Copper-Catalyzed Remote Enantioselective Sulfonylation of Yne-Allylic Esters with Sodium Sulfinates

Impressive progress has been made in the copper-catalyzed asymmetric propargylic substitution (APS) reaction, but its use in remote asymmetric yne-allylic substitution remains a challenging topic. Herein, we report the first remote enantioselective copper-catalyzed sulfonylation of yne-allylic esters with sodium sulfinates. The reaction is assumed to occur via a copper-vinylvinylidene species as the key reactive intermediate. The use of readily available starting materials, the mild reaction conditions, and the excellent regio-, enantio- and stereoselectivity, as well as broad substrate scope (>70 examples), show the practicality and attractiveness of this method.     

Enantio- and Regioselective Copper-Catalyzed 1,2-Dearomatization of Pyridines

A copper-catalyzed dearomative alkynylation of pyridines is reported with excellent regio- and enantioselectivities. The synthetically valuable enantioenriched 2-alkynyl-1,2-dihydropyridine products afforded are generated from the readily available feedstock, pyridine, and commercially available terminal alkynes. The three-component reaction between a pyridine, a terminal alkyne, and methyl chloroformate employs copper chloride and StackPhos, a chiral biaryl P,N- ligand, as the catalytic system. Under mild reaction conditions, the desired 1,2-addition products are delivered in up to 99 % yield with regioselectivity ratios up to 25 : 1 and enantioselectivities values of up to 99 % ee. Activated and non-activated terminal alkynes containing a wide range of functional groups are well tolerated. Even acetylene gas delivered mono-alkynylated products in high yield and ee. Application of the methodology in an efficient enantioselective synthesis of the chiral piperidine indolizidine, coniceine, is reported.     

Visible Light Induced Copper-Catalyzed Enantioselective Deaminative Arylation of Amino Acid Derivatives Assisted by Phenol

The exploration of value-added conversions of naturally abundant amino acids has received considerable attention from the synthetic community. Compared with the well-established asymmetric decarboxylative transformation, the asymmetric deaminative transformation of amino acids still remains a formidable challenge, mainly due to the lack of effective strategies for the C−N bond activation and the potential incompatibility with chiral catalysts. Here, we disclose a photoinduced Cu-catalyzed asymmetric deaminative coupling reaction of amino acids with arylboronic acids. This new protocol provides a series of significant chiral phenylacetamides in generally good yields and excellent stereoselectivity under mild and green conditions (42–85 % yields, up to 97 % ee). Experimental investigations and theoretical calculations were performed to reveal the crucial role of additional phenols in improving catalytic efficiency and enantiocontrol.     

Enantioselective Arylcyanation of Styrenes via Copper‐Catalyzed Radical Relay†

The first copper‐catalyzed enantioselective arylcyanation of styrenes has been developed using readily available anilines as aryl radical precursors under mild conditions, which enables easy access to chiral 2,3‐diaryl propionitriles with moderate to good enantioselectivities. This operationally straightforward reaction exhibits broad substrate scope and functional group tolerance. Notably, this method has been applied to the synthesis of chiral AIEgen as well as estrogen receptor‐β agonist (R)‐diarylpropionitrile (DPN).     

1,2-苯基异噁唑为氮源的铜催化苯乙烯不对称硼胺化

报道了一种以手性亚砜膦配体/铜络合物为催化剂的苯乙烯不对称硼胺化反应.该方法以联硼酸频哪醇酯(B2pin2)为硼源,以商业可得的1,2-苯基异噁唑为亲电氮源,合成了一类β-氨基硼酸酯类化合物,目标产物可以方便地转化为β-硼酯伯胺化合物,为结构多样的手性氨基化合物合成提供了一条技术途径.     

Synthesis of α-Quaternary β-Lactams via Copper-Catalyzed Enantioconvergent Radical C(sp3)−C(sp2) Cross-Coupling with Organoboronate Esters

The copper-catalyzed enantioconvergent radical C(sp³)−C(sp²) cross-coupling of tertiary α-bromo-β-lactams with organoboronate esters could provide the synthetically valuable α-quaternary β-lactams. The challenge arises mainly from the construction of sterically congested quaternary stereocenters between the tertiary alkyl radicals and chiral copper(II) species. Herein, we describe our success in achieving such transformations through the utilization of a copper/hemilabile N,N,N-ligand catalyst to forge the sterically congested chiral C(sp³)−C(sp²) bond via a single-electron reduction/transmetalation/bond formation catalytic cycle. The synthetic potential of this approach is shown in the straightforward conversion of the corresponding products into many valuable building blocks. We hope that the developed catalytic cycle would open up new vistas for more enantioconvergent cross-coupling reactions.     

