Catalytic Intermolecular Asymmetric [2π + 2σ] Cycloadditions of Bicyclo[1.1.0]butanes: Practical Synthesis of Enantioenriched Highly Substituted Bicyclo[2.1.1]hexanes.

The high percentage of sp-hybridized carbons and the presence of chiral carbon centers could contribute to increased molecular complexity, enhancing the likelihood of clinical success of drug candidates. Three-dimensional (3D) bridged motifs have recently garnered significant interest in medicinal chemistry. Bicyclo[2.

Copper-Catalyzed Enantioconvergent Radical C(sp)-N Cross-Coupling to Access Chiral α-Amino-β-lactams.

A copper-catalyzed enantioconvergent radical C(sp)-N cross-coupling of racemic tertiary α-bromo-β-lactams with aromatic amines is developed under mild thermal reaction conditions. The use of a sterically demanded oxazoline-derived sulfonamide N,N,N-ligand is crucial for the reaction initiation and effective enantio-discrimination of the azetidinone-derived cyclic alkyl radicals. The strategy provides an attractive approach to access chiral α-amino-β-lactams, an important structural motif in many biologically active molecules.

Copper-Catalyzed Enantioconvergent Radical -Alkylation of Diverse (Hetero)aromatic Amines.

The 3d transition metal-catalyzed enantioconvergent radical cross-coupling provides a powerful tool for chiral molecule synthesis. In the classic mechanism, the bond formation relies on the interaction between nucleophile-sequestered metal complexes and radicals, limiting the nucleophile scope to sterically uncongested ones. The coupling of sterically congested nucleophiles poses a significant challenge due to difficulties in transmetalation, restricting the reaction generality.

Copper-Catalyzed Enantioselective C(sp )-SCF Coupling of Carbon-Centered Benzyl Radicals with (Me N)SCF.

In contrast with the well-established C(sp )-SCF cross-coupling to forge the Ar-SCF bond, the corresponding enantioselective coupling of readily available alkyl electrophiles to forge chiral C(sp )-SCF bond has remained largely unexplored. We herein disclose a copper-catalyzed enantioselective radical C(sp )-SCF coupling of a range of secondary/tertiary benzyl radicals with the easily available (Me N)SCF reagent. The key to the success lies in the utilization of chiral phosphino-oxazoline-derived anionic N,N,P-ligands through tuning electronic and steric effects for the simultaneous control of the reaction initiation and enantioselectivity.

A general copper-catalysed enantioconvergent C(sp)-S cross-coupling via biomimetic radical homolytic substitution.

Although α-chiral C(sp)-S bonds are of enormous importance in organic synthesis and related areas, the transition-metal-catalysed enantioselective C(sp)-S bond construction still represents an underdeveloped domain probably due to the difficult heterolytic metal-sulfur bond cleavage and notorious catalyst-poisoning capability of sulfur nucleophiles. Here we demonstrate the use of chiral tridentate anionic ligands in combination with Cu(I) catalysts to enable a biomimetic enantioconvergent radical C(sp)-S cross-coupling reaction of both racemic secondary and tertiary alkyl halides with highly transformable sulfur nucleophiles. This protocol not only exhibits a broad substrate scope with high enantioselectivity but also provides universal access to a range of useful α-chiral alkyl organosulfur compounds with different sulfur oxidation states, thus providing a complementary approach to known asymmetric C(sp)-S bond formation methods.

Copper-Catalyzed Enantioconvergent Radical C(sp)-N Cross-Coupling of Activated Racemic Alkyl Halides with (Hetero)aromatic Amines under Ambient Conditions.

The enantioconvergent C(sp)-N cross-coupling of racemic alkyl halides with (hetero)aromatic amines represents an ideal means to afford enantioenriched -alkyl (hetero)aromatic amines yet has remained unexplored due to the catalyst poisoning specifically for strong-coordinating heteroaromatic amines. Here, we demonstrate a copper-catalyzed enantioconvergent radical C(sp)-N cross-coupling of activated racemic alkyl halides with (hetero)aromatic amines under ambient conditions. The key to success is the judicious selection of appropriate multidentate anionic ligands through readily fine-tuning both electronic and steric properties for the formation of a stable and rigid chelating Cu complex.

