High Enantioselectivity Research Articles

Engineering the enantioselectivity of a novel imine reductase from Streptomyces viridochromogenes for the dynamic kinetic reductive amination of cyclic β-ketoester

N-substituted β-amino esters as an important class of chiral amines, are widely used as building blocks in pharmaceuticals. A novel imine reductase SvIRED was identified through gene mining from Streptomyces viridochromogenes with high enantioselectivity of > 99 % ee (1R, 2S), 95 % de (cis:trans), towards 2-oxocyclohexane-1-carboxylate and cyclopropylamine. SvIRED exhibited the highest activity at pH 7.0 and 40 °C. A variety of amine donors could be used by SvIRED and produce chiral N-substituted β-amino esters with different enantioselectivity. Employing methylamine (i) and pyrrolidine (n) as amine donors, SvIRED exhibited reversed enantioselectivity of 23 % ee (1S, 2R) and 79 % ee (1S, 2R) respectively. Through alanine scanning, M183 and H244 were identified with remarkable roles in governing enantioselectivity towards i and n. Compared with WT SvIRED, the enantioselectivity of M183A was inverted to ee value of >99 % (1R, 2S) and de value of >99 % (cis:trans) towards i, and the enantioselectivity of H244A was inverted to ee value of 88 % (1R, 2S) and de value of >99 % (cis:trans) towards n. Interaction analysis indicated the orientation of ester group was vital for manipulation of enantioselectivity. This study provides novel Imine reductase mutants for enantioselective synthesis of N-substituted β-amino esters with different amine donors.

A concise and scalable chemoenzymatic synthesis of prostaglandins

Prostaglandins have garnered significant attention from synthetic chemists due to their exceptional biological activities. In this report, we present a concise chemoenzymatic synthesis method for several representative prostaglandins, achieved in 5 to 7 steps. Notably, the common intermediate bromohydrin, a radical equivalent of Corey lactone, is chemoenzymatically synthesized in only two steps, which allows us to complete the synthesis of prostaglandin F2α in five steps on a 10-gram scale. The chiral cyclopentane core is introduced with high enantioselectivity, while the lipid chains are sequentially incorporated through a cost-effective process involving bromohydrin formation, nickel-catalyzed cross-couplings, and Wittig reactions. This cost-efficient synthesis route for prostaglandins holds the potential to make prostaglandin-related drugs more affordable and facilitate easier access to their analogues.

Nickel-Catalyzed Hydrofluorination in Unactivated Alkenes: Regio- and Enantioselective C-F Bond Formation.

Catalytic formation of a regio- and enantioselective C-F bond chiral center from readily available alkenes is a crucial goal, yet it continues to pose significant challenges in organic synthesis. Here, we report the regioselective formation of C-F bonds facilitated by NiH catalysis and a coordination directing strategy that enables precise hydrofluorination of both terminal and internal alkenes. Notably, we have optimized this methodology to achieve high enantioselectivity in creating aliphatic C-F stereogenic centers especially with β,γ-alkenyl substrates, using a tailored chiral Bn-BOx ligand. Another pivotal finding in our research is the identification of the (+)-nonlinear effect under optimized conditions, allowing for high enantioselectivity even with moderately enantiomerically enriched chiral ligands. Given the significant role of fluorine in pharmaceuticals and synthetic materials, this research offers essential insights into the regioselective and enantioselective formation of C-F bond chiral centers, paving the way for the efficient production of valuable fluorinated compounds.

Nickel-Catalyzed Atroposelective C-H Alkylation Enabled by Bimetallic Catalysis with Air-Stable Heteroatom-Substituted Secondary Phosphine Oxide Preligands.

The catalytic asymmetric construction of axially chiral C-N atropisomers remains a formidable challenge due to their low rotational barriers and is largely reliant on toxic, cost-intensive, and precious metal catalysts. In sharp contrast, we herein describe the first nickel-catalyzed atroposelective C-H alkylation for the construction of C-N axially chiral compounds with the aid of a chiral heteroatom-substituted secondary phosphine oxide (HASPO)-ligated Ni-Al bimetallic catalyst. A wide range of alkenes, including terminal and internal alkenes, were well compatible with the reaction, providing a variety of benzimidazole derivatives in high yields and enantioselectivities (up to 97:3 e.r.). The key to success was the identification of novel HASPOs as highly effective chiral preligands. Mechanistic studies revealed the catalyst mode of action, and in-depth data science analysis elucidated the key features of the responsible chiral preligands in controlling the enantioselectivity.

