Asymmetric Allylic Alkylation Research Articles

Copper-catalyzed asymmetric allylic alkylation of racemic inert cyclic allylic ethers under batch and flow conditions.

Highly enantioselective Cu-catalyzed asymmetric allylic alkylation of racemic inert cyclic allylic ethers is accomplished in this work. The use of Grignard reagents in combination with BF3·OEt2 and CuBr·SMe2/L2 is the key to enable employment of long-challenging low reactive allylic substrates in this AAA reaction. In addition, the approach exhibited a remarkable superiority in the construction of a stereogenic center involving challenging sterically hindered nucleophiles for both primary and secondary alkyl groups. Extension of this method under continuous flow conditions was also performed with excellent enantioselectivity in a short residence time. Mechanistic experiments indicated that the reaction proceeded through an in situ generated allylic bromide intermediate. All these advantages demonstrated that this chiral catalytic system is a valuable complement for existing asymmetric catalytic methods.

A sensitive ratiometric fluorescence probe with a large spectral shift for sensing and imaging of palladium.

Palladium (Pd) is an important heavy metal with excellent catalytic properties and widely used in organic chemistry and the pharmaceutical industry. Efficient and convenient analytical techniques for Pd are urgently needed due to the hazardous effects of Pd on the environment and human health. Herein, we have developed five new ratiometric probes for the selective detection of Pd0 based on the Pd-catalyzed Tsuji-Trost reaction. Among them, the F-substituted probe PF-Pd showed the largest spectral shift (148 nm) and the most sensitive response (detection limit 2.11 nM). PF-Pd was employed to determine Pd0 in tap water or lake water samples, which presented satisfactory accuracy and precision. In addition, profiting from its distinct colorimetric response, visual detection of Pd0 was performed on PF-Pd loaded test strips or in field soil samples. Furthermore, fluorescence imaging of living 4T1 cells demonstrated that PF-Pd is suitable for imaging of intracellular Pd0. The good analytical performance of PF-Pd may enable it to be widely used in the convenient, rapid, sensitive and selective detection of Pd0 in environmental or biological analysis.

The emergence and advancement of Tsuji-Trost reaction triggered carbon monoxide recognition and bioimaging.

Considering that carbon monoxide is both a vital gasotransmitter and an obnoxious gas, tremendous efforts have been dedicated toward its recognition through various methods. However, the fluorescent light-up approach through the exploration of optical markers remains one of the most convenient methods owing to its several advantages. Amongst the different approaches towards the development of CO responsive optically active molecular markers, the Tsuji-Trost reaction-based CO recognition strategy has remained one of the most significant areas of interest across researchers working in this field. However, there have been no attempts to exclusively summarize the commendable work done in this area yet. The current review, therefore, attempts to summarize the developments of various optical probes following this reaction strategy until the year 2022. This review provides detailed mechanistic insights into the Tsuji-Trost mediated CO detection strategy. Besides, discussions on the strategic development and employment of probes based on various allyl derivatives - allyl carbamate/carbonate/ethers - will provide a thorough understanding of the detection method. The significant advancements of the Tsuji-Trost reaction as an interesting strategy that is accepted and extensively explored for monitoring CO in various media including air, aqueous solutions and living systems have been elaborately discussed. Various potential applications and utilization of these developed fluorogenic probes for tracing CO in different living systems have been examined systematically. Moreover, monitoring of exogenous/endogenous CO levels, modulation of intracellular CO concentration under various induced conditions and bioimaging of CO in in vivo models have also been detailed here. Briefly, this review summarizes the current prospects of this detection method and the future directions in related fields.

COAP/Pd-Catalyzed Linear Asymmetric Allylic Alkylation for Optically Active 3,3-Disubstituted Oxindole Derivatives with a Four-Carbon Amino Side Chain

An asymmetric linear selective allylic alkylation of vinylaziridines with 3-aryl oxindoles has been developed by using a chiral oxamide-phosphine (COAP-Bn-OMe-p)/palladium complex in methanol, which furnished a wide variety of 3,3-disubstituted oxindole derivatives in good yields with excellent regio- and enantioselectivities.

