Excellent Ee Research Articles

Chiral Calcium Phosphate Catalyzed Enantioselective Amination of 3-Aryl-2-benzofuranones.

A 4-tert-butyl-phenyl substituted (R)-[H8]-BINOL chiral calcium phosphate catalyzed enantioselective amination of 3-aryl-2-benzofuranones with dibenzyl azodicarboxylate is described. The catalyst loading of the reaction is 1 mol %. This transformation is facile and has a high degree atom economy, which gave products with good yields and high enantioselectivities (79% to 99%). This reaction has excellent ee and a broad substrate scope with mild reaction conditions.

Synthesis and Applications of Cinchona Squaramide‐Modified Poly(Glycidyl Methacrylate) Microspheres as Recyclable Polymer‐Grafted Enantioselective Organocatalysts

This work presents the immobilization of cinchona squaramide organocatalysts on poly(glycidyl methacrylate) solid supports. Preparation of the well‐defined monodisperse polymer microspheres was facilitated by comprehensive parameter optimization. By exploiting the reactive epoxy groups of the polymer support, three amino‐functionalized cinchona derivatives were immobilized on this carrier. To explore the effect of the amino linker, these structurally varied precatalysts were synthesized by modifying the cinchona skeleton at different positions. The catalytic activities of the immobilized organocatalysts were tested in the Michael addition of pentane‐2,4‐dione and trans‐β‐nitrostyrene with excellent yields (up to 98 %) and enantioselectivities (up to 96 % ee). Finally, the catalysts were easily recovered five times by centrifugation without loss of activity.

Enantioselective Synthesis of Polycyclic Aromatic Hydrocarbon (PAH)-Based Planar Chiral Bent Cyclophanes by Rhodium-Catalyzed [2+2+2] Cycloaddition.

The enantioselective synthesis of polycyclic aromatic hydrocarbon (PAH)-based planar chiral cyclophanes was achieved for the first time by the rhodium-catalyzed intramolecular regio- and enantioselective [2+2+2] cycloaddition of tethered diyne-benzofulvenes followed by stepwise oxidative transformations. The thus synthesized planar chiral bent cyclophanes, that possess bent p-terphenyl- and 9-fluorenone-cores, were converted to 9-fluorenol-based ones with excellent ee values of >99 % by diastereoselective 1,2-reduction. These 9-fluorenol-based cyclophanes exhibited high fluorescence quantum yields, which were significantly higher than that of an acyclic reference molecule (78-82 % vs. 48 %). The bending effect on the chiroptical property was also examined, which revealed that the anisotropy factors (gabs values) for electronic circular dichroism (ECD) of these 9-fluorenol-based planar chiral bent cyclophanes increase as the tether length becomes shorter.

Synthesis of α-tertiary allylsilanes by palladium-catalyzed hydrosilylation of 1,1-disubstituted allenes

We herein report an effective hydrosilylation of 1,1-disubstituted allenes with a palladium catalyst modified by a monophosphorus ligand, leading to a series of α-tertiary allylsilanes in high yields and exceptional regioselectivities. The employment of BI-DIME is essential for the high reactivities and selectivities. A chiral α-tertiary allylsilane is formed in excellent ee for the first time by employing a chiral monophosphorus ligand.

Imine Amidation Catalyzed by a Chiral VAPOL Calcium Phosphate.

Over the last 16 years, chiral phosphoric acids (CPAs) have been shown to be excellent asymmetric catalysts, very effectively used in constructing chiral molecules with high enantiocontrol. In 2010, Ishihara et al. discovered that chiral metal phosphate complexes (or salts) could be found in substantial quantities, as contaminates, in some reported CPA-catalyzed reactions (Hatano, M.; Moriyama, K.; Maki, T.; Ishihara, K. Angew. Chem., Int. Ed. 2010, 49, 3823-3826). These metal phosphates were shown to actually catalyze the reactions in addition to CPAs. In this work, we have investigated in depth a reaction first reported to be catalyzed by CPAs based on a vaulted bis-phenanthrol (VAPOL) backbone. We have found that VAPOL metal phosphates were, in fact, superior catalysts for this reaction. Upon optimization, a wide substrate scope, low catalyst loading, and mild conditions could provide intermolecular imine amidation reactions producing chiral N,N'-aminal products in high yields and with excellent ee values (up to >99% yield, >99% ee).

