Axially Chiral Dibenzazepinones by a Palladium(0)‐Catalyzed Atropo‐enantioselective C−H Arylation

Atropo‐enantioselective C?H functionalization reactions are largely limited to the dynamic kinetic resolution of biaryl substrates through the introduction of steric bulk proximal to the axis of chirality. Reported herein is a highly atropo‐enantioselective palladium(0)‐catalyzed methodology that forges the axis of chirality during the C?H functionalization process, enabling the synthesis of axially chiral dibenzazepinones. Computational investigations support experimentally determined racemization barriers, while also indicating C?H functionalization proceeds by an enantio‐determining CMD to yield configurationally stable eight‐membered palladacycles.     

Palladium‐Catalyzed Enantioselective Cacchi Reaction: Asymmetric Synthesis of Axially Chiral 2,3‐Disubstituted Indoles

We report herein the first examples of a palladium‐catalyzed enantioselective Cacchi reaction for the synthesis of indoles bearing a chiral C2‐aryl axis. In the presence of a catalytic amount of Pd(OAc)₂ and (R,R)‐QuinoxP* ligand, reaction of N‐aryl(alkyl)sulfonyl‐2‐alkynylanilides with arylboronic acids under oxygen atmosphere afforded enantioenriched 2,3‐disubstituted indoles in high yields and enantioselectivity. The indole ring is constructed de novo in this process and a complexation‐induced chirality transfer is proposed to account for the observed enantioselectivity.     

A Divergent Approach to the Diastereoselective Synthesis of 3,3‐Disubstituted Oxindoles from Atropisomeric N‐Aryl Oxindole Derivatives

3,3‐Disubstituted oxindoles were divergently synthesized by diastereoselective transformations including nucleophilic addition, alkylation, and cycloaddition using common, axially chiral N‐aryl oxindoles. Notably, high diastereoselectivities (up to >95:5) were observed with ortho‐monosubstituted N‐aryl oxindoles to give various oxindole scaffolds, and facile removal of the p‐(benzyloxy)aryl moiety in axially twisted amides was achieved by a mild, two‐step sequence.     

Access to P‐ and Axially Chiral Biaryl Phosphine Oxides by Enantioselective CpxIrIII‐Catalyzed C−H Arylations

An enantioselective C?H arylation of phosphine oxides with o‐quinone diazides catalyzed by an iridium(III) complex bearing an atropchiral cyclopentadienyl (Cp^x) ligand and phthaloyl tert‐leucine as co‐catalyst is reported. The method allows access to a) P‐chiral biaryl phosphine oxides, b) atropo‐enantioselective construction of sterically demanding biaryl backbones, and also c) selective assembly of axial and P‐chiral compounds in excellent yields and diastereo‐ and enantioselectivities. Enantiospecific reductions provide monodentate chiral phosphorus(III) compounds having structures and biaryl backbones with proven importance as ligands in asymmetric catalysis.     

Transition‐Metal‐Catalyzed Enantioselective [2+2+2] Cycloadditions for the Synthesis of Axially Chiral Biaryls

Tying up loose ends : Recent advances towards a development of novel transition‐metal‐catalyzed enantioselective [2+2+2] cycloadditions for the synthesis of biaryls are summarized in this Focus Review. Additionally, the enantioselective synthesis of axially chiral biaryls possessing non‐biaryl axial chirality is also presented. These novel asymmetric aromatization reactions allow the production of various axially chiral biaryl compounds with high enantioselectivity.

     

Enantioselective Synthesis of N–C Axially Chiral Compounds by Cu-Catalyzed Atroposelective Aryl Amination

N−C axially chiral compounds have emerged recently as appealing motifs for drug design. However, the enantioselective synthesis of such molecules is still poorly developed and surprisingly no metal-catalyzed atroposelective N-arylations have been described. Herein, we disclose an unprecedented Cu-catalyzed atroposelective N−C coupling that proceeds at room temperature. Such mild reaction conditions, which are a crucial parameter for atropostability of the newly generated products, are operative thanks to the use of hypervalent iodine reagents as a highly reactive coupling partners. A large panel of the N−C axially chiral compounds was afforded with very high enantioselectivity (up to >99 % ee) and good yields (up to 76 %). Post-modifications of thus accessed atropisomeric compounds allows further expansion of the diversity of these appealing compounds.     

Low‐Pressure Cobalt‐Catalyzed Enantioselective Hydrovinylation of Vinylarenes

An efficient and practical protocol for the enantioselective cobalt‐catalyzed hydrovinylation of vinylarenes with ethylene at low (1.2 bar) pressure has been developed. As precatalysts, stable [L₂CoCl₂] complexes are employed that are activated in situ with Et₂AlCl. A modular chiral TADDOL‐derived phosphine–phosphite ligand was identified that allows the conversion of a broad spectrum of substrates, including heterocyclic vinylarenes and vinylferrocene, to smoothly afford the branched products with up to 99 % ee and virtually complete regioselectivity. Even polar functional groups, such as OH, NH₂, CN, and CO₂R, are tolerated.     

