Enantioselective Reaction Research Articles

Enantioselective Oxidative Homocoupling of 2-Oxindoles with a Chiral Bisguanidinium Hypoiodite Catalyst

AbstractThe bisoxindole motif is present in a variety of biologically active compounds. Here, we report an enantioselective oxidative homocoupling reaction of 2-oxindoles in the presence of a chiral bisguanidinium hypoiodite catalyst, providing access to the corresponding optically active bisoxindoles in excellent yields and with moderate to high diastereo- and enantioselectivities.

Organocatalysis for Enantioselective Decarboxylative Nucleophilic Addition Reactions

AbstractThe catalytic decarboxylation of malonic acid half oxy‐ and thioesters, β‐ketocarboxylic acids, and their related compounds is a straightforward, powerful, and atom‐economical strategy for the in‐situ formation of enolates, which are important and well‐studied synthons for various functional materials and natural products. This strategy, inspired by the biosynthesis of polyketides and fatty acids, is an attractive method for synthesizing enols from carboxyl compounds with less reactive α‐hydrogen atoms under mild conditions. In addition, these reactions are environmentally friendly and are of great interest to chemists because the use of a stoichiometric amount of base can be avoided, and the only byproduct is CO2. Thus far, remarkable progress has been made, especially in the field of organocatalytic enantioselective decarboxylation reactions, allowing for the stereocontrolled formation of new C−H, C−C, C−heteroatom, and C−X bonds. This review provides a comprehensive overview of organocatalytic enantioselective decarboxylation reactions and highlights the significant progress made since 2020. In particular, it focuses on chiral catalyst systems and transition states as key parameters for decarboxylation reactions.

A Radical Revolution in the 21st Century

AbstractThis Special Collection on “Radical Chemistry in Homogeneous Catalysis and Organic Synthesis” organized in collaboration with the European Journal of Organic Chemistry and ChemCatChem showcases the maturity of field. Overall, this Special Collection encompasses 11 reviews and 27 research articles, covering a diverse range of topics. It presents the latest advancements in the controlled generation of radical species using transition metal catalysis, photoredox catalysis, or electrochemistry. It highlights the importance of moving towards more sustainable chemical processes, with particular focus on the development of novel organo(photo)catalysts, or efficient catalyst‐free reactions. It presents new transformations to access complex scaffolds as well as new building blocks and reagents, further simplifying single‐electron disconnection logic. In addition, it also highlights the key advancements in addressing some of the current challenges in radical chemistry, such the development of enantioselective reactions or how to scale‐up radical processes to meet the needs of the fine chemical industry.

On the gold(I)-catalyzed enantioselective addition of indole to diphenylallene via anion-binding catalysis

Neutral dual hydrogen bond donors (HBDs) are effective catalysts that enhance the electrophilicity of substrates or the Lewis/Brønsted acidity of reagents through an anion-binding mechanism. Despite their success in various enantioselective organocatalytic reactions, their application to transition metal catalysis remains rare. Herein, we report the activation of gold(I) precatalysts by chiral ureas, leading to enantioselective hydroarylation of allenes with indoles. Experimental and computational studies support an anion-binding mechanism for gold(I) precatalyst activation. Noncovalent interactions were identified as the source of enantiodifferentiation, providing insights into the cooperativity between achiral phosphine ligands and chiral ureas.

Enantioselective SN1-type reaction via electrochemically generated chiral α-Imino carbocation intermediate

Electrochemical reactions via carbocation intermediates remain fundamental transformations that build up molecular functionality and complexity in a sustainable manner. Enantioselective control of such processes is a great challenge in a highly ionic electrolyte solution. Here, we report an anodic generation of chiral α-imino carbocation intermediates by enamine catalysis. The chiral carbocation intermediates can be intercepted by a variety of nucleophiles such as alcohols, water and thiols with high stereoselectivity. The key SN1 step proceeds via a tertiary amine-mediated proton shuttle that facilitates facial selection in reacting with carbocation.

Asymmetric Hydrogenation of Ketones by Simple Alkane-Diyl-Based Ir(P,N,O) Catalysts: A Comparative Study.

