Construction of Acyclic Quaternary Carbon Stereocenters via Enantioselective Nickel Catalysis

The construction of acyclic quaternary carbon stereocenters,which are ubiquitous in many bioactive compounds,pharmaceuticals and natural products,has been a long persuit in synthetic organic chemistry.Among numerous methods,enantioselective nickel-catalysis has attracted incremental attention in recent years.This review summarizes the recent development in the asymmetric strategies,research progress,mechanistic investigations for the generation of acyclic quaternary carbon stereocenters via enantioselective nickel catalysis.

1,6-Conjugate addition of para-quinone methides using gem-diborylcarbanions: Practical access to gem-diborylalkanes bearing vicinal tertiary/quaternary stereocenters

A novel,efficient and pragmatic method to prepare gem-diboron products with vicinal tertiary/quaternary stereocenters using LiTMP-mediated 1,6-conjugate addition of gem-diborylalkanes to para-quinone methides was described for the first time.The results showed that various gem-diboron products with vicinal tertiary and quaternary stereocenters could be formed within 15 min at ambient temperature.This simple protocol has also been applied for the efficient synthesis of the analogue of Bedaquiline.

Construction of three stereocenters via hydrogenative desymmetrization of 2,2,5-trisubstituted cyclohexane-1,3-diones

A Ru-catalyzed hydrogenative desymmetrization of 2,2,5-trisubstituted cyclohexane-1,3-diones was developed for construction of three stereocenters including two coherent and discontiguous chiral centers and a chiral quaternary carbon with excellent enantio-and diastereoselectivities.Stereodivergent synthesis of four stereoisomers could be conducted with high enantioselectivities.The desymmetrization could be achieved at gram scale without loss of reactivity and optical purity,and a formal synthesis of bioactive molecule(-)-isocelorbicol was completed.

Synthetic studies towards daphniyunnine B: Construction of AC bicyclic skeleton with two vicinal all carbon quaternary stereocenters

The AC bicyclic skeleton of daphniyunnine B with the required 3 stereocenters(C4,C5 and C8)was accomplished in a concise route which featured two Claisen-type rearrangement reactions to construct the required vicinal all carbon quaternary stereocenters(C5 and C8)and an intramolecular iodocyclization reaction to assemble the cis-confused bicyclic lactam.

Ligand-Promoted,Enantioconvergent Synthesis of Aliphatic Alkanes Bearing Trifluoromethylated Stereocenters via Hydrotrifluoroalkylation of Unactivated Alkenes

While drug chirality remains one of the most important themes in medicinal chemistry and fluorine-containing drugs have comprised large portion of global pharmaceutical market,the synthesis of fluorine-containing compounds featuring a trifluoromethylated stereogenic carbon center is still underdeveloped.Recent strategy of enantioconvergent cross-coupling of trifluoromethylated alkyl halide has significantly updated previous toolbox that is dependent on additional functional group to achieve desired bond formation and highly enantioselective control.However,evident limitations were present in specific coupling candidate(sp?carbon)and/or prerequisite heteroatom in trifluoroalkyl source for inducing effective stereoconvergent differentiation.Leveraging novel design of sterically hindered bisoxazoline ligand and drastic increase of molecular complexity of in situ generated sp3 coupling partner via metal-hydride atom transfer,herein,we report a nickel-catalyzed,highly enantioselective hydrotrifluoroalkylation of unactivated alkenes for diverse synthesis of enantioenriched aliphatic alkanes featuring trifluoromehylated stereogenic carbon.Excellent stereochemical control(mostly>95:5 er),high catalytic reactivity,mild conditions,and broad substrate scope(40+examples),enable convenient late-stage asymmetric trifluoroalkylation of various biologically active complexmolecules.

Constructing Tertiary Alcohols with Vicinal Stereocenters:Highly Diastereo-and Enantioselective Cyanosilylation of α-Branched Acyclic Ketones and Their Kinetic Resolution

We report the first highly diastereo-and enantioselective C-C bond-forming reaction of racemic α-branched ketones to construct tertiary alcohols with adjacent stereocenters.Accordingly,a highly stereoselective cyanosilylation of racemic ketones is developed using our bifunctional cyanating reagent,Me_(2)(CH_(2)Cl)SiCN,giving C^(α)-tetrasubstituted silyl cyanohydrins withtwovicinal stereocenters inupto>20:1 diastereomeric ratio(dr)and 90-98% enantiomeric excess(ee)values,which can undergo various diversification reactions bymanipulating the chloromethyl group.A highly selective kinetic resolution of acyclicα-branched ketones is also developed that allows facile access to acyclic α-alkyl,allyl,and propargyl ketones with good recovery and excellent ee values.The synthetic value of this protocol is further demonstrated by the formal synthesis of the anti-obesity agent,taranabant(MK-0364).The activation of Jacobsen’s privileged catalyst(salen)AlCl by a suitable phosphorane plays a crucial role in the reaction.X-ray crystallographic analysis of single crystals of phosphorane-(salen)AlCl complexes and theoretical calculations help provide a working model.The present transformation opens a new path for the catalytic stereoselective synthesis of stereochemically complex tertiary alcohols featuring two stereocenters(adjacent or not)from racemic ketones.

