Switch in Selectivities by Dinuclear Nickel Catalysis: 1,4-Hydroarylation of 1,3-Dienes to Z-Olefins.

One of the most challenging tasks in organic synthesis is to control selectivities, especially switching the well-known selectivity to obtain new isomers that were previously inaccessible. Inspired by biological catalysis involving multiple metal centers, catalysis enabled by binuclear metal complexes offers the potential to induce reactivity and selectivity that might not be available to mononuclear catalysts. Herein, we describe that using a macrocyclic bis pyridyl diimine dinickel complex as the catalyst, the commonly observed 4,3-regioselectivity of hydroarylation of 1,3-dienes is switched to 1,4-hydroarylation with thermodynamically less stable Z-stereoselectivity, offering challenging synthetic target Z-olefins. DFT calculations show that the activation of 1,3-diene proceeds through dinuclear Ni-diolefin coordination, and the synergistic effects of two Ni nuclei enable reactivity and selectivity of this binuclear catalysis substantially different from those of mononuclear nickel complexes in the current reaction.

Rh(II)/Pd(0) Dual-Catalyzed Regio-Divergent Three-Component Propargylic Substitution.

Regio-divergent propargylic substitution to generate functionally diverse products from identical starting materials remains a formidable challenge, probably due to the unpredictable regiochemical complexity. In practically, the synthesis of α-quaternary propargylic-substituted products is still much less developed, and preprepared nucleophiles are generally applied in this type of reaction with propargylic substrates, which limits the reaction efficiency and diversity of the obtained products. Herein, we disclose unprecedented three-component propargylic substitution of α-diazo esters with amines and propargylic carbonates under dirhodium/palladium dual catalysis. The key to the success of this multicomponent propargylic substitution is to avoid two-component side reactions through a tandem process of dirhodium(II)-catalyzed carbene insertion and palladium-catalyzed regiodivergent propargylic substitution. The judicious selection of a diphosphine (dppf) or monophosphine (tBuBrettphos) as the ligand is crucial for the reaction to generate different products in a switchable way, α-quaternary 1,3-dienyl or propargylated products, with high regio- and chemoselectivities.

Nickel/SKP-Catalyzed Markovnikov Regio- and Enantioselective Hydroamination of Vinylarenes with Hydroxylamines.

A Ni-catalyzed enantioselective hydroamination of vinylarenes has been developed, affording a wide variety of α-branched chiral alkylamines in good yields with exclusive Markovnikov regioselectivity and excellent enantioselectivity. The SKP ligand was found to be crucial to both the reactivity enhancement and enantiocontrol of the reaction. The synthetic utility of the protocol was exemplified in a gram-scale reaction and late-stage modification of medicinally relevant molecules. The deuterium-labeling experiment revealed that the irreversible hydronickelation of vinylarenes is most likely the enantioselectivity-determining step.

Discovery of chiral 1,4-diarylazetidin-2-one-based hydroxamic acid derivatives as novel tubulin polymerization inhibitors with histone deacetylase inhibitory activity.

Tubulin and histone deacetylase have been clinically proven as promising targets for cancer therapy. Herein, we describe the design and synthesis of chiral 1,4-diarylazetidin-2-one-based hydroxamic acids as novel tubulin/HDAC dual inhibitors. Among them, compound 12a was validated to effectively disrupt tubulin polymerization, and exhibited potent HDAC1/8 inhibitory activities. Meanwhile, 12a showed good antiproliferative activities against four tumor cell lines. Further studies showed 12a works through blocking cellular cycle, inducing apoptosis and inhibiting colony formation. In addition, 12a has suitable physicochemical properties and high liver microsomal metabolic stability. Importantly, compound 12a was found to exhibit significant antitumor efficacy in vivo, thus warranting it as a promising tubulin/HDAC dual inhibitor for further development.

Cooperative Bimetallic Catalysis via One-Metal/Two-Ligands: Mechanistic Insights of Polyfluoroarylation-Allylation of Diazo Compounds.

Metal/ligand in situ assembly is crucial for tailoring the reactivity & selectivity in transition metal catalysis. Cooperative catalysis via a single metal/two ligands is still underdeveloped, since it is rather challenging to harness the distinct reactivity profiles of the species generated by self-assembly of a single metal precursor with a mixture of different ligands. Herein, we report a catalytic system composed of a single metal/two ligands for a three-component reaction of polyfluoroarene, α-diazo ester, and allylic electrophile, leading to highly efficient construction of densely functionalized quaternary carbon centers, that are otherwise hardly accessible. Mechanistic studies suggest this reaction follows a cooperative bimetallic pathway via two catalysts with distinct reactivity profiles, which are assembled in situ from a single metal precursor and two ligands and work in concert to escort the transformation.