The development of new chiral ligands with simple and modular structure represents a challenging direction in the design of efficient homogeneous transition metal catalysts. Herein, we report on the asymmetric hydrogenation of prochiral ketones catalyzed by the iridium complexes of simple alkane-diyl-based P,N,O-type chiral ligands with a highly modular structure. The role of (i) the P-N and N-O backbone in the potentially tridentate ligands, (ii) the number, position and relative configuration of their stereogenic elements and (iii) the effect of their NH and OH subunits on the activity and enantioselectivity of the catalytic reactions are studied. The systematic variation in the ligand structure and the comparative catalytic experiments shed light on different mechanistic aspects of the iridium-catalyzed reaction. The catalysts containing the simple alkane-diyl-based ligands with central chirality provided high enantioselectivities (up to 98% ee) under optimized reaction conditions and proved to be active and selective even at very high substrate concentrations (100 mmol substrate/mL solvent).

Kinetics of enantioselective heterogeneous nanocatalysis with limited cluster occupancy: Beyond the coverage concept

Theoretical analysis is presented for kinetics of enantioselective reactions on nanocatalysts, when the cross-section of the reacting molecules and the non-reacting modifiers is similar to the size of nanoclusters and only two or three molecules can be adsorbed on a cluster. The rate expressions have been derived, considering the exact configurations of the reactants and a non-reactive modifier, rather than utilizing the classical Langmuirian methodology of the surface coverage. The developed approach was used to explain rate acceleration, enantioselectivity and enantiomeric excess as a function of the modifier concentration, as well as the nonlinear behavior showing even maxima of enantiomeric excess for mixtures of modifiers.

Enantioselective Addition of Thiols to Acyclic Ketiminoesters Using Cinchona Alkaloid Amide/Zinc(II) Catalysts

The first enantioselective reaction of acyclic α‐ketiminoesters with thiols has been developed. Good yields and enantioselectivities were obtained using our original cinchona alkaloid amide/zinc(II) catalysts. The obtained products were converted into useful chiral thiazolidines. Based on experimental results and DFT calculation, transition states were proposed to explain the stereoselectivity of the reaction.

Asymmetric Auto-Tandem Catalysis with Chiral Organosuperbases: Intramolecular Cyclization/Enantioselective Direct Mannich-Type Addition Sequence.

An enantioselective addition reaction of alkynyl esters with imines was developed under asymmetric autotandem catalysis with a chiral Brønsted base. A chiral bis(guanidino)iminophosphorane organosuperbase, which has much higher basicity than that of conventional chiral organic bases, efficiently promoted both the intramolecular cyclization for the construction of a benzofuran ring or a benzothiophene ring and the sequential enantioselective direct Mannich-type reaction of diarylmethane derivatives, affording enantio-enriched diarylalkane derivatives that are otherwise difficult to access.

Is the E/Z Iminium Ratio a Good Enantioselectivity Predictor in Iminium Catalysis?

Developing new enantioselective reactions is an important part of chemical discovery but requires time and resources to test large arrays of potential reaction conditions. New techniques are required to analyse many different reactions quickly and efficiently. Mass spectrometry is a high-throughput method; when combined with ion-mobility spectrometry, this technique can monitor diastereomeric reaction intermediates and thus be a handle to study enantioselective reactions. Through this technique and others, it was noted before that in the organocatalytic 1,4-addition to α,β-unsaturated aldehydes, the abundance of initial diastereomeric intermediates correlates strongly to that of the final enantiomeric products. This work determines isomeric abundance for various catalysts and aldehydes and uses it to predict the enantiomeric excess of two control reactions. The prediction matches well for one reaction but does not predict the obtained results for the second. This finding confirms that the E/Z ratio of the iminium intermediates can be used as a predictor for some reactions, but the kinetics of the following steps can dramatically change the true enantioselectivity.

Nickel-Catalyzed Enantioselective Carbonyl Addition of Aryl Chlorides and Bromides to Aldehydes.