Catalytic diastereoselective construction of multiple contiguous quaternary carbon stereocenters via [2+2] cycloaddition and mechanistic insight

Multiple contiguous quaternary carbon stereocenters(CQS) are highly challenging, yet important structural motifs in organic synthesis. Here, we describe a visible light induced catalytic [2 + 2] cycloaddition approach that constructed up to four CQS in a pentacyclic fused ring system diastereoselectively, from the readily accessible dienamides with pendent heteroaryls. Variously substituted dienamides have been cyclized with heteroaryls to provide a range of novel CQS-containing scaffolds(26 examples, up to 96%yield and >20:1 dr ratio). Mechanistic studies revealed that it may proceed through an uncommon β-C radical initiated 7-endo cyclization from the biradical intermediate.

Highly enantioselective construction of CF_(3) -bearing all-carbon quaternary stereocenters: Chiral spiro-fused bisoxazoline ligands with 1,1'-binaphthyl sidearm for asymmetric Michael-type Friedel-Crafts reaction

A novel class of chiral spiro-fused bisoxazoline ligands possessing a deep chiral pocket was prepared.The developed ligands have been employed in the nickel-catalyzed highly enantioselective Michael-type Friedel-Crafts reaction, affording the products bearing a trifluoromethylated all-carbon quaternary stereocenter with moderate to excellent yields(up to 99%) and good to excellent enantioselectivies(up to> 99.9% ee). Moreover, a proposed model of chiral pocket revealed that the attack of indole from the Re-face of β-CF_(3)-β-disubstituted nitroalkene was favorable.

Asymmetric construction of all-carbon quaternary stereocenters in the total synthesis of natural products

Structure units containing all-carbon quaternary stereogenic center are found in many bioactive natural products. However, enantioselective construction of this type of structure units has been a formidable challenge for synthetic community due to the steric hindrance enforced by all-carbon quatemary stereocenters. In this review, we present the achievements made by Chinese scientists in the area of asymmetric synthesis of all-carbon quaternary stereocenters in natural products during the past two years.

Nickel-Catalyzed Enantioselective C(sp^(3))–H Arylation of Ketones with Aryl Ethers via Selective C_(Ar)–O Cleavage to Construct All-Carbon Quaternary Stereocenters

We designed thenickel-catalyzed enantioselective C(sp^(3))–H arylation of ketones with phenol-derived aryl pyrimidyl ethers via selective cleavage of the C(aryl)–O bond to construct all-carbon quaternary stereocenters.This method exhibits good functional group compatibility and broad substrate scope.Drug molecule donepezil can directly transform into corresponding highly optically pure derivatives with this developedmethodology.Mechanistic studies reveal that C(aryl)–O cleavage of aryl pyrimidyl ether probably proceeded by means of an anionic organo-Ni(0)intermediate.

Palladium/Xu-Phos Catalyzed Enantioselective Intramolecular Heck Reaction of Unactivated Alkenes

A highly enantioselective palladium-catalyzed intramolecular Heck reaction of unactivated alkenes is developed,which provides a powerful route to access a broad range of chiral 3,3-disubstituted-2,3-dihydrobenzofurans bearing all-carbon quaternary stereocenter of interest in pharmaceutical research.Its salient features include high yield,excellent chemo-and enantioselectivity,mild conditions,a broad substrate scope as well as versatile transformations of the product.

A General Protocol toward Oxindoles Bearing C_(3)-Allylic Quaternary Stereocenter via Domino Reaction:A Concise Synthesis of Heterocycle-Fused Indoline Alkaloids

An efficiently catalytic method toward the synthesis of indolin-2-ones featuring an allylic derived C_(3)-quaternary stereocenter via an intramolecular Heck cyclization/Suzuki coupling of N-substituted-N-(2-bromophenyl)acrylamides and organoboron reagents was successfully developed by using a 1,3-bis(2,6-diisopropylphenyl)acenaphthoimidazol-2-ylidene(AnIPr)-ligated oxazoline palladacycle.It enabled a very broad substrate scope tolerating different functional groups,electronic properties and steric bulkiness.Notably,it revealed a great potential to build diverse heterocycle-fused indoline alkaloids via the same intermediate 3-allyl-1,3-dimethylindolin-2-one.