Discovery of a 2,6-diarylpyridine-based hydroxamic acid derivative as novel histone deacetylase 8 and tubulin dual inhibitor for the treatment of neuroblastoma.

Herein, two series of HDAC/tubulin dual inhibitors via introducing the key pharmacophore of HDAC inhibitor into the skeletons of 2,6-diarylpyridine and 2'-arylchalcone were synthesized. Among them, 2,6-diarylpyridine-based hydroxamic acid 10a exhibited good inhibitory activity against HDAC8 (IC50 = 117 nM) with 50-fold and 42-fold high selectivity relative to HDAC1 and HDAC6, respectively. Meanwhile, 10a disrupted tubulin polymerization effectively and exhibited potent antiproliferative activity against BE-(2)-C cell line, with IC50 value of 17 nM. Mechanism studies revealed that 10a blocked cell cycle, induced cellular apoptosis and suppressed colony formation. Moreover, 10a possessed good physicochemical properties and metabolic stability. Importantly, 10a exhibited better antitumor effects in human neuroblastoma xenograft mice model than those of clinical HDAC inhibitor and tubulin inhibitor, whether used alone or in combination. These results highlighted the advantages of the HDAC8/tubulin dual inhibitor 10a as an outstanding antitumor agent.

Phosphine-catalyzed divergent domino processes between γ-substituted allenoates and carbonyl-activated alkenes.

Highly enantioselective and chemodivergent domino reactions between γ-substituted allenoates and activated alkenes have been developed. In the presence of NUSIOC-Phos, triketone enone substrates smoothly reacted with γ-substituted allenoates to form bicyclic furofurans in good yields with high stereoselectivities. Alternatively, the reaction between diester-activated enone substrates and γ-substituted allenoates formed chiral conjugated 1,3-dienes in good yields with excellent enantioselectivities. Notably, by employing substrates with subtle structural difference, under virtually identical reaction conditions, we were able to access two types of chiral products, which are of biological relevance and synthetic importance.

Targeting the tumor microenvironment by an enzyme-responsive prodrug of tubulin destabilizer for triple-negative breast cancer therapy with high safety.

In response to the long-term potential toxicity concerns of tubulin destabilizer, an enzyme-responsive prodrug therapy for triple-negative breast cancer was developed based on the different ß-glucuronidase levels between tumor and normal tissues in this study. All the prodrugs synthesized herein showed remarkable stability in phosphate buffer and bovine serum solution, among which 17a was found to be more susceptible to enzymatic cleavage. 17a exhibited excellent selectivity between the in vitro antiproliferative activities against ß-glucuronidase-pretreated and -untreated cancer cells (IC50 (+Enz) = 8.9-15.7 nM, IC50 (-Enz) > 50 µM), along with favorable liver microsomal metabolic stability and improved aqueous solubility. Furthermore, as a candidate prodrug 17a showed potent antitumor efficacy in MDA-MB-231 xenograft mouse model without causing perceptible injury to organs. Importantly, 17a exhibited superior safety profiles with higher LD50 value and no perceivable cardiotoxicity, which was a major dose-limiting adverse effect for the parent compound 1. These salient toxicity-reduced effects of 17a would merit further in-depth assessment of this compound for preclinical therapeutic usages.

A Powerful Chiral Super Brønsted C-H Acid for Asymmetric Catalysis.

A new type of chiral super Brønsted C-H acids, BINOL-derived phosphoryl bis((trifluoromethyl)sulfonyl) methanes (BPTMs), were developed. As compared to widely utilized BINOL-derived chiral phosphoric acids (BPAs) and N-triflyl phosphoramides (NTPAs), BPTMs displayed much higher Brønsted acidity, resulting in dramatically improved activity and excellent enantioselectivity as demonstrated in catalytic asymmetric Mukaiyama-Mannich reaction, allylic amination, three-component coupling of allyltrimethylsilane with 9-fluorenylmethyl carbamate and aldehydes, and protonation of silyl enol ether. These new strong Brønsted C-H acids have provided a platform for expanding the chemistry of asymmetric Brønsted acid catalysis.

