Chiral Ligands For Asymmetric Catalysis Research Articles

Nickel-Catalyzed Atroposelective Cross-Electrophile Coupling of Aryl Halides: A General and Practical Route to Diverse MOP-Type Ligands.

We report a highly cross- and atroposelective coupling between ortho-(chloro)arylphosphine oxides and ortho-(bromo)aryl ethers. This previously unknown asymmetric nickel-catalyzed reaction offers a direct route to highly enantioenriched axially chiral biaryl monophosphine oxides that are difficult to access by other means. These products can be readily reduced to generate chiral MOP-type ligands bearing complex skeletal backbones. The utility of these chiral ligands in asymmetric catalysis is also demonstrated.

Carbene-Catalyzed Atroposelective Construction of Chiral Diaryl Ethers.

Atropoisomeric chemotypes of diaryl ethers-related scaffolds are prevalent in naturally active compounds. Nevertheless, there remains considerable research to be carried out on the catalytic asymmetric synthesis of these axially chiral molecules. In this instance, we disclose an N-heterocyclic carbene (NHC)-catalyzed synthesis of axially chiral diaryl ethers via atroposelective esterification of dialdehyde-containing diaryl ethers. NHC desymmetrization produces axially chiral diaryl ether atropisomers with high yields and enantioselectivities in moderate circumstances. Chiral diaryl ether compounds may be precursors for highly functionalized diaryl ethers with bioactivity and chiral ligands for asymmetric catalysis.

Design and Application of New Pyridine-Derived Chiral Ligands in Asymmetric Catalysis.

ConspectusThe innovation of chiral ligands has been crucial for the asymmetric synthesis of functional molecules, as demonstrated by several types of widely applied "privileged" ligands. In this context, chiral pyridine-derived ligands, by far some of the oldest and most widely utilized ligands in catalysis, have attracted considerable research interest in the past half-century. However, the development of broadly applicable chiral pyridine units (CPUs) has been plagued by several intertwining challenges, thus delaying advancements in many asymmetric reactions.This Account aims to summarize the recent progress in new CPU-containing ligands, focusing on a rationally designed, modular, and tunable CPU developed in our laboratory. A significant problem thwarting conventional designs is the paradox between broad reactivity and stereoselectivity; that is, while enhanced stereoselectivity may be achieved by introducing chiral elements close to the N atom, the concomitant increase in local steric hindrance often limits catalytic activity and scope. Our newly developed CPU features a rigid [6-5-3] fused-ring framework and a tunable spirocyclic ketal side wall. The well-defined three-dimensional structure minimizes local (inner layer) steric hindrance and tunes the peripheral environment (outer layer) by remote substituents, thus securing reactivity and stereoselectivity. Different chelating ligands were readily assembled using this chiral structural module, with applications in mechanistically diverse transition-metal-catalyzed reactions. Thus, a series of chiral 2,2'-bipyridine ligands were successfully employed in the development of a general, efficient, and highly enantioselective nickel-catalyzed intermolecular reductive addition, Ullmann coupling of ortho-chlorinated aryl aldehydes, and carboxylation of benzylic (pseudo)halides with CO2. Notably, these chiral 2,2'-bipyridine ligands exhibited superior catalytic activity in the reactions compared to common N-based ligands. In addition, highly enantioselective iridium-catalyzed C-H borylation was developed using a CPU-containing N,B-bidentate ligand. Furthermore, mechanistically challenging, additive-free, and broad-scope transfer hydrogenative direct asymmetric reductive amination was achieved using a half-sandwich iridium catalyst supported by a chiral N,C-bidentate ligand. The new ligands demonstrated excellent performance in securing high catalytic activity and stereoselectivity, which, when combined with experimental and computational mechanistic investigations, supported the "double-layer control" design concept.Considering the broad applications of pyridine-derived ligands, the research progress described herein should inspire the creation of novel chiral catalysts and drive the development of many catalytic asymmetric reactions.

Cr-Catalyzed Asymmetric Cross Aza-Pinacol Couplings for β-Amino Alcohol Synthesis.

Chiral β-amino alcohols are crucial structural motifs found in pharmaceuticals, natural products, and chiral ligands in asymmetric catalysis. Despite previous advances, the development of catalytic approaches to access β-amino alcohols bearing vicinal stereocenters from readily available chemicals remains a prominent challenge. Herein, we describe the Cr-catalyzed asymmetric cross aza-pinacol coupling of aldehydes and N-sulfonyl imines. This protocol proceeds in a radical-polar crossover manner from the intermediacy of an α-amino radical instead of a ketyl radical. Key to the success is using a chiral chromium catalyst, which plays a triple role in the chemoselective single-electron reduction of the imine, fast radical interception to inhibit radical addition to imines, and chemo- and stereoselective addition to aldehydes instead of imines. This method provides a modular and efficient approach to accessing diverse β-amino alcohols bearing vicinal stereocenters.

