Remote C─H Bond Activation via Enantioselective Carbopalladation and 1,4-Pd Migration Cascade Process.

Carbopalladation-initiated cascade reaction involving 1,4-Pd migration is a straightforward and powerful approach to activate remote C─H bond, forging versatile fused polycyclic compounds containing fluorene fragment which are highly valuable synthetic targets. However, its asymmetric variants pose considerable challenges and have not been explored. Here the first asymmetric palladium-catalyzed tandem carbopalladation is reported, 1,4-Pd migration reaction of ortho-iodophenol-derived allyl ether under mild conditions, allowing the transformation of a wide range of substrates in good to excellent enantioselectivities, and providing a facile and straight forward access to tetracyclic dihydroindeno[1,2,3-de]chromene bearing a chiral fluorene skeleton. A good functional group tolerance, high stereoselectivity, as well as the good chiroptical properties (high fluorescence quantum yields, circular dichroism) of the products make this approach highly attractive. Moreover, density functional theory (DFT) calculations indicate that the protonation of five-membered palladacycle intermediate is more favorable rather than its direct reductive elimination process.

Pd-Catalyzed Enantioselective Three-Component Carboamination of 1,3-Cyclohexadiene.

Asymmetric Pd-catalyzed three-component carboamination reactions of dienes to construct chiral cyclohexenylamines, which are of great importance in many fields of chemistry, have remained largely unexplored. Here, we demonstrate a highly enantio- and regioselective Pd/Ming-Phos-catalyzed carboamination reactions of 1,3-cyclohexadiene with readily available aryl iodides and anilines for facile access to diverse valuable chiral cyclohexenylamines. The process shows excellent functional group tolerance, easy scalability, and mild conditions. Moreover, mechanistic studies suggest that this reaction has a first-order dependence on the concentration of the palladium catalyst and aniline.

Palladium/XuPhos-catalyzed enantioselective cascade Heck/intermolecular C(sp2)-H alkylation reaction.

Palladium-catalyzed enantioselective domino Heck/intramolecular C-H functionalization reaction, as a valuable strategy for creating molecular diversity, has remained a prominent challenge. Here, we describe a Pd/XuPhos catalyst for asymmetric domino Heck/intermolecular C-H alkylation of unactivated alkenes with diverse polyfluoro- and heteroarenes in a highly chemo- and enantioselective manner. This process enables efficient synthesis of various dihydrobenzofurans, indolines and indanes, which are of interest in pharmaceutical research and other areas. Late-stage modifications of the core structures of natural products are also well showcased. Moreover, synthetic transformations create a valuable platform for preparing a series of functionalized molecules. Several control experiments for mechanistic study are conducted to pursue a further understanding of the reaction.

Recent advances in Pd-catalyzed asymmetric cyclization reactions.

Over the past few decades, there have been major developments in transition metal-catalyzed asymmetric cyclization reactions, enabling the convenient access to a wide spectrum of structurally diverse chiral carbo- and hetero-cycles, common skeletons found in fine chemicals, natural products, pharmaceuticals, agrochemicals, and materials. In particular, a plethora of enantioselective cyclization reactions have been promoted by chiral palladium catalysts owing to their outstanding features. This review aims to collect the latest advancements in enantioselective palladium-catalyzed cyclization reactions over the past eleven years, and it is organized into thirteen sections depending on the different types of transformations involved.

Palladium/TY-Phos-Catalyzed Asymmetric Heck/Tsuji-Trost Reaction of o-Bromophenols with 1,3-Dienes.

2,3-Dihydrobenzofurans are crucial building blocks in the synthesis of natural products and pharmaceutical molecules. However, their asymmetric synthesis has been a long-standing formidable challenge so far. In this work, we developed a highly enantioselective Pd/TY-Phos-catalyzed Heck/Tsuji-Trost reaction of o-bromophenols with various 1,3-dienes, allowing expedient access to chiral substituted 2,3-dihydrobenzofurans. This reaction features excellent regio- and enantiocontrol, high functional group tolerance, and easy scalability. More importantly, the demonstration of this method as a highly valuable tool for the construction of optically pure natural products (R)-tremetone and fomannoxin is highlighted.