Copper-Catalyzed Enantioconvergent Radical C(sp )-N Cross-Coupling: Access to α,α-Disubstituted Amino Acids.

Transition-metal catalyzed enantioconvergent cross-coupling of tertiary alkyl halides with ammonia offers a rapid avenue to chiral unnatural α,α-disubstituted amino acids. However, the construction of chiral C-N bonds between tertiary-carbon electrophiles and nitrogen nucleophiles presented a great challenge owing to steric congestion. We report a copper-catalyzed enantioconvergent radical C-N cross-coupling of alkyl halides with sulfoximines (as ammonia surrogates) under mild conditions by employing a chiral anionic N,N,N-ligand with a long spreading side arm.

Enantioconvergent Cu-catalysed N-alkylation of aliphatic amines.

Chiral amines are commonly used in the pharmaceutical and agrochemical industries. The strong demand for unnatural chiral amines has driven the development of catalytic asymmetric methods. Although the N-alkylation of aliphatic amines with alkyl halides has been widely adopted for over 100 years, catalyst poisoning and unfettered reactivity have been preventing the development of a catalyst-controlled enantioselective version.

Cu(I)-Catalyzed Chemo- and Enantioselective Desymmetrizing C-O Bond Coupling of Acyl Radicals.

Transition-metal-catalyzed enantioselective functionalization of acyl radicals has so far not been realized, probably due to their relatively high reactivity, which renders the chemo- and stereocontrol challenging. Herein, we describe Cu(I)-catalyzed enantioselective desymmetrizing C-O bond coupling of acyl radicals. This reaction is compatible with (hetero)aryl and alkyl aldehydes and, more importantly, displays a very broad scope of challenging alcohol substrates, such as 2,2-disubstituted 1,3-diols, 2-substituted-2-chloro-1,3-diols, 2-substituted 1,2,3-triols, 2-substituted serinols, and meso primary 1,4-diols, providing enantioenriched esters characterized by challenging acyclic tetrasubstituted carbon stereocenters.

Copper-Catalyzed Chemo- and Enantioselective Radical 1,2-Carbophosphonylation of Styrenes.

The copper-catalyzed enantioselective radical difunctionalization of alkenes from readily available alkyl halides and organophosphorus reagents possessing a P-H bond provides an appealing approach for the synthesis of α-chiral alkyl phosphorus compounds. The major challenge arises from the easy generation of a P-centered radical from the P-H-type reagent and its facile addition to the terminal side of alkenes, leading to reverse chemoselectivity. We herein disclose a radical 1,2-carbophosphonylation of styrenes in a highly chemo- and enantioselective manner.

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

The copper-catalyzed enantioconvergent radical C(sp )-C(sp ) 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(sp )-C(sp ) bond via a single-electron reduction/transmetalation/bond formation catalytic cycle.

A Counterion/Ligand-Tuned Chemo- and Enantioselective Copper-Catalyzed Intermolecular Radical 1,2-Carboamination of Alkenes.

The copper-catalyzed enantioselective intermolecular radical 1,2-carboamination of alkenes with readily accessible alkyl halides is an appealing strategy for producing chiral amine scaffolds. The challenge arises from the easily occurring atom transfer radical addition between alkyl halides and alkenes and the issue of enantiocontrol. We herein describe a radical alkene 1,2-carboamination with sulfoximines in a highly chemo- and enantioselective manner.

Ligand Development for Copper-Catalyzed Enantioconvergent Radical Cross-Coupling of Racemic Alkyl Halides.

The enantioconvergent cross-coupling of racemic alkyl halides represents a powerful tool for the synthesis of enantioenriched molecules. In this regard, the first-row transition metal catalysis provides a suitable mechanism for stereoconvergence by converting racemic alkyl halides to prochiral radical intermediates owing to their good single-electron transfer ability. In contrast to the noble development of chiral nickel catalyst, copper-catalyzed enantioconvergent radical cross-coupling of alkyl halides is less studied.