Fe-Catalyzed Amidation of Allylic Alcohols by Borrowing Hydrogen Catalysis.

Allylic amines are useful building blocks in organic synthesis, so the development of green and efficient methods for the preparation of allylic amines are of great importance. An Fe-catalyzed amidation of allylic alcohols with chiral tert-butylsulfinamide has been developed. With water as the only by-product, a range of synthetically useful chiral sulfinamide olefin derivatives (30 examples) were obtained under mild reaction conditions. The reaction can be performed on a gram-scale, and the products could serve as chiral ligands for asymmetric catalysis. Mechanistic studies suggest that the reaction proceeds by an Fe-catalyzed borrowing hydrogen process, which is different from most of the reported allylic amination reactions.

Conformationally locked cis-1,2-diaminocyclohexane-based chiral ligands for asymmetric catalysis

An efficient synthesis for a new conformationally locked chiral cis-1,2-diaminocyclohexane scaffold has been developed. The conformational lock allows for convenient symmetrical derivatization of the amino groups through the reductive amination strategy. A series of optically pure chiral ligands based on the cis-DACH scaffold has been generated to demonstrate a proof-of-concept for these ligands as chiral catalysts in the asymmetric Henry reaction. Excellent yields with moderate enantioselectivity were demonstrated at room temperature, with an increase in enantioselectivity at lower temperatures, showing the potential of this new type of cis-DACH ligand.

Asymmetric Synthesis of Axially Chiral C-N Atropisomers.

Molecules with restricted rotation around a single bond or atropisomers are found in a wide number of natural products and bioactive molecules as well as in chiral ligands for asymmetric catalysis and smart materials. Although most of these compounds are biaryls and heterobiaryls displaying a C−C stereogenic axis, there is a growing interest in less common and more challenging axially chiral C−N atropisomers. This review offers an overview of the various methodologies available for their asymmetric synthesis. A brief introduction is initially given to contextualize these axially chiral skeletons, including a historical background and examples of natural products containing axially chiral C−N axes. The preparation of different families of C−N based atropisomers is then presented from anilides to chiral five‐ and six‐membered ring heterocycles. Special emphasis has been given to modern catalytic asymmetric strategies over the past decade for the synthesis of these chiral scaffolds. Applications of these methods to the preparation of natural products and biologically active molecules will be highlighted along the text.

Optical resolution of 1,16-dihydroxytetraphenylene by chiral gold(iii) complexation and its applications as chiral ligands in asymmetric catalysis.

We report herein a novel approach involving optical resolution of (±)-1,16-dihydroxytetraphenylene (DHTP) by chiral gold(iii) complexation. This method features several key advantages, i.e., recyclability of chiral resolution reagents, feasibility of scaling up to gram quantities, and operational simplicity. On the basis of this method, which led to optically pure DHTP, a library of 2,15-diaryl (S)-DHTPs and several (S)-DHTP-derived phosphoramidite ligands were synthesized. Finally, the superior performance of a (S)-DHTP phosphoramidite ligand was demonstrated by efficient iridium-catalyzed asymmetric allylic alkynylation reactions.

Conformationally Locked Cis-1,2-Diaminocyclohexane-Based Axially Chiral Ligands for Asymmetric Catalysis

Conformationally Locked Cis-1,2-Diaminocyclohexane-Based Axially Chiral Ligands for Asymmetric Catalysis

Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds.

In recent years, the synthesis of axially chiral compounds has received considerable attention due to their extensive application as biologically active compounds in medicinal chemistry and as chiral ligands in asymmetric catalysis. Chiral phosphoric acids are recognized as efficient organocatalysts for a variety of enantioselective transformations. In this review, we summarize the recent development of chiral phosphoric acid-catalyzed synthesis of a wide range of axially chiral biaryls, heterobiaryls, vinylarenes, N-arylamines, spiranes, and allenes with high efficiency and excellent stereoselectivity.

New Nitrogen, Sulfur-, and Selenium-Donating Ligands Derived from Chiral Pyridine Amino Alcohols. Synthesis and Catalytic Activity in Asymmetric Allylic Alkylation

Although many chiral ligands for asymmetric catalysis have been developed, there is still a need for new structures allowing the modular approach. Recently, easy synthesis of chiral pyridine-containing β-amino alcohols has been elaborated by opening respective epoxides with enantiomeric 1-phenylethylamine. This paper reports the synthetic transformation of β-amino alcohols into the new complexing pyridine-containing seleno- and thioethers. The amino alcohols were effectively converted to cyclic sulfonamidates, which were reacted with thiolates or phenyl selenide nucleophile. The reaction was diastereoselective, and its outcome depended on the configuration at the substitution center. The problem was discussed considering DFT optimized structures of both diastereomeric sulfonamidates. New amino-aldimine ligands were also synthesized from chiral pyridine-containing diamines. Nine new chiral ligands were tested in the Tsuji-Trost allylic alkylation resulting in the enantiomerically enriched product in up to 75% ee. The observed stereochemical induction agrees with the prevailing nucleophilic attack at the allylic carbon laying opposite to the complexing nitrogen of pyridine in η3-allylic intermediate complexes.