Synthesis of W-Phos Ligand and Its Application in the Copper-Catalyzed Enantioselective Addition of Linear Grignard Reagents to Ketones.

The asymmetric catalytic addition of linear Grignard reagents to ketones has been a long-standing challenge in organic synthesis. Herein, a novel family of PNP ligands (W-Phos) was designed and applied in copper-catalyzed asymmetric addition of linear Grignard reagents to aryl alkyl ketones, allowing facile access to versatile chiral tertiary alcohols in good to high yields with excellent enantioselectivities (up to 94 % yield, 96 % ee). The process can also be used to synthesize chiral allylic tertiary alcohols from more challenging α,ß-unsaturated ketones. Notably, the potential utility of this method is demonstrated in the gram-scale synthesis and modification of various densely functionalized medicinally relevant molecules.

Enantioselective difunctionalization of alkenes by a palladium-catalyzed Heck/borylation sequence.

A palladium catalyzed enantioselective Heck/borylation reaction of alkene-tethered aryl iodides was realized, delivering a variety of 2,3-dihydrobenzofuranyl boronic esters in high yield with excellent enantioselectivity. Asymmetric synthesis of chromane boronic ester, indane boronic ester and indoline boronic ester was also accomplished. The protocol offers an efficient access to the corresponding chiral benzocyclic boronic esters, which are notably important chemical motifs in synthetic transformations.

Palladium-Catalyzed Asymmetric Cross-Coupling Reactions of Cyclobutanols and Unactivated Olefins.

Transition-metal-catalyzed activations of carbon-carbons bonds of small strained rings have widespread applications in synthetic and medicinal chemistry. However, coupling reactions of cyclobutanols involving ß-carbon elimination to construct C(sp3)-C(sp3) bonds have scarcely been developed. Here, we demonstrate a highly enantioselective Pd-catalyzed intermolecular C(sp3)-C(sp3) coupling reaction of a broad range of cyclobutanol derivatives and unactivated alkenes, allowing convenient access to a series of chiral benzene-fused cyclic compounds in a highly regio-, chemo-, and enantioselective manner.

Pd-Catalyzed Enantioselective Syntheses of Trisubstituted Allenes via Coupling of Propargylic Benzoates with Organoboronic Acids.

Enabled by the newly developed ligand, Ming-Phos, the first example of palladium-catalyzed highly enantioselective coupling of racemic propargylic benzoates with organoboronic acids for chiral allenes synthesis has been developed. Excellent asymmetric induction has been achieved with a decent substrate scope. Synthetic potentials for the construction of polycyclic compounds with multiple chiral centers have been demonstrated.

Enantioselective Difunctionalization of Alkenes by a Palladium-Catalyzed Heck/Sonogashira Sequence.

Sonogashira-type cross-couplings are one of the most significant alkynylations in organic chemistry. One of the first palladium-catalyzed intramolecular Heck/Sonogashira reactions of alkenes with terminal alkynes is now reported. With this method, a variety of uniquely substituted chiral benzene-fused heterocycles bearing a propargyl-substituted all-carbon quaternary stereocenter were obtained in a straightforward, high-yielding, and highly stereoselective manner under mild conditions. Salient features of this process include the use of readily available substrates, high selectivities, a broad substrate scope as well as versatile product functionalizations.

Enantioselective Dicarbofunctionalization of Unactivated Alkenes by Palladium-Catalyzed Tandem Heck/Suzuki Coupling Reaction.