Palladium-Catalyzed Enantioselective Intramolecular Heck Carbonylation Reactions: Asymmetric Synthesis of 2-Oxindole Ynones and Carboxylic Acids.

Herein, we report a Pd-catalyzed enantioselective domino Heck carbonylation reaction of o-iodoacrylanilides with terminal alkynes and water as the nucleophiles, affording a diversity of ß-carbonylated 2-oxindole derivatives bearing a 3,3-disubstituted all-carbon quaternary stereocenter, in high yields (55-99 %) with good to excellent enantioselectivities (up to 99 % ee). The synthetic utilities of the protocol were demonstrated in the gram-scale synthesis of 2-oxindole-derived ynone 3 ea and carboxylic acid 4 a, as well as the facile synthesis of chiral 2-oxindoles with a pyrazole or isoxazole moiety.

Ni-Catalyzed Regioselective Hydroarylation of 1-Aryl-1,3-Butadienes with Aryl Halides.

An efficient nickel-catalyzed regioselective hydroarylation of 1,3-dienes with aryl halides and a silane has been developed, affording a range of allylic arenes in good to excellent yields under mild conditions. This method exhibits broad substrate scope, and excellent functional group tolerance. Late-stage modification of complex architectures was demonstrated.

Bifunctional chiral selenium-containing 1,4-diarylazetidin-2-ones with potent antitumor activities by disrupting tubulin polymerization and inducing reactive oxygen species production.

Organoselenium compounds have attracted growing interests as promising antitumor agents over recent years. Herein, four series of novel selenium-containing chiral 1,4-diarylazetidin-2-ones were asymmetrically synthesized and biologically evaluated for antitumor activities. Among them, compound 7 was found to be about 10-fold more potent than its prototype compound 1a, and compound 9a exhibited the most potent cytotoxicity against five human cancer cell lines, including a paclitaxel-resistant human ovarian cancer cell line A2780T, with IC50 values ranging from 1 to 3 nM. Mechanistic studies revealed that compound 9a worked by disrupting tubulin polymerization, inducing reactive oxygen species (ROS) production, decreasing mitochondrial membrane potential, blocking the cell cycle in the G2/M phase, inducing cellular apoptosis and suppressing angiogenesis. Additionally, compound 9a exhibited appropriate human-microsomal metabolic stability and physicochemical properties. Importantly, compound 9a was found to inhibit tumor growth effectively in a xenograft mice model with low toxicity profile, which rendered 9a a highly promising candidate for further pre-clinical development.

Pd-Catalyzed Regio- and Enantioselective Aminoarylation of Allenols with Aryl Iodides and 2-Pyridones.

A new asymmetric catalytic protocol for the synthesis of enantioenriched N-allyl 2-pyrodones has been developed via the first Pd-catalyzed regio- and enantioselective aminoarylation of allenols with aryl iodides and 2-pyridones. By using a palladium complex generated in situ from Pd2(dba)3·CHCl3 and (S,S,S)-SKP as a catalyst, the three-component aminoarylation proceeded smoothly to afford a variety of functionalized N-allylic 2-pyridones in high yields with good regioselectivities and excellent enantioselectivities.

Rhodium-Catalyzed Regioselective Hydroformylation of Alkynes to α,ß-Unsaturated Aldehydes Using Formic Acid.

A rhodium-catalyzed hydroformylation of alkynes with formic acid was developed. The method provides α,ß-unsaturated aldehydes in high yield and E-selectivity without the need to handle toxic CO gas.

Enantioselective Synthesis of Pyroglutamic Acid Esters from Glycinate via Carbonyl Catalysis.

Direct α-functionalization of NH2 -free glycinates with relatively weak electrophiles such as α,ß-unsaturated esters still remains a big challenge in organic synthesis. With chiral pyridoxal 5 d as a carbonyl catalyst, direct asymmetric conjugated addition at the α-C of glycinate 1 a with α,ß-unsaturated esters 2 has been successfully realized, to produce various chiral pyroglutamic acid esters 4 in 14-96 % yields with 81-97 % ee's after in situ lactamization. The trans and cis diastereomers can be obtained at the same time by chromatography and both of them can be easily converted into chiral 4-substituted pyrrolidin-2-ones such as Alzheimer's drug Rolipram (11) with the same absolute configuration via tert-butyl group removal and subsequent Barton decarboxylation.