The Ni-catalyzed enantioselective addition reaction of aryl halides to aldehydes was studied with cyanobis(oxazoline) as chiral ligands and Mn as reductant. Aryl and heteroaryl bromides reacted with phenyl aldehyde at room temperature to produce dibenzyl alcohols in 16-99 % yields with 53-92 % ees. Moreover, the coupling of phenyl chloride with a variety of aryl, heteroaryl and alkyl aldehydes was demonstrated in the presence of cyanobis(oxazoline)/Ni(II) at 60 °C in generally high yields with moderate enantioselectivities.

Diastereo- and Enantioselective Construction of Stereochemical Arrays Exploiting Non-Classical Hydrogen Bonding in Enolborates.

We report a copper-catalyzed reductive aldol addition to aldehydes and ketones, with pinacolborane as stoichiometric reductant, that results in the generation of stereodefined syn-aldol products. Cyclic, acyclic, fused and spirocyclic aldols bearing contiguous stereocenters are obtained with excellent yields and diastereoselectivities. Moreover, enantioselective reactions could be carried out with cycloalkenones to deliver aldols bearing three contiguous stereocenters and with up to 98 % ee. Computations reveal that the enolborate intermediate undergoes the syn-aldol reaction via a twist-boat transition state that is stabilized by non-classical hydrogen bonding interactions.

Enantioselective Synthesis of Spiro[cyclopentane-1,3'-oxindole] Scaffolds with Five Consecutive Stereocenters.

A highly diastereo- and enantioselective cascade annulation reaction of Morita-Baylis-Hillman (MBH) maleimides of isatins with ortho-hydroxychalcones was achieved by a chiral N,N'-dioxide/Mg(II) complex Lewis acid catalyst. This strategy provides a concise and efficient route to densely functionalized spiro[cyclopentane-1,3'-oxindole] compounds with five consecutive stereocenters. The reaction itself features mild conditions, good functional group compatibility, and broad substrate scope (62 examples, up to 99% yield, up to >20:1 dr, 97% ee). In addition, an obvious ligand acceleration effect and chiral amplification effect were observed. DFT calculations were performed to elucidate the stereoselectivity observed. The gram-scale synthesis and the inhibitory effect of two products on the viability of A549 cells demonstrate the potential utility of the current method.

Catalysis of an SN2 pathway by geometric preorganization.

Bimolecular nucleophilic substitution (SN2) mechanisms occupy a central place in the historical development and teaching of the field of organic chemistry1. Despite the importance of SN2 pathways in synthesis, catalytic control of ionic SN2 pathways is rare and notably uncommon even in biocatalysis2,3, reflecting the fact that any electrostatic interaction between a catalyst and the reacting ion pair necessarily stabilizes its charge and, by extension, reduces polar reactivity. Nucleophilic halogenase enzymes navigate this tradeoff by desolvating and positioning the halide nucleophile precisely on the SN2 trajectory, using geometric preorganization to compensate for the attenuation of nucleophilicity4. Here we show that a small-molecule (646 Da) hydrogen-bond-donor catalyst accelerates the SN2 step of an enantioselective Michaelis-Arbuzov reaction by recapitulating the geometric preorganization principle used by enzymes. Mechanistic and computational investigations show that the hydrogen-bond donor diminishes the reactivity of the chloride nucleophile yet accelerates the rate-determining dealkylation step by reorganizing both the phosphonium cation and the chloride anion into a geometry that is primed to enter the SN2 transition state. This new enantioselective Arbuzov reaction affords highly enantioselective access to an array of H-phosphinates, which are in turn versatile P-stereogenic building blocks amenable to myriad derivatizations. This work constitutes, to our knowledge, the first demonstration of catalytic enantiocontrol of the phosphonium dealkylation step, establishing a new platform for the synthesis of P-stereogenic compounds.

Organocatalytic Enantioselective Synthesis of Inherently Chiral Calix[4]arenes.

Inherently chiral calix[4]arenes are an excellent structural scaffold for enantioselective synthesis, chiral recognition, sensing, and circularly polarized luminescence. However, their catalytic enantioselective synthesis remains challenging. Herein, we report an efficient synthesis of inherently chiral calix[4]arene derivatives via cascade enantioselective cyclization and oxidation reactions. The three-component reaction features a broad substrate scope (33 examples), high efficiency (up to 90 % yield), and excellent enantioselectivity (>95 % ee on average). The potential applications of calix[4]arene derivatives are highlighted by their synthetic transformation and a detailed investigation of their photophysical and chiroptical properties.