Decarboxylative Asymmetric Allylic Alkylation for the Synthesis of α‑Difunctionalized Cyclic Sulfones

Decarboxylative Asymmetric Allylic Alkylation for the Synthesis of α‑Difunctionalized Cyclic Sulfones

P,S-Bidentate Phosphoramidites with (Ra)-BINOL Core in Palladium-Catalyzed Asymmetric Allylic Substitution

New P,S-bidentate phosphoramidite ligands, including these having a stereogenic phosphorus atom in the 1,3,2-dioxaphosphepine ring, have been synthesized on the basis of (Ra)-BINOL and its adamantanyl derivatives. With their participation in the Pd-catalyzed asymmetric allylic alkylation of (E)-1,3-diphenylallyl acetate with dimethyl malonate and the amination with pyrrolidine involving these ligands have afforded selectivity up to 84 and 75% ee, respectively.

Regio- and Enantioselective Synthesis of Dihydropyrido[1,2-a]indoles via Catalytic Asymmetric Annulative Allylic Alkylation.

A palladium-catalyzed asymmetric annulative allylic alkylation reaction of 2-[(1H-indol-2-yl)methyl]malonates with (E)-but-2-ene-1,4-diyl dicarbonates is described, leading to the regio- and enantioselective synthesis of dihydropyrido[1,2-a]indoles with a chiral cyclic allyl stereocenter adjacent to the ring-junction nitrogen atom in moderate to good yields. The salient features of this protocol include mild conditions, a broad substrate scope, and good compatibility with substituents as well as high regio- and stereoselectivities, providing a catalytic asymmetric entry for fabricating chiral pyridoindole scaffolds.

Influence of Achiral Phosphine Ligands on a Synergistic Organo- and Palladium-Catalyzed Asymmetric Allylic Alkylation.

An unusual diastereodivergent stereoselective allylation reaction is presented. It consists of a palladium-catalyzed allylation reaction of an organocatalytically generated amino isobenzofulvene, where the diastereoselectivity is controlled by the electronic properties of a monodentate, achiral ligand on palladium. One major diastereoisomer is formed using triarylphosphines substituted with neutral or electron-donating substituents of the aryl group, while those with electron-withdrawing substituents favor the other diastereoisomer. The diastereoselectivity correlates with the Taft inductive parameter of substituents on the triarylphosphine ligand on palladium. The synergistic reaction involves both a catalytic secondary amine catalyst for the indene-aldehyde activation and the monodentate phosphine ligands on palladium, affording a highly enantioselective reaction with up to 98 % enantiomeric excess. Based on computational investigations, the role of the monodentate phosphine ligand on the diastereoselectivity is discussed.

Investigating Oxidative Addition Mechanisms of Allylic Electrophiles with Low-Valent Ni/Co Catalysts Using Electroanalytical and Data Science Techniques.

The catalysis by a π-allyl-Co/Ni complex has drawn significant attention recently due to its distinct reactivity in reductive Co/Ni-catalyzed allylation reactions. Despite significant success in reaction development, the critical oxidative addition mechanism to form the π-allyl-Co/Ni complex remains unclear. Herein, we present a study to investigate this process with four catalysis-relevant complexes: Co(MeBPy)Br2, Co(MePhen)Br2, Ni(MeBPy)Br2, and Ni(MePhen)Br2. Enabled by an electroanalytical platform, Co(I)/Ni(I) species were found responsible for the oxidative addition of allyl acetate. Kinetic features of different substrates were characterized through linear free-energy relationship (Hammett-type) studies, statistical modeling, and a DFT computational study. In this process, a coordination-ionization-type transition state was proposed, sharing a similar feature with Pd(0)-mediated oxidative addition in Tsuji-Trost reactions. Computational and ligand structural analysis studies support this mechanism, which should provide key information for next-generation catalyst development.

