Asymmetric Alkylation Reaction Research Articles

Phen-2NO, a new C2-symmetric rigid-featured tetradentate ligand, and its application in the asymmetric alkylation reaction of indoles

A new class of C2-symmetric rigid-featured chiral phen ligands that provide the N,N,O,O-tetradentate coordination of the phen moiety and two additional N,N-dioxides were rationally designed and developed.

W-Phos Ligand Enables Copper-Catalyzed Enantioselective Alkylation of N-Sulfonyl Ketimines with Grignard Reagents

Catalytic asymmetric addition of reactive Grignard reagents to ketimines poses a considerable challenge. Herein, a PNP-type W-Phos ligand developed recently by our group showed a unique effect toward this end, paving the way to a Cu(I)-catalyzed asymmetric alkylation reaction of N-sulfonyl ketimines, delivering optically active α-tertiary amines in high enantioselectivities. This catalytic protocol shows an unprecedented substrate scope with more than 80 examples, not only compatible with benzo five- and six-membered cyclic N-sulfonyl ketimines but also suitable for geometrically unstable (E or Z) acyclic N-sulfonyl ketimines. The application potential of the protocol is featured by the extensive presence of α-tertiary amines in natural products and pharmaceutical compounds and also demonstrated by downstream transformations with maintenance of the enantioselectivity.

Chiral Bismuth-Rhodium Paddlewheel Complexes Empowered by London Dispersion: The C-H Functionalization Nexus.

Heterobimetallic [BiRh] tetracarboxylate catalysts endowed with 1,3-disilylated phenylglycine paddlewheels benefit from interligand London dispersion. They were originally designed for asymmetric cyclopropanation but are now shown to perform very well in asymmetric C-H functionalization reactions too. Because of the confined ligand sphere about the derived donor/acceptor carbenes, insertions into unhindered methyl groups are kinetically favored, although methylene units also react with excellent levels of asymmetric induction; even gaseous ethane is a suitable substrate. Moreover, many functional groups in both partners are tolerated. The resulting products are synthetically equivalent to the outcome of traditional asymmetric ester alkylation, allylation, benzylation, propargylation and aldol reactions and therefore constitute a valuable nexus to more conventional chemical logic.

Chiral Bismuth‐Rhodium Paddlewheel Complexes Empowered by London Dispersion: The C−H Functionalization Nexus

AbstractHeterobimetallic [BiRh] tetracarboxylate catalysts endowed with 1,3‐disilylated phenylglycine paddlewheels benefit from interligand London dispersion. They were originally designed for asymmetric cyclopropanation but are now shown to perform very well in asymmetric C−H functionalization reactions too. Because of the confined ligand sphere about the derived donor/acceptor carbenes, insertions into unhindered methyl groups are kinetically favored, although methylene units also react with excellent levels of asymmetric induction; even gaseous ethane is a suitable substrate. Moreover, many functional groups in both partners are tolerated. The resulting products are synthetically equivalent to the outcome of traditional asymmetric ester alkylation, allylation, benzylation, propargylation and aldol reactions and therefore constitute a valuable nexus to more conventional chemical logic.

Kinetic Resolution of Sulfinamides via Asymmetric N-Allylic Alkylation.

An efficient kinetic resolution of sulfinamides via an asymmetric N-allylic alkylation reaction was realized using hydroquinine as a catalyst under mild conditions. The kinetic resolution of a range of Morita-Baylis-Hillman adducts and N-aryl tert-butylsulfinamides was highly effective. In addition, the synthetic utility of the protocol was demonstrated by a scaled-up reaction. Density functional theory calculations provide convincing evidence for the interpretation of stereoselection.

Enantioselective Construction of Single and Vicinal All-Carbon Quaternary Stereocenters through Ion-Pair-Catalyzed 1,6-Conjugate Addition.

An asymmetric 1,6-conjugate addition to presynthesized δ-aryl-δ-cyano-disubstituted para-quinone methides through bifunctional phosphonium-amide-promoted ion-pair catalysis for acyclic all-carbon quaternary stereocenter construction has been described. Both acyclic and cyclic 1,3-dicarbonyls participate in the asymmetric alkylation reaction, furnishing a wide array of diarylmethanes bearing a single acyclic quaternary carbon stereocenter or vicinal cyclic and acyclic quaternary carbon stereocenters with high efficiency and excellent stereoselectivity. Computational studies elucidate the origin of the enantioselectivity.

