Asymmetric Synthesis of Trifluoromethylated Amines via Catalytic Enantioselective Isomerization of Imines

A new approach toward the asymmetric synthesis of optically active trifluoromethylated amines was enabled by an unprecedented, highly enantioselective catalytic isomerization of trifluoromethyl imines with a new chiral organic catalyst. Not only aryl but also alkyl trifluoromethylated amines could be obtained in high enantioselectivities.     

Catalytic Asymmetric 1,3‐Dipolar Cycloaddition of β‐Fluoroalkylated α,β‐Unsaturated 2‐Pyridylsulfones with Nitrones for Chiral Fluoroalkylated Isoxazolidines and γ‐Amino Alcohols

2‐Pyridylsulfone‐ and fluoroalkylated group‐activated olefins underwent highly efficient diastereo‐ and enantioselective 1,3‐dipolar cycloadditions across various aromatic and aliphatic nitrones in the presence of a chiral Ni^II/bis(oxazoline) catalyst. The process was tuned by 4 Å molecular sieves, chiral bis(oxazoline) ligands, reaction solvents, and temperature. A wide array of optically pure fluoroalkylated isoxazolidines were obtained, thus facilitating the asymmetric synthesis of an enantioenriched α‐trifluoromethylated γ‐amino alcohol in gram‐scale and a trifluoromethylated derivative of 1,3‐oxazinan‐2‐one with potential pharmaceutical interest. A stereochemical model, based on the absolute configuration of one adduct and some control experiments, was postulated to account for the observed endo‐ and enantioselectivity.     

A chiral pyrrolidine-pyrazole catalyst for the enantioselective Michael addition of carbonyls to nitroolefins

An enantioselective Michael reaction of carbonyl compounds to nitroolefins has been accomplished using a novel chiral pyrrolidine-pyrazole catalyst. This newly prepared catalyst was found to be very effective in providing good yields as well as good diastereo- and enantio-selectivities. The mechanism of the reaction has also been substantiated by mass spectral studies.     

Catalytic enantioselective peroxidation of alpha,beta-unsaturated ketones

Despite the potential of chiral peroxides as biologically interesting or even clinically important compounds, no catalytic enantioselective peroxidation has been reported. With a chiral catalyst not only to induce enantioselectivity but also to convert a well established epoxidation pathway into a peroxidation pathway, the first efficient catalytic peroxidation has been successfully developed. Employing readily available alpha,beta-unsaturated ketones and hydroperoxides and an easily accessible cinchona alkaloid catalyst, this novel reaction will open new possibilities in the asymmetric synthesis of chiral peroxides. Under different conditions a highly enantioselective epoxidation with the same starting materials, reagents, and catalyst has was also established.     

Catalytic Asymmetric Synthesis of Trifluoromethylated γ‐Amino Acids through the Umpolung Addition of Trifluoromethyl Imines to Carboxylic Acid Derivatives

Novel cinchona alkaloid derived chiral phase‐transfer catalysts enabled the highly chemo‐, regio‐, diastereo‐, and enantioselective umpolung addition of trifluoromethyl imines to α,β‐unsaturated N‐acyl pyrroles. With a catalyst loading ranging from 0.2 to 5.0 mol %, this new catalytic asymmetric transformation provides facile and high‐yielding access to highly enantiomerically enriched chiral trifluoromethylated γ‐amino acids and γ‐lactams.     

Catalytic asymmetric synthesis of stable oxetenes via Lewis acid-promoted [2+2] cycloaddition

A highly enantioselective and atom-economical [2 + 2] cycloaddition of various alkynes with trifluoropyruvate using a dicationic (S)-BINAP-Pd catalyst has been established. This is the first enantioselective synthesis of stable oxetene derivatives, whose structure has been clarified by X-ray analysis. This catalytic process offers a practical synthetic method for oxetene derivatives (catalyst loading: up to 0.1 mol %), which can serve as novel chiral building blocks for pharmaceuticals and agrochemicals and can also be transformed into a variety of enantiomerically enriched CF(3)-substituted compounds with high stereoselectivity.     

对映选择性亲电氟化反应研究进展

含氟有机化合物, 特别是手性氟化物在医药、农药及功能性材料等相关领域的作用备受注目. 尽管在分子中有立体选择性地引入一个氟原子一直是有机化学家面临的一个挑战性问题, 近年来在化学家们的不断努力下, 对映选择性氟化反应研究取得重要进展. 高光学活性的手性氟化物可通过手性亲电氟化试剂诱导的立体选择性氟化反应, 基于底物的手性氟化反应以及手性催化剂诱导的不对称催化氟化反应等来制备. 特别是, 手性金属配合物和有机催化剂诱导的不对称催化氟化反应被广泛应用于各类手性氟化物的合成, 已成为不对称氟化反应研究的热点. 全面介绍对映选择性亲电氟化反应研究概况和最新进展, 讨论各种不对称氟化反应的特点及应用范围.     

