Stereodivergent assembly of δ-valerolactones with an azaarene-containing quaternary stereocenter enabled by Cu/Ru relay catalysis.

Developing methodologies for the expedient construction of biologically important δ-valerolactones bearing a privileged azaarene moiety and a sterically congested all-carbon quaternary stereocenter is important and full of challenges. We present herein a novel multicatalytic strategy for the stereodivergent synthesis of highly functionalized chiral δ-valerolactones bearing 1,4-nonadjacent quaternary/tertiary stereocenters by orthogonally merging borrowing hydrogen and Michael addition between α-azaaryl acetates and allylic alcohols followed by lactonization in a one-pot manner. Enabled by Cu/Ru relay catalysis, this cascade protocol offers the advantages of atom/step economy, redox-neutrality, mild reaction conditions, and broad substrate tolerance.

Rational Design and Stereodivergent Construction of Enantioenriched Tetrahydro-β-Carbolines Containing Multistereogenic Centers.

Chiral tetrahydro-β-carbolines, as one of the most intriguing subtypes of indole alkaloids, have emerged as the privileged units in plenty of natural products and biologically active molecules with an impressive range of bioactive properties. However, the stereodivergent construction of these valuable skeletons containing multistereogenic centers from readily available starting materials remains very challenging, especially, in view of the introduction of an axial chirality. Herein, we developed an efficient method toward enantioenriched tetrahydro-β-carbolines with readily available tryptophan-derived aldimine esters and allylic carbonates under mild reaction conditions.

Copper/ruthenium relay catalysis enables 1,6-double chiral inductions with stereodivergence.

The dual catalysis strategy is an efficient and powerful tool to fulfill the stereodivergent synthesis of stereoisomeric products from the same set of starting materials. Great attention has been given to the construction of chiral compounds with two contiguous stereocenters. However, the synthesis of two remote noncontiguous stereocenters is more challenging and is less developed, despite the high demand for synthetic tactics.

Visible-light-enabled stereoselective synthesis of functionalized cyclohexylamine derivatives [4 + 2] cycloadditions.

An unprecedented intermolecular [4 + 2] cycloaddition of benzocyclobutylamines with α-substituted vinylketones, enabled by photoredox catalysis, has been developed. The current method enables facile access to highly functionalized cyclohexylamine derivatives that were otherwise inaccessible, in moderate to good yields with excellent diastereoselectivities. This protocol has some excellent features, such as full atom economy, good functional-group compatibility, mild reaction conditions, and an overall redox-neutral process.

Iridium-catalyzed asymmetric cascade dearomative allylation/acyl transfer rearrangement: access to chiral -substituted 2-pyridones.

Iridium-catalyzed dearomative allylation/acyl transfer rearrangement has been developed using easily available 2-pyridinyl benzoates and vinyl ethylene carbonate. This protocol enabled the expedient synthesis of a variety of chiral -substituted 2-pyridones in good to high yields with excellent enantioselectivity. It has the advantages of high atom economy, wide substrate scope, gram-scale synthesis, and versatile synthetic transformations.

Challenging Task of Ni-Catalyzed Highly Regio-/Enantioselective Semihydrogenation of Racemic Tetrasubstituted Allenes via a Kinetic Resolution Process.

The first earth-abundant transition metal Ni-catalyzed highly regio- and enantioselective semihydrogenation of racemic tetrasubstituted allenes via a kinetic resolution process as a challenging task was well established. This protocol furnishes expedient access to a diversity of structurally important enantioenriched tetrasubstituted allenes and chiral allylic molecules with high regio-, enantio-, and /-selectivity. Remarkably, this semihydrogenation proceeded with one carbon-carbon double bond of allenes, which was regioselective complementary to the Rh-catalyzed asymmetric version.

Primary activation of -quinone methides by chiral phosphoric acid for enantioselective construction of tetraarylmethanes.

Demonstrated here is an asymmetric nucleophilic addition primary activation of -quinone methides (-QMs) based on a chiral phosphoric acid catalytic system. In sharp contrast to previous CPA-based bifunctional activation processes that all required the nucleophiles to have an effective hydrogen bond donor unit (, OH, NH), here no such unit is required in the nucleophile. -protected indole nucleophiles were successfully utilized for the synthesis of chiral tetraarylmethanes with high efficiency and enantioselectivity under mild conditions.

