic cycle and liberate products. R–SO2Cl/R–Cl product ratios appear to be primarily governed by the relative rates of direct catalyst regeneration {i.e., [Cu(dap)2SO2Cl]•+ + R•} and ligand exchange {i.e., [Cu(dap)2SO2Cl]•+ + Cl– }. Through this work, a more consistent and more complete conceptual framework has been developed to better understand this chemistry and how catalyst regeneration occurs. It is this important ground state process, which closes the catalytic cycle, and ultimately controls the enantioselectivity of ATRA reactions employing chiral copper photocatalysts

Investigating Competing Inner- and Outer-Sphere Electron-Transfer Pathways in Copper Photoredox-Catalyzed Atom-Transfer Radical Additions: Closing the Cycle.

This integrated computational and experimental study comprehensively examines the viability of competing inner-sphere electron transfer (ISET) and outer-sphere electron transfer (OSET) processes in [Cu(dap)2]+-mediated atom-transfer radical additions (ATRA) of olefins and CF3SO2Cl that can deliver both R-SO2Cl and R-Cl products. Five sterically- and electronically-varied representative alkenes were selected from which to explore and reconcile the range of experimentally observed outcomes. Findings are consistent with photoexcited [Cu(dap)2]+ initiating photoelectron transfer via ISETand the subsequent regeneration of the oxidized catalyst via single-electron transfer in the ground state via ISETto close the catalytic cycle and liberate products. R-SO2Cl/R-Cl product ratios appear to be primarily governed by the relative rates of direct catalyst regeneration {i.e., [Cu(dap)2SO2Cl]•+ + R•} and ligand exchange {i.e., [Cu(dap)2SO2Cl]•+ + Cl- }. Through this work, a more consistent and more complete conceptual framework has been developed to better understand this chemistry and how catalyst regeneration occurs. It is this important ground state process, which closes the catalytic cycle, and ultimately controls the enantioselectivity of ATRA reactions employing chiral copper photocatalysts.