Stereodivergent Construction of 1,5/1,7-Nonadjacent Tetrasubstituted Stereocenters Enabled by Pd/Cu-Cocatalyzed Asymmetric Heck Cascade Reaction.

The construction of chiral motifs containing nonadjacent stereocenters in an enantio- and diastereoselective manner has long been a challenging task in synthetic chemistry, especially with respect to their stereodivergent synthesis. Herein, we describe a protocol that enables the enantio- and diastereoselective construction of 1,5/1,7-nonadjacent tetrasubstituted stereocenters through a Pd/Cu-cocatalyzed Heck cascade reaction. Notably, a C=C bond relay strategy involving the shift of the π-allyl palladium intermediate was successfully applied in the asymmetric construction of 1,7-nonadjacent stereocenters. The current method allows for the efficient preparation of chiral molecules bearing two privileged scaffolds, oxindoles and non-natural α-amino acids, with good functional group tolerance. The full complement of the four stereoisomers of products bearing 1,5/1,7-nonadjacent stereocenters could be readily accessed by a simple combination of two chiral metal catalysts with different enantiomers.

Synergistic Pd/Cu-Catalyzed 1,5-Double Chiral Inductions.

Much attention has been focused on the catalytic asymmetric creation of single chiral centers or two adjacent stereocenters. However, the asymmetric construction of two nonadjacent stereocenters is of significant importance but is challenging because of the lack of remote chiral induction models. Herein, based on a C═C bond relay strategy, we report a synergistic Pd/Cu-catalyzed 1,5-double chiral induction model. All four stereoisomers of the target products bearing 1,5-nonadjacent stereocenters involving both allenyl axial and central chirality could be obtained divergently by simply changing the combination of two chiral catalysts with different configurations. Control experiments and DFT calculations reveal a novel mechanism involving 1,5-oxidative addition, contra-thermodynamic η3-allyl palladium shift, and conjugate nucleophilic substitution, which play crucial roles in the control of reactivity, regio-, enantio-, and diastereoselectivity. It is expected that this C═C bond relay strategy may provide a general protocol for the asymmetric synthesis of structural motifs bearing two distant stereocenters.

Prediction of chemical reaction yields with large-scale multi-view pre-training.

Developing machine learning models with high generalization capability for predicting chemical reaction yields is of significant interest and importance. The efficacy of such models depends heavily on the representation of chemical reactions, which has commonly been learned from SMILES or graphs of molecules using deep neural networks. However, the progression of chemical reactions is inherently determined by the molecular 3D geometric properties, which have been recently highlighted as crucial features in accurately predicting molecular properties and chemical reactions. Additionally, large-scale pre-training has been shown to be essential in enhancing the generalization capability of complex deep learning models. Based on these considerations, we propose the Reaction Multi-View Pre-training (ReaMVP) framework, which leverages self-supervised learning techniques and a two-stage pre-training strategy to predict chemical reaction yields. By incorporating multi-view learning with 3D geometric information, ReaMVP achieves state-of-the-art performance on two benchmark datasets. Notably, the experimental results indicate that ReaMVP has a significant advantage in predicting out-of-sample data, suggesting an enhanced generalization ability to predict new reactions. Scientific Contribution: This study presents the ReaMVP framework, which improves the generalization capability of machine learning models for predicting chemical reaction yields. By integrating sequential and geometric views and leveraging self-supervised learning techniques with a two-stage pre-training strategy, ReaMVP achieves state-of-the-art performance on benchmark datasets. The framework demonstrates superior predictive ability for out-of-sample data and enhances the prediction of new reactions.

Direct α-Arylation of Benzo[b]furans Catalyzed by a Pd3 Cluster.

As an interim paradigm for the catalysts between those based on more conventional mononuclear molecular Pd complexes and Pdn nanoparticles widely used in organic synthesis, polynuclear palladium clusters have attracted great attention for their unique reactivity and electronic properties. However, the development of Pd cluster catalysts for organic transformations and mechanistic investigations is still largely unexploited. Herein, we disclose the use of trinuclear palladium (Pd3Cl) species as an active catalyst for the direct C-H α-arylation of benzo[b]furans with aryl iodides to afford 2-arylbenzofurans in good yields under mild conditions. With this method, broad substrate adaptability was observed, and several drug intermediates were synthesized in high yields. Mechanistic studies indicated that the Pd3 core most likely remained intact throughout the reaction course.

Desymmetrization of Geminal Difluoromethylenes using a Palladium/Copper/Lithium Ternary System for the Stereodivergent Synthesis of Fluorinated Amino Acids.