Organocatalytic enantioselective one-pot synthesis of β-aminoketones via Mannich reaction

An effective protocol for the asymmetric synthesis of β-amino carbonyl compounds using pyrrolidine based organocatalyst has been developed via one-pot three-component Mannich reaction. The organocatalyst (S)-N-(2,4-dinitrophenyl) pyrrolidine-2-carboxamide 3b confirmed to be the superior organocatalyst in solvent acetonitrile to obtain corresponding products in up to 89% yield and with excellent ee (90%). This organocatalytic reaction reveals productive result with a range of other aldehydes. Aromatic aldehydes having electron withdrawing substituent show the best results. Excellent yields, high enantioselectivity, mild reaction condition, and simple experimental work-up procedure are some of the advantages of this method.

Enantioselective Hydroboration of Ketones Catalyzed by Rare-Earth Metal Complexes Containing Trost Ligands

Four chiral dinuclear rare-earth metal complexes [REL1]2 (RE = Y(1), Eu(2), Nd(3), La (4)) stabilized by Trost proligand H3L1 (H3L1 = (S,S)-2,6-bis[2-(hydroxydiphenylmethyl)pyrrolidin-1-ylmethyl]-4-methylphenol) were first prepared, and all were characterized by X-ray diffraction. Complex 4 was employed as the catalyst for enantioselective hydroboration reaction of substituted ketones, and the corresponding secondary alcohols with excellent yields and high ee values were obtained using reductant HBpin. The same result was also achieved using the combination of lanthanium amides La[N(SiMe3)2]3 with Trost proligand H3L1 in a 1:1 molar ratio. The experimental findings and DFT calculation revealed the possible mechanism of the enantioselective hydroboration reaction and defined the origin of the enantioselectivity in the current system.

Catalytic Asymmetric Three-component Hydroacyloxylation/ 1,4-Conjugate Addition of Ynamides.

A highly enantioselective three-component hydroacyloxylation/1,4-conjugate addition of ortho-hydroxybenzyl alcohols, ynamides and carboxylic acids was developed under mild reaction conditions in the presence of a chiral N,N'-dioxide/Sc(OTf)3 complex, which went through in situ generated ortho-quinone methides with α-acyloxyenamides, delivering a range of corresponding chiral α-acyloxyenamides derivatives containing gem(1,1)-diaryl skeletons in moderate to good yields with excellent ee values. The scale-up experiment and further derivation showed the practicality of this catalytic system. In addition, a possible catalytic cycle and transition state model was proposed to elucidate the origin of the stereoselectivity based on X-ray crystal structure of the α-acyloxyenamide intermediate and product.

Diaza-Crown Ether-Bridged Chiral Diphosphoramidite Ligands: Synthesis and Applications in Asymmetric Catalysis.

A small library of diaza-crown ether-bridged chiral diphosphoramidite ligands was prepared. In the rhodium-catalyzed asymmetric hydrogenation and hydroformylation reactions, these ligands exhibited distinct properties in catalytic activity and/or enantioselectivity. Hydrogenated products with opposite absolute configurations could be obtained in high yields with excellent ee values by utilizing (S,S)-L1 and (S,S)-L3, respectively. Meanwhile, the addition of alkali metal cations caused variations in catalytic outcomes, showing the supramolecular tunability of these Rh/diphosphoramidite catalytic systems.

Catalytic Enantiodivergent Michael Addition by Subtle Adjustment of Achiral Amino Moiety of Dipeptide Phosphines.