Asymmetric Synthesis of N‐Fmoc‐(S)‐7‐aza‐tryptophan via Alkylation of Chiral Nucleophilic Glycine Equivalent

AbstractNi(II)‐complexes, derived from glycine Schiff bases with chiral tridentate ligands, have been used as powerful tools for the synthesis of structurally diverse tailor‐made amino acids. In this manuscript, asymmetric alkylation reaction between chiral nucleophilic glycine derived Ni‐complex and 3‐(chloromethyl)‐1H‐pyrrolo[2,3‐b]pyridine has been developed under convenient conditions, which affords the corresponding alkylated Ni‐complex in 74 % yield and excellent diastereoselectivity (only one isomer). This reaction features convenient conditions and completely controlled diastereoselectivity, which provides a highly valuable approach for asymmetric synthesis of 7‐aza‐tryptophan.

Direct Catalytic Asymmetric α-Allylic Alkylation of Aza-aryl Methylamines by Chiral-Aldehyde-Involved Ternary Catalysis System

A ternary catalytic system comprising a chiral aldehyde, a transition metal, and a Lewis acid is rationally designed for the asymmetric α-allylic alkylation reaction of aza-aryl methylamines and π-allylmetal electrophiles. Structural diversity chiral amines bearing carbon-carbon double bonds and aza-heterocycles are produced in moderate to good yields with good to excellent enantioselectivities. These products can be readily converted into other chiral amines without the loss of enantioselectivity. A reasonable reaction mechanism is proposed to illustrate the stereoselective control results.

Dinuclear helicate or mononuclear pincer lanthanide complexes from one ligand: stereo-controlled assembly and catalysis

By varying the metal/ligand ratio, either dinuclear triple helicate or mononuclear pincer can be stereo-selectively obtained from the same chiral ligand. Their catalytic properties have been demonstrated with the asymmetric FC alkylation reactions.

Enantioselective Synthesis of 3-Allylindolizines via Sequential Rh-Catalyzed Asymmetric Allylation and Tschitschibabin Reaction.

The first highly regio- and enantioselective synthesis of 3-allylindolizines has been developed by the sequential Rh-catalyzed asymmetric allylation and Tschitschibabin reaction. Above the 20:1 branch/linear ratio, up to a 96% yield and 99% ee could be obtained with the help of tert-butyl-substituted chiral bisoxazolinephosphine ligand. In situ generated highly nucleophilic 2-alkylpyridinium ylides are utilized to undergo the asymmetric alkylation reaction before cyclization.

Asymmetric Ruthenium-Catalyzed Hydrogenation of Terpyridine-Type N-Heteroarenes: Direct Access to Chiral Tridentate Nitrogen Ligands.

The first enantioselective hydrogenation of terpyridine-type N-heteroarenes has been successfully developed by using Ru(diamine) complexes as catalysts, providing partially reduced chiral pyridine-amine-type products in high yield (up to 93%) with excellent diastereo- and enantioselectivity (up to 94:6 dl/meso, > 99% ee). These pyridine-amine-type compounds can be served as a new class of chiral multidentate nitrogen-donor ligands, which were successfully applied to the Cu-catalyzed asymmetric Friedel-Crafts alkylation reaction of indoles with nitroalkenes.

Probing Trends in Enantioinduction via Substrate Design: Palladium-Catalyzed Decarboxylative Allylic Alkylation of α-Enaminones

Herein, we report the palladium-catalyzed decarboxylative asymmetric allylic alkylation of α-enaminones. In addition to serving as valuable synthetic building blocks, we exploit the α-enaminone scaffold and its derivatives as probes to highlight structural and electronic factors that govern enantioselectivity in this asymmetric alkylation reaction. Utilizing the (S)-t-BuPHOX ligand in a variety of nonpolar solvents, the alkylated products are obtained in up to 99% yield and 99% enantiomeric excess.

Asymmetric Synthesis of β-Indolyl Cyclopentanones and Cyclopentylamides with an All-Carbon Quaternary Stereocenter via Chiral Phosphoric Acid Catalyzed Friedel-Crafts Alkylation Reactions.

The asymmetric Friedel-Crafts alkylation reactions of indoles with β-substituted cyclopentenimines enabled by chiral phosphoric acid catalysis has been developed, which affords adducts possessing an all-carbon stereocenter with high levels of enantioselectivities. Furthermore, the addition products could be readily converted into two types of useful but previously challenging chiral building blocks, such as β-alkyl-β-indolyl cyclopentanones and β-alkyl-β-indolyl cyclopentylamides, in one pot via in situ hydrolysis or reduction without erosion of chiral information.

Enantioselective Alkylation of N-Arylhydrazones Derived from α-Keto Esters and Isatin Derivatives through Asymmetric Phase-Transfer Catalysis.

The phase-transfer-catalyzed asymmetric alkylation reactions of N-arylhydrazones derived from α-keto-esters and isatin derivatives afford enantioenriched azo compounds that bear a tetra-substituted carbon stereocenter in good yields with high chemo- and enantioselectivity. The alkylation products can be readily converted into chiral amino esters, hydrazine derivatives, and aza-β-lactams without loss of enantiopurity.