Cooperative Catalyst-Enabled Regio- and Stereodivergent Synthesis of α-Quaternary α-Amino Acids via Asymmetric Allylic Alkylation of Aldimine Esters with Racemic Allylic Alcohols.

We describe cooperative bimetallic catalysis that enables regio-/stereodivergent asymmetric α-allylations of aldimine esters. By employing Et3 B as the key activator, racemic allylic alcohols can be directly ionized to form Pd or Ir-π-allyl species in the presence of achiral Pd or chiral Ir complexes, respectively. The less or more substituted allylic termini of the metal-π-allyl species are amenable to nucleophilic attack by the chiral Cu-azomethine ylide, the formation of which is simultaneously facilitated by Et3 B, affording α-quaternary α-amino acids with high regioselectivity and excellent stereoselectivity. The use of readily available allylic alcohols as electrophilic precursors represents an improvement from an environmental and atom/step economy perspective. Computational mechanistic studies reveal the crucial role of the Et3 B additive and the origins of stereo- and regioselectivities by analyzing steric effects, dispersion interactions, and frontier orbital population.

Cooperative Catalyst‐Enabled Regio‐ and Stereodivergent Synthesis of α‐Quaternary α‐Amino Acids via Asymmetric Allylic Alkylation of Aldimine Esters with Racemic Allylic Alcohols

AbstractWe describe cooperative bimetallic catalysis that enables regio‐/stereodivergent asymmetric α‐allylations of aldimine esters. By employing Et3B as the key activator, racemic allylic alcohols can be directly ionized to form Pd or Ir‐π‐allyl species in the presence of achiral Pd or chiral Ir complexes, respectively. The less or more substituted allylic termini of the metal‐π‐allyl species are amenable to nucleophilic attack by the chiral Cu‐azomethine ylide, the formation of which is simultaneously facilitated by Et3B, affording α‐quaternary α‐amino acids with high regioselectivity and excellent stereoselectivity. The use of readily available allylic alcohols as electrophilic precursors represents an improvement from an environmental and atom/step economy perspective. Computational mechanistic studies reveal the crucial role of the Et3B additive and the origins of stereo‐ and regioselectivities by analyzing steric effects, dispersion interactions, and frontier orbital population.

Diastereo- and Enantioselective Metathesis Dimerization/Kinetic Resolution of Racemic Planar-Chiral Vinylferrocenes.

Diastereo- and enantioselective kinetic resolution of racemic planar-chiral 1-R-2-vinylferrocenes (rac-1) was attained by the molybdenum-catalyzed asymmetric metathesis dimerization (AMD). Two sequential AMD reactions of rac-1a (R = Br) provided (E)-(S,S)-1,2-di(2-bromoferrocenyl)ethylene in >99% ee, which was converted to (S,S)-1,2-bis[(2-diphenylphosphino)ferrocenyl]ethane (S,S)-5. Planar-chiral bisphosphine (S,S)-5 coordinated to a dichloropalladium(II) fragment in a trans-chelating fashion, which was applied as a chiral ligand in the palladium-catalyzed asymmetric allylic alkylation showing enantioselectivity of up to 90% ee.

Asymmetric Total Synthesis of Iheyamine B.

Herein, we report the first asymmetric total synthesis of iheyamine B from 2,2'-bisindoloazepinone using the stereoselective construction of the trans-vicinal 2-oxopropyl moiety in the azepine scaffold. The asymmetric decarboxylative allylic alkylation provided the α-allylated 2,2'-bisindoloazepinone intermediate. The subsequent conversion of the lactam moiety into another allyl group in a trans-selective manner followed by Wacker oxidation of each allyl unit to the corresponding 2-oxopropyl group completed the total synthesis of iheyamine B.

