High Enantioselectivity Research Articles

Asymmetric Bromination/Semipinacol Rearrangement Enabled by Brønsted Acids of Stereogenic-at-Cobalt(III) Complexes.

On the basis of the chiral ion pair between catalytic anionic stereogenic-at-cobalt(III) complexes and halonium ion intermediates, an asymmetric halogenation/semipinacol rearrangement reaction has been established using N-bromosuccinimide as the halogen source. This protocol provides an alternative approach for accessing a diverse set of chiral β-bromocycloketones in good yields with high enantioselectivities (≤96% yield, 95.5:4.5 er).

Catalytic Asymmetric Barbier Reaction of Ketones with Unactivated Alkyl Electrophiles.

The Barbier reaction is a reductive-type addition of an aldehyde or ketone with an organic electrophile in the presence of a terminal metal reductant, providing a straightforward and efficient method for carbon-carbon bond formation. This reaction possesses the advantage of circumventing the preparation of moisture- and air-sensitive organometallic reagents. However, the catalytic Barbier reaction of ketones to construct tetrasubstituted stereogenic centers is largely underdeveloped, despite its great potential for accessing synthetically challenging chiral tertiary alcohol. Particularly, the leveraging of unactivated alkyl electrophiles as coupling components is still rarely exploited. Herein, we disclose a photoredox-assisted cobalt-catalyzed asymmetric alkylative Barbier-type addition reaction of ketones to address the aforementioned challenges, thereby allowing for the construction of highly congested tetrasubstituted carbon centers. The alkyl addition fragments could be either readily accessible unactivated alkyl halides or redox-active esters generated through a decarboxylative pathway. Both types of alkyl electrophiles include primary, secondary, and tertiary ones, thus affording diverse enantioenriched tertiary alcohols with a broad substrate scope. This enantioselective protocol is applied for the expedient synthesis of core structure of Sofdra, a very recent FDA-approved drug in 2024. The newly developed bisoxazolinephosphine (NPN) ligand enables high enantioselectivity in this asymmetric reductive addition process.

Visible-light-driven photobiocatalytic synthesis of chiral sulfoxides over immobilized chloroperoxidase on magnetic yolk–shell Fe3O4@Cu-H-TiO2 photocatalyst

Chloroperoxidase (CPO) is promising for the asymmetric synthesis of sulfoxides from sulfides, owing to its high enantioselectivity under mild reaction conditions. However, suffering from the stability and recyclability issue, the application of free CPO is heavily restricted in current stage. In this work, an integrated photobiocatalyst was designed and fabricated by immobilizing CPO on a magnetically recyclable photocatalyst, Fe3O4@Cu-H-TiO2, which can supply H2O2 for CPO in situ continuously and suppress the destruction of CPO caused by excess H2O2. The obtained CPO@Fe3O4@Cu-H-TiO2 can catalyze the synthesis of enantiopure (R)-sulfoxides from sulfides with high yield up to 88% and high ee value up to >99% over this TiO2-based photobiocatalyst. The enhanced performance of the integrated photobiocatalyst is attributed to the controllable supply of H2O2, the improved stability of immobilized CPO and the enhanced proximity effect between photo- and bio- catalytic modules.

Brønsted acid catalyzed green and efficient construction of α-amino peroxides from 3-hydroxyisoindolinones and hydroperoxides

A Brønsted acid-catalyzed peroxidation of 3-hydroxyisoindolinones with hydroperoxides has been established for the first time, which constructs α-amino peroxides bearing a tetrasubstituted stereocenter in good to high yields and enantioselectivities. The transformation uses of environmentally benign solvents, and features operational simplicity, and high atom economy. The synthetic utility was demonstrated with the gram-scale reactions and further transformations of the products. Notably, preliminary bioactivity studies reveal that these valuable α-amino peroxides show potential anticancer activity.

Organocatalytic enantio- and diastereoselective synthesis of trifluoro-ethylamine allenoate derivatives containing axial and central chiralities.

Herein, we report an example of a stereoselective γ-addition reaction of trifluoromethyl ketimines to 1-alkynyl ketones mediated by an isothiourea, BTM, under mild conditions, which afforded tetrasubstituted allenes with central chiralities in high yields (up to 94% yield), good enantioselectivities (up to 91% ee), and excellent diastereoselectivities (all >20 : 1 dr). In addition, the BTM-catalyzed γ-addition reaction was successfully applied to the gram-scale reaction, and an unexpected benzopyrrolothiazine derivative was successfully converted, albeit racemic.