铜催化苯乙烯不对称硼胺化反应

报道了一种以手性亚砜膦配体/铜络合物为催化剂的苯乙烯不对称硼胺化反应,该方法以联硼酸频哪醇酯（pinB-Bpin）和亲电性胺试剂分别作为硼源和氮源,合成手性β-氨基烷基硼酯,该产物可方便地转化为有用的手性β-羟胺类化合物.     

Copper-Catalyzed Enantioselective Trifluoromethoxylation of Propargyl Sulfonates

Due to the strong electron-withdrawing nature and high lipophilicity of trifluoromethoxy group (OCF₃), methods for introducing OCF₃ into organic molecules are in high demand. However, the research area of direct enantioselective trifluoromethoxylation is still in the embryonic stage, with limited enantioselectivity and/or reaction types. Here, we describe the first copper-catalyzed enantioselective trifluoromethoxylation of propargyl sulfonates using trifluoromethyl arylsulfonate (TFMS) as the trifluoromethoxy source in up to 96 % ee.     

Asymmetric Radical Oxyboration of β-Substituted Styrenes via Late-Stage Stereomutation

Herein, we report an unprecedented copper-catalyzed highly enantio- and diastereoselective radical oxyboration of β-substituted styrenes. The lynchpin of success is ascribed to the development of a late-stage stereomutation strategy, which enables enantioenriched cis-isomers among a couple of early-generated diastereomers to be converted into trans-isomer counterparts, thus fulfilling high diastereocontrol; while the degree of enantio-differentiation is determined by the borocupration process of the C=C bond. This reaction provides an efficient protocol to access enantioenriched trans-1,2- dioxygenation products. The value of this method has further been highlighted in a diversity of follow-up stereospecific transformations and further modifying complex molecules.     

Copper-Catalyzed Enantioselective C1,N-Dipolar (3+2) Cycloadditions of 2-Aminoallyl Cations with Indoles

2-Aminoallyl cations are versatile 1,3-dipoles that could potentially be used for diverse (3+n) cycloaddition reactions. Despite some preliminary studies, the asymmetric catalytic transformation of these species is still underdeveloped. We herein report a binuclear copper-catalyzed generation of 2-aminoallyl cations from ethynyl methylene cyclic carbamates and their enantioselective (3+2) cycloaddition reaction with indoles to construct chiral pyrroloindolines. This transformation features a novel C1,N-dipolar reactivity for 2-aminoallyl cations.     

Oxidation and Reduction Pathways in the Knowles Hydroamination via a Photoredox-Catalyzed Radical Reaction**

Systematic reaction path exploration revealed the entire mechanism of Knowles's light-promoted catalytic intramolecular hydroamination. Bond formation/cleavage competes with single electron transfer (SET) between the catalyst and substrate. These processes are described by adiabatic processes through transition states in an electronic state and non-radiative transitions through the seam of crossings (SX) between different electronic states. This study determined the energetically favorable SET path by introducing a practical computational model representing SET as non-adiabatic transitions via SXs between substrate's potential energy surfaces for different charge states adjusted based on the catalyst's redox potential. Calculations showed that the reduction and proton shuttle process proceeded concertedly. Also, the relative importance of SET paths (giving the product and leading back to the reactant) varies depending on the catalyst's redox potential, affecting the yield.     

Regioselective and Enantioselective Copper-Catalyzed Hydroaminocarbonylation of Unactivated Alkenes and Alkynes

Given the prevalence of amide backbones in marketed pharmaceuticals and their ubiquity as critical binding units in natural peptides and proteins, it remains important to develop novel methods to construct amide bonds. We report here a general method for the anti-Markovnikov hydroaminocarbonylation of unactivated alkenes under mild conditions, using copper catalysis in combination with hydroxylamine electrophile reagents and poly(methylhydrosiloxane) (PMHS) as a cheap and environmentally friendly hydride source. The reaction tolerates a variety of functional groups and efficiently converts unactivated terminal alkenes, 1,1-disubstituted alkenes, and cyclic alkenes to the corresponding amides with exclusive anti-Markovnikov selectivity (and high enantioselectivities/diastereoselectivities). Additionally, with minimal modification of the reaction conditions, alkynes can also undergo tandem hydrogenation-hydroaminocarbonylation to alkyl amides.     

Copper-Catalyzed Dynamic Kinetic Asymmetric P−C Coupling of Secondary Phosphine Oxides and Aryl Iodides

Transition-metal-catalyzed enantioselective P−C cross-coupling of secondary phosphine oxides (SPOs) is an attractive method for synthesizing P-stereogenic phosphorus compounds, but the development of such a dynamic kinetic asymmetric process remains a considerable challenge. Here we report an unprecedented highly enantioselective dynamic kinetic intermolecular P−C coupling of SPOs and aryl iodides catalyzed by copper complexes ligated by a finely modified chiral 1,2-diamine ligand. The reaction tolerates a wide range of SPOs and aryl iodides, affording P-stereogenic tertiary phosphine oxides (TPOs) in high yields and with good enantioselectivity (average 89.2 % ee). The resulting enantioenriched TPOs were transformed into structurally diverse P-chiral scaffolds, which are highly valuable as ligands and catalysts in asymmetric synthesis.     