Copper‐Catalyzed Asymmetric Allylic Alkylation of Racemic Cyclic Allyl Bromides with Organolithium Compounds

AbstractOrganolithium reagents are one of the most widely used reagents in chemical synthesis. Herein, we reported the first study of organolithium reagents used in asymmetric allylic alkylation (AAA) reactions with racemic cyclic substrates. A simple and efficient Cu‐catalyzed synthesis of enantiomerically enriched cycloalkene derivatives from various racemic cyclic allylic bromides was developed. The standard method employed 5 % CuBr⋅SMe2 in combination with phosphoramidite ligand L2 in DCM. Meanwhile, transfer of the reactions into flow condition for more convenient application was also studied. This new Cu‐catalyzed protocol was speculated to undergo an enantioconvergent transformation mechanism here.

Discrimination of Pd-species by an ultra-fast, long wavelength and biocompatible fluorescent sensor: Its on-site kit assay, drug, and cancer/epithelial cell studies

Extensive use of palladium in many catalysts and catalytic converters causes a high degree of pollution of water and soil resources. Therefore, there is an urgent need to develop rapid and sensitive palladium probes. Herein, a novel “turn-on” near-infrared (NIR) fluorescence and colorimetric probe for Pd has been designed on the basis of the deallylation of the probe, followed by the release of NIR emissive fluorophore through the Tsuji-Trost reaction. The probe can selectively discriminate between the oxidation states of Pd0 and Pd2+. Sensing results demonstrates that the probe has excellent selectivity, sensitivity, fast response time, NIR fluorescence, high biocompatibility, and low detection limit for the Pd detection over a series metal ion. The probe has been successfully applied in visualization of residual Pd content from water, soil, drug and living cell samples by fluorescence observation with the naked eye.

Catalytic Asymmetric Allylic Alkylation with Arylfluoroacetonitriles.

A palladium(phosphinoxazoline) catalyzed method for asymmetric allylic alkylation of α-aryl-α-fluoroacetonitriles is introduced. This reaction achieves C-C bond formation and incorporation of two adjacent chirality centers with moderate to good yields, high enantioselectivities, and up to 15:1 dr.

Hydrogen bond-directed coordination of phosphine-amino-alcohol (P,N,OH) ligands: Stereochemical considerations and catalytic studies

Novel phosphine-aminoalcohol type chiral ligands of the chemical formula Ph2PCH(CH3)CH2CH(CH3)NHCH(R)CH2OH (1a: (R,R)-(S), R = CH3, 1b: (S,S)-(S), R = CH3, 1c: (S,S), R = H) have been synthesized in two simple steps using cyclic sulfates. The coordination behavior of 1a-c having stereochemically labile nitrogen donor to square planar Pd(II) center was investigated by X-ray crystallography, 1D and 2D NMR methods and by DFT calculations. In the solid state of complex [Pd(1a)Cl2] an intramolecular hydrogen bond could be observed between the OH-moiety and one of the Cl co-ligands, while intermolecular hydrogen bonds were detected in the case of [Pd(1b)Cl2] between the same functionalities. In the dichloromethane solution of the complexes the hydrogen bond was identified as a crucial factor in determining ring conformation and nitrogen configuration. Ligand 1a coordinated stereoselectively to the metal in [Pd(1a)Cl2] leading to a complex having a single conformationally rigid six-membered chelate and a configurationally fixed N-donor. In contrast, coordination of ligands 1b-c resulted in the formation of a mixture of isomers with different chelate conformation and nitrogen configuration. The ligands were utilized in Pd-catalyzed asymmetric allylic alkylation where high enantioselectivities (ees up to 96 %) and activities could be obtained.

Reductive Cross-Coupling of Unreactive Electrophiles.