A highly enantioselective dicarbofunctionalization of unactivated alkenes was implemented by a Pd-catalyzed asymmetric tandem Heck/Suzuki coupling reaction. This reaction represents the first example of a highly enantioselective intramolecular cyclization/cross-coupling of olefin-tethered aryl halides with alkyl-, alkenyl- or arylboronic acids, and provides rapid access to a number of chiral compounds, such as dihydrobenzofurans, indolines, chromanes, and indanes bearing a quaternary stereocenter, in good yields with excellent enantioselectivities. The practicality of this reaction was validated in the modification of biologically complex molecules such as peptides, piperitol, CB2 receptor agonists, etc. Moreover, the synthesis of two enantiomers can be easily realized by simple change in the order of the steps in the coupling sequence.

Palladium/XuPhos-Catalyzed Enantioselective Carboiodination of Olefin-Tethered Aryl Iodides.

A highly enantioselective palladium-catalyzed iodine atom transfer cycloisomerization of unactivated alkenes has been developed. This represents the first example of highly enantioselective carboiodination of olefin-tethered aryl iodides, which provides a perfect atom economy method to construct a series of optically active 2,3-dihydrobenzofuran, indolines and chromane bearing an alkyl iodide group in moderate to good yields. Moreover, the use of readily available starting materials, a broad substrate scope, high selectivity, mild reaction conditions, as well as versatile transformation of the product make this approach attractive. The mechanism of this Pd(0)-catalyzed asymmetric carboiodination of alkenes has been investigated with density functional theory.

Enantioselective Gold(I)-Catalyzed Heterocyclization-Intermolecular Exo [4 + 3]-Cycloaddition Reactions for the Synthesis of Chiral Oxa-Bridged Benzocycloheptanes.

The highly exo- and enantioselective gold-catalyzed tandem heterocyclization/[4 + 3] cycloaddition of 2-(1-alkynyl)-2-alken-1-ones and 1,3-diphenylisobenzofuran was implemented by utilizing Ming-Phos, which provides a facile access to chiral seven-membered oxa-bridged rings in 80-98% yield with high exo selectivity ( exo/ endo up to 50:1) and up to 97% ee.

A new trifluoromethylated sulfonamide phosphine ligand for Ag(i)-catalyzed enantioselective [3 + 2] cycloaddition of azomethine ylides.

A newly developed Ming-Phos ligand with a 3,5-bis(trifluoromethyl)phenyl substituent was demonstrated to be highly efficient for Ag-catalyzed asymmetric [3 + 2] cycloaddition reactions of azomethine ylides with maleimides, cyclopentene-1,3-diones, and N-(2-t-butylphenyl)maleimide. Being easily prepared on the gram scale in one step, the ligand in combination with a Ag catalyst enables the synthesis of a variety of highly functionalized bicyclic pyrrolidine derivatives in good yields and excellent enantioselectivities under mild conditions.

Ming-Phos/Gold(I)-Catalyzed Diastereo- and Enantioselective Synthesis of Indolyl-Substituted Cyclopenta[ c]furans.

A highly enantioselective gold(I)-catalyzed intermolecular tandem cyclization/[3 + 2] cycloaddition of 2-(1-alkynyl)-2-alken-1-ones with 3-stylindoles was achieved by using Ming-Phos as a chiral ligand. A variety of chiral highly substituted cyclopenta[ c]furans were obtained in good yields (up to 99%) with excellent diastereoselectivities (>20:1) and enantioselectivities (up to 97% ee). The salient features of the present protocol include mild conditions, excellent yields, and high diastereo- and enantioselectivities, using readily available starting materials and a chiral ligand.

Gold(I)/Xiang-Phos-Catalyzed Asymmetric Intramolecular Cyclopropanation of Indenes and Trisubstituted Alkenes.

