Enantioselective Synthesis of Oxazocines via MQ-Phos Enabled Palladium-Catalyzed Asymmetric Formal [4+4]-Cycloadditions.

Oxazocines are key structural intermediates in the synthesis of natural products and pharmaceutical molecules. However, the synthesis of oxazocines especially in a highly enantioselective manner, is a long-standing formidable challenge due to unfavorable energetics involved in cyclization. Herein, a series of new PNP-Ligand P-chiral stereocenter is first designed and synthesized, called MQ-Phos, and successfully applied it in the Pd-catalyzed enantioselective higher-order formal [4+4]-cycloaddition of α, ß-unsaturated imines with 2-(hydroxymethyl)-1-arylallyl carbonates. The reaction features mild conditions, excellent regio- and enantiocontrol and a broad substrate scope (54 examples). Various medium-sized rings can be afforded in moderate to excellent yields (up to 92%) and excellent enantioselectivity (up to 99% ee). The newly developed MQ-Phos is critical for synthesis of the medium-sized ring in excellent catalytic reactivity and enantioselectivity.

Recent advances in ligand-enabled palladium-catalyzed divergent synthesis.

Developing efficient and straightforward strategies to rapidly construct structurally distinct and diverse organic molecules is one of the most fundamental tasks in organic synthesis, drug discovery and materials science. In recent years, divergent synthesis of organic functional molecules from the same starting materials has attracted significant attention and has been recognized as an efficient and powerful strategy. To achieve this objective, the proper adjustment of reaction conditions, such as catalysts, solvents, ligands, etc., is required. In this review, we summarized the recent efforts in chemo-, regio- and stereodivergent reactions involving acyclic and cyclic systems catalyzed by palladium complexes. Meanwhile, the reaction types, including carbonylative reactions, coupling reactions and cycloaddition reactions, as well as the probable mechanism have also been highlighted in detail.

Recent Advances in Palladium-Catalyzed [4 + n] Cycloaddition of Lactones, Benzoxazinanones, Allylic Carbonates, and Vinyloxetanes.

Palladium-catalyzed allylation cyclization reaction has recently emerged as an efficient and powerful synthetic platform for the construction of diverse and valuable carbo- and heterocycles. Thus the development of new allylic motifs for achieving this type of transformations in high reactivity and selectivity is of great importance. Generally, these substrates have been utilized as 1,3-, 1,4-, 1,5-, 1,6-dipoles in many reactions, which are applied to prepare highly functionalized products with complete control of chemo-, regio-, diastereo-, and enantioselectivity. In this review, we focus our attention on the development of palladium-catalyzed [4 + n] cycloaddition of allylic motifs and describe a comprehensive and impressive advances in this area. Meanwhile, the related mechanism and the application of these annulation strategies in natural product total synthesis will be highlighted in detail.

Rigid P-Chiral Phosphorus Ligands for Highly Selective Palladium-Catalyzed (4+2) and (4+4) Annulations.

We developed novel shackled P-chiral ligands based on 1-phosphanorbornenes and oxazolines. They were subsequently evaluated in palladium-catalyzed (4+2) annulations, producing enantioenriched tetrahydropyran scaffolds in good yields with high site selectivity and enantioselectivity. Moreover, chemoselective (4+4) products were also achieved by using acyclic imines. In addition, density functional theory calculations were performed to afford the energy profile of the Michael addition step and ring formation step. This demonstrated that the enantioselective (4+2) annulations and the chemoselective reaction between (4+2) and (4+4) products were mostly under thermodynamic control.

Ligand-dependent, palladium-catalyzed stereodivergent synthesis of chiral tetrahydroquinolines.

