Enantioselective Ni-Catalyzed 1,2-Borylalkynylation of Unactivated Alkenes.

Enantioselective three-component difunctionalization of alkenes with boron reagents represents an attractive strategy for assembling three-dimensional chiral organoboron compounds. However, regio- and enantiocontrol comprise the pivot challenges in these transformations, which predominantly require the use of activated conjugated alkenes. Herein, by utilizing various carbonyl directing groups, including amides, sulfinamides, ketones, and esters, we succeed in realizing a nickel-catalyzed 1,2-borylalkynylation of unactivated alkenes to enable the simultaneous incorporation of a boron entity and an sp-fragment across the double bond. The products contain boryl, alkynyl, and carbonyl functional groups with orthogonal synthetic reactivities, offering three handles for further derivatization to access valuable intermediates. The utility of this ligand-enabled asymmetric protocol has been highlighted through the late-stage decoration of drug-relevant molecules.

Palladium-Catalyzed Enantioselective Multicomponent Cross-Coupling of Trisubstituted Olefins.

The development of a catalytic method for stereogenic carbon center formation holds immense significance in organic synthesis. Transition-metal-catalyzed cross-coupling reaction has been regarded as a straightforward and efficient tool for stereoselectively forging C-C bond. Nevertheless, the creation of acyclic all-carbon quaternary-containing vicinal stereocenters remains notoriously challenging within the domain of cross-coupling chemistry despite their prominence in various bioactive small molecules. Herein, we describe a palladium-catalyzed asymmetric multicomponent cross-coupling of trisubstituted alkene with aryl diazonium salts and arylboronic acids to realize the formation of tertiary-quaternary carbon centers with high regio-, distereo-, and enantioselectivity. Specifically, the precise manipulation of the stereoconfiguration of trisubstituted alkenes enables the divergent stereoselective cross-coupling reaction, thus allowing for the facile construction of all four enantiomers. Harnessing the ligand-swap strategy involving a chiral bisoxazoline and an achiral fumarate individually accelerates the enantioselective migratory insertion and reductive elimination step in the cross-coupling process, as supported by density functional theory (DFT) calculations, thus obviating the requirement for a neighboring directing group within the internal olefin skeleton.

Rhodium-Catalyzed Enantioselective Formal [4+1] Cyclization of Benzyl Alcohols and Benzaldimines: Facile Access to Silicon-Stereogenic Heterocycles.

The carbon-to-silicon switch in formation of bioactive sila-heterocycles with a silicon-stereogenic center has garnered significant interest in drug discovery. However, metal-catalyzed synthesis of such scaffolds is still in its infancy. Herein, a rhodium-catalyzed enantioselective formal [4+1] cyclization of benzyl alcohols and benzaldimines has been realized by enantioselective difunctionalization of a secondary silane reagent, affording chiral-at-silicon cyclic silyl ethers and sila-isoindolines, respectively. Mechanistic studies reveal a dual role of the rhodium-hydride catalyst. The coupling system proceeds via rhodium-catalyzed enantio-determining dehydrogenative OH silylation of the benzyl alcohol or hydrosilylation of the imine to give an enantioenriched silyl ether or silazane intermediate, respectively. The same rhodium catalyst also enables subsequent intramolecular cyclative C-H silylation directed by the pendent Si-H group. Experimental and DFT studies have been conducted to explore the mechanism of the OH bond silylation of benzyl alcohol, where the Si-O reductive elimination from a Rh(III) hydride intermediate has been established as the enantiodetermining step.

Diastereo- and Enantioselective Synthesis of Tetracyclic Cycloheptanols through (4+3) Annulation via C-C/C-H Activation Cascade.

Transition metal-catalyzed annulations of four-membered rings via C-C activation are powerful tools to construct complex fused and bridged ring systems. Despite significant progress in (4+1), (4+2) and (4+4) annulations, the (4+3) annulation remains unexplored. Herein, we develop an asymmetric Rh-catalyzed intramolecular (4+3) annulation of α-arylalkene-tethered benzocyclobutenols for the synthesis of dihydrofuran-annulated dibenzocycloheptanols with two discontinuous chiral carbon centers via a C-C and C-H activation cascade. The reaction features excellent diastereo- and enantioselectivities and 100 % atom economy, and is applicable to late-stage modification of complex molecules.

Nickel/Photoredox Dual-Catalyzed Regiodivergent Aminoalkylation of Unactivated Alkyl Halides.