Catalytic asymmetric inverse-electron-demand Diels–Alder reaction of 2-pyrones with aryl enol ethers

Chiral aryl cyclohex-3-en ether scaffold is widely present in bioactive natural products and drugs. The exploitation of efficient and enantioselective methods for the construction of aryl cyclohex-3-en ether scaffold is significant. Herein we disclose a chiral N,N’-dioxide/Lewis acid complex-catalyzed asymmetric inverse-electron-demand Diels–Alder (IEDDA) reaction using electron-deficient 3-carboalkoxyl-2-pyrones and less electron-enriched aryl enol ethers as reactants. A wide range of non- and 1,2-disubstituted acyclic aryl enol ethers are applicable to deliver diverse chiral bridged bicyclic lactones in high yields and stereoselectivities (up to 95% yield, >20:1 dr, 97:3 er). The bridged bicyclic lactone core can be easily converted into chiral aryl cyclohex-3-en ether scaffold. Notably, DFT calculations revealed a stepwise and endo mechanism to explain the high enantioselectivity controlled by the cooperative effect of the steric factors and the dispersion interactions between ligands and enol ethers.

Nickel-Catalyzed Enantioselective Alkylation of Primary Phosphines.

Functional molecules derived from stereogenic phosphorus centers have important applications in the discovery of drugs and agrochemicals. They are also widely utilized as chiral ligands or organocatalysts for diverse asymmetric transformations. However, access to P-stereogenic motifs has always been regarded as a highly challenging yet desirable goal in organic synthesis. The development of general and practical methods for the stereoselective construction of synthetically versatile P(III)-stereogenic phosphines is particularly appealing but remains elusive. Herein, we describe a nickel-catalyzed asymmetric alkylation of primary phosphines with alkyl halides for the synthesis of P-stereogenic secondary phosphine-boranes with high enantioselectivity and broad substrate scope. The resulting optically active secondary phosphine-boranes allow for further stereospecific transformations, thereby establishing a modular and efficient platform for the diversity-oriented construction of P-stereogenic phosphine compounds.

Advances in Chiral Pincer Complexes: Insights and Applications in Catalytic Asymmetric Reactions.

Chiral pincer complexes, characterized by their rigid tridentate coordination framework, have emerged as powerful catalysts in asymmetric synthesis. This review provides a comprehensive overview of recent advancements in the development of chiral pincer-type ligands and their corresponding transition metal complexes. We highlight the latest progress in their application across a range of catalytic asymmetric reactions, including the (transfer) hydrogenation of polar and non-polar bonds, hydrophosphination, alkynylation, Friedel-Crafts reactions, enantioselective reductive cyclization of alkynyl-tethered cyclohexadienones, enantioselective hydrosilylation, as well as Aza-Morita-Baylis-Hillman reactions. The structural rigidity and tunability of chiral pincer complexes enable precise control over stereoselectivity, resulting in high enantioselectivity and efficiency in complex molecular transformations. As the field advances, innovations in ligand design and the exploration of new metal centers are expected to expand the scope and utility of these catalysts, bearing significant implications for the synthesis of enantioenriched compounds in pharmaceuticals, materials science, and beyond.

Direct asymmetric synthesis of β-branched aromatic α-amino acids using engineered phenylalanine ammonia lyases

β-Branched aromatic α-amino acids are valuable building blocks in natural products and pharmaceutically active compounds. However, their chemical or enzymatic synthesis is challenging due to the presence of two stereocenters. We design phenylalanine ammonia lyases (PAL) variants for the direct asymmetric synthesis of β-branched aromatic α-amino acids. Based on extensive computational analyses, we unravel the enigma behind PAL’s inability to accept β-methyl cinnamic acid (β-MeCA) as substrate and achieve the synthesis of the corresponding amino acids of β-MeCA and analogs using a double (PcPAL-L256V-I460V) and a triple mutant (PcPAL-F137V-L256V-I460V). The reactions are scaled-up using an optimized E. coli based whole-cell biotransformation system to produce ten β-branched phenylalanine analogs with high diastereoselectivity (dr > 20:1) and enantioselectivity (ee > 99.5%) in yields ranging from 41-71%. Moreover, we decipher the mechanism of PcPAL-L256V-I460V for the acceptance of β-MeCA and converting it with excellent stereoselectivity by computational simulations. Thus, this study offers an efficient method for synthesizing β-branched aromatic α-amino acids.

Recent advances in the synthesis of highly substituted imidazolidines.

Imidazolidine is a saturated heterocycle with a cyclic aminal core that can be found in natural products and biologically active molecules. Additionally, these heterocyclic compounds have been utilized as chiral ligands, N-heterocyclic carbene precursors, and catalysts in organic synthesis. This review is an attempt to compile the literature of various synthetic procedures of highly substituted imidazolidines, chiral imidazolidines with high diastereoselectivities and enantioselectivities, bis-imidazolidines, and spiro-imidazolidines, as well as their pharmacological properties during the period from 1949 to 2023.