The most fundamental tasks in asymmetric synthesis are the development of fully stereodivergent strategies to access the full complement of stereoisomers of products bearing multiple stereocenters. Although great progress has been made in the past few decades, developing general and practical strategies that allow selective generation of any diastereomer of a reaction product bearing multiple stereocentres through switching distinct chiral catalysts is a significant challenge. Here, attaining precise switching of the product stereochemistry, we develop a novel P-chirogenic ligand, i.e.YuePhos, which can be easily derived from inexpensive and commercially available starting materials in four chemical operations. Through switching of three chiral ligands, an unprecedented ligand-dependent diastereodivergent Pd-catalyzed asymmetric intermolecular [4 + 2] cycloaddition reaction of vinyl benzoxazinanone with α-arylidene succinimides was developed. This novel method provides an efficient route for the stereodivergent synthesis of six stereoisomers of pyrrolidines bearing up to three adjacent stereocenters (one quaternary center). Despite the anticipated challenges associated with controlling stereoselectivity in such a complex system, the products are obtained in enantiomeric excesses ranging up to 98% ee. In addition, the synthetic utilities of optically active hexahydrocarbazoles are also shown.

Recent Advances in Lewis Base-Catalysed Chemo-, Diastereo- and Enantiodivergent Reactions of Electron-Deficient Olefins and Alkynes.

Lewis base catalysis provides powerful synthetic strategies for the selective construction of carbon-carbon and carbon-heteroatom bonds. Thus continuous efforts have been deployed to develop effective methodologies involving Lewis base catalysis. The nucleophilicity and steric hindrance of Lewis base catalyst often plays a major role in catalytic reactivity and selectivity in the reaction. In the past decades, tremendous progress has been made in the divergent construction of valuable motifs under Lewis base catalysis. In this review, we provide a comprehensive and updated summary of Lewis base-catalysed chemo-, diastereo- and enantiodivergent reaction, as well as the related mechanism will be highlighted in detail.

Phosphine-Catalyzed (4 + 2) Cycloaddition of Conjugated Dienes with Enones and Its Asymmetric Variant.

Herein we reported a novel phosphine-catalyzed (4 + 2) cyclization reaction of electron-deficient conjugated dienes with enones to generate functionalized dihydropyran skeletons. A mechanistic investigation reveals that the reaction produces a new phosphonium zwitterion, which undergoes consecutive reactions. In addition, an asymmetric variant was developed by efficient and economical chiral phosphine catalysis.

Design of 1-Phosphanorbornene Derivatives as Chiral Organocatalysts for Enantioselective (4 + 2) Annulation Reactions of γ-Benzyl Allenoates.

Two novel diastereoisomeric P-chirogenic phosphine catalysts, i.e., JiaPhos, which can be easily derived from inexpensive and commercially available starting materials in five chemical operations (totally 4.16g scale), are introduced. To our delight, the JiaPhos catalysts display good performance in enantioselective (4 + 2) annulations involving 3-methylene-2-oxindoles and γ-benzyl allenoates, providing a wide range of 3,3'-spirocyclic oxindoles with good efficiency and enantioselectivity.

Concise Synthesis of Phospholene and Its P-Stereogenic Derivatives.

A simple method to build phospholene derivatives has been achieved in a one-pot reaction with readily available o-alkynylaryl bromides and alkylphosphine oxides. This method is also applicable to synthesize P-stereogenic phospholenes, and the resulting chiral phosphine was utilized as a ligand for coordination chemistry.

Copper(i)/Ganphos catalysis: enantioselective synthesis of diverse spirooxindoles using iminoesters and alkyl substituted methyleneindolinones.

A copper-catalyzed asymmetric 1,3-dipolar cycloaddition of glycine iminoesters with alkyl substituted 3-methylene-2-oxindoles is described. By using de novo design of P-stereogenic phosphines as ligands, spiro[pyrrolidin-3,3'-oxindole]s are generated in good to excellent yields with high asymmetric induction. A further reduced catalyst loading of 0.1 mol% is sufficient to achieve a satisfactory enantioselectivity of 90% ee. The DFT calculations suggest the second Michael addition of the 1,3-dipole to be the rate- and enantio-determining step. A key feature of this 1,3-dipolar cycloaddition is the wide substrate applicability, even with alkyl aldehyde-derived azomethine ylide; thus it has streamlined a highly enantioselective access to a new class of antiproliferative agents, MDM2-p53.