A mild and regiodivergent aminoalkylation of unactivated alkyl halides is disclosed via a dual photoredox/nickel catalysis. Bipyridyl-type ligands without an ortho-substituent control the site-selective coupling at the original position, while ortho-disubstituted ligands tune the site-selectivity at a remote, unprefunctionalized position. Mechanistic studies combined with DFT calculations give insight into the mechanism and the origins of the ligand-controlled regioselectivity. Notably, this redox-neutral, regiodivergent alkyl-alkyl coupling features mild conditions, broad substrate scope for both alkyl coupling partners, and excellent site-selectivity and offers a straightforward way for α-alkylation of tertiary amines to synthesize structurally diverse alkylamines and value-added amino acid derivatives.

Sigma-Bond Metathesis as an Unusual Asymmetric Induction Step in Rhodium-Catalyzed Enantiodivergent Synthesis of C-N Axially Chiral Biaryls.

Mechanistic understanding of asymmetric induction plays a crucial role in designing new catalytic asymmetric reactions. Reported herein is atroposelective access to C-N axially chiral isoquinolones via rhodium-catalyzed C-H activation of N-alkoxy benzamides and annulation with imidoyl sulfoxonium ylides. The coupling system proceeded with excellent functional group tolerance, and different conditions were identified to afford one or the other enantiomeric product each in excellent enantioselectivity for a representative class of the sulfoxonium ylide reagent, thus making both enantiomers readily available using the same catalyst. Experimental and computational studies revealed a pathway of C-H alkylation and enantio-determining formal nucleophilic substitution-C-N cyclization that is mediated by the rhodium catalyst via σ-bond metathesis as the asymmetric induction mechanism. Computational studies indicated that the solvent-dependent enatiodivergence originated from different levels of σ-bond metathesis mediated by neutral versus cationic rhodium species.

Stereoselective Photoredox Catalyzed (3+3) Dipolar Cycloaddition of Nitrone with Aryl Cyclopropane.

By resorting to the principle of remote activation, we herein demonstrate the first photoredox catalyzed (3+3) dipolar cycloaddition of nitrones with aryl cyclopropanes. Key to the fidelity of the reaction resides in a facile manner of substrate activation by single-electron transfer (SET) oxidation with photoredox catalysis, and the reaction takes place through a stepwise cascade encompassing a three-electron-type nucleophilic substitution triggered cyclopropane ring-opening and a diastereoselective 6-endo-trig radical cyclization manifold. The reaction proceeds under mild conditions with excellent regio- and stereoselectivity, nicely complementing the well-developed Lewis acid catalyzed cycloaddition of donor-acceptor cyclopropanes. Other merits of the protocol include wide scope of aryl cyclopropanes with diversified substitution patterns and good functional-group compatibility. A mechanism involving an aryl radical cation promoted remote activation mode was also proposed and supported by mechanistic experiments.

Enantioselective C2-H Alkylation of Pyridines with 1,3-Dienes via Ni-Al Bimetallic Catalysis.

A chiral phosphine oxide-ligated Ni-Al bimetallic catalyst was used to realize an enantioselective C2-H alkylation of pyridines without the need of a C2-block. A wide range of pyridines, including unsubstituted pyridine, C3, C4, and C2-substituted pyridines, and even complex pyridine-containing bioactive molecules are well compatible with the reaction, providing up to 81% yield and up to 97% ee.

Mechanism and Origins of Enantioselectivity of Cobalt-Catalyzed Intermolecular Hydroarylation/Cyclization of 1,6-Enynes with N-Pyridylindoles.

Density functional theory calculations were performed to investigate the cobalt-catalyzed intermolecular hydroarylation/cyclization of 1,6-enynes with N-pyridylindoles. The computations reveal that the reaction begins with the oxidative cyclization of 1,6-enyne to afford the five-membered cobaltacycle, from which the metal-assisted σ-bond metathesis/C-C reductive elimination led to the final hydroarylation/cyclization product. The initial oxidative cyclization constitutes the rate-determining step of the overall reaction. The steric repulsion and π···π interaction were found to play a crucial role in dictating the experimentally observed enantioselectivity.

Computational and Experimental Study of Turbo-Organomagnesium Amide Reagents: Cubane Aggregates as Reactive Intermediates in Pummerer Coupling.

The dynamic equilibria of organomagnesium reagents are known to be very complex, and the relative reactivity of their components is poorly understood. Herein, a combination of DFT calculations and kinetic experiments is employed to investigate the detailed reaction mechanism of the Pummerer coupling between sulfoxides and turbo-organomagnesium amides. Among the various aggregates studied, unprecedented heterometallic open cubane structures are demonstrated to yield favorable barriers through a concerted anion-anion coupling/ S-O cleavage step. Beyond a structural curiosity, these results introduce open cubane organometallics as key reactive intermediates in turbo-organomagnesium amide mixtures.