A Type of Structurally Adaptable Aromatic Spiroketal Based Chiral Diphosphine Ligands in Asymmetric Catalysis.

ConspectusWhile spectacular successes have been achieved in homogeneous catalysis with the use of achiral diphosphine ligands featuring a wide natural bite angle, such as XantPhos, chiral diphosphines that can induce a large P-M-P bite angle in their transition metal complexes are conspicuously less explored in asymmetric catalysis, probably due to the challenges in the identification and efficient construction of a suitable chiral backbone. In the past decade, a highly efficient synthesis of chiral aromatic spiroketals and the corresponding diphosphine ligands (SKPs) has been developed in this group.Based on a one-pot catalytic tandem double asymmetric hydrogenation-spiroketalization ring-closure reaction sequence, these SKP ligands featuring an extraordinarily long P···P distance and a flexible backbone have been readily prepared in large scale. Remarkably versatile coordination modes have been found in the complexes of SKP with some catalysis-relevant transition metals, for example, Pd, Cu, Au, and Rh. Whereas SKP enforces an unusually large bite angle in [Pd(SKP)Cl2] and [Cu(SKP)Cl] complexes (160.1° and 132.8°, respectively), it also allows for a bimetallic Au-Au interaction (3.254 Å) in the complex of [Au2(SKP)Cl2] or a square-planar coordination geometry for the [Rh(SKP)(cod)]SbF6 complex. Such an adaptable nature of SKP ligands for transition metal coordination has profound consequences in homogeneous asymmetric catalysis, as demonstrated by their unique performance in several types of catalytic asymmetric reactions. One of the most exciting examples is SKP/Pd-catalyzed asymmetric allylic amination of Morita-Baylis-Hillman (MBH) adducts, in which SKP/Pd complexes demonstrated excellent control of regio- and enantioselectivities and exhibited exceptionally high efficiency (with a TON up to 4750) in the catalysis. SKP ligands have also found a diversity of successful applications in Cu-, Au-, or Rh-catalyzed asymmetric reactions, further attesting their wide utilities in asymmetric catalysis. Overall, this class of readily accessible SKP ligands featuring a chiral aromatic spiroketal skeleton have demonstrated unique adaptable structures in a variety of transition metal complexes and provided outstanding performance in some difficult asymmetric transformations. The works delineated herein would be expected to stimulate further research efforts on the application of this type of chiral ligand and to provide useful clues in the design of new chiral diphosphine ligands with adaptable bite angles for transition metal catalyzed asymmetric reactions.

Iridium-Catalyzed Enantioselective Hydrogenation of Indole and Benzofuran Derivatives.

Enantioselective hydrogenation of a broad spectrum of N-, O-, and S-containing aromatic benzoheterocycles or nonaromatic unsaturated heterocycles has been realized by using an Ir/SpinPHOX (SpinPHOX=spiro[4,4]-1,6-nonadiene-based phosphine-oxazoline) complex as the catalyst, affording an array of the corresponding chiral benzoheterocycles (30 examples) with excellent enantioselectivities (>99 % ee in most cases) and turnover numbers up to 500.

Manganese-Catalyzed anti-Selective Asymmetric Hydrogenation of α-Substituted ß-Ketoamides.

A Mn-catalyzed diastereo- and enantioselective hydrogenation of α-substituted ß-ketoamides has been realized for the first time under dynamic kinetic resolution conditions. anti-α-Substituted ß-hydroxy amides, which are useful building blocks for the synthesis of bioactive molecules and chiral drugs, were prepared in high yields with excellent selectivity (up to >99 % dr and >99 % ee) and unprecedentedly high activity (TON up to 10000). The origin of the excellent stereoselectivity was clarified by DFT calculations.

Highly Enantioselective [3 + 2] Annulation of 3-Butynoates with ß-Trifluoromethyl Enones Promoted by an Amine-Phosphine Binary Catalytic System.

We report a highly enantioselective [3 + 2] annulation between 3-butynoates and ß-trifluoromethyl enones, furnishing trifluoromethylated cyclopentenes with three contiguous stereogenic centers in good yields, high diastereoselectivities, and excellent enantioselectivities. A unique catalytic system consisting of a simple amine and a chiral phosphine was devised, and the synergistic play of Lewis basic amine and phosphine was crucial for alkyne isomerization and subsequent cyclization. The protocol disclosed herein allows facile activation of 3-butynoates in phosphine-mediated asymmetric transformations.