Combinatorial chemistry approach to chiral catalyst engineering and screening: rational design and serendipity

An efficient asymmetric catalyst relies on the successful combination of a large number of interrelated variables, including rational design, intuition, persistence, and good fortune-not all of which are necessarily well-understood; this renders such practice largely empirical. As a result, the possibility of using combinatorial chemistry methods in asymmetric catalysis research has been widely recognized to be highly desirable. In this account, we attempt to show the principle and application of combinatorial approach in the discovery of chiral catalysts for enantioselective reactions. The concept focuses on the strategy for the creation of a modular chiral catalyst library by two-component ligand modification of metal ions on the basis of molecular recognition and assembly. The self-assembled chiral catalyst with two different ligands indeed exhibited synergistic effects in terms of both enantioselectivity and activity in comparison with its corresponding homocombinations in many reactions. The examples described in this paper demonstrated the powerfulness of combinatorial approach for the discovery of novel chiral catalyst systems, particularly for the development of highly efficient, enantioselective, and practical catalysts for enantioselective reactions. We hope this concept will stimulate further work on the discovery of more highly efficient and enantioselective catalysts, as well as unexpected classes of catalysts or catalytic enantioselective reactions in the future with the help of a combinatorial chemistry approach.     

Trifluoromethylated amino alcohols as chiral ligands for highly enantioselective Reformatsky reaction

The enantioselective Reformatsky reaction of PhCHO was achieved by the use of trifluoromethylated amino alcohols as chiral ligands to afford the corresponding optically active β-hydroxy ester with up to 90% ee.     

New Developments in Chiral Cooperative Ion Pairing Organocatalysis by Means of Ammonium Oxyanions and Fluorides: From Protonation to Deprotonation Reactions.

This personal account summarizes our contribution to the ion pairing organocatalysis mainly by use of chiral quaternary or tertiary ammonium fluorides, aryloxides and carboxylates. Starting from an experimental observation, we were able to develop several approaches for the enantioselective protonation of silyl enolates and enol esters giving rise to chiral carbonyl compounds bearing a stereogenic center at the α‐position. Moving from protonation to deprotonation reactions, chiral ammonium ion pair catalysts were successfully applied to several asymmetric transformations such as an Henry reaction or a direct vinylogous aldol reaction to cite a few. An outlook of further possible developments in this field of research will also be discussed.     

Enantioselective organocatalytic route to trifluoromethyl-β-amino acids using chiral bases

Herein are studied new aspects of enantioselective (1,3) proton transfer of ethyl-4,4,4-trifluoroacetoacetate (ETFAA) amino derivatives. When catalyzed by an appropriate chiral base, ee's as high as 71% are observed. Special emphasis is given to mechanistic insights of the reaction by use of deuterated derivative. All results converge on a deprotonation as both rate and asymmetric determining step. This study opens a new route to trifluoromethylated chiral building blocks.     

Access to N‐Substituted 2‐Pyridones by Catalytic Intermolecular Dearomatization and 1,4‐Acyl Transfer

A novel rhodium‐catalyzed dearomatization of O‐substituted pyridines to access N‐substituted 2‐pyridones has been developed. A computational study suggests a mechanism involving the formation of a pyridinium ylide followed by an unprecedented 1,4‐acyl migratory rearrangement from O to C. Furthermore, the chiral dirhodium complexes serve as the catalyst for the asymmetric transformation with excellent enantioselective control. DFT calculations indicate the chirality is transferred from axial chirality to the central stereogenic centre. The stronger π–π interaction and CH–π interaction account for the high enantioselectivity.     

Enantioselective Formal [3+2] Cycloaddition of Epoxides with Imines under Brønsted Base Catalysis: Synthesis of 1,3‐Oxazolidines with Quaternary Stereogenic Center

The formal [3+2] cycloaddition of epoxides and unsaturated compounds is a powerful methodology for the synthesis of densely functionalized five‐membered heterocyclic compounds containing oxygen. Described is a novel enantioselective formal [3+2] cycloaddition of epoxides under Brønsted base catalysis. The bis(guanidino)iminophosphorane as a chiral organosuperbase catalyst enabled the enantioselective reaction of β,γ‐epoxysulfones with imines, owing to its strong basicity and high stereocontrolling ability, to provide enantioenriched 1,3‐oxazolidines having two stereogenic centers, including a quaternary one, in a highly diastereo‐ and enantioselective manner.     