Organocatalytic Enantioselective Synthesis of Inherently Chiral Calix[4]arenes

AbstractInherently chiral calix[4]arenes are an excellent structural scaffold for enantioselective synthesis, chiral recognition, sensing, and circularly polarized luminescence. However, their catalytic enantioselective synthesis remains challenging. Herein, we report an efficient synthesis of inherently chiral calix[4]arene derivatives via cascade enantioselective cyclization and oxidation reactions. The three‐component reaction features a broad substrate scope (33 examples), high efficiency (up to 90 % yield), and excellent enantioselectivity (>95 % ee on average). The potential applications of calix[4]arene derivatives are highlighted by their synthetic transformation and a detailed investigation of their photophysical and chiroptical properties.

Synthesis of Chiral 3H‐pyrrolo[1,2‐a]indoles via Organocatalytic Enantioselective Addition of Alkynyl Biphenyl Quinone Methides

An organocatalytic enantioselective reaction utilizing α‐[4‐(4‐hydroxyphenyl)phenyl]propargyl alcohols and 3‐substituted indoles has been successfully established for the synthesis of chiral 3H‐pyrrolo[1,2‐a]indoles. Through the assistance of an appropriate chiral phosphoric acid, a cascade sequence is facilitated, beginning with the dehydration of α‐[4‐(4‐hydroxyphenyl)phenyl]propargyl alcohols to form alkynyl 4,4′‐biphenyl quinone methides (4,4′‐BQMs). Subsequently, 1,12‐addition of 3H‐pyrrolo[1,2‐a]indoles to these alkynyl 4,4′‐BQMs results in the formation of allenes, which are then protonated and regenerate 4,4′‐BQMs. Finally, an enantioselective intramolecular annulation of 4,4′‐BQMs occurs smoothly, leading to the production of a range of 3H‐pyrrolo[1,2‐a]indoles with high efficiency and asymmetric induction.

Transition‐Metal Catalyzed Enantioselective Aziridination Reaction: Recent Development in Catalysis and Future Perspectives

Chiral aziridines are important motifs in natural products and biologically significant compounds, as well as one of the most valuable and versatile building blocks for the construction of diverse chiral functionalized amines. Because of the importance of chiral aziridines, various novel transition‐metal‐based catalytic systems and synthetic strategies have been established to investigate the highly effective and enantioselective aziridination process. This review outlined the recent significant advances made in the transition‐metal catalyzed enantioselective aziridination reactions, as well as the challenges and potential of the field at the current stage.

Asymmetric Synthesis of (-)-Cannabidiol (CBD), (-)-Δ9-Tetrahydrocannabinol (Δ9-THC) and Their cis Analogs Using an Enantioselective Organocatalyzed Diels-Alder Reaction.

Herein we describe an asymmetric synthesis of the pharmacologically relevant natural (-)-trans-CBD and psychoactive (-)-trans-Δ9-THC, as well as their synthetic cis diastereomers. The key step is an enantioselective Diels-Alder reaction catalyzed by a prolinol-based catalyst, which provides the cyclohexene carbaldehyde intermediate in good yield and high enantiomeric excess. Optimization of the substituted resorcinol protecting groups to avoid harsh and low-yield deprotection of the acid sensitive resorcinol moiety is also described.

Enantioselective Carbon Isotope Exchange.

The synthesis of isotopically labeled organic molecules is vital for drug and agrochemical discovery and development. Carbon isotope exchange is emerging as a leading method to generate carbon-labeled targets, which are sought over hydrogen-based labels due to their enhanced stability in biological systems. While many bioactive small molecules bear carbon-containing stereocenters, direct enantioselective carbon isotope exchange reactions have not been established. We describe the first example of an enantioselective carbon isotope exchange reaction, where (radio)labeled α-amino acids can be generated from their unlabeled precursors using a stoichiometric chiral aldehyde receptor with isotopically labeled CO2 followed by imine hydrolysis. Many proteinogenic and non-natural derivatives undergo enantioselective labeling, including the late-stage radiolabeling of complex drug targets.