Enantioselective Hydroxylation of Dihydrosilanes to Si-Chiral Silanols Catalyzed by In Situ Generated Copper(II) Species.

Catalytic enantioselective hydroxylation of prochiral dihydrosilanes with water is expected to be a highly efficient way to access Si-chiral silanols, yet has remained unknown up to date. Herein, we describe a strategy for realizing this reaction: using an alkyl bromide as a single-electron transfer (SET) oxidant for invoking Cu species and chiral multidentate anionic N,N,P-ligands for effective enantiocontrol. The reaction readily provides a broad range of Si-chiral silanols with high enantioselectivity and excellent functional group compatibility.

Mechanism-based ligand design for copper-catalysed enantioconvergent C(sp)-C(sp) cross-coupling of tertiary electrophiles with alkynes.

In contrast with the well-established enantioconvergent radical C(sp)-C cross-coupling of racemic secondary alkyl electrophiles, the corresponding coupling of tertiary electrophiles to forge all-carbon quaternary stereocentres remains underexplored. The major challenge arises from the steric hindrance and the difficult enantio-differentiation of three distinct carbon substituents of prochiral tertiary radicals. Here we demonstrate a general copper-catalysed enantioconvergent C(sp)-C(sp) cross-coupling of diverse racemic tertiary alkyl halides with terminal alkynes (87 examples).

Design of Hemilabile N,N,N-Ligands in Copper-Catalyzed Enantioconvergent Radical Cross-Coupling of Benzyl/Propargyl Halides with Alkenylboronate Esters.

The enantioconvergent radical C(sp)-C(sp) cross-coupling of alkyl halides with alkenylboronate esters is an appealing tool in the assembly of synthetically valuable enantioenriched alkenes owing to the ready availability, low toxicity, and air/moisture stability of alkenylboronate esters. Here, we report a copper/chiral N,N,N-ligand catalytic system for the enantioconvergent cross-coupling of benzyl/propargyl halides with alkenylboronate esters (>80 examples) with good functional group tolerance. The key to the success is the rational design of hemilabile N,N,N-ligands by mounting steric hindrance at the ortho position of one coordinating quinoline ring.

Copper-Catalyzed -Selective Radical 1,2-Alkylarylation of Terminal Alkynes.

A copper-catalyzed highly -selective radical 1,2-alkylarylation of terminal alkynes with aryl boronic acids and alkyl bromides has been established. The reaction exhibits high compatibility with a wide range of terminal alkynes and diverse aryl boronic acids, thus providing facile access to various stereodefined trisubstituted alkenes in high yield under mild reaction conditions. Preliminary mechanistic investigations support the formation of alkyl radicals and their subsequent addition to alkynes in the reaction.

Copper-Catalyzed Intermolecular Enantioselective Radical Oxidative C(sp )-H/C(sp)-H Cross-Coupling with Rationally Designed Oxazoline-Derived N,N,P(O)-Ligands.

The intermolecular asymmetric radical oxidative C(sp )-C(sp) cross-coupling of C(sp )-H bonds with readily available terminal alkynes is a promising method to forge chiral C(sp )-C(sp) bonds because of the high atom and step economy, but remains underexplored. Here, we report a copper-catalyzed asymmetric C(sp )-C(sp) cross-coupling of (hetero)benzylic and (cyclic)allylic C-H bonds with terminal alkynes that occurs with high to excellent enantioselectivity. Critical to the success is the rational design of chiral oxazoline-derived N,N,P(O)-ligands that not only tolerate the strong oxidative conditions which are requisite for intermolecular hydrogen atom abstraction (HAA) processes but also induce the challenging enantiocontrol.

Enantioconvergent Cu-Catalyzed Radical C-N Coupling of Racemic Secondary Alkyl Halides to Access α-Chiral Primary Amines.

