Asymmetric Allylic Alkylation Research Articles

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.

COAP/Pd-catalyzed asymmetric linear allylic alkylation for synthesizing chiral 3,3′-disubstituted oxindoles bearing all-carbon quaternary stereocenters and primary allylic alcohol structures

A linear asymmetric allylic alkylation of vinyloxirane catalyzed by a chiral oxalamide–phosphine (COAP)/Pd(0) complex was reported. Various chiral 3,3′-oxindole derivatives were achieved in good yields with excellent regio- and enantioselectivity.

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.

Total synthesis of dissectol A, using an enediolate-based Tsuji-Trost reaction.

Dissectol A is a rearranged terpene glycoside isolated from several flowering plants. Starting from glucose, the densely functionalized bicyclic structure has been prepared via site-selective oxidation and an intramolecular allylic alkylation reaction with an enediolate as the nucleophile. Despite earlier reports, dissectol A is not effective at inhibiting DevRS signaling in whole-cell Mycobacterium tuberculosis and does not inhibit growth of the bacterium.

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

Dispersion Interactions in Asymmetric Induction for Constructing Vicinal Stereogenic Centers.

ConspectusVicinal stereogenic centers are prevalent structural motifs of primary functional relevance in natural products and bioactive molecules. The quest for the rapid and controllable construction of vicinal stereogenic centers stands as a frontier endeavor in asymmetric organic synthesis. Over the past decade, stereodivergent synthesis has been intensely researched within the realm of bimetallic catalysis, aiming at establishing novel transition-metal dual-catalytic reactions that efficiently generate all stereochemical combinations of multichiral molecules from identical starting materials, thus offering new opportunities toward rapid complexity building and diversity-oriented chiral compound library generation. In this Account, we summarize our recent advancements in computational investigations of stereodivergent asymmetric allylic alkylation, an important reaction class heavily studied for the purpose of constructing vicinal stereogenic centers. Our discussions focus on synergistic bimetallic catalysis for the syntheses of α,α-disubstituted α-amino acids and cascade allylation/cyclization toward enantiomerically enriched indole-containing heterocycles. We describe our series of studies that converge in establishing the molecular mechanism of asymmetric induction for chiral copper-azomethine ylide, a nucleophile that holds widespread utility and is characterized by a distinctive, sterically biased surrounding enveloping the prochiral center. Notably, our studies revealed that attacks at the prochiral site by allylmetal species are significantly favored by dispersion attraction from one face (-PPh2) but blocked by steric repulsion and associated structural distortions on the opposite face (oxazoline), therefore building up a multimodal and highly robust face-selective stereoinduction. We showcase how a suite of systematic computational analyses generates precise atomistic insights into a number of systems of relevance. We also discuss how the same methodologies can be applied to chiral intermediates with shared interaction patterns, including the rhodium-Josiphos catalyst in asymmetric hydrogenation to create two continuous stereocenters. In the selectivity-controlling migratory insertion step, our computational models unveiled that the reaction is favored by ligand-substrate dispersion attraction on the -PPh2 side and hindered by steric repulsion on the opposite -PtBu2 side. These noncovalent interactions along with the distal ligand-auxiliary structural distortions enable strictly oriented three-dimensional stereoinduction. Our analysis of ligand-substrate dispersion interactions and steric effects in competing pathways highlights certain interaction-level similarities between PHOX-type and Josiphos-type ligands in asymmetric induction. In summary, this Account underscores the foundational significance and broad applicability of nonbonded dispersion interactions in asymmetric inductions for the construction of vicinal stereogenic centers. We envisage that the computational methodologies employed in these studies will shift toward a paradigm of interaction-based rational molecular and reaction design.

Enantioselective Rh(I)-Catalyzed C-H Arylation of Ferroceneformaldehydes.