The first intramolecular enantioselective cyclopropanation of indenes and trisubstituted alkenes was accomplished by using new chiral phosphine X5 derived gold(I) complexes. This reaction is a straightforward, efficient method for constructing [5-3-6] fused-ring compounds with two vicinal all-carbon quaternary stereogenic centers, a core structure shared by numerous pharmacological products, and bioactive compounds. The salient features of this transformation include high enantioselectivity (up to >98% ee), excellent yield (>97%), and nice functional group tolerance.

Palladium-Catalyzed Enantioselective Reductive Heck Reactions: Convenient Access to 3,3-Disubstituted 2,3-Dihydrobenzofuran.

The first example of highly enantioselective intramolecular hydroarylation of allyl aryl ethers was realized by palladium-catalyzed reductive heck reactions utilizing a new chiral sulfinamide phosphine ligand (N-Me-XuPhos). N-Me-XuPhos can be easily prepared on gram scale from readily available starting materials in a one-pot synthesis approach. A series of optically active 2,3-dihydrobenzofurans bearing a quaternary stereocenter were obtained in good yields and with excellent enantioselectivities. The practicality of this reaction was validated in the straightforward synthesis of CB2 receptor agonists. Moreover, deuterium was efficiently incorporated into the products.

Direct Asymmetric Formal [3 + 2] Cycloaddition Reaction of Isocyanoesters with ß-Trifluoromethyl ß,ß-Disubstituted Enones Leading to Optically Active Dihydropyrroles.

A highly enantioselective copper-catalyzed [3 + 2] cycloaddition reaction of α-isocyanoesters with ß,ß-disubstituted enones has been developed. Dihydropyrroles were obtained in excellent yields and enantioselectivity by employing an inexpensive copper catalyst. This process provides a scalable and efficient route for the synthesis of highly enantioselective 2,3-dihydropyrroles bearing a trifluoromethylated all-carbon quaternary stereocenter. The salient feautures of this reaction include high efficiency, operational simplicity, high diastereoselectivity and enantioselectivity, a broad substrate scope, outstanding functional group tolerance, and products exhibiting high utility for further transformations.

Enantioselective Regiodivergent Synthesis of Chiral Pyrrolidines with Two Quaternary Stereocenters via Ligand-Controlled Copper(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloadditions.

An unprecedented ligand-controlled regiodivergent Cu(I)-catalyzed asymmetric intermolecular (3 + 2) cycloaddition reaction of α-substituted iminoesters with ß-fluoromethyl ß,ß-disubstituted enones was developed. This novel strategy provides an efficient method for the enantioselective regiodivergent synthesis of pyrrolidines bearing two adjacent quaternary stereocenters or two discrete quaternary stereocenters, opening up a new era for medicinal chemistry and diversity-oriented synthesis. DFT calculations showed that the P,N-ligand L2 acts as a pseudobidentate ligand. The formation of a O-Cu bond with the carbonyl oxygen atom of the enone and dissociation of the amine nitrogen of L2 from the Cu(I) center occurs during the catalytic cycle; this is the main reason for the tuning the regioselectivity of the cycloaddition reaction caused by switching of the ligand. The salient features of this work include high yields (up to >99%), a general substrate scope, the use of commercially available ligands, and high regio-(up to >20:1 rr), diastereo- (up to >20:1 dr), and enantioselectivity (up to >99% ee).

Gold-Catalyzed Asymmetric Intramolecular Cyclization of N-Allenamides for the Synthesis of Chiral Tetrahydrocarbolines.

Highly enantioselective gold-catalyzed intramolecular cyclization of N-allenamides was implemented by utilizing a designed chiral sulfinamide phosphine ligand (PC-Phos). This represents the first example of highly enantioselective intramolecular cyclization of N-allenamides. The practicality of this reaction was validated in the total synthesis of (R)-desbromoarborescidine A and formal synthesis of (R)-desbromoarborescidine C and (R)-deplancheine. Moreover, the catalyst system PC-Phos/AuNTf2 proved to be specifically efficient to promote the desymmetrization of N-allenamides in excellent yields with satisfactory ee values.