Copper-Catalyzed Highly Selective Protoboration of CF3 -Containing 1,3-Dienes.

The copper-catalyzed highly selective protoboration of CF3 -containing conjugated diene with proton source and B2 Pin2 has been developed. This chemistry could suppress the well-known defluorination and provide borated reagents with an intact CF3 -group. Further studies indicated that the functional group tolerance of this chemistry is very well, and the products could be used as versatile precursors for different types of transformations. Importantly, using chiral diphosphine ligand, we have developed the first example for using such starting material to synthesis allylic boron-reagents which bearing a CF3 -containing chiral center. Notably, the reaction mechanism was intensively studied by DFT calculations, which could reveal the reason that defluorination was inhibited.

NiH-Catalyzed Migratory Defluorinative Olefin Cross-Coupling: Trifluoromethyl-Substituted Alkenes as Acceptor Olefins to Form gem-Difluoroalkenes.

We report a NiH-catalyzed migratory defluorinative coupling between two electronically differentiated olefins. A broad range of unactivated donor olefins can be joined directly to acceptor olefins containing an electron-deficient trifluoromethyl substituent in both intra- and intermolecular fashion to form gem-difluoroalkenes. This migratory coupling shows both site- and chemoselectivity under mild conditions, with the formation of a tertiary or quaternary carbon center.

Mechanism and Origins of Enantioselectivity of Iridium-Catalyzed Intramolecular Silylation of Unactivated C(sp3)-H Bonds.

Density functional theory calculations were performed to investigate the iridium-catalyzed intramolecular silylation of unactivated C(sp3)-H bonds. The computations show that the in situ generated iridium(III) silyl dihydride species is the active catalyst, from which the followed migratory insertion and the transmetalation would generate the iridium(III) disilyl hydride species. The reaction was found to take place through an Ir(III)/Ir(V) catalytic cycle, and the C(sp3)-H bond oxidative addition constitutes the rate- and enantioselectivity-determining step. The steric repulsion and C-H···π interaction were found to account for the experimentally observed enantioselectivity.

Mechanism and Origins of Regioselectivity of Copper-Catalyzed Borocyanation of 2-Aryl-Substituted 1,3-Dienes: A Computational Study.

Density functional theory calculations were performed to investigate the copper-catalyzed borocyanation of 2-aryl-substituted 1,3-dienes. The computations show that the regioselectivity of the overall reaction is governed by the combination of the inherent regioselectivity of the borocupration and electrophilic cyanation steps. The π-conjugation effect of the 1,3-diene makes the terminal carbon atoms more electrophilic compared with the internal carbon atoms, which coupled with the steric effect results in the 4,3- and 1,2-borocupration being intrinsically more favorable than the other possibilities. The steric repulsion around the breaking Cu-C bond was found to be the key factor in determining the regioselectivity of the electrophilic cyanation. The origins of the experimentally observed ligand-controlled regioselectivity were ascribed to the electronic and steric effects. For the bulky XantPhos ligand, the 4,3-borocupration was found to be more favorable than the 1,2-borocupration due to the steric repulsion around the forming Cu-C bond, resulting in the formation of the 4,3-borocyantion product. On the other hand, the reversed regioselectivity with a small PCy3 ligand is mainly caused by the electronic effect that the π-electron-withdrawing aryl group at the C2 atom makes the C1 atom more electrophilic than the C4 atom, enabling the 1,2-borocupration to be more favorable than the 4,3-borocupration.

A Mechanistic Analysis of the Palladium-Catalyzed Formation of Branched Allylic Amines Reveals the Origin of the Regio- and Enantioselectivity through a Unique Inner-Sphere Pathway.

A recently reported palladium-catalyzed allylic substitution of vinyl-substituted cyclic carbonates (VCCs) with aryl amines represents a rare example of a regio- and enantioselective synthesis of α,α-disubstituted allylic N-aryl amines. However, the underlying reasons for this unusual selectivity profile remain elusive. In the present work, density functional theory (DFT) calculations in combination with mechanistic control experiments were performed to elucidate in detail this allylic amination manifold and the origin of the regio- and enantioselectivity. The combined data show that after oxidative addition of the VCC to Pd0 , the nucleophilic attack via an originally proposed outer-sphere pathway gives, however, the opposite regioisomer compared to the experimental results. Instead, nucleophilic attack of the amine reagent via a unique type of chelation-assisted, inner-sphere pathway accounts for the experimentally observed "branched" regioselectivity and high enantio-control.

