Ortho‐Quinone Methides as Reactive Intermediates in Asymmetric Brønsted Acid Catalyzed Cycloadditions with Unactivated Alkenes by Exclusive Activation of the Electrophile

An efficient method for the highly enantioselective synthesis of chiral chromanes bearing multiple stereogenic centers was developed. A chiral BINOL‐based N‐triflylphosphoramide proved to be an effective catalyst for the in situ generation of ortho‐quinone methides (o‐QMs) and their subsequent cycloaddition reaction with unactivated alkenes provided chromanes with excellent diastereo‐ and enantioselectivity.     

Enantioselective Template‐Directed [2+2] Photocycloadditions of Isoquinolones: Scope,Mechanism and Synthetic Applications

A strategy for the enantioselective [2+2] photocycloaddition of isoquinolones with alkenes is presented, in which the formation of a supramolecular complex between a chiral template and the substrate ensures high enantioface differentiation by shielding one face of the substrate. Fifteen different electron‐deficient alkenes and ten different substituted isoquinolones undergo efficient photocycloaddition, yielding the cyclobutane products in excellent yields and with outstanding regio‐, diastereo‐ and enantioselectivities (up to 99 % ee). The mechanism of the reaction is investigated by means of triplet sensitization/quenching and radical clock experiments, the results of which are consistent with the involvement of a triplet excited state and a 1,4‐biradical intermediate. The variety of functionalized cyclobutanes obtained using this approach can be further increased by straightforward synthetic transformations of the photoadducts, allowing rapid access to libraries of compounds for various applications.     

Highly Diastereo‐ and Enantioselective Cu‐Catalyzed Borylative Coupling of 1,3‐Dienes and Aldimines

A Cu‐catalyzed diastereo‐ and enantioselective borylative coupling reaction of 1,3‐dienes with imines was realized. Branched homoallylic amines are readily prepared in a syn‐selective manner with high regio‐, diastereo‐ and enantioselectivity. Moreover, these three‐component coupling reactions feature good functional‐group compatibility and easy access to the substrates and catalyst.     

Highly Regio‐ and Stereodivergent Access to 1,2‐Amino Alcohols or 1,4‐Fluoro Alcohols by NHC‐Catalyzed Ring Opening of Epoxy enals

Described is an unprecedented NHC‐catalyzed (NHC=N‐heterocyclic carbene), stereoselective ring opening of epoxy and cyclopropyl enals to deliver valuable compounds bearing multiple stereocenters. A straightforward three‐step procedure involving two catalytic enantioselective transformations has been developed and leads to a regio‐ and stereodivergent synthesis of either 1,2‐amino alcohols/diamines or 1,4‐fluoro alcohols with excellent diastereo‐ and enantiopurity.     

Bifunctional Brønsted Base Catalyst Enables Regio‐, Diastereo‐, and Enantioselective Cα‐Alkylation of β‐Tetralones and Related Aromatic‐Ring‐Fused Cycloalkanones

The catalytic asymmetric synthesis of both α‐substituted and α,α‐disubstituted (quaternary) β‐tetralones through direct α‐functionalization of the corresponding β‐tetralone precursor remains elusive. A designed Brønsted base‐squaramide bifunctional catalyst promotes the conjugate addition of either unsubstituted or α‐monosubstituted β‐tetralones to nitroalkenes. Under these reaction conditions, not only enolization, and thus functionalization, occurs at the α‐carbon atom of the β‐tetralone exclusively, but adducts including all‐carbon quaternary centers are also formed in highly diastereo‐ and enantioselective manner.     

Rh/Lewis Acid Catalyzed Regio‐, Diastereo‐ and Enantioselective Addition of 2‐Acyl Imidazoles with Allenes

A highly regio‐, diastereo‐ and enantioselective addition of 2‐acyl imidazoles or 2‐acyl pyridines with allenes promoted by Rh/Lewis acid synergistically catalytic system is described. This atom economic approach leads to the formation of the branched allylic alkylated products including acyclic quaternary all‐carbon stereogenic centres in good yields with good to excellent diastereo‐ and enantioselectivities. Kinetic studies reveal that the rate‐determining step in this process is the oxidative addition of Rh(I) with C—H bond.     

Catalytic Double Stereoinduction in Asymmetric Allylic Alkylation of Oxindoles

A highly regio‐, diastereo‐, and enantioselective allylic alkylation reaction of 3‐monosubstituted oxindoles catalyzed by molybdenum is described. The reaction is affected by the electronic and steric variations of the nucleophile. The use of appropriate N‐protecting group is particularly important for achieving high regio‐ and diastereoselectivity. Products from this reaction, containing vicinal quaternary‐tertiary stereogenic centers, are valuable synthetic intermediates and should find utility in alkaloid synthesis.     