SummaryOver the past decades, asymmetric catalysis has been intensely investigated as a powerful tool for the preparation of numerous chiral biologically active compounds. However, developing general and practical strategies for preparation of both enantiomers of a chiral molecule via asymmetric catalysis is still a challenge, particularly when the two enantiomers of a chiral catalyst are not easily prepared from natural chiral sources. Inspired by the biologic system, we report herein an unprecedented catalytic enantiodivergent Michael addition of pyridazinones to enones by subtle adjustment of achiral amino moiety of dipeptide phosphine catalysts. These two dipeptide phosphine catalysts, P5 and P8, could deliver both enantiomers of a series of N2-alkylpyridazinones in good yields (up to 99%) with high enantioselectivities (up to 99% ee) via the catalyst-controlled enantiodivergent addition of pyridazinones to enones.

Process Optimisation Studies and Aminonitrile Substrate Evaluation of Rhodococcus erythropolis SET1, A Nitrile Hydrolyzing Bacterium.

A comprehensive series of optimization studies including pH, solvent and temperature were completed on the nitrile hydrolyzing Rhodococcus erythropolis bacterium SET1 with the substrate 3‐hydroxybutyronitrile. These identified temperature of 25 °C and pH of 7 as the best conditions to retain enantioselectivity and activity. The effect of the addition of organic solvents to the biotransformation mixture was also determined. The results of the study suggested that SET1 is suitable for use in selected organo‐aqueous media at specific ratios only. The functional group tolerance of the isolate with unprotected and protected β‐aminonitriles, structural analogues of β‐hydroxynitriles was also investigated with disappointingly poor isolated yields and selectivity obtained. The isolate was further evaluated with the α‐ aminonitrile phenylglycinonitrile generating acid in excellent yield and ee (>99 % (S) – isomer and 50 % yield). A series of pH studies with this substrate indicated pH 7 to be the optimum pH to avoid product and substrate degradation.

Highly Enantioselective Cobalt-Catalyzed Hydroboration of Diaryl Ketones.

A highly enantioselective cobalt-catalyzed hydroboration of diaryl ketones with pinacolborane was developed using chiral imidazole iminopyridine as a ligand to access chiral benzhydrols in good to excellent yields and ee. This protocol could be carried out in a gram scale under mild reaction conditions with good functional group tolerance. Chiral biologically active 3-substituted phthalide and (S)-neobenodine could be easily constructed through asymmetric hydroboration as a key step.

Enantioselective Dehydroxyhydrogenation of 3-Indolylmethanols by the Combined Use of Benzothiazoline and Chiral Phosphoric Acid: Construction of a Tertiary Carbon Center.

The chiral indole is an important structure in organic chemistry. We have developed an enantioselective hydrogen transfer reaction of indolylmethanol, which is characterized by the combined use of benzothiazoline and a newly synthesized chiral phosphoric acid. The reaction furnished indoles bearing a chiral tertiary carbon center at the 3-position in high to excellent yields and with excellent enantioselectivities, most of which are greater than 95% ee. The chiral indole was converted into an inhibitor of leukotriene production while retaining excellent ee.

Cover Feature: Rhodium‐Catalyzed Asymmetric [2+2+2] Cycloaddition of 1,6‐Enynes with Racemic Secondary Allylic Alcohols through Kinetic Resolution (Chem. Eur. J. 17/2020)

We have established that a cationic rhodium(I)/P-phos complex catalyzes the asymmetric [2+2+2] cycloaddition of 1,6-enynes with racemic secondary allylic alcohols to produce the corresponding chiral bicyclic cyclohexenes, possessing three stereogenic centers, as a single diastereomer with excellent ee values. Mechanistic experiments revealed that the present cycloaddition proceeds through the kinetic resolution of the racemic secondary allylic alcohols, in which one enantiomer preferentially reacts with the 1,6-enyne. This cover feature uses a mirror to portray how one enantiomer reacts preferentially over the other enantiomer. Also, the starry sky on the background is inspired by the structure of the bicyclic cyclohexene. More information can be found in the Communication by K. Tanaka et al. on page 3698.