BKCa participates in E2 inducing endometrial adenocarcinoma by activating MEK/ERK pathway.

BACKGROUND: The large-conductance, voltage-gated, calcium (Ca (2+))-activated potassium channel (BKCa) plays an important role in regulating Ca (2+) signaling and cell physiological function, and is aberrantly expressed in some types of cancers. The present study focuses on identifying the oncogenic potential and clinical significance of BKCa in endometrial adenocarcinoma, as well as exploring the mechanistic relevance by 17ß -estradiol (E2) inducing aberrant activation of MEK1/2 and ERK1/2 via BKCa. METHODS: The expression of BKCa, ERK1/2 and p-ERK1/2 were examined by immunohistochemical staining in 263 cases, including 185 primary types I endometrial cancer tissues, 38 atypical endometrial hyperplasia tissues and 40 normal endometrium tissues. Cell growth, cycle, apoptosis rate, migration and invasion was separately tested in Ishikawa cells using siRNA-BKCa and/or E2 treatment, as well as the expression of these interested proteins by western blot analysis. RESULTS: We showed that expression of BKCa is significantly elevated in 185 types I endometrial adenocarcinoma tissues compared to those of the normal endometrium and atypical endometrial hyperplasia tissues. Furthermore, in vitro observations revealed that down-regulation of BKCa expression inhibited cell growth by both enhancing apoptosis and blocking G1/S transition, suppressed cell migration and invasion in Ishakiwa cells, and decreased the expression of p-MEK1/2 and p-ERK1/2. Additionally, RNAi-mediated knockdown of BKCa attenuated the increased cellular growth and invasion, as well as the elevated expression of p-MEK1/2 and p-ERK1/2 proteins, induced by E2 stimulation. More importantly, the aberrant expression of BKCa and p-ERK1/2 were closely related with poor prognostic factors in type I endometrial cancer, and up-regulated expression of p-ERK1/2 was significantly associated with shorter disease-free survival (DFS) and overall survival (OS) and was an independent prognostic factor in type I endometrial cancer patients. CONCLUSION: Our results demonstrated that BKCa and the key downstream effectors p-ERK1/2 could be involved in important signaling pathways in initiation and development of endometrial adenocarcinoma and may provide a new therapeutic approach for women with endometrial cancer.

Mechanism and Origins of Regio- and Enantioselectivities of Iridium-Catalyzed Hydroarylation of Alkenyl Ethers.

The iridium-catalyzed hydroarylation of alkenyl ethers developed by Nishimura and co-workers (Ebe, Y.; Onoda, M.; Nishimura, T.; Yorimitsu, H. Angew. Chem. Int. Ed. 2017, 56, 5607-5611) represents a rare example of regio- and enantioselective hydroarylation of challenging internal alkenes. In the present study, density functional theory calculations were performed in order to investigate the detailed reaction mechanism and the origins of the experimentally observed regio- and enantioselectivities. The computations show that the initial C-H oxidative addition and the isomerization between the allylic ethers and the 1-alkenyl ethers via the migratory insertion into the Ir-H bond/ß-hydride elimination are both feasible. The reaction was found to proceed through the modified Chalk-Harrod-type mechanism via the migratory insertion into the Ir-C bond/C-H reductive elimination. The migratory insertion into the Ir-C bond constitutes the rate- and selectivity-determining step of the overall reaction. The calculations reproduced quite well the experimentally observed regio- and enantioselectivities. The enantioselectivity of the reaction was found to arise from the reactions of the (E)- and (Z)-1-alkenyl ethers, which afford the opposite enantiomers of product with the aryl group installed at the α-position to the alkoxy group. It turns out that the strong electron-donating character of the alkoxy group plays an important role in determining the regioselectivity, since it can stabilize the developed positive charge of the α-insertion transition state, leading to the aryl group being selectively installed at the α-position.

Mechanisms of Rhodium(III)-Catalyzed C-H Functionalizations of Benzamides with α,α-Difluoromethylene Alkynes.

