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.

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.

Iridium-Catalyzed Remote Site-Switchable Hydroarylation of Alkenes Controlled by Ligands.

An iridium-catalyzed remote site-switchable hydroarylation of alkenes was reported, delivering the products functionalized at the subterminal methylene and terminal methyl positions on an alkyl chain controlled by two different ligands, respectively, in good yields and with good to excellent site-selectivities. The catalytic system showed good functional group tolerance and a broad substrate scope, including unactivated and activated alkenes. More importantly, the regioconvergent transformations of mixtures of isomeric alkenes were also successfully realized. The results of the mechanistic studies demonstrate that the reaction undergoes a chain-walking process to give an [Ar-Ir-H] complex of terminal alkene. The subsequent processes proceed through the modified Chalk-Harrod-type mechanism via the migratory insertion of terminal alkene into the Ir-C bond followed by C-H reductive elimination to afford the hydrofunctionalization products site-selectively.

Rh-Catalyzed Enantioselective Desymmetric Hydrogenation of α-Acetamido-1,3-indanediones Using Ether-Bridged Biphenyl Diphosphine Ligands.

Novel axially chiral biphenyl diphosphine ligands Enm-BridgePhos, bearing an ether chain bridge at the 5,5'-position of the biphenyl backbone, have been developed and successfully applied in the Rh-catalyzed enantioselective desymmetric hydrogenation of α-acetamido-1,3-indanediones, providing chiral α-acetamido-ß-hydroxybenzocyclic pentones in high yields (up to 97%) and with excellent enantioselectivities (up to 99% ee). The reaction could be carried out on a gram scale, and the corresponding products were used as vital intermediates for the synthesis of analogues of chiral spirobenzylisoquinoline alkaloids. Both the crystal structure analysis and the DFT calculations revealed that the large dihedral angle of the Enm-BridgePhos-Rh complexes is highly related to the excellent enantioselectivities.

Copper-Catalyzed Chemoselective Asymmetric Hydrogenation of C=O Bonds of Exocyclic α,ß-Unsaturated Pentanones.

A highly chemoselective earth-abundant transition metal copper catalyzed asymmetric hydrogenation of C=O bonds of exocyclic α,ß-unsaturated pentanones was realized using H2 . The desired products were obtained with up to 99 % yield and 96 % ee (enantiomeric excess) (99 % ee, after recrystallization). The corresponding chiral exocyclic allylic pentanol products can be converted into several bioactive molecules. The hydrogenation mechanism was investigated via deuterium-labelling experiments and control experiments, which indicate that the keto-enol isomerization rate of the substrate is faster than that of the hydrogenation and also show that the Cu-H complex can only catalyze chemoselectively the asymmetric reduction of the carbonyl group. Computational results indicate that the multiple attractive dispersion interactions (MADI effect) between the catalyst with bulky substituents and substrate play important roles which stabilize the transition states and reduce the generation of by-products.

Cu-Catalyzed Asymmetric Kinetic Boron Conjugate Addition of γ-Substituted α,ß-Unsaturated γ-Lactams.

Chiral α,ß-unsaturated γ-lactams bearing simple γ- substituents are found in biologically active molecules and natural products, however, their synthesis still remains difficult. Herein, we report an efficient kinetic resolution (KR) of γ-substituted α,ß-unsaturated γ-lactams via a Cu-catalyzed asymmetric boron conjugate addition, which also leads to the efficient synthesis of chiral ß-hydroxy-γ-lactams with ß,γ-stereogenic carbon centers. The KR proceeded smoothly with a wide range of γ-alkyl or aryl substituted substrates including those bearing aromatic heterocycles and different N-protected substrates in up to 347 of s value. Their highly versatile transformations, synthetic utility in biologically active molecules, and inhibitory activities against cisplatin-sensitive ovarian cancer cell A2780 have also been demonstrated. Differing from the well-known mechanism involving Cu-B species in Cu-catalyzed boron conjugate additions, our mechanistic studies using density functional theory (DFT) calculations and experiments indicate that a Lewis acid CuI -catalyzed mechanism is the likely pathway in the catalytic reaction.

Coumarinacyl Anilinium Salt: A Versatile Visible and NIR Photoinitiator for Cationic and Step-Growth Polymerizations.

A coumarinacyl anilinium (CAA) salt, facilely synthesized via a one-pot reaction, is shown to be a versatile visible and NIR photoinitiator for cationic and step-growth polymerizations. CAA salt exhibits superior photoinitiation performance as compared to commercial iodonium salt in cationic polymerization. Upon visible-light irradiation, this salt undergoes hemolytic and heterolytic cleavage and subsequent electron transfer and hydrogen abstraction reactions, forming reactive species capable of initiating cationic polymerization of epoxides and vinyl monomers. After a short irradiation period, polymerization also proceeds in the dark due to the non-nucleophilic nature of the counteranion. NIR-induced polymerizations were successfully conducted based on upconversion photochemistry. CAA salt can also initiate step-growth polymerization of N-ethyl carbazole (NEC) by oxidation of the monomer by the photochemically formed anilium radical cations. Subsequent proton release and radical coupling reactions essentially yield polycarbazole. CAA salt, featuring straightforward synthesis and long-wavelength sensitivity as well as versatile photoinitiating performance, has great potential in various applications.

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).

Iridium-Catalyzed 1,3-Rearrangement of Allylic Alcohols.

