Asymmetric Allylic Alkylation Research Articles

Enantioselective Synthesis of Sterically Hindered α‐Allyl‐α‐Aryl Lactams via Palladium‐Catalysed Decarboxylative Asymmetric Allylic Alkylation

AbstractThe Pd‐catalysed decarboxylative asymmetric allylic alkylation (DAAA) of sterically hindered α‐aryl,β‐amido allyl ester lactams has been developed. The key step in the synthesis of a range of α‐aryl lactam substrates for catalysis was a Pb‐mediated α‐arylation of a β‐amido allyl ester affording 14 novel examples of α‐aryl‐β‐amido allyl ester lactams in good yields (up to 80 %). The Pd‐catalysed DAAA was optimised with the 2,4,6‐trimethoxyphenyl‐containing substrate. Using (S,S)‐DACH‐phenyl Trost as the optimal chiral ligand, enantioselectivities of up to 82 % ee were obtained. A substrate scope of 11 examples of α‐aryl‐β‐amido allyl ester lactams showed that products containing the di‐ortho‐methoxy‐substituted phenyls and naphthyl groups gave rise to the highest ees, whereas products not bearing this substitution pattern showed lower enantioselectivities (<60 % ee). Transition states to rationalise the observed stereochemical outcome are proposed.

Asymmetric Synthesis of Quaternary α-Aryl Stereocentres in Benzofuran-3(2H)-ones using Decarboxylative Asymmetric Allylic Alkylation.

The Pd-catalysed decarboxylative asymmetric allylic alkylation (DAAA) has been applied to the enantioselective synthesis of sterically hindered benzofuran-3(2H)-one-derived α-aryl-β-keto esters employing the (R,R)-ANDEN phenyl Trost ligand. A range of substrates were synthesised, employing previously developed aryllead triacetate methodology to install various aryl groups. The resulting α-aryl-α-allyl benzofuran-3(2H)-one DAAA products were obtained in moderate to high yields and in enantioselectivities of up to 96% ee, with the best results observed for substrates containing a di-ortho-substitution pattern on the aryl ring as well as naphthyl-containing substrates.

Asymmetric Additions Empowered by OrganoCatalysts, Metal Catalysts, and Deep Natural Eutectic Solvents (NADES).

This article is a history of an industrial-academic partnership that started almost two decades ago and details the evolution of a relationship between a small academic research group and a spin-out company located in Portugal. Their activities have ranged from the development of new metal-based catalytic systems for asymmetric epoxidations, allylic alkylations, and arylations to the development of novel cinchona-based organocatalysts for asymmetric hydrosilylations and Michael additions. Current common interests are centered on the development of novel chiral Natural Deep Eutectic Solvent systems, which they are investigating in different types of reaction systems.

Enantioselective Synthesis of α-Chiral Bicyclo[1.1.1]pentanes via Multicomponent Asymmetric Allylic Alkylation.

Bicyclo[1.1.1]pentanes (BCPs) have emerged as important structural motifs in drug design. However, asymmetric transformations that provide chiral BCPs bearing an adjacent stereocenter are still scarce. Here, we report a catalytic methodology for the enantioselective synthesis of α-chiral 1,3-difunctionalized BCPs from a three-component coupling of [1.1.1]propellane, a Grignard reagent, and an allylic phosphate. The reaction proceeds via the addition of the Grignard reagent to [1.1.1]propellane followed by an asymmetric N-heterocyclic carbene (NHC)-catalyzed allylic substitution of the resulting BCP-Grignard, providing a broad range of α-chiral BCPs with excellent levels of regioselectivity and enantioselectivity.