Enantioselective [2π + 2σ] Cycloadditions of Bicyclo[1.1.0]butanes with Vinylazaarenes through Asymmetric Photoredox Catalysis.

Here we present a highly enantioselective [2π + 2σ] photocycloaddition of bicyclo[1.1.0]butanes (BCBs). The reaction uses a variety of vinylazaarenes as partners and is catalyzed by a polycyclic aromatic hydrocarbon (PAH)-containing chiral phosphoric acid as a bifunctional chiral photosensitizer. A wide array of pharmaceutically important bicyclo[2.1.1]hexane (BCH) derivatives have been synthesized with high yields, enantioselectivity, and diastereoselectivity. In addition to the diverse 1-ketocarbonyl-3-substituted BCBs, α/β-substituted vinylazaarenes are compatible with such an unprecedented photoredox catalytic pathway, resulting in the successful assembly of an all-carbon quaternary stereocenter or two adjacent tertiary stereocenters on the product.

Chiral Memory in Dynamic Transformation from Porous Organic Cages to Covalent Organic Frameworks for Enantiorecognition Analysis.

The preservation of chirality during a transformation process, known as the "chiral memory" effect, has garnered significant attention across multiple research disciplines. Here, we first report the retention of the original chiral structure during dynamic covalent chemistry (DCC)-induced structural transformation from porous organic cages into covalent organic frameworks (COFs). A total of six two-dimensional chiral COFs constructed by entirely achiral building blocks were obtained through the DCC-induced substitution of chiral linkers in a homochiral cage (CC3-R or -S) using achiral amine monomers. Homochirality of these COFs resulted from the construction of 3-fold-symmetric benzene-1,3,5-methanimine cores with a propeller-like configuration of one single-handedness throughout the cage-to-COF transformation. The obtained chiral COFs can be further utilized as fluorescence sensors or chiral stationary phases for gas chromatography with high enantioselectivity. The present study thus highlighted the great potential to expand the scope of functional chiral materials via DCC-induced crystal-to-crystal transformation with the chiral memory effect.

Enantioselective Zirconium-catalyzed Transformations

Abstract: The cheaper and less-toxic metals of Group 4 compared with common metals used in catalysis are increasingly applied in catalysis, resulting in the development of many novel greener transformations. Zirconium is abundant, non-toxic, and exhibits a remarkably diversified chemical reactivity among these metals. Since the first asymmetric zirconium-catalyzed reaction disclosed by Nugent in 1992, a wide variety of chiral zirconium catalysts have been proven to be capable of promoting many types of highly enantioselective transformations, spanning from standard reactions, such as Friedel‒Crafts reactions, cycloadditions, aldol reactions, Mannich reactions, epoxidations, nucleophilic additions to carbonyl compounds and derivatives, cyanations, ring-opening reactions, hydroxylations, hydroformylations, carboaluminations among others, to more modern and complex domino and tandem processes. This review aims to collect the major progress achieved in the field of enantioselective transformations of all types promoted by chiral zirconium catalysts, covering the literature since the beginning of 2003 and illustrating the power of these non-toxic catalysts to provide high enantioselectivity in almost all kinds of asymmetric organic reactions. It is divided into ten parts, focussing consecutively on enantioselective Friedel‒Crafts reactions, cycloadditions, aldol reactions, Mannich reactions, epoxidations, additions of alkylzinc reagents to imines, cyanations, ring-opening reactions, hydroxylations, and domino/ tandem reactions. The diversity of these transformations well reflects that of the products synthesized. For example, chiral indole and pyrrole derivatives were prepared from Friedel‒Crafts reactions; pyranones, pyridones and pyrazolidines from cycloadditions; β-hydroxy α-diazo carbonyl compounds, βhydroxy (thio)esters and β-hydroxy-α-amino acid derivatives from aldol reactions; β-amino (thio)esters from Mannich reactions; functionalized epoxides from epoxidations; amines from additions of alkylzinc reagents to imines; amino nitriles from cyanations; 1,2-diamines and β-vinyloxy alcohols from ring-opening processes; 2- hydroxy 1-indanones from hydroxylations; various amines, 1,3-anti-diol monoesters, β-amino esters, α,βdihydroxy acid derivatives, α-amino ketones, indoles, cyclopentane and aryl α-aminophosphonates from domino/ tandem reactions. Furthermore, the utility of these novel methodologies was demonstrated in the total synthesis of numerous essential bioactive products, such as (+)-prelactone C, (+)-9-deoxygoniopypyrone, (+)- coniine, vancomycin, (+)-fusarisetin A, mycolipenic acid, onchidin, indoxacarb, tachykinin receptor antagonists, cerebroprotecting agent MS-153, and L-erythro-sphingosine. The advances achieved in the last three decades demonstrate that the non-toxicity, abundance, and efficiency of zirconium make its application in catalysis suiting the growing demand for more environmentally benign processes, offering the real opportunity to replace other toxic and expensive metals in the near future.