Copper-Catalyzed Aryne Insertion into the Carbon-Iodine Bond of Heteroaryl Iodides

Aryne insertions into the carbon-iodine bond of heteroaryl iodides has been achieved for the first time. This novel reaction provides an efficient pathway for the synthesis of valuable building blocks 2-iodoheterobiaryls from heteroaryl iodides and o-silylaryl triflates in excellent regioselectivity. The copper(I) catalyst, which bears a N-heterocyclic carbene (NHC) ligand, is essential to accomplish the reaction. Control reactions and DFT calculations indicate that the coordination of copper, as a Lewis acid, with nitrogen atoms of heteroaryl iodides mediates the insertion of arynes into heteroaryl carbon-iodine bonds.     

Enantioselective Synthesis of Chiral Amides by a Phosphoric Acid Catalyzed Asymmetric Wolff Rearrangement**

The enantioselective addition of potent nucleophiles to ketenes poses challenges due to competing background reactions and poor stereocontrol. Herein, we present a method for enantioselective phosphoric acid catalyzed amination of ketenes generated from α-aryl-α-diazoketones. Upon exposure to visible light, the diazoketones undergo Wolff rearrangement to generate ketenes. The phosphoric acid not only accelerates ketene capture by amines to form a single configuration of aminoenol intermediates but also promotes an enantioselective proton-transfer reaction of the intermediates to yield the products. Mechanistic studies elucidated the reaction pathway and explained how the catalyst expedited the transformation and controlled the enantioselectivity.     

Copper-Catalyzed Asymmetric Acylboration of 1,3-Butadienylboronate with Acyl Fluorides

We report herein a Cu-catalyzed regio-, diastereo- and enantioselective acylboration of 1,3-butadienylboronate with acyl fluorides. Under the developed conditions, the reactions provide (Z)-β,γ-unsaturated ketones bearing an α-tertiary stereocenter with high Z-selectivity and excellent enantioselectivities. While direct access to highly enantioenriched E-isomers was not successful, we showed that such molecules can be synthesized with excellent E-selectivity and optical purities via Pd-catalyzed alkene isomerization from the corresponding Z-isomers. The orthogonal chemical reactivities of the functional groups embedded in the ketone products allow for diverse chemoselective transformations, which provides a valuable platform for further derivatization.     

Trinuclear Gold-Catalyzed 1,2-Difunctionalization of Alkenes

Activated alkyl halides have been extensively explored to generate alkyl radicals with Ru- and Ir- photocatalysts for 1,2-difunctionalization of alkenes, but unactivated alkyl bromides remain challenging substrates due to their strong reduction potential. Here we report a three-component 1,2-difunctionalization reaction of alkenes, unactivated alkyl bromides and nucleophiles (e.g., amines and indoles) using a trinuclear gold catalyst [Au₃(tppm)₂](OTf)₃. It can achieve the 1,2-aminoalkylation and 1,2-alkylarylation readily. This protocol has a broad reaction scope and excellent functional group compatibility (>100 examples with up to 96 % yield). It also affords a robust formal [2+2+1] cyclization strategy for the concise construction of pyrrolidine skeletons under mild reaction conditions. Mechanistic studies support an inner-sphere single electron transfer pathway for the successful cleavage of inert C−Br bonds.     

Iron‐Catalyzed Intermolecular 1,2‐Difunctionalization of Styrenes and Conjugated Alkenes with Silanes and Nucleophiles

The first iron‐catalyzed 1,2‐difunctionalization of styrenes and conjugated alkenes with silanes and either N or C, using an oxidative radical strategy, is described. Employing FeCl₂ and di‐tert ‐butyl peroxide allows divergent alkene 1,2‐difunctionalizations, including 1,2‐aminosilylation, 1,2‐arylsilylation, and 1,2‐alkylsilylation, which rely on a wide range of nucleophiles, namely, amines, amides, indoles, pyrroles, and 1,3‐dicarbonyls, thus providing a powerful platform for producing diverse silicon‐containing alkanes.     

Copper-Phosphido Catalysis: Enantioselective Addition of Phosphines to Cyclopropenes**

We describe a copper catalyst that promotes the addition of phosphines to cyclopropenes at ambient temperature. A range of cyclopropylphosphines bearing different steric and electronic properties can now be accessed in high yields and enantioselectivities. Enrichment of phosphorus stereocenters is also demonstrated via a Dynamic Kinetic Asymmetric Transformation (DyKAT) process. A combined experimental and theoretical mechanistic study supports an elementary step featuring insertion of a Cu^I-phosphido into a carbon-carbon double bond. Density functional theory calculations reveal migratory insertion as the rate- and stereo-determining step, followed by a syn-protodemetalation.