Dual-Catalysis-Enabled Construction of Vicinal Stereogenic Centers through Diastereo- and Enantioselective Allylic Substitution

AbstractVicinal stereogenic centers represent prevalent structural motifs in organic synthetic chemistry, and their construction poses a longstanding challenge. Transition-metal-catalyzed asymmetric allylic substitution has become a well-established enantioselective C–C bond-forming reaction. When these reactions involve a prochiral nucleophile and an allylic electrophile with a terminal substituent, the creation of vicinal stereogenic centers becomes feasible. However, despite remarkable achievements having been accomplished, realizing this transformation with precise control over both the enantio- and diastereoselectivity remains a significant challenge. To address the stereoselective challenges, the introduction of a second catalyst to the transition-metal-catalyzed asymmetric allylic alkylation to control the diastereoselectivity during C–C bond formation has proven particularly fruitful. In this short review, we aim to highlight recent advances in dual catalysis that enable diastereo- and enantioselective allylic substitutions.1 Introduction2 Construction of Vicinal Stereogenic Centers by Organo and Metal Dual Catalysis2.1 Chiral Phase-Transfer Catalysis and Transition-Metal Dual Catalysis2.2 Chiral Amine and Transition-Metal Dual Catalysis2.3 NHC and Transition-Metal Dual Catalysis2.4 Chiral Aldehyde and Transition-Metal Dual Catalysis2.5 Chiral Lewis Base and Transition-Metal Dual Catalysis3 Construction of Vicinal Stereogenic Centers by Metal and Metal Dual Catalysis3.1 Lewis Acidic Metal and Iridium Dual Catalysis3.2 Lewis Acidic Metal and Palladium Dual Catalysis3.3 Palladium and Ruthenium Dual Catalysis3.4 Other Advancements in the Construction of Vicinal Stereogenic Centers through Synergistic Bimetallic Catalysis Enabling Asymmetric Allylic Alkylation4 Conclusions and Future Outlook

Asymmetric Total Synthesis of (+)-Verrubenzospirolactone and (+)-Capillobenzopyranol.

The first asymmetric total synthesis of (+)-verrubenzospirolactone (1), a distinctive highly fused benzosesquiterpenoid, characterized by a pentacyclic skeletal structure, is realized through a concise 10-step synthetic pathway with an impressive 22.8% overall yield. Notable highlights of this synthetic endeavor include (i) the introduction of a Ru-catalyzed ortho C-H activation step, (ii) the application of Pd-catalyzed asymmetric allylic alkylation to establish a pivotal stereocenter at C-3 with an excellent enantiomeric excess, (iii) B-alkyl Suzuki-Miyaura coupling to construct a Diels-Alder precursor, and, ultimately, (iv) the successful deployment of an intramolecular Diels-Alder reaction to complete the synthesis of (+)-verrubenzospirolactone without erosion of the enantiomeric excess.

A Review on the Development of Polymer Supported Heterogeneous Palladium Materials for Organic Synthesis and Electrochemical Applications