Spiro-Josiphos Ligands for the Ir-Catalyzed Asymmetric Synthesis of Chiral Amines under Hydrogenation Conditions.

Transition metal-catalyzed asymmetric hydrogenation possesses unparalleled advantages to prepare chiral amines. Here we reported a novel ligand that combined Josiphos and a spirobiindane scaffold and simultaneously investigated its application in Ir-catalyzed asymmetric hydrogenation for the synthesis of chiral amines. Excellent catalytic activity (5000 TON), high enantioselectivity (up to 99% ee), and broad substrate scope (different C═N substrates) make it highly promising for both academic research and industrial applications.

Asymmetric Brominative Dearomatization of 2-Naphthols Using a Cinchona Alkaloid-Based Organocatalyst.

A cinchona alkaloid-based organocatalyst enables asymmetric brominative dearomatization of 2-naphthols, providing the corresponding bromonaphthalenones with high enantioselectivities. The first metal-free reaction can accommodate a variety of functional groups and give useful frameworks bearing a Br-containing tetrasubstituted stereogenic center.

Specific Discrimination Polymerization for Highly Isotactic Polyesters Synthesis.

Isotactic polymers have emerged with unique and excellent properties in material sciences. Specific discrimination polymerization provides an ideal pathway to achieve highly isotactic polymers from their racemic monomers, which is of great significance and a challenge in polymeric chemistry. Although an enantioselective catalyst-mediated asymmetric kinetic resolution polymerization (AKRP) process makes it possible, a general and well-defined strategy for catalyst design is still rarely reported. Here, based on a novel dual-ligand strategy, a new type of chiral (BisSalen)Al complex with high enantioselectivity has been described, in which perfect AKRP of racemic phenethylglycolide (Pegl) is achieved for the first time. The more confined asymmetric microenvironment formed by a dual ligand is the key to improve the enantioselectivity of the original catalyst. To illustrate the generality of this strategy, a series of (BisSalen)Al complexes with homo- or heterodual ligands were designed for the AKRP of Pegl.

Chiral Phenol‐2NO Ligand Cooperation with Achiral Organic Base in the Zn(II)‐Catalyzed Asymmetric Alkylation Reaction of Indoles

Comprehensive SummaryThe privileged C2‐symmetric rigid phenol‐type ligand is more attractive but challenging in asymmetric catalysis. Herein, we designed and synthesized a class of rigid‐featured chiral tridentate Phenol‐2NO ligands, that incorporate the advantages of both the phenol skeleton and pyrroloimidazolone‐based N‐oxide moiety, from readily available L‐prolinamides in operationally simple two steps and up to 44% overall yield. More importantly, using an achiral quinoline derivative as an additive, the newly developed Phenol‐2NO ligand could serve as the anioic ligand upon deprotonative activation to coordinate to Zn(II) to form a highly enantioselective catalyst for the asymmetric Michael‐type Friedel‐Crafts alkylation reaction of indoles with 2,3‐dioxopyrrolidines. Excellent yields (up to 90%) and high enantioselectivities (up to 99% ee) are obtained for a wide range of substrates under mild conditions. Experiments and DFT calculations revealed the reaction mechanism and the origins of the enantioselectivity. This also represented the first activation of phenol‐type ligand/metal complex by an achiral organic base as the additive in asymmetric catalysis.

Tridentate Sulfoxide-N-olefin Hybrid Ligands in Rhodium-Catalyzed Asymmetric Allylic Substitution.

A well-defined tridentate chiral sulfoxide-N-olefin ligand has been designed and applied in rhodium-catalyzed asymmetric allylic substitutions of racemic allylic carbonates, providing the branched allylic products in good yields with good to high enantioselectivities and excellent regioselectivities. This reaction mechanism, which involves the possible hemilability of olefin coordination on sulfoxide-N-olefin hybrid ligands with rhodium, is elaborated as well.

Kinetic Resolution of Sulfoximines via Asymmetric Organocatalyzed Formation of Benzothiadiazine-1-oxides.