Modular access to chiral bridged piperidine-γ-butyrolactones via catalytic asymmetric allylation/aza-Prins cyclization/lactonization sequences.

Chiral functionalized piperidine and lactone heterocycles are widely spread in natural products and drug candidates with promising pharmacological properties. However, there remains no general asymmetric methodologies that enable rapid assemble both critical biologically important units into one three-dimensional chiral molecule. Herein, we describe a straightforward relay strategy for the construction of enantioenriched bridged piperidine-γ-butyrolactone skeletons incorporating three skipped stereocenters via asymmetric allylic alkylation and aza-Prins cyclization/lactonization sequences.

Copper/Ruthenium Relay Catalysis for Stereodivergent Access to δ-Hydroxy α-Amino Acids and Small Peptides.

An atom- and step-economical and redox-neutral cascade reaction enabled by asymmetric bimetallic relay catalysis by merging a ruthenium-catalyzed asymmetric borrowing-hydrogen reaction with copper-catalyzed asymmetric Michael addition has been realized. A variety of highly functionalized 2-amino-5-hydroxyvaleric acid esters or peptides bearing 1,4-non-adjacent stereogenic centers have been prepared in high yields with excellent enantio- and diastereoselectivity. Judicious selection and rational modification of the Ru catalysts with careful tuning of the reaction conditions played a pivotal role in stereoselectivity control as well as attenuating undesired α-epimerization, thus enabling a full complement of all four stereoisomers that were otherwise inaccessible in previous work.

Synthesis of medium-sized heterocycles from oxetanes based on an allylic amination/ring-opening strategy.

The construction of medium-sized ring compounds has been a prominent research area in synthetic chemistry. In this study, we developed a tandem strategy that combines allylic amination and ring-opening of oxetanes to synthesize medium-sized heterocycles. Specifically, -aryl oxetan-3-amines undergo allylic amination with zwitterionic π-allylpalladium, followed by intramolecular ring-opening, resulting in the formation of medium-sized heterocycles.

Organocatalytic atroposelective synthesis of axially chiral ,'-pyrrolylindoles indole formation.

The first organocatalytic atroposelective synthesis of axially chiral ,'-pyrrolylindoles based on -alkynylanilines was successfully established indole formation catalyzed by chiral phosphoric acid (CPA). This new synthetic strategy introduced CPA-catalyzed asymmetric 5- cyclization of new well-designed -alkynylanilines containing a pyrrolyl unit, resulting in a wide range of axially chiral ,'-pyrrolylindoles in high yields with exclusive regioselectivity and excellent enantioselectivity (up to 99% yield, >20 : 1 rr, 95 : 5 er). Considering the potential biological significance of N-N atropisomers, preliminary biological activity studies were performed and revealed that these structurally important ,'-pyrrolylindoles had a low IC value with promising impressive cytotoxicity against several kinds of cancer cell lines.

Studies on the [4 + 2] cycloaddition and allylic substitution of indole-fused zwitterionic π-allylpalladium.

The zwitterionic π-allylpalladium species, also known as dipoles, are important synthons widely used in various reactions including cycloaddition and allylic substitution. This study reported the development of a new indole-fused zwitterionic π-allylpalladium precursor compound and its application in [4 + 2] cycloaddition and allylic substitution reactions. As a result, the synthesis of pyrrolo[3,2,1-]quinazolin-3-one and 7-vinyl indole compounds was achieved with moderate to good yields.

Enantio- and diastereodivergent synthesis of fused indolizines enabled by synergistic Cu/Ir catalysis.

Highly diastereo-/enantioselective assembly of 2,3-fused indolizine derivatives could be easily available through a cascade allylation/Friedel-Crafts type reaction enabled by a synergistic Cu/Ir catalysis. This designed protocol provides an unprecedented and facile route to enantioenriched indolizines bearing three stereogenic centers in moderate to high yields with excellent stereoselective control, which also featured broad substrate generality. Remarkably, four stereoisomers of the 2,3-fused indolizine products could be efficiently constructed in a predictable manner through the pairwise combination of copper and iridium catalysts.

Iridium-Catalyzed Intramolecular Asymmetric Allylation of Vinyl Benzoxazinones for the Synthesis of Chiral 4-3,1-Benzoxazines via Kinetic Resolution.