α-Chiral alkyl primary amines are virtually universal synthetic precursors for all other α-chiral N-containing compounds ubiquitous in biological, pharmaceutical, and material sciences. The enantioselective amination of common alkyl halides with ammonia is appealing for potential rapid access to α-chiral primary amines, but has hitherto remained rare due to the multifaceted difficulties in using ammonia and the underdeveloped C(sp)-N coupling. Here we demonstrate sulfoximines as excellent ammonia surrogates for enantioconvergent radical C-N coupling with diverse racemic secondary alkyl halides (>60 examples) by copper catalysis under mild thermal conditions.

Desymmetrization of unactivated bis-alkenes chiral Brønsted acid-catalysed hydroamination.

Although great success has been achieved in catalytic asymmetric hydroamination of unactivated alkenes using transition metal catalysis and organocatalysis, the development of catalytic desymmetrising hydroamination of such alkenes remains a tough challenge in terms of attaining a high level of stereocontrol over both remote sites and reaction centers at the same time. To address this problem, here we report a highly efficient and practical desymmetrising hydroamination of unactivated alkenes catalysed by chiral Brønsted acids with both high diastereoselectivity and enantioselectivity. This method features a remarkably broad alkene scope, ranging from mono-substituted and -/1,2-disubstituted to the challenging tri- and tetra-substituted alkenes, to provide access to a variety of diversely functionalized chiral pyrrolidines bearing two congested tertiary or quaternary stereocenters with excellent efficiency under mild and user-friendly synthetic conditions.

Copper-Catalyzed Radical 1,2-Carbotrifluoromethylselenolation of Alkenes under Ambient Conditions.

We have described a copper-catalyzed radical 1,2-carbotrifluoromethylselenolation of alkenes using the readily available alkyl halides and (MeN)SeCF salt. Critical to the success is the use of a proline-based N,N,P-ligand to enhance the reducing capability of copper for easy conversion of diverse alkyl halides to the corresponding radicals via a single-electron transfer process. The reaction features a broad substrate scope, including various mono-, di-, and trisubstituted alkenes with many functional groups.

Catalytic enantioselective C(sp)-H functionalization involving radical intermediates.

Recently, with the boosted development of radical chemistry, enantioselective functionalization of C(sp)-H bonds via a radical pathway has witnessed a renaissance. In principle, two distinct catalytic modes, distinguished by the steps in which the stereochemistry is determined (the radical formation step or the radical functionalization step), can be devised. This Perspective discusses the state-of-the-art in the area of catalytic enantioselective C(sp)-H functionalization involving radical intermediates as well as future challenges and opportunities.

Copper-Catalyzed Enantioconvergent Radical Suzuki-Miyaura C(sp)-C(sp) Cross-Coupling.

A copper-catalyzed enantioconvergent Suzuki-Miyaura C(sp)-C(sp) cross-coupling of various racemic alkyl halides with organoboronate esters has been established in high enantioselectivity. Critical to the success is the use of a chiral cinchona alkaloid-derived N,N,P-ligand for not only enhancing the reducing capability of copper catalyst to favor a stereoablative radical pathway over a stereospecific S2-type process but also providing an ideal chiral environment to achieve the challenging enantiocontrol over the highly reactive radical species. The reaction has a broad scope with respect to both coupling partners, covering aryl- and heteroarylboronate esters, as well as benzyl-, heterobenzyl-, and propargyl bromides and chlorides with good functional group compatibility.

Copper-Catalyzed Asymmetric Coupling of Allenyl Radicals with Terminal Alkynes to Access Tetrasubstituted Allenes.

In contrast to the wealth of asymmetric transformations for generating central chirality from alkyl radicals, the enantiocontrol over the allenyl radicals for forging axial chirality represents an uncharted domain. The challenge arises from the unique elongated linear configuration of the allenyl radicals that necessitates the stereo-differentiation of remote motifs away from the radical reaction site. We herein describe a copper-catalyzed asymmetric radical 1,4-carboalkynylation of 1,3-enynes via the coupling of allenyl radicals with terminal alkynes, providing diverse synthetically challenging tetrasubstituted chiral allenes.