Abstract:: This comprehensive review explores the advancements in catalytic transformation, focusing on the use of heterogeneous catalytic systems with a particular emphasis on polymeric-supported palladium (Pd) complexes. This study explores the limitations associated with conventional homogeneous reagents, emphasizes the transition to eco-friendly catalytic systems, and emphasizes the importance of Pd nanoparticles. These nanoparticles are particularly noteworthy for their distinctive properties, including elevated catalytic activity, making them promising for various applications in organic synthesis. The review thoroughly examines the design and synthesis of heterogeneous catalysts, emphasizing the crucial selection of safe and recyclable supports to augment the longevity and reusability of metallic catalysts. Diverse polymer varieties, including polystyrene (PS), polyethylene (PE), polyacrylate derivatives, polyethylene glycol (PEG), and grafted polymers, are investigated as viable supports for Pd complexes. The authors intricately describe the synthesis techniques for these polymer-supported Pd catalysts and furnish illustrative examples showcasing their effectiveness in organic transformation. This comprehensive review additionally highlights the synthesis of polymer-supported palladium (Pd) materials and discusses their applications in electrochemistry. The focus extends to the electrocatalytic properties of Pdbased polymeric nanomaterials, showcasing their effectiveness in glucose sensing, hydrogen peroxide detection, and the sensing of other biological analytes. Furthermore, the catalytic capabilities of Pd nanoparticles in various electrochemical applications, including wastewater treatment and electrochemical capacitors, are explored. Integrating polymer-supported Pd materials into these electrochemical processes underscores their versatility and potential contributions to advancements in catalysis and electrochemical sensing. Catalytic applications featuring polymer-supported palladium complexes with polymeric ligands in organic synthesis processes use the Sonogashira reaction, Suzuki-Miyaura coupling, Heck reaction, Catalytic asymmetric transformations, etc. The subsequent section of the paper focuses on the creation of polymeric palladium complexes, achieved by the complexation of polymeric ligands with palladium precursors. It delves into noteworthy examples of catalytic processes employing polymer-supported palladium complexes featuring polymeric ligands, emphasizing distinct polymers, such as PS, PE, polyacrylate derivatives, PEG, and grafting polymers. The review concludes by exploring catalytic asymmetric transformations using chiral palladium complexes immobilized on polymer supports and discusses various chiral ligands and their immobilization on polymer supports, emphasizing their application in asymmetric allylic alkylation. The review furnishes a comprehensive summary of recent advancements, challenges, and prospective avenues in catalytic oxidation facilitated by polymer- supported palladium catalysts with electrochemical applications.

Chiral Phosphine Ligands of COAP and SKP Switched Regiodivergent Asymmetric Allylic Alkylation of MBH Adducts.

The palladium-catalyzed highly regioselective asymmetric allylic alkylation of 3'-indolyl-3-oxindole derivatives with Morita-Baylis-Hillman (MBH) carbonates was developed to facilely construct chiral 3,3'-bisindole derivatives under mild reaction conditions. The regioselectivity (α/γ) of MBH carbonates was efficiently switched in the presence of chiral oxalamide phosphine or spiroketal-based diphosphine/Pd(0) complexes as a chiral catalyst. A series of multifunctional 3,3'-bisindole derivatives with all-carbon quaternary stereogenic centers were obtained in high yields with good to excellent enantio-, diastereo-, and regioselectivity. The present process is endowed with some salient features such as broad substrate scope, N-protecting group-free, excellent stereoselectivity, as well as adjustable regioselectivity.

The Catalytic Asymmetric Allylic Alkylation of Acyclic Enolates for the Construction of Quaternary and Tetrasubstituted Stereogenic Centres.

To facilitate the discovery and development of new pharmaceuticals, the demand for novel stereofunctionalised building blocks has never been greater. Whilst molecules bearing quaternary and tetrasubstituted stereogenic centres are ideally suited to explore untapped areas of chemical space, the asymmetric construction ofsterically congested carbon centres remains a longstanding challenge in organic synthesis. The enantioselective assembly of acyclic stereogenic centres is even more demanding due to the need to restrict a much wider range of geometries and conformations of the intermediates involved. In this context, the catalytic asymmetric allylicalkylation (AAA) of acyclic prochiral nucleophiles, namely enolates, has become an indispensable tool to access a range of linearα-quaternary andα-tetrasubstituted carbonyl compounds. However, unlike the AAA of cyclic enolates with a fixed enolate geometry, to achieve high levels of stereocontrol in the AAA of acyclic enolates, the stereoselectivity of enolisation must be considered. The aim of this review is to offer acomprehensivediscussion of catalytic AAA reactions of acyclic prochiral enolates and their analogues to generate congested quaternary and tetrasubstituted chiral centres using metal, non-metal and dual catalysis, with particular focus given to the control of enolate geometry and its impact on the stereochemical outcome of the reaction.

Asymmetric Construction of Carbon-Fluorine Quaternary Stereogenic Centers via Synergistic Pd/Cu Catalysis.