Chiral benzoxazinones and 4-3,1-benzoxazines as important motifs are widely found in abundant pharmaceuticals and biological molecules. We herein successfully developed the first kinetic resolution (KR) process of racemic benzoxazinones through Ir-catalyzed asymmetric intramolecular allylation, furnishing a wide range of chiral benzoxazinones and 4-3,1-benzoxazines with excellent results via outstanding KR performances (with the factor up to 170). This protocol exhibited broad substrate scope generality and good functional group tolerance, and the chiral 4-3,1-benzoxazine products could be readily transformed to other useful optically active heterocycles.

Ni-Catalyzed Asymmetric Hydrogenation of α-Substituted α,β-Unsaturated Phosphine Oxides/Phosphonates/Phosphoric Acids.

Efficient Ni/(,)-Ph-BPE-catalyzed asymmetric hydrogenation of α-substituted α,β-unsaturated phosphine oxides/phosphonates/phosphoric acids has been successfully developed, and a wide range of chiral α-substituted phosphines hydrogenation products were obtained in generally high yields with excellent enantioselective control (92%-99% yields, 84%->99% ee). This method features a cheap transition metal nickel catalytic system, high functional group tolerance, wide substrate scope generality, and excellent enantioselectivity. A plausible catalytic cycle was proposed for this asymmetric hydrogenation according to the results of deuterium-labeling experiments.

Iridium-Catalyzed Asymmetric Cascade Allylation/Lactonization of Indole Esters: Access to Chiral Tricyclic Oxazinoindolones.

Ir-catalyzed asymmetric cascade allylation/lactonization of indole 2-carboxylates with vinyl cyclic carbonate was successfully developed, which provided efficient access to chiral tricyclic oxazinoindolones with excellent results (up to 85% yield, 99% ee). This protocol could be well extended to pyrroles and other nitrogen-containing aromatic heterocycles. A reasonable reaction pathway was provided on the basis of preliminary mechanistic investigation.

Base-promoted cascade β-F-elimination/electrocyclization/Diels-Alder/retro-Diels-Alder reaction: efficient access to δ-carboline derivatives.

A serendipitous and highly efficient approach for the construction of a variety of δ-carboline derivatives was developed through base-promoted cascade β-F-elimination/electrocyclization/Diels-Alder/retro-Diels-Alder reaction of -2,2,2-trifluoroethylisatin ketoimine esters with alkynes in good to high yields with excellent regio-/chemoselectivity control. Moreover, a reasonable reaction pathway was proposed, which was in accordance with the prepared reaction intermediate and control experiment results. The δ-carboline product could be easily converted into a new chiral Py-box-type ligand through simple synthetic transformations.

Iridium-Catalyzed Asymmetric Cascade Allylation/Retro-Claisen Reaction.

An enantiomerically enriched 3-hydroxymethyl pentenal unit is one of the key structural cores in plenty of natural products and drug candidates with significant biological activities. However, very few synthetic methodologies for the facile construction of the related skeletons have been reported to date. Herein, an elegant iridium-catalyzed asymmetric cascade allylation/retro-Claisen reaction of readily available β-diketones with VEC was successfully developed, and a wide range of functionalized chiral 3-hydroxymethyl pentenal derivatives could be prepared in good yields with excellent enantioselectivities.

Stereodivergent synthesis of α-fluoro α-azaaryl γ-butyrolactones cooperative copper and iridium catalysis.

The development of stereodivergent synthetic methods to access all four stereoisomers of biologically important α-fluoro γ-butyrolactones containing vicinal stereocenters is of great importance and poses a formidable challenge owing to ring strain and steric hindrance. Herein, a novel asymmetric [3+2] annulation of α-fluoro α-azaaryl acetates with vinylethylene carbonate was successfully developed through Cu/Ir-catalyzed cascade allylic alkylation/lactonization, affording a variety of enantioenriched α-fluoro γ-butyrolactones bearing vicinal stereogenic centers with high reaction efficiency and excellent levels of both stereoselectivity and regioselectivity (up to 98% yield, generally >20:1 dr and >99% ee). Notably, all four stereoisomers of these pharmaceutically valuable molecules could be accessed individually simple permutations of two enantiomeric catalysts.