The rhodium(III)-catalyzed C-H functionalizations of benzamides with α,α-difluoromethylene alkynes have been investigated by means of density functional theory calculations. The computations show that after the formation of seven-membered rhodacycle via consecutive N-H deprotonation/C-H activation/migratory insertion, a novel redox-neutral process without the engagement of otherwise widely accepted Rh(V) nitrenoid species has been formulated in the hydroarylation reaction. It turns out that the seven-membered rhodacycle undergoes a concerted Lossen rearrangement/migration of OPiv from N to Rh to generate the isocyanate intermediate, from which the ensuing nucleophilic addition of MeOH and protodemetalation lead to the generation of final products. By preventing formation of Rh(V) nitrenoid species, the intriguing role of fluorine substituents in hydroarylation reaction has also been disclosed. Furthermore, the coordination of carbonyl oxygen of OPiv group to the Rh center proves to be crucial for both [4 + 2] annulation and hydroarylation. However, in the case of using directing group with N-OMe, the lack of such assistance would engender a considerable buildup of energy with respect to the transition state, making both [4 + 2] annulation and hydroarylation processes kinetically unfavorable. Accordingly, the alternative [4 + 1] annulation takes place as the most favored pathway via consecutive twofold ß-F eliminations.

Elucidation of Mechanisms and Selectivities of Metal-Catalyzed Reactions using Quantum Chemical Methodology.

Quantum chemical techniques today are indispensable for the detailed mechanistic understanding of catalytic reactions. The development of modern density functional theory approaches combined with the enormous growth in computer power have made it possible to treat quite large systems at a reasonable level of accuracy. Accordingly, quantum chemistry has been applied extensively to a wide variety of catalytic systems. A huge number of problems have been solved successfully, and vast amounts of chemical insights have been gained. In this Account, we summarize some of our recent work in this field. A number of examples concerned with transition metal-catalyzed reactions are selected, with emphasis on reactions with various kinds of selectivities. The discussed cases are (1) copper-catalyzed C-H bond amidation of indoles, (2) iridium-catalyzed C(sp(3))-H borylation of chlorosilanes, (3) vanadium-catalyzed Meyer-Schuster rearrangement and its combination with aldol- and Mannich-type additions, (4) palladium-catalyzed propargylic substitution with phosphorus nucleophiles, (5) rhodium-catalyzed 1:2 coupling of aldehydes and allenes, and finally (6) copper-catalyzed coupling of nitrones and alkynes to produce ß-lactams (Kinugasa reaction). First, the methodology adopted in these studies is presented briefly. The electronic structure method in the great majority of these kinds of mechanistic investigations has for the last two decades been based on density functional theory. In the cases discussed here, mainly the B3LYP functional has been employed in conjunction with Grimme's empirical dispersion correction, which has been shown to improve the calculated energies significantly. The effect of the surrounding solvent is described by implicit solvation techniques, and the thermochemical corrections are included using the rigid-rotor harmonic oscillator approximation. The reviewed examples are chosen to illustrate the usefulness and versatility of the adopted methodology in solving complex problems and proposing new detailed reaction mechanisms that rationalize the experimental findings. For each of the considered reactions, a consistent mechanism is presented, the experimentally observed selectivities are reproduced, and their sources are identified. Reproducing selectivities requires high accuracy in computing relative transition state energies. As demonstrated by the results summarized in this Account, this accuracy is possible with the use of the presented methodology, benefiting of course from a large extent of cancellation of systematic errors. It is argued that as the employed models become larger, the number of rotamers and isomers that have to be considered for every stationary point increases and a careful assessment of their energies is therefore necessary in order to ensure that the lowest energy conformation is located. This issue constitutes a bottleneck of the investigation in some cases and is particularly important when analyzing selectivities, since small energy differences need to be reproduced.

Mechanism and Origins of the Chemo- and Regioselectivities in Nickel-Catalyzed Intermolecular Cycloadditions of Benzocyclobutenones with 1,3-Dienes.

The nickel-catalyzed intermolecular cycloadditions of benzocyclobutenones with 1,3-dienes developed by Martin and co-workers are featured with the exclusive proximal C-C bond cleavage and a high chemoselectivity of the [4+4] over the [4+2] cycloaddition. In this report, the detailed reaction mechanism and the origins of the selectivities were investigated by means of density functional theory calculations. The results show that the reaction is initiated by a C-C oxidative addition of the benzocyclobutenone to form the five-membered nickelacycles. A subsequent exo 1,4-insertion/C-C reductive elimination and an endo 1,4-insertion/C-C reductive elimination lead to the [4+4] and [4+2] cycloaddition products, respectively. The 1,4-insertion of the 1,3-diene into the Ni-C bond was calculated to be the rate- and selectivity-determining step of the reaction. The calculations reproduced quite well the experimentally observed exclusive proximal C-C bond cleavage and the high chemoselectivity of the [4+4] over the [4+2] cycloaddition. In particular, it was found that the steric repulsion between the phosphine ligand and the α-substituent of the benzocyclobutenone has a dramatic impact on the 1,4-insertion, which enables the experimentally observed selectivities.