We developed an asymmetric decarboxylative allylic alkylation of vinylethylene carbonates with α-fluoro pyridinyl acetates through a synergistic palladium/copper catalysis. This protocol provides chiral allylic alcohol with carbon-fluorine quaternary stereogenic centers in good yield with good enantioselectivities and excellent regioselectivities. The utility of this approach was further demonstrated via a gram-scale experiment and derivatizations of the product.

Enantioselective Ir-Catalyzed Allyl Alkylation/Semipinacol Rearrangement.

The semipinacol rearrangement is a powerful and versatile method for constructing all-carbon quaternary stereocenters. The development of catalytic asymmetric semipinacol rearrangements using multifunctionalizable electrophiles remains highly sought-after in organic synthesis. In this study, a catalytic enantioselective allylic cation-induced semipinacol rearrangement reaction was presented that enables the simultaneous construction of two skipped chiral carbon centers. Chiral Ir(I)-(P,olefin) and Sc(OTf)3 catalysts cooperatively initiate the asymmetric allylic alkylation of alkenyl cyclobutanols with allylic alcohols, triggering ring expansion of the cyclobutanol moiety through a stereoselective 1,2-alkyl migration. The reaction afforded a range of cyclopentanones bearing an α-quaternary carbon that is adjacent to a chiral allyl scaffold. The products were applied to synthesize enantioenriched fused tricyclopentanoids bearing four stereogenic carbon centers.

Catalytic Decarboxylative Asymmetric Allylic Alkylation for the Synthesis of Axially Chiral Biaryls

AbstractHerein, we report a palladium‐catalyzed atroposelective decarboxylative asymmetric allylic alkylation. A chiral palladium complex with a phosphoramidite ligand effectively desymmetrizes biaryls containing cinnamyl carbonate with excellent enantioselectivities. The addition of a catalytic amount of base accelerates the reaction process without loss of enantioselectivity. Cross‐over experiment provides mechanistic insight, suggesting that allyl palladium complex primarily dissociates from the original biaryl substrate and deliver allyl species intermolecularly. Analysis of product distribution at various time points indicates that secondary kinetic resolution plays a crucial role in achieving remarkable atroposelectivity.

Tsuji-Trost Based Cascades: From Passerini Adducts of Cinnamaldehyde to Allylated Oxazolones.

The Passerini coupling of cinnamaldehyde derivatives affords allylic esters that may behave as both electrophiles and nucleophiles in Tsuji-Trost reactions. We present herein the interaction of the latter with methylallylcarbonate, leading to the formation of oxazolidine-diones. The efficiency of the process relies on the building up of a CO2 overpressure in the medium. A reaction mechanism highlighting the reversibility of the Tsuji-Trost reaction is proposed for the process.

Pd-Catalysed asymmetric allylic alkylation of heterocycles: a user's guide.

This review provides an in-depth analysis of recent advances and strategies employed in the Pd-catalysed asymmetric allylic alkylation (Pd-AAA) of nucleophilic prochiral heterocycles. The review is divided into sections each focused on a specific family of heterocycle, where optimisation data and reaction scope have been carefully analysed in order to bring forward specific reactivity and selectivity trends. The review eventually opens on how computer-based technologies could be used to predict an ideally matched catalytic system for any given substrate. This user-guide targets chemists from all horizons interested in running a Pd-AAA reaction for the preparation of highly enantioenriched heterocyclic compounds.

An integrative sustainability assessment of the Tsuji–Trost reaction simulating allylic amination under non-conventional (vs. conventional) conditions

The article describes sustainability aspects of the Tsuji-Trost reaction in terms of productivity (reactivity-coupled utility), side reaction assessment, and environmental impact of allylic precursors.

Application of sSPhos as a Chiral Ligand for Palladium-Catalyzed Asymmetric Allylic Alkylation.