Asymmetric Alkynylation of Tertiary Carbon-Centered Radical via Copper-Catalyzed Radical Relay

Alkynes are frequently found in a high proportion of natural products and bioactive moleculars,as well as a common synthon in organic synthesis,which can be easily transformed to an alkenyl,alkyl,heteroaryl,or carboxylic acid group.The enantioselective construction of alkyne substituted all carbon quaternary stereocenters is rarely reported and still a big challenge.As part of our continuous effort on developing asymmetric radical transformations,we found introducing an amidyl group(CONHAr)adjacent to the tertiary carbon radical could enable the asymmetric radical coupling with alkyne reagents.The amidyl group may stabilize the tertiary carbon radical or coordination with the chiral copper catalyst.Herein,we communicate a copper-catalyzed asymmetric trifluoromethyl-alkynylation ofα-aryl substituted acrylamides,which provides a straightforward and efficient access to chiral quaternary all-carbon centers bearing alkynyl groups in good yields and enantioselectivities.This reaction was also applied for the synthesis of chiral functionalized dipeptide.

Palladium-catalyzed asymmetric carbamoyl-carbonylation of alkenes

An unprecedented palladium-catalyzed asymmetric carbamoyl-carbonylation of tethered alkenes with CO and alcohols has been developed.This reaction provided an efficient route to access oxindoles andγ-lactams bearingβ-carbonyl substituted quaternary carbons in good yields with excellent chemo-,regio-and enantioselectivity.Gram-scale synthetic capability and facile transformations of the products to chiral spirooxindole and other functional molecules further illustrated the practicability of this reaction.

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 a-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.

Asymmetric Catalytic Concise Synthesis of Hetero-3,3′-Bisoxindoles for the Construction of Bispyrroloindoline Alkaloids

Asymmetric nucleophilic addition of 3-substituted NBoc oxindoles to 3-bromooxindoles was designed to directly construct hetero-3,3′-bisoxindoles,with varying vicinal quaternary carbon stereocenters and N-substituents.The reaction progressed efficiently with high yields,good diastereo-and enantioselectivity(up to>99%ee)under mild reaction conditions catalyzed by chiral N,N′-dioxide/metal complexes.This methodology enabled the facile transformation of the generated hetero-3,3’-bisoxindoles into diverse hexahydropyrroloindole alkaloids with potential antiparasitic and anticancer properties.

Palladium/Xu-Phos Catalyzed Enantioselective Tandem Heck/Cacchi Reaction of Unactivated Alkenes

A highly enantioselective palladium-catalyzed intermolecular tandem Heck/Cacchi reaction of unactivated alkenes with ortho-ethynyl-anilines was developed,which provides a powerful route to access a broad range of enantioenriched 2,3-dihydrobenzofuran-or indo-line-substituted indoles bearing all-carbon quaternary stereocenter of interest in pharmaceutical research.Its salient features include inherent atom-and step-economy,high functional group tolerance,mild conditions,broad structural diversity together with excellent enantioselectivities.

Remote Stereocontrol of All-Carbon Quaternary Centers via Cobalt-Catalyzed Asymmetric Olefin Isomerization

Asymmetric olefin isomerization has become a powerful tool for positional migration of C=C double bonds to afford valuable chiral olefins.However,the synthesis of optically active all-carbon quaternary stereocenters via this strategy is still rare.Herein,we report a cobaltcatalyzed desymmetric olefin isomerization to access 1-methylcyclohexenes bearingβ-quaternary stereocenters in a chemo-,site-,and stereoselective fashion.Preliminary mechanistic studies have revealed the Co-H insertion/β–Helimination reaction pathway and the origin of remote stereocontrol of all-carbon quaternary centers.The gram-scale synthesis and stereoretentive transformations of spirocyclic products demonstrate the synthetic utility of this reaction.

Expert system for elucidation of structures of organic compounds (ESESOC)——Algorithm on stereoisomer generation

An algorithm for enumeration of stereoisomers due to asymmetric carbon, C=C double bond and so on has been developed. It consists of three steps. The output of stereoisomers can be represented by 2.5-dimensional connection table.

Highly Site-and Enantioselective N-H Functionalization of N-Monosubstituted Aniline Derivatives Affording Pyrazolones Bearing a Quaternary Stereocenter

Chiral phosphoric acid catalyzed the regio-and enantioselective N-H functionalization of N-alkylaniline with pyrazolones derived ketimines as electrophiles,providing a variety of chiral pyrazolones containing a tetrasubstituted stereocenter bearing a new N,N'-acetal motif in excellent yields and high enantioselectivities.This strategy was featured by low catalyst loading,mild conditions,and high efficiency and selectivity.