The allylic alcohol structural motif is prevalent in many important molecules and valuable building blocks. The rearrangement reaction is one of the most important transformations, however there are only a few reports for the 1,3-rearrangement of allylic alcohols. Herein, a 1,3-rearrangement of allylic alcohols catalyzed by an Ir(III) dihydride complex is described. This reaction could provide the corresponding less accessible allylic alcohols regio- and stereoselectively from readily available E/Z mixtures of the substrates. Furthermore, a tandem alkene isomerization followed by 1,3-rearrangement of homoallylic alcohols was also realized. In addition, this rearrangement reaction could be used to synthesize the natural product Navenone B. Mechanistic investigation indicated that the reaction pathway involved a π-allyl-Ir(V) intermediate and that the dihydride in the iridium catalyst acts as a hydrogen switch to modulate the valence of the iridium center.

Rh-Catalyzed Sequential Asymmetric Hydrogenations of 3-Amino-4-Chromones Via an Unusual Dynamic Kinetic Resolution Process.

Rh-catalyzed sequential asymmetric hydrogenations of 3-amino-4-chromones have been achieved for the first time via an unprecedented dynamic kinetic resolution under neutral conditions, providing (S,R)-3-amino-4-chromanols in high yields (up to 98%) with excellent enantio- and diastereoselectivities (up to 99.9% ee and 20:1 dr). The mechanistic studies based on control experiments and density functional theory (DFT) calculations suggest that the dynamic kinetic resolution process for the intermediate enantiomers generated in the first hydrogenation step proceeded via a stereomutation (or called chiral assimilation) pathway from an undesired enantiomer to the desired enantiomer rather than via traditional racemization of the undesired enantiomer. The protocol can be performed on a gram scale with a relatively low catalyst loading and offers a practical and convenient pathway for synthesizing a series of bioactive chromanols and their derivatives.

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.

Cu-catalyzed asymmetric addition of alcohols to ß,γ-alkynyl-α-imino esters for the construction of linear chiral N,O-ketals.

N,O-acetals are part of many synthetic intermediates and important skeletons of numerous natural products and pharmaceutical drugs. The most straightforward method of the synthesis of N,O-acetals is the enantioselective addition of O-nucleophiles to imines. However, using this method for the synthesis of linear chiral N,O-ketals still remains challenging due to the instability of raw materials under acidic or basic conditions. Herein, we developed a Cu-catalyzed asymmetric addition of alcohols to ß,γ-alkynyl-α-imino esters under mild conditions, providing the corresponding linear chiral N,O-ketals with up to 96% ee. The method tolerates some variation in the ß,γ-alkynyl-α-imino ester and alcohol scope, including some glucose and natural amino acid derivatives. Computational results indicate that the Boc group of the substrates assist in the extraction of hydrogen atoms from the alcohols to promote the addition reactions. These products could be synthesized on a gram-scale and can be used in several transformations. This asymmetric addition system provides an efficient, mild, gram-scale, and transition-metal-catalyzed synthesis of linear chiral N,O-ketals.

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.

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.

DFT study of the stabilization effect on anthocyanins via secondary interactions.

Anthocyanins, which are the labile flavonoid pigments in botanical food, are attracting intensive attention because they can reduce the risk of noncommunicable diseases. Thus, many dietary molecules have been explored to minimize anthocyanin degradation. This study developed a novel model based on the density functional theory (DFT) and conceptual density functional theory (CDFT) to screen small dietary compounds that can stabilize aqueous anthocyanins. The progression of anthocyanin degradation, which was modeled as an aqueous food system, was illustrated using thermodynamic computation and relaxed scanning. The nucleophilic index and dipole moment were applied to quantify van der Waals interaction between anthocyanins and stabilizers. Two equations based on first-order kinetics were established to demonstrate that the equilibrium constant and free energy of the binding reaction between anthocyanins and stabilizers were theoretically important. The change in binding free energy change (ΔG) may be the best indicator of the protection offered by dietary stabilizers on anthocyanins, which was demonstrated by comparisons of computational ΔG with the thermal half time from the previous study on the effects of gallic/ferulic/caffeic acids on anthocyanin stability. Based on established forecasting methods, trans-resveratrol (ΔG = -35.63 kJ/mol) was found to be the best stabilizer among dietary compounds.

Molecular Interaction of Protein-Pigment C-Phycocyanin with Bovine Serum Albumin in a Gomphosis Structure Inhibiting Amyloid Formation.

Accumulation of amyloid fibrils in organisms accompanies many diseases. Natural extracts offer an alternative strategy to control the process with potentially fewer side effects. In this study, the inhibition of C-phycocyanin from Spirulina sp. on amyloid formation of bovine serum albumin (BSA) during a 21-day incubation was investigated using fluorescence and circular dichroism (CD), and mechanisms were explored via kinetic fitting and molecular docking. C-phycocyanin (0-50 µg/mL) hindered the amyloid formation process of BSA with increased half-lives (12.43-17.73 days) based on fluorescence intensity. A kinetic model was built and showed that the k1 decreased from 1.820 × 10-2 d-1 to 2.62 × 10-3 d-1 with the increase of C-phycocyanin, while k2 showed no changes, indicating that the inhibition of BSA fibrillation by C-phycocyanin occurred in a spontaneous process instead of self-catalyzed one. CD results show that C-phycocyanin inhibited conformational conversion (α-helices and ß-sheets) of BSA from day 6 to day 18. Molecular docking suggested that C-phycocyanin may hinder BSA fibrillation by hydrogen-bonding > 6 of 27 α-helices of BSA in a gomphosis-like structure, but the unblocked BSA α-helices might follow the self-catalytic process subsequently.