Nickel‐Catalyzed Asymmetric Michael Addition of Acyl‐Imidazoles to Acrolein or β‐Ester Enones

AbstractAn enantioselective Michael addition of α‐substituted acyl‐imidazoles to acrolein catalyzed by a nickel‐bisoxazoline complex has been developed. The use of strong Lewis acid TMSOTf as an additive to activate the Michael acceptors proved to be vital to the success of this process. This process tolerates a wide range of acyl‐imidazoles, and a series of conjugate adducts are obtained in high yields and good enantioselectivities. Besides acrolein, β‐ester ennones are also applicable in this process affording the corresponding conjugate adducts in high yields with good diastereoselectivities and enantioselectivites in most cases. The potential utility of the reaction system is confirmed through 2 mmol‐scale reaction and derivatization experiments.

Enantioselective Decarboxylative C(sp3)-C(sp3) Cross-Coupling of Aliphatic Redox-Active Esters with gem-Borazirconocene Alkanes.

Asymmetric decarboxylative cross-couplings of carboxylic acids are powerful methods for synthesizing chiral building blocks essential in medicinal chemistry and material science. Despite their potential, creating versatile chiral alkylboron derivatives through asymmetric decarboxylative C(sp3)-C(sp3) cross-coupling from readily available primary aliphatic acids and mild organometallic reagents remains challenging. In this study, we present a visible light-induced Ni-catalyzed enantioconvergent C(sp3)-C(sp3) cross-coupling of unactivated primary aliphatic acid NHPI esters with gem-borazirconocene alkanes, producing a diverse array of valuable chiral alkylboron building blocks. The method boasts a broad substrate scope, high functional group tolerance, and the ability for late-stage modification of complex drug molecules and natural products with high enantioselectivity, showcasing its synthetic potential. Mechanistic investigations suggest a nickel-catalyzed enantioconvergent radical cross-coupling pathway, wherein the primary radical from a redox-active ester is generated through single-electron reduction with ZrIII species. This represents an unprecedented example of enantioselective radical C(sp3)-C(sp3) cross-coupling in the absence of photocatalysts.

Cinchona alkaloids-derived chiral ligands for Mn-catalyzed ATH of ketones: Improvement of enantioselectivity through π-π stacking-induced hydrogen bond

Inexpensive and readily available manganese metals combined with novel chiral ligands derived from cinchona alkaloids catalyzed the asymmetric transfer hydrogenation of aromatic ketones. All tested aromatic ketones were highly enantioselectively converted to the corresponding chiral alcohols, obtaining up to 99.4% ee. Based on control experiments and density functional theory (DFT) calculations, a plausible mechanism was discussed. During catalysis, π-π stacking in the catalyst promoted the formation of hydrogen bonds between the substrate and the catalyst, and the stronger the stacking, the stronger the hydrogen bonds, while stronger hydrogen bonds were more favourable for achieving high enantioselectivity in manganese-catalyzed asymmetric transfer hydrogenation.

Conformational Locking Induced Enantioselective Diarylcarbene Insertion into B-H and O-H Bonds Using a Cationic Rh(I)/Diene Catalyst.

Transition-metal-catalyzed enantioselective transformations of aryl/aryl carbene are inherently challenging due to the difficulty in distinguishing between two arene rings in the reaction process thus remain largely less explored. The few successful examples reported so far, without exception, have all been catalyzed by Rh(II)-complexes. Herein, we describe our successful development of a novel cationic Rh(I)/chiral diene catalytic system capable of efficient enantioselective B-H and O-H insertions with diaryl diazomethanes, allowing the access to a broad range of gem-diarylmethine boranes and gem-diarylmethine ethers in good yields with high enantioselectivities. Notably, previously unattainable asymmetric diarylcarbene insertion into the O-H bond was achieved for the first time. A remarkable feature of this newly designed Rh(I)/diene catalyst bearing two ortho-amidophenyl substitutents is that it can distinguish between two arene rings of the diaryl carbene through a stereochemically selective control of π-π stacking interactions. DFT calculations indicate that the rotation-restricted conformation of Rh(I)/diene complex played an important role in the highly enantioselective carbene transformations. This work provides an interesting and unprecedented stereocontrol mode in diaryl metal carbene transformations.

Synthesis of chiral sulfilimines by organocatalytic enantioselective sulfur alkylation of sulfenamides.