Fluorinated amino acids and related peptides/proteins have been found widespread applications in pharmaceutical and agricultural compounds. However, strategies for introducing a C-F bond into amino acids in an enantioselective manner are still limited and no such asymmetric catalysis strategy has been reported. Herein, we have successfully developed a Pd/Cu/Li ternary system for stereodivergent synthesis of chiral fluorinated amino acids. This method involves a sequential desymmetrization of geminal difluoromethylenes and allylic substitution with amino acid Schiff bases via Pd/Li and Pd/Cu dual activation, respectively. A series of non-natural amino acids bearing a chiral allylic/benzylic fluorine motif are easily synthesized in high yields with excellent regio-, diastereo-, and enantioselectivities (up to >20 : 1 dr and >99 % ee). A density functional theory (DFT) study revealed the F-Cu interaction of the allylic substrate and the Cu catalyst significantly influence the stereoselectivity.

Stereodivergent Synthesis of Allenes with α,ß-Adjacent Central Chiralities Empowered by Synergistic Pd/Cu Catalysis.

The stereodivergent synthesis of allene compounds bearing α,ß-adjacent central chiralities has been realized via the Pd/Cu-catalyzed dynamic kinetic asymmetric alkylation of racemic allenylic esters. The matched reactivity of bimetallic catalytic system enables the challenging reaction of racemic aryl-substituted allenylic acetates with sterically crowded aldimine esters smoothly under mild reaction conditions. Various chiral non-natural amino acids bearing a terminal allenyl group are easily synthesized in high yields and with excellent diastereo- and enantioselectivities (up to >20 : 1 dr, >99 % ee). Importantly, all four stereoisomers of the product can be readily accessed by switching the configurations of the two chiral metal catalysts. Furthermore, the easy interconversion between the uncommon η3 -butadienyl palladium intermediate featuring a weak C=C/Pd coordination bond and a stable Csp2 -Pd bond is beneficial for the dynamic kinetic asymmetric transformation process (DyKAT).

Bimetallic Catalysis in Stereodivergent Synthesis.

Bimetallic catalysis has emerged as an efficient strategy for the development of new chemical reactions. Importantly, this strategy also provides a simple and powerful platform for stereodivergent synthesis, whereby all the possible stereoisomers of products bearing two stereocenters can be easily prepared from the same set of starting materials. In this Minireview, the development of stereodivergent allylic substitution, propargylic substitution, hydrofunctionalization, and annulation based on bimetallic catalysis has been summarized. It is expected that more bimetallic catalytic systems will be developed and applied for the stereodivergent synthesis of valuable molecules.

Stereodivergent Desymmetrization of Simple Dicarboxylates via Branch-Selective Pd/Cu Catalyzed Allylic Substitution.

Asymmetric desymmetrization has been demonstrated to be a powerful strategy for building stereocenters in asymmetric synthesis. Herein, a Pd/Cu catalyzed asymmetric desymmetrization reaction with a simple geminal dicarboxylate is reported. A wide scope of imino esters bearing an aryl or heteroaromatic group were compatible with this bimetallic catalytic system. The reactions proceeded smoothly, giving the desired products in good yields with high to excellent regio-, diastereo-, and enantioselectivity (up to 20 : 1 branched:linear, >20 : 1 dr, >99 % ee). Notably, the reaction favored branched selectivity, which is unusual for the Pd-catalyzed allylic alkylation reaction. In addition, the standard product could be easily transformed to other valuable molecules such as chiral allylic alcohols, carbamates, and organic boron compounds. Furthermore, DFT calculations were conducted to explain the origin of the branched selectivity.

Nickel/Copper-Cocatalyzed Asymmetric Benzylation of Aldimine Esters for the Enantioselective Synthesis of α-Quaternary Amino Acids.

The first asymmetric Ni/Cu cocatalyzed benzylation of aldimine esters is reported. A series of benzyl-substituted α-quaternary amino acids could be synthesized in high yield and with high levels of enantioselectivity (up to 90 % yield and 99 % ee). The experimental and theoretical calculation results suggested that the strong electrophilicity of the η3 -benzylnickel intermediate is crucial for the high reactivity, enabling the reaction under base-free conditions. Furthermore, this method has been applied to the synthesis of the cell adhesion inhibitor BIRT-377 analogues, and the key intermediate of the NK1 receptor antagonist PD154075 and CCK-B receptor antagonist CI-988.

Chemical Synthesis of the Anti-COVID-19 Drug Remdesivir.