Organocatalytic enantioselective Michael addition of 2,4-pentandione to nitroalkenes promoted by bifunctional thioureas with central and axial chiral elements

Two novel bifunctional amine-thiourea organocatalysts 1 and 2, which both bear central and axial chiral elements, have been developed to promote enantioselective Michael reaction between 1,3-dicarbonyl compounds and nitro olefins. The catalyst 2 afforded the desired products with good levels of enantioselectivity (up to 96% ee), showing clearly that two chiral elements of 2 are matched, and enhance the stereochemical control.     

Ruthenium-catalyzed enantioselective carbon-carbon bond forming reaction via allenylidene-ene process: synthetic approach to chiral heterocycles such as chromane, thiochromane, and 1,2,3,4-tetrahydroquinoline derivatives

Our previously disclosed ruthenium-catalyzed carbon-carbon bond forming reactions between propargylic alcohols and alkenes via an allenylidene-ene type pathway have been successfully applied to an enantioselective intramolecular cyclization for a variety of chiral heterocycles such as chromane, thiochromane, and 1,2,3,4-tetrahydroquinoline derivatives (up to 99% ee) by use of a suitable optically active diruthenium complex as a catalyst. The methodology described in this paper becomes a novel synthetic approach to chiral heterocycles, the structures of which are widely found in many natural and biologically active compounds.     

Access to P‐ and Axially Chiral Biaryl Phosphine Oxides by Enantioselective CpxIrIII‐Catalyzed C−H Arylations

An enantioselective C?H arylation of phosphine oxides with o‐quinone diazides catalyzed by an iridium(III) complex bearing an atropchiral cyclopentadienyl (Cp^x) ligand and phthaloyl tert‐leucine as co‐catalyst is reported. The method allows access to a) P‐chiral biaryl phosphine oxides, b) atropo‐enantioselective construction of sterically demanding biaryl backbones, and also c) selective assembly of axial and P‐chiral compounds in excellent yields and diastereo‐ and enantioselectivities. Enantiospecific reductions provide monodentate chiral phosphorus(III) compounds having structures and biaryl backbones with proven importance as ligands in asymmetric catalysis.     

Squaramide-catalyzed enantioselective Michael addition of malononitrile to chalcones

A highly enantioselective Michael addition of malononitrile to chalcones catalyzed by a chiral quinine-derived squaramide catalyst has been developed. This organocatalytic reaction at a very low catalyst loading (0.5 mol%) led to chiral γ-cyano carbonyl compounds in good yields with high enantioselectivities (up to 96% ee) under mild reaction conditions.     

Synthesis of Novel Chiral Phosphoric Acid‐Bearing Two Acidic Phenolic Hydroxyl Groups and its Catalytic Evaluation for Enantioselective Friedel‐Crafts Alkylation of Indoles and Enones

A novel chiral phosphoric acid catalyst bearing two acidic phenolic hydroxyl groups was synthesized. Its catalytic activity as a chiral Brøsted acid has been examined in the enantioselective Friedel‐Crafts alkylation of indoles and enones as a model reaction. In comparison with the other chiral phosphoric acid catalysts, the reaction catalyzed by the novel chiral catalyst afforded the desired 3‐substituted indoles in a higher enantioselectivity (up to 69% ee).     

Enantioselective synthesis of enol lactones from tandem Michael addition/lactonization catalyzed by a chiral squaramide catalyst

The enantioselective tandem Michael addition reaction of dimedone and related 1,3-dicarbonyl compounds with α,β-unsaturated N-acylated succinimides catalyzed by a chiral squaramide catalyst has been investigated. This reaction provides a new approach for the synthesis of chiral enol lactones in good yields with moderate to high enantioselectivities (up to 88% ee) through the enantioselective Michael addition followed by lactonization and removal of the succinimide auxiliary.     

Synthesis of new chiral fluorescent sensors and their applications in enantioselective discrimination

Five novel sensors (R,R)-3–6 and (S, S)-6 were synthesized and developed for enantioselective recognition of chiral compounds. Sensor 6 with two thiourea groups and steric π-conjugation frameworks could discriminate different chiral substrates, including acidic compounds, basic compounds, and neutral compounds. These results disclosed that the outstanding performance of enantioselective discrimination could be attributed to the thiourea group which acted as a hydrogen-bonding donor and the bulky steric moiety of the hosts which provided appropriate chiral environment. This result will be of great practical value in the designation of chiral sensors and high-throughput assay of chiral products.