Double Regioselective Asymmetric C‐Allylation of Isoxazolinones: Iridium‐Catalyzed N‐Allylation Followed by an Aza‐Cope Rearrangement

Isoxazolinones are biologically and synthetically interesting densely functionalized heterocycles, which for a long time were not accessible in enantioenriched form by asymmetric catalysis. Next to the deficit of enantioselective methods, the functionalization of isoxazolinones is often plagued by regioselectivity issues due to the competition of various nucleophilic centers within the heterocycles. We report the first regio‐ and enantioselective C‐allylations of isoxazolinones. These occur with high regioselectivity in favor of the linear allylation products, although Ir phosphoramidite catalysts were used, which commonly results in branched isomers. Our studies suggest that this outcome is the result of a reaction cascade via an initial regio‐ and enantioselective N‐allylation to provide a branched allyl intermediate, followed by a spontaneous [3,3]‐rearrangement resulting in chirality transfer.     

Copper(I)‐Catalyzed Asymmetric [3+2]‐Cycloaddition of α‐Substituted Iminoesters with α‐Trifluoromethyl α,β‐Unsaturated Esters

Reported herein is an example of highly regio‐, diastereo‐ and enantioselective Cu(I)‐catalyzed intermolecular [3+2] cycloaddition reaction of α‐substituted iminoesters with α‐trifluoromethyl α,β‐unsaturated esters. This novel strategy provided a facile access to pyrrolidines with two skipped (aza)quaternary stereocenters including a CF₃ all‐carbon quaternary stereocenter. A broad substrate scope was observed and high yields (up to 94%) with excellent diastereoselectivity (up to >20 : 1 d.r.) and enantioselectivity (up to 98% ee) were obtained.     

Highly Enantioselective Synthesis of Propargyl Amide with Vicinal Stereocenters through Ir‐Catalyzed Hydroalkynylation

Chiral propargyl amines are valuable synthetic intermediates for the preparation of biologically active compounds and functionalized amines. Catalytic methods to access propargyl amines containing vicinal stereocenters with high diastereoselectivity are particularly rare. We report an unprecedented strategy for the synthesis of enantioenriched propargyl amines with two stereogenic centres. An iridium complex, ligated by a phosphoramidite ligand, catalyzes the hydroalkynylation of β,β‐disubstituted enamides to afford propargyl amides in a highly regio‐, diastereo‐, and enantioselective fashion. Stereodivergent synthesis of all four possible stereoisomers was achieved using this strategy.     

Enantioselective Copper‐Catalyzed Carboetherification of Unactivated Alkenes

Chiral saturated oxygen heterocycles are important components of bioactive compounds. Cyclization of alcohols onto pendant alkenes is a direct route to their synthesis, but few catalytic enantioselective methods enabling cyclization onto unactivated alkenes exist. Herein reported is a highly efficient copper‐catalyzed cyclization of γ‐unsaturated pentenols which terminates in C? C bond formation, a net alkene carboetherification. Both intra‐ and intermolecular C? C bond formations are demonstrated, thus yielding functionalized chiral tetrahydrofurans as well as fused‐ring and bridged‐ring oxabicyclic products. Transition‐state calculations support a cis‐oxycupration stereochemistry‐determining step.     

Quaternary Stereogenic Centers through Enantioselective Heck Arylation of Acyclic Olefins with Aryldiazonium Salts: Application in a Concise Synthesis of (R)‐Verapamil

We describe herein a highly regio‐ and enantioselective Pd‐catalyzed Heck arylation of unactivated trisubstituted acyclic olefins to provide all‐carbon quaternary stereogenic centers. Chiral N,N ligands of the pyrimidine‐ and pyrazino‐oxazoline class were developed for that purpose, providing the desired products in good to high yields with enantiomeric ratios up to >99:1. Both linear and branched substituents on the olefins were well‐tolerated. The potential of this new method is demonstrated by the straightforward synthesis of several O‐methyl lactols and lactones containing quaternary stereocenters, together with a concise enantioselective total synthesis of the calcium channel blocker verapamil.     

Enantioselective CH Bond Functionalization Triggered by Radical Trifluoromethylation of Unactivated Alkene

An asymmetric unactivated alkene/C? H bond difunctionalization reaction for the concomitant construction of C? CF₃ and C? O bonds was realized by using a Cu/Brønsted acid cooperative catalytic system, thus providing facile access to valuable chiral CF₃‐containing N,O‐aminals with excellent regio‐, chemo‐, and enantioselectivity. Mechanistic studies revealed that this reaction may proceed by an unprecedented 1,5‐hydride shift involving activation of unactivated alkenes and a radical trifluoromethylation to initiate subsequent enantioselective functionalization of C? H bonds. Control experiments also suggested that chiral Brønsted acid plays multiple roles and not only controls the stereoselectivity but also increases the reaction rate through activation of Togni’s reagent.     