Transition-metal-catalyzed reductive coupling of electrophiles has emerged as a powerful tool for the construction of molecules. While major achievements have been made in the field of cross-couplings between organic halides and pseudohalides, an increasing number of reports demonstrates reactions involving more readily available, low-cost, and stable, but unreactive electrophiles. This account summarizes the recent results in our laboratory focusing on this topic. These findings typically include deoxygenative C-C coupling of alcohols, reductive alkylation of alkenyl acetates, reductive C-Si coupling of chlorosilanes, and reductive C-Ge coupling of chlorogermanes.The reductive deoxygenative coupling of alcohols with electrophiles is synthetically appealing, but the potential of this chemistry remains to be disclosed. Our initial study focused on the reaction of allylic alcohols and aryl bromides by the combination of nickel and Lewis acid catalysis. This method offers a selectivity that is opposite to that of the classic Tsuji-Trost reactions. Further investigation on the reaction of benzylic alcohols led to the foundation of a dynamic kinetic cross-coupling strategy with applications in the nickel-catalyzed reductive arylation of benzylic alcohols and cobalt-catalyzed enantiospecific reductive alkenylation of allylic alcohols. The titanium catalysis was later established to produce carbon radicals directly from unactivated tertiary alcohols via C-OH cleavage. The development of their coupling reactions with carbon fragments delivers new methods for the construction of all-carbon quaternary centers. These reactions have shown high selectivity for the functionalization of tertiary alcohols, leaving primary and secondary alcohols intact. Alkenyl acetates are inexpensive, stable, and environmentally friendly and are considered the most attractive alkenyl reagents. The development of reductive alkylation of alkenyl acetates with benzyl ammoniums and alkyl bromides offers mild approaches for the conversion of ketones into aliphatic alkenes.Extensive studies in this field have enabled us to extend the cross-electrophile coupling from carbon to silicon and germanium chemistry. These reactions harness the ready availability of chlorosilanes and chlorogermanes but suffer from the challenge of their low reactivity toward transition metals. Under reductive nickel catalysis, a broad range of alkenyl and aryl electrophiles couple well with vinyl- and hydrochlorosilanes. The use of alkyl halides as coupling partners led to the formation of functionalized alkylsilanes. The C-Ge coupling seems less substrate-dependent, and various common chlorogermanes couple well with aryl, alkenyl, and alkyl electrophiles. In general, functionalities such as Grignard-sensitive groups (e.g., acid, amide, alcohol, ketone, and ester), acid-sensitive groups (e.g., ketal and THP protection), alkyl fluoride and chloride, aryl bromide, alkyl tosylate and mesylate, silyl ether, and amine are tolerated. These methods provide new access to organosilicon and organogermanium compounds, some of which are challenging to obtain otherwise.

Development of an Enantioselective Allylic Alkylation of Acyclic α-Fluoro-β-ketoesters for Asymmetric Synthesis of 3-Fluoropiperidines.

The first useful enantioselective Pd-catalyzed asymmetric allylic alkylation of α-fluoro-β-ketoesters has been achieved using the Trost family of chiral ligands yielding products in up to 92 % ee. This work provides new insights regarding the typically modest selectivities associated with acyclic α-fluoroenolates and shows experimental evidence that the typically poor levels of enantiocontrol associated with these systems are not necessarily due to the presence of E/Z enolate mixtures. Finally, this methodology allows the easy preparation of useful 3-fluoropiperidine intermediates, and it is demonstrated that these systems are applicable to a range of functionalization reactions leading to new building blocks for the discovery of bioactive products.

Synthesis of enantioenriched 2,2-disubstituted pyrrolidines via sequential asymmetric allylic alkylation and ring contraction

The synthesis of a variety of enantioenriched 2,2-disubstituted pyrrolidines is described. A stereogenic quaternary center is first formed utilizing an asymmetric allylic alkylation reaction of a benzyloxy imide, which can then be reduced to a chiral hydroxamic acid. This compound can then undergo a thermal “Spino” ring contraction to afford a carbamate protected 2,2-disubstituted pyrrolidine stereospecifically. These pyrrolidines can be further advanced to enantioenriched indolizidine compounds. This reaction sequence allows access to new molecules that could be useful in the development of pharmaceutical agents.