Sulfilimines are versatile synthetic intermediates and important moieties in bioactive molecules. However, their applications in drug discovery are underexplored, and efficient asymmetric synthetic methods are highly desirable. Here, we report a transition metal-free pentanidium-catalyzed sulfur alkylation of sulfenamides with exclusive chemoselectivity over nitrogen and high enantioselectivity. The reaction conditions were mild, and a wide range of enantioenriched aryl and alkyl sulfilimines were obtained. The synthetic utility and practicability of this robust protocol were further demonstrated through gram-scale reactions and late-stage functionalization of drugs.

N-Heterocyclic Carbene-Catalyzed Asymmetric SN2 Alkylation via Noncovalent Activation.

The field of asymmetric catalysis has been developed by exploring noncovalent interactions, particularly within N-heterocyclic carbene-mediated processes. Despite challenges due to the limited number of compatible electrophiles (predominantly π-acceptors), this study introduces the first asymmetric α-alkylation of 3-aryl oxindoles using Csp3 electrophiles. The innovative protocol integrates diverse oxindoles and alkyl, allyl, and propargyl electrophiles, achieving high yields and enantioselectivities. Preliminary mechanistic explorations support a noncovalent catalytic mechanism, enhancing the tool kit for constructing complex chiral molecules with potential applications.

Stereospecific supramolecular polymerization of nanoclusters into ultra-long helical chains and enantiomer separation

During the construction of supramolecular polymers of smaller nanoparticles/nanoclusters bearing hierarchy and homochirality, the mechanism understanding via intuitive visualization and precise cross-scale chirality modulation is still challenging. For this goal, a cooperative self-assembly strategy is here proposed by using ionic complexes with uniform chemical composition comprising polyanionic nanocluster cores and surrounded chiral cationic organic components as monomers for supramolecular polymerization. The single helical polymer chains bearing a core-shell structure at utmost length over 20 μm are demonstrated showing comparable flexibility resembling covalent polymers. A nucleation-elongation growth mechanism that is not dealt with in nanoparticle systems is confirmed to be accompanied by strict chiral self-sorting. A permeable membrane prepared by simple suction of such supramolecular polymers displays high enantioselectivity (e.e. 98% after four runs) for separating histidine derivatives, which discloses a benefiting helical chain structure-induced functionalization for macroscopic supramolecular materials in highly efficient racemate separation.

A General Enantioselective α-Alkyl Amino Acid Derivatives Synthesis Enabled by Cobalt-Catalyzed Reductive Addition.

Enantioenriched unnatural amino acids represent a prevalent motif in organic chemistry, with profound applications in biochemistry, medicinal chemistry, and materials science. Herein, we report a cobalt-catalyzed aza-Barbier reaction of dehydroglycines with unactivated alkyl halides to afford unnatural α-amino esters with high enantioselectivity. This catalytic reductive alkylative addition protocol circumvents the use of moisture-, air-sensitive organometallic reagents, and stoichiometric chiral auxiliaries, enabling the conversion of a variety of primary, secondary, and even tertiary unactivated alkyl halides to α-alkyl-amino esters under mild conditions, thus leading to broad functional group tolerance. The expedient access to biologically active motifs demonstrates the practicality of this protocol by reducing the number of synthetic steps and enhancing the reaction efficiency.

Copper Complexes with Protein-Based N-Donor Ligands as cis-Selective Nascent Cyclopropanases.

In this study, we aimed to develop protein-based metal ligands to catalyze cis-selective cyclopropanation using the TM1459 cupin protein superfamily. Copper complexes with TM1459 mutants containing the 3-His metal-binding site exhibited excellent diastereoselectivity in cyclopropanation reactions with styrene and ethyl diazoacetate. Further mutations in the secondary coordination sphere increased the cis-preference with t-butyl diazoacetate as the substrate with up to 80 : 20 (cis:trans ratio) and high enantioselectivity (90 % ee).

Palladium‐Catalyzed Enantioselective Migratory Hydroamidocarbonylation of Amide‐Linked Alkenes to Access Chiral α‐Alkyl Succinimides

AbstractA Pd‐catalyzed asymmetric isomerization‐hydroamidocarbonylation of amide‐containing alkenes was developed, affording a variety of chiral α‐alkyl succinimides in moderate to good yields with high enantioselectivities. The key to success was introducing bulky 1‐adamentyl P‐substitution and 2,3,5,6‐tetramethoxyphenyl group into the rigid P‐chirogenic bisphosphine ligand to create stronger steric hinderance and deeper catalytic pocket. By this approach, regio‐ or stereo‐convergent synthesis of enantiomeric succinimides from the mixture of olefin isomers was achieved.