Palladium-catalyzed asymmetric allylic alkylation is a versatile method for C-C bond formation. Many established classes of chiral ligands can perform allylic alkylation reactions enantioselectively, but identification of new ligand classes remains important for future development of the field. We demonstrate that enantiopure sSPhos, a bifunctional chiral monophosphine ligand, when used as its tetrabutyl ammonium salt, is a highly effective ligand for a benchmark Pd-catalyzed allylic alkylation reaction. We explore the scope and limitations and perform experiments to probe the origin of selectivity. In contrast with reactions previously explored using enantiopure sSPhos, it appears that steric bulk around the sulfonate group is responsible for the high enantioselectivity in this case, rather than attractive noncovalent interactions.

Catalytic stereodivergent allylic alkylation of 2-acylimidazoles for natural product synthesis

The stereocontrolled allylic alkylation of carbonyl compounds with the goal of producing the full range of stereoisomers presents an effective approach for increasing the productivity of collective natural product synthesis and the creation of chiral molecule libraries for drug exploration. The simultaneous control of regio-, diastereo-, and enantioselectivity poses a significant synthetic challenge in contemporary organic synthesis. Herein, we describe a catalytic stereodivergent α-allylation protocol applicable to both aliphatic and aromatic 2-acylimidazoles, thereby providing a practical blueprint for the divergent synthesis of important chiral building blocks. Each of the six isomeric α-allylated compounds can be readily obtained with remarkable yields and exceptional stereoselectivities, by judiciously selecting the appropriate leaving group and permutations of enantiomers adapted from nickel and iridium catalysts. The versatility of this asymmetric allylic alkylation has been successfully utilized in the enantioselective synthesis of (R)-arundic acid and (S,S)-cinamomumolide, as well as in the stereodivergent total synthesis of tapentadol.

Off-label use of molecular glue: 3-hydroxythalidomide derived fluorescent probe for selective detection of palladium based on Tsuji-Trost reaction

3-Hydroxythalidomide draws more and more attentions as a molecular glue in the field of biomedicine and analysis, due to its unique bonding mode to CRBN protein and the novel fluorescent properties. However, there is rare reports about the application in the field of chemosensor. Herein, we designed and synthesized a fluorescence turn-on probe using 3-hydroxythalidomide as a fluorophore for the detection of palladium based on Tsuji-Trost reaction. The mechanism of the chemosensor for palladium and the effects of the phosphine ligands were investigated systematically. The results indicated that the probe displayed an excellent linear relationship with palladium concentration (region factor, R2 = 0.998) over the range of 1 × 10−7 M − 4 × 10−6 M, presenting a low detection limit of 1.2 nM. Furthermore, it was successfully applied to the determination of palladium in the samples of pharmaceutical wastewater and spiked water with different oxidation states.

Chiral, air stable, and reliable Pd(0) precatalysts applicable to asymmetric allylic alkylation chemistry

Stereoselective carbon-carbon bond formation via palladium-catalyzed asymmetric allylic alkylation is a crucial strategy to access chiral natural products and active pharmaceutical ingredients. However, catalysts based on the privileged Trost and Pfaltz-Helmchen-Williams PHOX ligands often require high loadings, specific preactivation protocols, and excess chiral ligand. This makes these reactions uneconomical, often unreproducible, and thus unsustainable. Here we report several chiral single-component Pd(0) precatalysts that are active and practically-applicable in a variety of asymmetric allylic alkylation reactions. Despite the decades-long history and widespread use of Trost-type ligands, the precatalysts in this work are the only reported examples of stable, isolable Pd(0) complexes with these ligands. Evaluating these precatalysts across nine asymmetric allylic alkylation reactions reveals high reactivity and selectivity at low Pd loading. Importantly, we also report an unprecedented Pd-catalyzed enantioselective allylation of a hydantoin, achieved on gram scale in high yield and enantioselectivity with only 0.2 mol% catalyst.

Regioselective and asymmetric allylic alkylation of vinyl epoxides for the construction of allylic alcohols via synergistic catalysis

Regioselective and asymmetric allylic alkylation of vinyl epoxides for the construction of allylic alcohols via synergistic catalysis