Enantioselective C-H Alkenylation of Ferrocenes with Alkynes by Half-Sandwich Scandium Catalyst.

The enantioselective C-H alkenylation of ferrocenes with alkynes is, in principle, a straightforward and atom-efficient route for the construction of planar-chiral ferrocene scaffolds bearing alkene functionality but has remained scarcely explored to date. Here we report for the first time the highly enantioselective C-H alkenylation of quinoline- and pyridine-substituted ferrocenes with alkynes by a half-sandwich scandium catalyst. This protocol features broad substrate scope, high enantioselectivity, and 100% atom efficiency, selectively affording a new family of planar-chiral ferrocenes bearing N/alkene functionalities. The mechanistic details have been clarified by DFT analyses. The use of a quinoline/alkene-functionalized ferrocene product as a chiral ligand for asymmetric catalysis is also demonstrated.

A One‐Pot Two‐Step Enzymatic Pathway for the Synthesis of Enantiomerically Enriched Vicinal Diols

AbstractEnantiomerically enriched 1,2‐diols are prominent compounds that find numerous applications in organic chemistry. They are privileged building blocks for the synthesis of APIs (Active Pharmaceutical Ingredients), broadly used as chiral ligands in asymmetric catalysis, and efficient auxiliaries employed to control the stereochemical outcome of total synthesis. Among the number of strategies developed for the preparation of these molecules, enzyme mediated reactions have gained a crucial role in the toolbox of organic chemists for their high efficiency and sustainability. Herein we describe a one‐pot two‐step protocol designed by combining a thiamine diphosphate (ThDP)‐dependent lyase and a NADH‐dependent reductase. The ThDP‐dependent acetoin:dichlorophenolindophenol oxidoreductase (Ao : DCPIP OR) is exploited to produce enantioenriched α‐hydroxyketones through the benzoin‐type condensation of methylacetoin with either aldehydes or activated ketones. The enantioenriched α‐hydroxyketones undergo the selective reduction into the corresponding 1,2‐diols in the same reaction mixture due to the addition of NAD+ and of the NADH‐dependent acetylacetoin reductase (AAR). Sodium formate was selected as the sacrificial reductive reactant to generate and recycle in situ the precious NADH by formate‐dehydrogenase. Unprecedented reported details on the cloning and expression of the AAR are reported as well.

Catalytic Lewis and Brønsted acid syn-diastereoselective benzylic substitutions of α-hydroxy-β-nitro- and α-hydroxy-β-azido-alkyl arenes

A series of alkyl and alkenyl p-methoxy arenes containing α,β-disubstituted diamino and amino alcohol groups were synthesized from β-nitro and β-azido benzylic alcohols in the presence of AuCl3 as catalyst. The formation of predominantly syn-disubstituted products were rationalized on the basis of mechanistic considerations and transition state models relying on A1,3-allylic strain. The products could have utility in the design of medicinally relevant compounds and as chiral ligands for asymmetric catalysis. A new synthesis of (+)-sertraline (Zoloft) was achieved.

Rapid Synthesis of Chiral 1,2-Bisphosphine Derivatives through Copper(I)-Catalyzed Asymmetric Conjugate Hydrophosphination.

1,2-Bisphosphines have been identified as one class of important and powerful chiral ligands in asymmetric catalysis with transition metals. Herein, a copper(I)-catalyzed asymmetric hydrophosphination of α,β-unsaturated phosphine sulfides was developed with the assistance of "soft-soft" interaction between copper(I)-catalyst and the phosphine sulfide moiety, which afforded 1,2-bisphosphine derivatives with diversified electronic nature and steric hindrance in high to excellent yields with high to excellent enantioselectivity. Moreover, the challenging catalytic asymmetric hydrophosphination/protonation reaction was achieved with excellent enantioselectivity. Strikingly, the dynamic kinetic resolution of racemic diarylphosphines was also successfully carried out with high to excellent diastereo- and enantioselectivities. Interestingly, the nucleophilic copper(I)-diphenylphosphide species was characterized by 31 P NMR spectrum and mass spectrum. At last, three products were transformed to chiral 1,2-bisphosphines, which were employed as ligands in Rh-catalyzed asymmetric hydrogenation of α-amino-α,β-unsaturated ester. The α-amino acid derivative was produced in high enantioselectivity, which demonstrated the utility of the present methodology.