Organocatalyzed Decarboxylative Trifluoromethylation of β-Ketoacids

A new protocol has been developed for the synthesis of α-trifluoromethyl ketones via organocatalyzed decarboxylative trifluoromethylation of β-ketoacids with Togni’s reagent. Among various simple amine catalysts, primary amines and secondary amines were identified to be more effective than tertiary amines, with piperazine being the most effective. Mechanistic investigations suggested that the primary or secondary amine-catalyzed reactions proceed mainly through trifluoromethylation of an enamine intermediate, which is more effective than the tertiary amine-catalyzed pathway that involves an enol intermediate. By using piperazine as the optimal organocatalyst, various β-ketoacids, including the sterically hindered α,α-disubstituted ones, were converted into the corresponding α-trifluoromethyl ketones in good yields. This research not only provides a useful strategy for the efficient synthesis of a wide range of α-trifluoromethyl ketones under mild conditions, but also constitutes one of the few studies on decarboxylative alkylation of β-ketoacids, which can intrigue further exploitation on organocatalyzed asymmetric decarboxylative alkylation reactions.

New Progress in Asymmetric Synthesis of Quaternary α-Amino Acids

Background: Quaternary α-amino acids with a tetrasubstituted carbon stereocenter have a variety of biological activities. Due to the steric hindrance of the quaternary carbon centers, highly efficient asymmetric catalytic synthesis is greatly challenging. Objective: In this paper, with a focus on the asymmetric formation of chemical bonds in reactions, the asymmetric catalytic synthesis of quaternary α-amino acids in recent years is reviewed. Conclusion: Several representative catalytic asymmetric reactions are introduced, and the effects of different catalysts on the reaction results are discussed. Keywords: Quaternary a-amino acids, asymmetric catalytic synthesis, quaternary stereocenters, formation of C-C bond, formation of C-N bond, asymmetric alkylation reaction.

Directing the Cation Recognition Ability of Calix[4]arenes toward Asymmetric Phase‐Transfer Catalysis

The recognition abilities of chiral calixarene hosts toward alkali cation guests have been exploited for the first time in asymmetric phase‐transfer catalysis. The binding affinities of a series of chiral α‐methylbenzylamine‐derived calix[4]arene‐amides toward Na+ guest have been determined by 1H NMR spectroscopic titration experiments. The good apparent association constant values are consistent with the macrocycles' catalytic efficiency in the asymmetric alkylation reaction of N‐(diphenylmethylene)glycine esters under phase‐transfer conditions.

Enantioconvergent Copper Catalysis: In Situ Generation of the Chiral Phosphorus Ylide and Its Wittig Reactions.

The Wittig reaction, which produces alkenes from phosphorus ylides (P-ylides) and carbonyls, is one of the most powerful tools in chemical synthesis. This Nobel Prize-winning reaction is widely used in natural product synthesis, fine chemical production (i.e., medicines and agricultural agents), and polymer functionalization. Despite these great achievements, the potential of the Wittig reaction, particularly regarding the access of chiral alkene building blocks, has not been fully exploited. The main area that requires additional exploration is the development of general and practical methods to efficiently prepare chiral P-ylides. Here, we show that highly functionalized chiral P-ylides can be easily synthesized through a copper-catalyzed asymmetric propargylic alkylation reaction from phosphonium salts and racemic propargylic esters. The subsequent Wittig reactions enable the synthesis of versatile alkene building blocks, chiral α-propargylic acrylates, and α-propargylic allenoates, with a wide substrate scope and satisfactory functional group compatibility. This transformation features inexpensive transition-metal catalysts, user-friendly conditions, easily available feedstock, and high-valued products.

Chiral N,N'-Dioxide-Scandium(III) Complex-Catalyzed Asymmetric Friedel-Crafts Alkylation Reaction of ortho-Hydroxybenzyl Alcohols with C3-Substituted N-Protected Indoles.

The first Lewis acid catalyzed asymmetric Friedel-Crafts alkylation reaction of ortho-hydroxybenzyl alcohols with C3-substituted indoles is described. A chiral N,N'-dioxide Sc(OTf)3 complex served not only to promote formation of ortho-quinone methides (o-QMs) in situ but also induced the asymmetry of the reaction. This methodology enables a novel activation of ortho-hydroxybenzyl alcohols, thus affording the desired chiral diarylindol-2-ylmethanes in up to 99 % yield and 99 % ee. A range of functional groups were also tolerated under the mild reaction conditions. Moreover, this strategy gives concise access to enantioenriched indole-fused benzoxocines.

Enantioselective Alkylation of Glycine Imine Promoted by Amino‐Acid‐Derived Phosphonium Salts

AbstractChiral phosphonium salts derived from natural amino acids were prepared and applied to the asymmetric alkylation reaction of glycine imine with substituted benzyl bromides, and the desired alkylation products were obtained in high yields and with excellent enantioselectivities.