Silver/palladium relay catalyzed 1,3-dipole annulation/allylation reactions to access fully substituted allyl imidazolidines.

A silver/palladium relay catalyzed 1,3-dipole annulation/allylation reaction of iminoesters and Baylis-Hillman acetates for the construction of fully substituted allyl imidazolidines is reported. The reaction of both iminoesters and Baylis-Hillman acetates affords the fully substituted allyl imidazolidines in high yields and regioselectivities. The three component reaction is triggered by silver-catalyzed 1,3-dipole annulation, followed by the sequential palladium catalyzed allylation. Mechanistic studies reveal that the dual catalytic system plays a key role in the reaction. The developed methodology provides straightforward access to allyl imidazolidines under simple reaction conditions.

Recent advances in phosphine catalysis involving γ-substituted allenoates.

Organophosphine catalysis of allenoates has doubtlessly been one of the most ideal and powerful synthetic strategies for the generation of highly functionalized carbo-/hetero-cycle motifs, which are important structural motifs in biologically active natural products and pharmaceuticals. Because of their diverse and amazing reactivity, chemists usually pay more attention to the study of 2,3-butadienoates and α-substituted allenoates. More recently, there is a growing interest in the study of phosphine catalysis of γ-substituted allenoates, which usually have low reactivity and selectivity. This feature article will describe the selected examples of organophosphine catalysis of γ-substituted allenoates with a wide range of electrophiles.

Phosphine/Palladium Cooperative Catalysis: (4 + 3) Annulations of Morita-Baylis-Hillman Carbonates and Vinyl Benzoxazinanones.

A novel (4 + 3) annulation reaction of Morita-Baylis-Hillman carbonates and vinyl benzoxazinanones has been developed by using phosphine/palladium dual catalysis. This reaction demonstrates a wide substrate scope, providing a range of vinyl 2, 3-dihydro-1H-benzo[b]azepine derivatives in moderate to good yields and diastereoselectivities. Experimental results indicate that both palladium and phosphine play crucial roles in the annulation reactions.

Phosphine-catalyzed regiodivergent annulations of γ-substituted allenoates with conjugated dienes.

A phosphine catalyzed regiodivergent annulation of γ-substituted allenoates with conjugated dienes is reported, and highly functionalized cyclohexenes or cyclopentenes were obtained in high yields and regioselectivities. This transformation takes advantage of mild conditions, wide substrate scope and significant functional group tolerance. The high regioselectivity can be achieved by tuning the nucleophilicity of the phosphine catalyst.

Ag/P-Stereogenic Phosphine-Catalyzed Enantioselective 1,3-Dipolar Cycloadditions: A Method to Optically Active Pyrrolidines.

A Ag/P-stereogenic phosphine-complex-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with electron-deficient olefins is reported. In this reaction, highly functionalized pyrrolines with a spiro-quaternary stereogenic center were obtained in good yields (up to 99%) with excellent levels of diastereo- (up to >20:1 dr) and enantioselectivities (up to >99% ee). The chirality of adducts was controlled predominantly by the P-stereogenic phosphines.

P-Stereogenic Phosphines Directed Copper(I)-Catalyzed Enantioselective 1,3-Dipolar Cycloadditions.

A new pair of P-stereogenic ligands with multiple chiral centers were synthesized and used in the copper(I)-catalyzed enatioselective [3 + 2] cycloaddition of iminoesters with alkenes. A variety of highly functionalized pyrrolidines were obtained in excellent yield and enatioselectivity. This is the first example of a pair of P-stereogenic ligands working as pseudoenantiomers to tune the enantio- and diastereoselective 1,3-dipolar cycloaddition, and providing a pair of enantiomerically pure pyrrolidines, respectively.