Remdesivir has become an important compound for the treatment of COVID-19. Here, we describe the catalytic asymmetric synthesis of this anti-COVID-19 drug. First, the P-racemic phosphoryl chloride is synthesized in a facile procedure. Then, it is possible to obtain the protected remdesivir via the organocatalytic asymmetric phosphorylation of protected nucleoside GS441524 with P-racemic phosphoryl chloride catalyzed by chiral bicyclic imidazole. Finally, remdesivir is easily prepared by deprotection. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Synthesis of 2-ethylbutyl (chloro(phenoxy)phosphoryl)-L-alaninate rac-4 Basic Protocol 2: Synthesis of chiral bicyclic imidazole Ad-DPI Basic Protocol 3: Synthesis of remdesivir.

Enantio- and Diastereodivergent Synthesis of Spirocycles through Dual-Metal-Catalyzed [3+2] Annulation of 2-Vinyloxiranes with Nucleophilic Dipoles.

The development of efficient and straightforward methods for obtaining all optically active isomers of structurally rigid spirocycles from readily available starting materials is of great value in drug discovery and chiral ligand development. However, the stereodivergent synthesis of spirocycles bearing multiple stereocenters remains an unsolved challenge owing to steric hindrance and ring strain. Herein, we report an enantio- and diastereodivergent synthesis of rigid spirocycles through dual-metal-catalyzed [3+2] annulation of oxy π-allyl metallic dipoles with less commonly employed nucleophilic dipoles (imino esters). A series of spiro compounds bearing a pyrroline and an olefin were easily synthesized in an enantio- and diastereodivergent manner (up to 19:1 dr, >99 % ee), which showed great promise as a new type of N-olefin ligand. Preliminary mechanistic studies were also carried out to understand the process of this bimetallic catalysis.

Enantio- and Diastereodivergent Construction of 1,3-Nonadjacent Stereocenters Bearing Axial and Central Chirality through Synergistic Pd/Cu Catalysis.

In contrast to the widely explored methods for the asymmetric synthesis of molecules bearing a single stereocenter or adjacent stereocenters, the concurrent construction of 1,3-stereogenic centers in an enantio- and diastereoselective manner remains a challenge, especially in acyclic systems. Herein, we report an enantio- and diastereodivergent construction of 1,3-nonadjacent stereocenters bearing allenyl axial and central chirality through synergistic Pd/Cu-catalyzed dynamic kinetic asymmetric allenylation with racemic allenylic esters. The protocol is suitable for a wide range of substrates including the challenging allenylic esters with less sterically bulky substituents and provided chiral allenylic products bearing 1,3-nonadjacent stereocenters with high levels of enantio- and diastereoselectivities (up to >20:1 dr and >99% ee). Furthermore, several representative transformations involving axial-to-central chirality transfer were conducted, affording useful structural motifs containing nonadjacent stereocenters in a diastereodivergent manner.

Synergistic Ir/Cu Catalysis for Asymmetric Allylic Alkylation of Oxindoles: Enantio- and Diastereoselective Construction of Quaternary and Tertiary Stereocenters.

3,3-Disubstituted oxindoles bearing quaternary and tertiary stereogenic centers are privileged structural motifs, which widely exist in pharmaceutical and natural products. Herein, a highly regio-, enantio-, and diastereoselective allylic alkylation of 3-alkyl oxindoles through synergistic iridium and copper catalysis is described, which provides a series of 3,3-disubstituted oxindole derivatives containing adjacent quaternary and tertiary stereogenic centers in excellent yields, enantiomeric excess, and diastereomeric ratio (for 30 examples, up to 97 % yield, >99 % ee, and >20 : 1 dr). This method provides exclusive branched selectivity, excellent enantio- and diastereoselectivities, and good functional compatibility. Control experiments suggested that the chiral copper catalyst is required for achieving high reactivities and diastereoselectivities under mild reaction conditions.

Stereodivergent Pd/Cu catalysis: asymmetric alkylation of racemic symmetrical 1,3-diphenyl allyl acetates.

We report a stereodivergent Pd/Cu catalyst system that was successfully applied to the asymmetric allylic alkylation of symmetrical 1,3-disubstituted allyl acetates with prochiral imino esters, providing efficient access to enantiopure products bearing vicinal stereocenters in a fully stereodivergent manner. The protocol proceeds smoothly under mild reaction conditions and can accommodate a range of imino esters, delivering the substituted products in high yields and with excellent diastereoselectivities (up to >20 : 1 dr) and enantioselectivities (up to >99% ee).

Catalytic Asymmetric Synthesis of the anti-COVID-19 Drug Remdesivir.