Copper-catalyzed asymmetric propargylic substitution with salicylaldehyde-derived imine esters.

Copper-catalyzed asymmetric propargylic substitution with salicylaldehyde-derived imine esters and propargylic carbonates has been successfully realized, generating a wide range of chiral amino acid derivatives containing propargylic groups with excellent results (up to 95% yield and 94% ee). The -hydroxy group of the salicylaldehyde-derived imine esters is crucial to increase the reactivity and stabilize the azomethine ylide, which may be due to the formation of an intramolecular hydrogen bond between the hydroxyl group and the imine group. A series of synthetic transformations were carried out to access other important chiral compounds, which displayed the synthetic versatility.

Stereodivergent synthesis of enantioenriched azepino[3,4,5-]-indoles cooperative Cu/Ir-catalyzed asymmetric allylic alkylation and intramolecular Friedel-Crafts reaction.

The development of enantioselective annulation reactions using readily available substrates for the construction of structurally and stereochemically diverse heterocycles is a compelling topic in diversity-oriented synthesis. Herein, we report efficient catalytic asymmetric formal 1,3-dipolar (3 + 4) cycloadditions of azomethine ylides with 4-indolyl allylic carbonates for the construction of azepino[3,4,5-]-indoles fused with a challenging seven-membered N-heterocycle, a frequently occurring tricyclic indole scaffold in bioactive compounds and pharmaceuticals. Through cooperative Cu/Ir-catalyzed asymmetric allylic alkylation followed by intramolecular Friedel-Crafts reaction, an array of azepino[3,4,5-]-indoles were obtained in good yields with excellent diastereo-/enantioselective control.

Asymmetric Synthesis of Chiral Aza-macrodiolides via Iridium-Catalyzed Cascade Allylation/Macrolactonization.

Iridium-catalyzed cascade allylation/macrolactonization between vinylethylene carbonate (VEC) and isatoic anhydride derivatives was successfully developed, readily generating a wide range of -symmetric chiral macrodiolides bearing 14-membered rings in moderate to good yields with excellent diastereoselectivities and enantioselectivities (generally 99% ee). Control experiments revealed that racemic VEC as the precursor of electrophilic iridium-π-allyl species underwent kinetic resolution process. This expedient protocol features easily available substrates, excellent stereoselective control, and high step economy.

Iridium-catalyzed asymmetric double allylic alkylation of azlactone: efficient access to chiral α-amino acid derivatives.

An unprecedented Ir-catalyzed enantioselective double allylic alkylation of less bulky cyclic imine glycinate (azlactone) was rationally designed and developed, providing various bisallylated chiral amino acid derivatives. Control experiments revealed that this transformation proceeds in a sequential manner featuring -dynamic kinetic resolution of the initially-formed monoallylation intermediates.

Synergistic Cu/Pd-catalyzed asymmetric allylation: a facile access to α-quaternary cysteine derivatives.

An efficient synthetic methodology to access biologically important and synthetically useful α-quaternary cysteine derivatives via asymmetric catalytic α-allylation of readily available 2-thiazoline-4-carboxylates was successfully developed through a synergistic Cu/Pd catalytic system. A wide array of α-quaternary cysteine derivatives were obtained in moderate to high yields with good to excellent enantioselectivities (45-98% yields and 69->99% ee). Gram-scale asymmetric allylation was performed to obtain high yields maintaining the enantioselectivity.

Nickel-Catalyzed Asymmetric Hydrogenation of Cyclic Alkenyl Sulfones, Benzo[]thiophene 1,1-Dioxides, with Mechanistic Studies.

A highly efficient catalytic system based on the cheap transition metal nickel for the asymmetric hydrogenation of challenging cyclic alkenyl sulfones, 3-substituted benzo[]thiophene 1,1-dioxides, was first successfully developed. A series of hydrogenation products, chiral 2,3-dihydrobenzo[]thiophene 1,1-dioxides, were obtained in high yields (95-99%) with excellent enantioselectivities (90-99% ee). According to the results of nonlinear effect studies, deuterium-labeling experiments, and DFT calculation investigations, a reasonable catalytic mechanism for this nickel-catalyzed asymmetric hydrogenation was provided, which displayed that the two added hydrogen atoms of the hydrogenation products could be from H through the insertion of Ni-H and subsequent hydrogenolysis.