A catalytic kinetic resolution of sulfoximines has been developed through chiral phosphoric acid-catalyzed intramolecular dehydrative cyclizations. A variety of racemic sulfoximines bearing an ortho-amidophenyl moiety underwent asymmetric dehydrative cyclizations using this method, yielding both the recovered sulfoximines and benzothiadiazine-1-oxide products with good to high enantioselectivities (with s-factor up to 61). The diverse derivatizations of the chiral products into a wide range of S-stereogenic center-containing S,N-heterocycles have demonstrated the value of this method.

Chiral Covalent Organic Cages: Structural Isomerism and Enantioselective Catalysis.

Covalent organic cages are a prominent class of discrete porous architectures; however, their structural isomerism remains relatively unexplored. Here, we demonstrate the structural isomerism of chiral covalent organic cages that renders distinct enantioselective catalytic properties. Imine condensations of tetra-topic 5,10-di(3,5-diformylphenyl)-5,10-dihydrophenazine and ditopic 1,2-cyclohexanediamine produce two chiral [4 + 8] organic cage isomers with totally different topologies and geometries that depend on the orientations of four tetraaldehyde units with respect to each other. One isomer (PN-1) has an unprecedented Johnson-type J26 structure, whereas another (PN-2) adopts a tetragonal prismatic structure. After the reduction of the imine linkages, the cages are transformed into two amine bond-linked isomers PN-1R and PN-2R. After binding to Ni(II) ions, both can serve as efficient catalysts for asymmetric Michael additions, whereas PN-2R affords obviously higher enantioselectivity and reactivity than PN-1R presumably because of its large cavity and open windows that can concentrate reactants for the reactions. Density-functional theory (DFT) calculations further confirm that the enantioselective catalytic performance varies depending on the isomer.

Rhodium-Catalyzed Asymmetric Macrocyclization towards Crown Ethers Using Hydroamination of Bis(allenes).

Enantiomerically enriched crown ethers (CE) exhibit strong asymmetric induction in phase transfer catalysis, supramolecular catalysis and molecular recognition processes. Traditional methods have often been used to access these valuable compounds, which limit their diversity and consequently their applicability. Herein, a practical catalytic method is described for the gram scale synthesis of a class of chiral CEs (aza-crown ethers; ACEs) using Rh-catalyzed hydroamination of bis(allenes) with diamines. Using this approach, a wide range of chiral vinyl functionalized CEs with ring sizes ranging from 12 to 36 have been successfully prepared in high yields of up to 92 %, dr of up to >20 : 1 and er of up to >99 : 1. These vinyl substituted CEs allow for further diversification giving facile access to various CE derivatives as well as to their three-dimensional analogues using ring-closing metathesis. Some of these chiral CEs themselves display high potential for use in asymmetric catalysis.

Rhodium‐Catalyzed Asymmetric Macrocyclization towards Crown Ethers Using Hydroamination of Bis(allenes)

AbstractEnantiomerically enriched crown ethers (CE) exhibit strong asymmetric induction in phase transfer catalysis, supramolecular catalysis and molecular recognition processes. Traditional methods have often been used to access these valuable compounds, which limit their diversity and consequently their applicability. Herein, a practical catalytic method is described for the gram scale synthesis of a class of chiral CEs (aza‐crown ethers; ACEs) using Rh‐catalyzed hydroamination of bis(allenes) with diamines. Using this approach, a wide range of chiral vinyl functionalized CEs with ring sizes ranging from 12 to 36 have been successfully prepared in high yields of up to 92 %, dr of up to >20 : 1 and er of up to >99 : 1. These vinyl substituted CEs allow for further diversification giving facile access to various CE derivatives as well as to their three‐dimensional analogues using ring‐closing metathesis. Some of these chiral CEs themselves display high potential for use in asymmetric catalysis.

Enantioselective Construction of C−SCF3 Stereocenters via Nickel Catalyzed Asymmetric Negishi Coupling Reaction

AbstractThe construction of the SCF3‐containing 1,1‐diaryl tertiary carbon stereocenters with high enantioselectivities is reported via a nickel‐catalyzed asymmetric C−C coupling strategy. This method demonstrates simple operations, mild conditions and excellent functional group tolerance, with newly designed SCF3‐containing synthon, which can be easily obtained from commercially available benzyl bromide and trifluoromethylthio anion in a two‐step manner. Further substrate exploration indicated that the reaction system could be extended to diverse perfluoroalkyl sulfide (SC2F5, SC3F7, SC4F9, SCF2CO2Et)‐substituted 1,1‐diaryl compounds with excellent enantioselectivities. The synthetic utility of this transformation was further demonstrated by convenient derivatization to optical SCF3‐containing analogues of bioactive compounds without an apparent decrease in enantioselectivity.