The catalytic asymmetric synthesis of the anti-COVID-19 drug Remdesivir has been realized by the coupling of the P-racemic phosphoryl chloride with protected nucleoside GS441524. The chiral bicyclic imidazole catalyst used is crucial for the dynamic kinetic asymmetric transformation (DyKAT) to proceed smoothly with high reactivity and excellent stereoselectivity (96 % conv., 22:1 SP :RP ). Mechanistic studies showed that this DyKAT is a first-order visual kinetic reaction dependent on the catalyst concentration. The unique chiral bicyclic imidazole skeleton and carbamate substituent of the catalyst are both required for the racemization process, involving the phosphoryl chloride, and subsequent stereodiscriminating step. A 10 gram scale reaction was also conducted with comparably excellent results, showing its potential for industrial application.

Stereodivergent Pd/Cu Catalysis for the Dynamic Kinetic Asymmetric Transformation of Racemic Unsymmetrical 1,3-Disubstituted Allyl Acetates.

A stereodivergent Pd/Cu catalyst system has been developed for the unprecedented dynamic kinetic asymmetric transformation (DyKAT) of racemic unsymmetrical 1,3-disubstituted allylic acetates with prochiral aldimine esters. A series of α,α-disubstituted α-amino acids bearing vicinal stereocenters were easily prepared with excellent enantioselectivities (up to >99% ee) and diastereoselectivities (up to >20:1 dr). Moreover, all four stereoisomers of the product can be readily obtained simply by switching the configurations of the two chiral metal catalysts. Furthermore, the present work highlights the power of synergistic Pd/Cu catalysis consisting of two common bidentate chiral ligands for stereodivergent synthesis.

Asymmetric synthesis of allylic compounds via hydrofunctionalisation and difunctionalisation of dienes, allenes, and alkynes.

Hydrofunctionalisation and difunctionalisation of dienes, allenes, and alkynes are widely utilized in the synthesis of valuable allylic compounds. In the past decades, asymmetric catalysis has emerged as one of the most attractive fields in organic synthesis. Recently, the asymmetric versions of hydrofunctionalisation and difunctionalisation reactions have become powerful and compelling tools to afford enantiopure allylic compounds, appealing to a large range of chemists. Various metal complexes modified with a large number of chiral ligands and several chiral organocatalysts have been developed to promote the hydrofunctionalisation and difunctionalisation reactions and expand substrate scope. This review provides an overview of this field, and aims at summarizing the chiral ligand used in this area of research. A detailed discussion of the development of these reactions and the general reaction mechanisms is provided.

Synergistic Pd/Cu Catalysis in Organic Synthesis.

Synergistic Pd/Cu catalysis has been utilized in the Sonogashira reaction since 1975. However, this strategy has not received much attention from the organic chemist community until recently. Synergistic Pd/Cu catalysis is becoming a proficient method for the development of catalytic reactions, including several new and efficient cross-coupling reactions. Additionally, several challenging asymmetric reactions, including stereodivergent synthesis, have been discovered by the combined use of a chiral metal catalyst and a second achiral metal catalyst or two chiral metal catalysts. This review provides an overview of this field, with the aims of highlighting both the development of synergistic Pd/Cu catalysis in organic synthesis and the reaction mechanisms involved in this research area.

Stereoselective Allylic Alkylation of 1-Pyrroline-5-carboxylic Esters via a Pd/Cu Dual Catalysis.

The asymmetric allylation of 1-pyrroline-5-carboxylic esters has been accomplished through a synergistic Pd/Cu catalyst system under mild reaction conditions. The mechanistic studies suggested that (1) nucleophilic attack is the enantiodiscriminating step; (2) the cooperative action of two chiral reactive species, N-metalated azomethine ylides and π-allylpalladium, is most likely responsible for its high reactivity and excellent enantioselectivity (up to >99% ee); and (3) the steric hindrance and electronic factors of the allylic electrophiles and imino ester substrates are crucial for the formation of the linear products. A series of 3,4-2 H-pyrrole derivatives bearing a quaternary stereogenic center were easily synthesized in high yields and with high to excellent regioselectivity and enantioselectivity.

Iridium-Catalyzed Enantioselective and Diastereoselective Allylation of Dioxindoles: A One-Step Synthesis of 3-Allyl-3-hydroxyoxindoles.

An iridium-catalyzed asymmetric allylation of dioxindoles, 3-hydroxyoxindoles, regulated by prosthetic groups has been accomplished under mild conditions. The methodology is applicable to a diverse array of 3-hydroxyoxindole and cinnamyl acetate substrates. A range of 3-allyl-3-hydroxyoxindoles containing vicinal tetrasubstituted and trisubstituted stereocenters can be efficiently synthesized in one-step with excellent enantioselectivity (up to >99% enaniomeric excess (ee)) and good diastereoselectivity (up to 11:1 diastereomeric ratio (dr)).