As an important class of platform molecules, planar chiral ferrocene carbonyl compounds could be transformed into various functional groups offering facile synthesis of chiral ligands and catalysts. However, developing efficient and straightforward methods for accessing enantiopure planar chiral ferrocene carbonyl compounds, especially ferroceneformaldehydes, remains highly challenging. Herein, we report a rhodium(I)/phosphoramidite-catalyzed enantioselective C-H bond arylation of ferroceneformaldehydes. Readily available aryl halides such as aryl iodides, aryl bromides, and even aryl chlorides are suitable coupling partners in this transformation, leading to a series of planar chiral ferroceneformaldehydes in good yields and excellent enantioselectivity (up to 83% yield and >99% ee). The aldehyde group could be transformed into diverse functional groups smoothly, and enantiopure Ugi's amine and PPFA analogues could be synthesized efficiently. The latter was found to be a highly efficient ligand in Pd-catalyzed asymmetric allylic alkylation reactions. Mechanistic experiments supported the formation of imine intermediates as the key step during the reaction.

Palladium‐Catalyzed Asymmetric Trifluoromethylated Allylic Alkylation of N‐Substituted Glycine Ethyl Esters with α‐(Trifluoromethyl)alkenyl Acetates

AbstractAn efficient strategy for asymmetric trifluoromethylated allylic alkylation of easily available N‐substituted glycine ethyl esters with α‐(trifluoromethyl)alkenyl acetates has been developed. Catalyzed by a [Pd(C3H5)Cl]2/(R)‐BINAP, various trifluoromethyl‐containing N‐substituted glycine ethyl ester derivatives are afforded with good yields and excellent enantioselectivities. The product can be readily converted into diverse fluoro‐substituted species, which shows the practicability of this method.

Axially Chiral N,N-Ligand-Promoted Pd-Catalyzed Enantioselective Allylic Amination and Alkylation.

An axially chiral N,N-ligand developed from a [1,1'-binaphthalene]-2,2'-diol (BINOL)-based skeleton and phenanthroline is found to be capable of promoting Pd-catalyzed asymmetric allylic amination and alkylation of allyl acetates. The reaction is compatible with cyclic and acyclic secondary amines, primary aliphatic amines, malononitrile, and dialkyl malonates, affording the corresponding chiral products in up to 99% yield and with up to >99% enantiomeric excess.

Amino-Acid-Derived Amides as Stereodirecting Leaving Groups for Ferrier Rearrangement via Pd(0)-Catalyzed Tsuji-Trost Reactions.

Ferrier rearrangement on glycals is an efficient tool to form 2,3-dideoxy glycosides that provide access to various sugar derivatives through olefin functionalization. The classical acid-mediated transformation delivers the α-O-glycosides selectively. In this protocol, amides obtained from amino acids, glycine and proline, have been utilized as sustainable β-directing leaving groups on glycal substrates. The directing groups facilitate β-selective Ferrier rearrangements for hard alcohol nucleophiles by following the Pd(0)-catalyzed Tsuji-Trost inner sphere pathway.

COAP-Pd Catalyzed Asymmetric Allylic Alkylation of Azlactones with MBH Carbonates: Access to Unnatural α-Quaternary Stereogenic Glutamic Acid Derivatives.

A palladium-catalyzed regioselective and asymmetric allylic alkylation of azlactones with MBH carbonates has been developed with chiral oxalamide-phosphine ligands. The corresponding reaction afforded a range of optically active γ-arylidenyl glutamic acid derivatives bearing an α-chiral quaternary stereocenter in good yields with excellent linear regio- and high enantioselectivity. This protocol furnishes an alternative approach for the construction of enantio-enriched unnatural α-amino acid derivatives.

Ir‐Catalyzed Enantioselective Synthesis of gem‐Diborylalkenes Enabled by 1,2‐Boron Shift

AbstractAsymmetric cross‐couplings based on 1,2‐carbon migration from B‐ate complexes have been developed efficiently to access valuable organoboronates. However, enantioselective reactions triggered by 1,2‐boron shift have remained to be unaddressed synthetic challenge. Here, Ir‐catalyzed asymmetric allylic alkylation enabled by 1,2‐boron shift was developed. In this reaction, we disclosed that excellent enantioselectivities were achieved through an interesting dynamic kinetic resolution (DKR) process of allylic carbonates at the elevated temperature. Notably, the highly valuable (bis‐boryl)alkenes have enabled an array of diversifications to access versatile molecules. Extensive experimental and computational studies were conducted to elucidate the reaction mechanism of DKR process and clarify the origin of excellent enantioselectivities.