Rhodium-Catalyzed Asymmetric [2+2+2] Cycloaddition of 1,6-Enynes with Racemic Secondary Allylic Alcohols through Kinetic Resolution.

It has been established that a cationic rhodium(I)/P-phos complex catalyzes the asymmetric [2+2+2] cycloaddition of 1,6-enynes with racemic secondary allylic alcohols to produce the corresponding chiral bicyclic cyclohexenes, possessing three stereogenic centers, as a single diastereomer with excellent ee values. Mechanistic experiments revealed that the present cycloaddition proceeds through the kinetic resolution of the racemic secondary allylic alcohols, in which one enantiomer preferentially reacts with the 1,6-enyne.

Enantioselective Cu(I)-Catalyzed Cycloaddition of Prochiral Diazides with Terminal or 1-Iodoalkynes.

We report an unprecedented highly enantioselective desymmetric Cu(I)-catalyzed 1,3-dipolar cycloaddition of diazides with terminal alkynes and 1-iodoalkynes, affording tertiary alcohols bearing a 1,2,3-triazole moiety in high yield and excellent ee value. PYBOX ligands with a C4 shielding group once again show the promising ability to achieve higher enantioselectivity.

Catalytic Asymmetric Tandem Cycloisomerization/[5+2] Cycloaddition Reaction of N-Aryl Nitrone Alkynes with Methyleneindolinones.

An asymmetric tandem cycloisomerization and intermolecular [5+2] cycloaddition reaction of 2-ethynylphenyl-substituted nitrones with methyleneindolinones was realized. The process includes the palladium(II)-promoted in situ formation of azomethine ylide and the following chiral N,N'-dioxide-Co(II) complex-catalyzed regio-, diastereo-, and enantioselective [5+2] cycloaddition reaction. The desired spiro-tropanyl oxindoles were obtained in good yields with excellent dr and ee values. On the basis of the determination of the catalyst structure, a possible transition state model was proposed.

Enantioselective amination of 4-alkylisoquinoline-1,3(2H,4H)-dione derivatives.

A mild and efficient enantioselective amination of 4-alkylisoquinoline-1,3(2H,4H)-dione derivatives was established, which is compatible with a broad range of substrates and delivers the final products in excellent yields (up to 99%) and ee values (up to 99%) with low catalyst loading (down to 1 mol%). The synthetic potential of this methodology was also demonstrated in the gram scale level.

Enantioselective Palladium(II)-Catalyzed Oxidative Aminofluorination of Unactivated Alkenes with Et4 NF⋅3 HF as a Fluoride Source.

The first asymmetric PdII -catalyzed aminofluorination of unactivated alkenes using chiral quinoline-oxazolines (Quox) as ligands has been developed. This reaction provides easy access to a wide array of enantiomerically enriched β-fluoropiperidines in good yields and with excellent enantioselectivity. Notably, Et4 NF⋅3 HF as a readily accessible nucleophilic fluoride source was found to play an essential role in the enantioselective control, and CsOCF3 also acts a key additive to improve the excellent ee value of products.

Enantioselective Palladium(II)‐Catalyzed Oxidative Aminofluorination of Unactivated Alkenes with Et4NF⋅3 HF as a Fluoride Source

AbstractThe first asymmetric PdII‐catalyzed aminofluorination of unactivated alkenes using chiral quinoline‐oxazolines (Quox) as ligands has been developed. This reaction provides easy access to a wide array of enantiomerically enriched β‐fluoropiperidines in good yields and with excellent enantioselectivity. Notably, Et4NF⋅3 HF as a readily accessible nucleophilic fluoride source was found to play an essential role in the enantioselective control, and CsOCF3 also acts a key additive to improve the excellent ee value of products.