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 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.

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.

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.

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.

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 intramolecular Rauhut-Currier reaction: enantioselective synthesis of hydro-2H-indole derivatives.

A highly enantioselective intramolecular Rauhut-Currier reaction catalyzed by a multifunctional chiral aminophosphine catalyst was reported. A series of hydro-2H-indole derivatives that bear an all-carbon quaternary center were obtained in high yields (up to 94%), and excellent diastereo- and enantioselectivities (up to >20 : 1 dr and >99% ee). And this reaction could be performed on a gram scale using 2 mol% catalyst loading.

Bifunctional-Phosphine-Catalyzed Sequential Annulations of Allenoates and Ketimines: Construction of Functionalized Poly-heterocycle Rings.

A highly stereoselective sequential annulation reaction between γ-substituted allenoates and ketimines was reported. By using bifunctional N-acyl aminophosphine catalysts, poly-heterocycle rings were obtained with high stereocontrol in good to excellent yields. The desired products have four contiguous stereogenic centers (one quaternary and three tertiary carbon centers), and only one isomer was obtained in all reactions.

Highly enantioselective intermolecular cross Rauhut-Currier reaction catalyzed by a multifunctional Lewis base catalyst.

The highly enantioselective intermolecular cross Rauhut-Currier reaction of different active olefins catalyzed by a multifunctional chiral Lewis base was reported. The RC products were obtained in excellent yields (up to 98 %), high chemo- and enantioselectivity (up to 96 % ee). The reaction could be performed on a gram scale using 1 mol % of the multifunctional phosphine catalyst.

Phosphine-catalyzed domino reactions: a route to functionalized bicyclic skeletons.

A novel strategy that involves phosphine-catalyzed sequential [2+3] and [3+2] annulation reactions was developed. In this domino reaction, γ-substituted allenoates were used as novel C4 synthons, and the bicyclic cyclopenta[b]dihydrofuran derivatives were produced in good to excellent diastereoselectivities and yields under mild conditions. Furthermore, preliminary studies on an asymmetric variant of this reaction proceeded with moderate enantioselectivity.

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.

Symptom clusters and unplanned hospital readmission in Chinese patients with acute myocardial infarction on admission.

Backgroud: Acute myocardial infarction (AMI) has a high morbidity rate, high mortality rate, high readmission rate, high health care costs, and a high symptomatic, psychological, and economic burden on patients. Patients with AMI usually present with multiple symptoms simultaneously, which are manifested as symptom clusters. Symptom clusters have a profound impact on the quality of survival and clinical outcomes of AMI patients. Objective: The purpose of this study was to analyze unplanned hospital readmissions among cluster groups within a 1-year follow-up period, as well as to identify clusters of acute symptoms and the characteristics associated with them that appeared in patients with AMI. Methods: Between October 2021 and October 2022, 261 AMI patients in China were individually questioned for symptoms using a structured questionnaire. Mplus 8.3 software was used to conduct latent class analysis in order to find symptom clusters. Univariate analysis is used to examine characteristics associated with each cluster, and multinomial logistic regression is used to analyze a cluster membership as an independent predictor of hospital readmission after 1-year. Results: Three unique clusters were found among the 11 acute symptoms: the typical chest symptom cluster (64.4%), the multiple symptom cluster (29.5%), and the atypical symptom cluster (6.1%). The cluster of atypical symptoms was more likely to have anemia and the worse values of Killip class compared with other clusters. The results of multiple logistic regression indicated that, in comparison to the typical chest cluster, the atypical symptom cluster substantially predicted a greater probability of 1-year hospital readmission (odd ratio 8.303, 95% confidence interval 2.550-27.031, P < 0.001). Conclusion: Out of the 11 acute symptoms, we have found three clusters: the typical chest symptom, multiple symptom, and atypical symptom clusters. Compared to patients in the other two clusters, those in the atypical symptom cluster-which included anemia and a large percentage of Killip class patients-had worse clinical indicators at hospital readmission during the duration of the 1-year follow-up. Both anemia and high Killip classification suggest that the patient's clinical presentation is poor and therefore the prognosis is worse. Intensive treatment should be considered for anemia and high level of Killip class patients with atypical presentation. Clinicians should focus on patients with atypical symptom clusters, enhance early recognition of symptoms, and develop targeted symptom management strategies to alleviate their discomfort in order to improve symptomatic outcomes.

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.

Phosphine-catalyzed domino reaction: an efficient method for the synthesis of highly functionalized spirooxazolines.

A novel phosphine-catalyzed intermolecular [3 + 2] cycloaddition of ynones and N-substituted isatins was developed. In this reaction, substituted ynones, serving as a C(3) synthon, were successfully applied in intermolecular annulation reactions. A number of functionalized spirooxazolines were obtained in high yields and stereoselectivity.

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.

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.

Domino reaction for the chemo- and stereoselective synthesis of trans-2,3-dihydrobenzofurans from N-thiophosphinyl imines and sulfur ylides.

A novel domino annulation between sulfur ylides and salicyl N-thiophosphinyl imines was developed. The method allows the synthesis of a highly substituted trans-2,3-dihydrobenzofuran skeleton with high yield and excellent chemo- and stereoselectivity.

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.

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.

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.