Chiral N,N′‐Dioxide‐Organocatalyzed Regio‐, Diastereo‐ and Enantioselective Michael Addition–Alkylation Reaction

A highly regio‐, diastereo‐ and enantioselective Michael addition–alkylation reaction between α‐substituted cyano ketones and (Z)‐bromonitrostyrenes has been realized by using a chiral N,N′‐dioxide as organocatalyst. A variety of substrates performed well in this reaction, and the corresponding multifunctionalized chiral 2,3‐dihydrofurans were obtained in up to 95 % yield with 95:5 dr and 93 % ee.     

Pd/PC‐Phos‐Catalyzed Enantioselective Intermolecular Denitrogenative Cyclization of Benzotriazoles with Allenes and N‐Allenamides

Reported herein is an asymmetric Pd/PC‐Phos‐catalyzed denitrogenative cyclization of benzotriazoles with allenes and N‐allenamides, representing the first example of enantioselective denitrogenative cyclizations of benzotriazoles. A series of optically active 3‐methyleneindolines were obtained in good yields with high ee values. The use of inexpensive and readily available starting materials, high regio‐ and enantioselectivity, a broad substrate scope, mild reaction conditions, no need for base, as well as versatile functionalization of the 3‐methyleneindolines make this approach attractive.     

Highly para‐Selective C−H Alkylation of Benzene Derivatives with 2,2,2‐Trifluoroethyl α‐Aryl‐α‐Diazoesters

Compared to the most popular directing‐group‐assisted strategy, the “undirected” strategy for C−H bond functionalization represents a more flexible but more challenging approach. Reported herein is a gold‐catalyzed highly site‐selective C(sp²)−H alkylation of unactivated arenes with 2,2,2‐trifluoroethyl α‐aryl‐α‐diazoesters. This protocol demonstrates that high site‐selective C−H bond functionalization can be achieved without the assistance of a directing group. In this transformation, both the gold catalyst and trifluoroethyl group on the ester of the diazo compound play vital roles for achieving the chemo‐ and regioselectivity.     

Iron‐Catalyzed Asymmetric Hydrosilylation of 1,1‐Disubstituted Alkenes

The highly regio‐ and enantioselective iron‐catalyzed anti‐Markovnikov hydrosilylation of 1,1‐disubstituted aryl alkenes was developed using iminopyridine oxazoline ligands to afford chiral organosilanes. Additional derivatization of these products lead to chiral organosilanols, cyclic silanes, phenol derivatives, and 3‐substituted 2,3‐dihydrobenzofurans.     

Double Transfer of Chirality in Organocopper‐Mediated bis(Alkylating) Cycloisomerization of Enediynes

An original synthesis of chiral benzofulvenes triggered by organocopper reagents is reported. These enantiopure products are available through a highly chemo‐, regio‐, diastereo‐, and enantioselective bis(alkylating) cycloisomerization process. A double chirality transfer (central‐to‐axial‐to‐central) is observed.     

Direct Cross‐Coupling of Allylic C(sp3)−H Bonds with Aryl‐ and Vinylbromides by Combined Nickel and Visible‐Light Catalysis

An efficient protocol for the direct allylic C(sp³)?H bond activation of unactivated tri‐ and tetrasubstituted alkenes and their functionalization with aryl‐ and vinylbromides by nickel and visible‐light photocatalysis has been developed. The method allows C(sp²)?C(sp³) formation under mild reaction conditions with good functional‐group tolerance and excellent regioselectivity.     

A Highly Efficient Chirality Switchable Synthesis of Dihydropyran‐Fused Benzofurans by Fine‐Tuning the Phenolic Proton of β‐Isocupreidine (β‐ICD) Catalyst with Methyl

A highly enantioselective β‐isocupreidine (β‐ICD) catalyzed synthesis of dihydropyran‐fused benzofurans through [4+2] cycloaddition of allenoates and benzofuranone alkenes was developed. Switchable chirality inversion of cycloaddition products was achieved by replacing the phenolic proton of the catalyst with a methyl, demonstrating an amazing effect of minimal structural variation on inverting enantioselectivity. DFT calculations were utilized to elucidate the origin of the observed phenomena. Computation also provided a clue for a rational design in which the multi‐hydrogen bond with the alcohol additive was found to improve the enantioselectivity of the cycloaddition. Finally, the substrate scope was examined, in which a number of functionalized dihydropyran‐fused benzofurans could be obtained in high yields (up to 97 %) with very good regio‐ (>20:1) and enantioselectivities (up to 98:2 e.r.).