Enantioselective Construction of C-SCF3 Stereocenters via Nickel Catalyzed Asymmetric Negishi Coupling Reaction.

The construction of the SCF3-containing 1,1-diaryl tertiary carbon stereocenters with high enantioselectivities is reported via a nickel-catalyzed asymmetric C-C coupling strategy. This method demonstrates simple operations, mild conditions and excellent functional group tolerance, with newly designed SCF3-containing synthon, which can be easily obtained from commercially available benzyl bromide and trifluoromethylthio anion in a two-step manner. Further substrate exploration indicated that the reaction system could be extended to diverse perfluoroalkyl sulfide (SC2F5, SC3F7, SC4F9, SCF2CO2Et)-substituted 1,1-diaryl compounds with excellent enantioselectivities. The synthetic utility of this transformation was further demonstrated by convenient derivatization to optical SCF3-containing analogues of bioactive compounds without an apparent decrease in enantioselectivity.

Molecular basis for the high enantioselectivity of the Ser47Leu variant of Candida antarctica lipase B toward (R)-But-3-yn-2-ol

It is known that Candida antarctica lipase B (CAL-B) exhibits low enantioselectivity towards sec-alcohols bearing small substituents such as (±)-but-3-yn-2-ol (E = 5.4) or (±)-butan-2-ol (E = 7), although it possesses high enantioselectivity towards various chiral sec-alcohols. In a previous study, we reported that the Ser47Asn variant, prepared based on the sequence of a homologous enzyme (lipase from Pseudozyma brasiliensis GHG001, PBL), exhibits high enantioselectivity towards (R)-but-3-yn-2-ol (E > 200). However, the molecular basis of high enantioselectivity was unclear because the residue is quite distant from the substituents, making it challenging to establish any interaction. In this study, we prepared a series of variants at the Ser47 residue to understand the molecular basis. We introduced Asp, Glu, Gln, and Leu at the position 47 and found that the Ser47Leu variant also exhibits high enantioselectivity (E > 200). We conducted a molecular dynamics study to elucidate its high enantioselectivity. The introduced leucine shifted the side chain of Trp104, which is a component for constructing the binding pocket for medium substituents, thereby interfering with the binding of the larger substituent of the slow enantiomer.

Pd(0)-Catalyzed Asymmetric Cyclization/Coupling Cascade of Alkyne-Tethered Unsaturated Carbonyls: Development and Mechanism Elucidation.

While the Pd(0)-catalyzed cyclization of alkyne-tethered unsaturated carbonyl substrates has been reported, the mechanism has not been well elucidated, and the potential asymmetric version remains to be developed. Here, we disclose that a chiral Pd(0) complex can efficiently promote the desymmetrizative cyclization of alkyne-tethered cyclohexadienones in CH3OH, and the resultant Pd(II) intermediates further undergo an array of tandem coupling reactions, including Suzuki, Sonogashira, and even chemoselective reduction by CH3OH in the absence of additional coupling partners. As a result, a broad spectrum of hydrobenzofuran derivatives, having a tetra- or trisubstituted exo-alkene motif, is constructed with moderate to outstanding enantioselectivity in an exclusive cis-difunctionalization pattern. In addition, this enantioselective protocol can be well expanded to linear alkyne-tethered unsaturated carbonyls, and a new desymmetrizative and asymmetric cyclization/coupling cascade of bis-alkyne-tethered enones is further realized efficiently, furnishing diversely structured frameworks with high stereoselectivity. Moreover, kinetic transformation for various racemic alkyne-tethered enones can be accomplished under similar catalytic conditions, and unusual kinetic reactions by chemoselectively undertaking Suzuki or Sonogashira coupling, or reduction by CH3OH, occur sequentially, finally yielding two types of chiral products, both with high enantioselectivity via either ligand- or substrate-based control. The experimental results demonstrate that the current Pd(0)-based strategy is superior to the classical Pd(II)-catalyzed carbopalladation/cyclization process of the identical substrates with regard to enantioselectivity and synthetic versatility. Moreover, density functional theory calculations are conducted to rationalize the Pd(0)-catalyzed oxidative cyclometalation pathway in the key cyclization step, which leads to the observed cis-difunctionalized products exclusively.