Enantioselective Access to Spirocyclic Sultams by Chiral Cpx–Rhodium(III)‐Catalyzed Annulations

Chiral spirocyclic sultams are a valuable compound class in organic and medicinal chemistry. A rapid entry to this structural motif involves a [3+2] annulation of an N‐sulfonyl ketimine and an alkyne. Although the directing‐group properties of the imino group for C?H activation have been exploited, the developments of related asymmetric variants have remained very challenging. The use of rhodium(III) complexes equipped with a suitable atropchiral cyclopentadienyl ligand, in conjunction with a carboxylic acid additive, enables an enantioselective and high yielding access to such spirocyclic sultams.     

Chiral Phosphoric Acid-Catalyzed Enantioselective Synthesis of Axially Chiral Compounds Involving Indole Derivatives

Indoles are one of the most ubiquitous subclass of N-heterocycles and are increasingly incorporated to design new axially chiral scaffolds. The rich profile of reactivity and N−H functionality allow chemical derivatization for enhanced medicinal, material and catalytic properties. Although asymmetric C−C coupling of two arenes gives the most direct access of axially chiral biaryl scaffolds, this chemistry has been the remit of metal catalysis and works efficiently on limited substrates. Our group has devoted special interest in devising novel organocatalytic arylation reactions to fabricate biaryl atropisomers. In this realm, indoles and derivatives have been reliably used as the arylation partners in combination with azoarenes, nitrosonapthalenes and quinone derivatives. Their efficient interaction with chiral phosphoric acid catalyst as well as the tunability of electronics and sterics have enabled excellent control of stereo-, chemo- and regioselectivity to furnish diverse scaffolds. In addition, indoles could act as nucleophiles in desymmetrization of 1,2,4-triazole-3,5-diones. This account provides a succinct illustration of these developments.     

Regioselective Synthesis of N‐Heteroaromatic Trifluoromethoxy Compounds by Direct O−CF3 Bond Formation

The first one‐step method for the synthesis of ortho‐N‐heteroaromatic trifluoromethoxy derivatives by site‐specific O?CF₃ bond formation using hydroxylated N‐heterocycles and Togni's reagent is described. The approach enables the unprecedented syntheses of a wide range of six or five‐membered N‐heteroaromatic trifluoromethoxy compounds containing one or two heteroatoms from most commonly used hydroxylated N‐heterocycles. Notable advantages of this method include its simplicity and mild conditions, avoidance of the need for metals or toxic reagents, and compatibility with a variety of functional groups. Furthermore, this method is especially suitable for the larger scale application.     

A Chiral Nitrogen Ligand for Enantioselective,Iridium‐Catalyzed Silylation of Aromatic C−H Bonds

Iridium catalysts containing dative nitrogen ligands are highly active for the borylation and silylation of C−H bonds, but chiral analogs of these catalysts for enantioselective silylation reactions have not been developed. We report a new chiral pyridinyloxazoline ligand for enantioselective, intramolecular silylation of symmetrical diarylmethoxy diethylsilanes. Regioselective and enantioselective silylation of unsymmetrical substrates was also achieved in the presence of this newly developed system. Preliminary mechanistic studies imply that C−H bond cleavage is irreversible, but not the rate‐determining step.     

NH‐Heterocyclic Aryliodonium Salts and their Selective Conversion into N1‐Aryl‐5‐iodoimidazoles

The synthesis of N‐arylimidazoles substituted at the sterically encumbered 5‐position is a challenge for modern synthetic approaches. A new family of imidazolyl aryliodonium salts is reported, which serve as a stepping stone on the way to selective formation of N1‐aryl‐5‐iodoimidazoles. Iodine acts as a “universal” placeholder poised for replacement by aryl substituents. These new λ³‐iodanes are produced by treating the NH‐imidazole with ArI(OAc)₂, and are converted to N1‐aryl‐5‐iodoimidazoles by a selective copper‐catalyzed aryl migration. The method tolerates a variety of aryl fragments and is also applicable to substituted imidazoles.     

Enantioselective Copper(I)/Chiral Phosphoric Acid Catalyzed Intramolecular Amination of Allylic and Benzylic C−H Bonds

Radical‐involved enantioselective oxidative C?H bond functionalization by a hydrogen‐atom transfer (HAT) process has emerged as a promising method for accessing functionally diverse enantioenriched products, while asymmetric C(sp³)?H bond amination remains a formidable challenge. To address this problem, described herein is a dual Cu^I/chiral phosphoric acid (CPA) catalytic system for radical‐involved enantioselective intramolecular C(sp³)?H amination of not only allylic positions but also benzylic positions with broad substrate scope. The use of 4‐methoxy‐NHPI (NHPI=N‐hydroxyphthalimide) as a stable and chemoselective HAT mediator precursor is crucial for the fulfillment of this transformation. Preliminary mechanistic studies indicate that a crucial allylic or benzylic radical intermediate resulting from a HAT process is involved.     