Rapid Synthesis of Chiral 1,2‐Bisphosphine Derivatives through Copper(I)‐Catalyzed Asymmetric Conjugate Hydrophosphination

Abstract1,2‐Bisphosphines have been identified as one class of important and powerful chiral ligands in asymmetric catalysis with transition metals. Herein, a copper(I)‐catalyzed asymmetric hydrophosphination of α,β‐unsaturated phosphine sulfides was developed with the assistance of “soft–soft” interaction between copper(I)‐catalyst and the phosphine sulfide moiety, which afforded 1,2‐bisphosphine derivatives with diversified electronic nature and steric hindrance in high to excellent yields with high to excellent enantioselectivity. Moreover, the challenging catalytic asymmetric hydrophosphination/protonation reaction was achieved with excellent enantioselectivity. Strikingly, the dynamic kinetic resolution of racemic diarylphosphines was also successfully carried out with high to excellent diastereo‐ and enantioselectivities. Interestingly, the nucleophilic copper(I)‐diphenylphosphide species was characterized by 31P NMR spectrum and mass spectrum. At last, three products were transformed to chiral 1,2‐bisphosphines, which were employed as ligands in Rh‐catalyzed asymmetric hydrogenation of α‐amino‐α,β‐unsaturated ester. The α‐amino acid derivative was produced in high enantioselectivity, which demonstrated the utility of the present methodology.

Chiral Bis(oxazoline) Ligands as C2-Symmetric Chiral Auxiliaries for the Synthesis of Enantiomerically Pure Bis-Cyclometalated Rhodium(III) Complexes

The synthesis of enantiomerically pure bis-cyclometalated rhodium(III) complexes using chiral bis(oxazoline) ligands as C2-symmetric chiral auxiliaries is described. Bis(oxazolines) are versatile chiral ligands for asymmetric catalysis but have not been applied to the resolution of racemic mixtures of transition-metal complexes. Due to their C2 symmetry, chiral bis(oxazolines) are particularly useful for the synthesis of nonracemic transition-metal complexes with lower symmetry, and this is demonstrated with the synthesis of an enantiomerically pure rhodium(III) complex containing two different cyclometalated ligands.

Atroposelective Construction of Arylindoles by Chiral Phosphoric Acid-Catalyzed Cross-Coupling of Indoles and Quinones.

Structurally novel atropisomeric arylindole frameworks have been successfully constructed through chiral phosphoric acid-catalyzed asymmetric cross-coupling of indoles and quinone derivatives in a precise regioselective manner. This approach features high convergence and functional group tolerance to efficiently deliver diverse heteroaryl atropisomers with excellent enantiocontrol. The dominant formation of axial chirality but not central chirality, as the major unmet challenge for this type of reactions, was conquered by the rational and accurate modulation of the electronic and steric effects on both coupling partners. Preliminary investigation demonstrated the practicality of such axially chiral arylindoles as chiral ligands in asymmetric catalysis.

A one-pot electrophilic cyanation–functionalization strategy for the synthesis of disubstituted malononitriles

Malononitriles are valuable synthetic intermediates for many applications, including the synthesis of herbicides and other biologically active molecules, and the synthesis of chiral ligands for asymmetric catalysis. This article describes the development of a procedure for the conversion of primary nitriles to malononitriles using dimethylmalononitrile, a commercial, non-toxic, carbon-bound source of electrophilic cyanide. This procedure avoids the use of toxic cyanide or malononitrile as a starting material. This protocol is further applied to the dicyanation of benzyl Grignard reagents, generated from benzyl bromides, yielding fully functionalized malononitriles from a nitrile-free precursor.

Phosphoric acid-catalyzed atroposelective construction of axially chiral arylpyrroles

Axially chiral arylpyrroles are key components of pharmaceuticals and natural products as well as chiral catalysts and ligands for asymmetric transformations. However, the catalytic enantioselective construction of optically active arylpyrroles remains a formidable challenge. Here we disclose a highly efficient strategy to access enantioenriched axially chiral arylpyrroles by means of organocatalytic atroposelective desymmetrization and kinetic resolution. Depending on the remote control of chiral catalyst, the arylpyrroles were obtained in high yields and excellent enantioselectivities under mild reaction conditions. This strategy tolerates a wide range of functional groups, providing a facile avenue to approach axially chiral arylpyrroles from simple and readily available starting materials. Selected arylpyrrole products proved to be efficient chiral ligands in asymmetric catalysis and also important precursors for further synthetic transformations into highly functionalized pyrroles with potential bioactivity, especially the axially chiral fully substituted arylpyrroles.