Chiral Iodine‐Catalyzed Dearomatizative Spirocyclization for the Enantioselective Construction of an All‐Carbon Stereogenic Center

The first enantioselective dearomatizative spirocyclization of 1‐hydroxy‐N‐aryl‐2‐naphthamide derivatives has been accomplished by chiral organoiodine catalysis to stereoselectively create an all‐carbon stereogenic center, providing a straightforward approach to access spirooxindole derivatives in good yields and with high to excellent levels of enantioselectivity. Chiral hypervalent phenyl‐λ³‐iodanes generated in situ from the oxidation of the chiral phenyl iodine actually participate in the asymmetric oxidative dearomatizative spirocyclization reaction.     

Enantioselective Synthesis of Chiral Isotopomers of 1‐Alkanols by a ZACA–Cu‐Catalyzed Cross‐Coupling Protocol

Chiral compounds arising from the replacement of hydrogen atoms by deuterium are very important in organic chemistry and biochemistry. Some of these chiral compounds have a non‐measurable specific rotation, owing to very small differences between the isotopomeric groups, and exhibit cryptochirality. This particular class of compounds is difficult to synthesize and characterize. Herein, we present a catalytic and highly enantioselective conversion of terminal alkenes to various β and more remote chiral isotopomers of 1‐alkanols, with ≥99 % enantiomeric excess (ee), by the Zr‐catalyzed asymmetric carboalumination of alkenes (ZACA) and Cu‐catalyzed cross‐coupling reactions. ZACA‐in situ iodinolysis of allyl alcohol and ZACA‐in situ oxidation of TBS‐protected ω‐alkene‐1‐ols protocols were applied to the synthesis of both (R)‐ and (S)‐difunctional intermediates with 80–90 % ee. These intermediates were readily purified to provide enantiomerically pure (≥99 % ee) compounds by lipase‐catalyzed acetylation. These functionally rich intermediates serve as very useful synthons for the construction of various chiral isotopomers of 1‐alkanols in excellent enantiomeric purity (≥99 % ee) by introducing deuterium‐labeled groups by Cu‐catalyzed cross‐coupling reactions without epimerization.     

The Multiple Facets of Iodine(III) Compounds in an Unprecedented Catalytic Auto‐amination for Chiral Amine Synthesis

Iodine(III) reagents are used in catalytic one‐pot reactions, first as both oxidants and substrates, then as cross‐coupling partners, to afford chiral polyfunctionalized amines. The strategy relies on an initial catalytic auto C(sp³)?H amination of the iodine(III) oxidant, which delivers an amine‐derived iodine(I) product that is subsequently used in palladium‐catalyzed cross‐couplings to afford a variety of useful building blocks with high yields and excellent stereoselectivities. This study demonstrates the concept of self‐amination of the hypervalent iodine reagents, which increases the value of the aryl moiety.     

Enantioselective Nazarov Cyclizations Catalyzed by an Axial Chiral C6F5‐Substituted Boron Lewis Acid

A chiral variant of B(C₆F₅)₃ with a 3,3′‐disubstituted binaphthyl backbone is shown to catalyze Nazarov cyclizations with high levels of enantio‐ and diastereocontrol. The parent B(C₆F₅)₃ also promotes these ring closures efficiently. This electrocyclization is another example of the still small family of C?C bond formations mediated by B(C₆F₅)₃ as the catalyst.     

Rhodium(III)‐Catalyzed Atroposelective Synthesis of Biaryls by C−H Activation and Intermolecular Coupling with Sterically Hindered Alkynes

Reported herein is the atroposelective synthesis of biaryl NH isoquinolones by Rh^III‐catalyzed C?H activation of benzamides and intermolecular [4+2] annulation for a broad scope of 2‐substituted 1‐alkynylnaphthalenes, as well as sterically hindered, symmetric diarylacetylenes. The axial chirality is constructed based on dynamic kinetic transformation of the alkyne in redox‐neutral annulation with benzamides, with alkyne insertion being stereodetermining. The reaction accommodates both benzamides and heteroaryl carboxamides and proceeds in excellent regioselectivity (if applicable) and enantioselectivities (average 91.8 % ee). An enantiomerically and diastereomerically pure rhodacyclic complex was prepared and offers insight into enantiomeric control of the coupling system, wherein the steric interactions between the amide directing group and the alkyne substrate dictate both the regio‐ and enantioselectivity.     

Regio‐ and Enantioselective Synthesis of N‐Allylindoles by Iridium‐Catalyzed Allylic Amination/Transition‐Metal‐Catalyzed Cyclization Reactions

Regio‐ and enantioselective synthesis of N‐allylindoles was realized through an iridium‐catalyzed asymmetric allylic amination reaction with 2‐alkynylanilines and subsequent transition‐metal‐catalyzed cyclization reactions. The highly enantioenriched allylic amines prepared from Ir‐catalysis were treated with catalytic amount of NaAuCl₄ ? 2 H₂O or PdCl₂ providing various substituted N‐allylindoles in excellent yields and enantioselectivities.