Asymmetric Synthesis Research Articles

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.

Palladium-Catalyzed Ligand-Controlled Switchable Hetero-(5 + 3)/Enantioselective [2σ+2σ] Cycloadditions of Bicyclobutanes with Vinyl Oxiranes.

For nearly 60 years, significant research efforts have been focused on developing strategies for the cycloaddition of bicyclobutanes (BCBs). However, higher-order cycloaddition and catalytic asymmetric cycloaddition of BCBs have been long-standing formidable challenges. Here, we report Pd-catalyzed ligand-controlled, tunable cycloadditions for the divergent synthesis of bridged bicyclic frameworks. The dppb ligand facilitates the formal (5+3) cycloaddition of BCBs and vinyl oxiranes, yielding valuable eight-membered ethers with bridged bicyclic scaffolds in 100% regioselectivity. The Cy-DPEphos ligand promotes selective hetero-[2σ+2σ] cycloadditions to access pharmacologically important 2-oxabicyclo[3.1.1]heptane (O-BCHeps). Furthermore, the corresponding catalytic asymmetric synthesis of O-BCHeps with 94-99% ee has been achieved using chiral (S)-DTBM-Segphos, representing the first catalytic asymmetric cross-dimerization of two strained rings. The obtained O-BCHeps are promising bioisosteres for ortho-substituted benzenes.

Preparation of (S)-epichlorohydrin using a novel halohydrin dehalogenase by selective conformation adjustment.

Chiral epichlorohydrin (ECH) is an attractive intermediate for chiral pharmaceuticals and chemicals preparation. The asymmetric synthesis of chiral ECH using 1,3-dicholoro-2-propanol (1,3-DCP) catalyzed by a haloalcohol dehalogenase (HHDH) was considered as a feasible approach. However, the reverse ring opening reaction caused low optical purity of chiral ECH, thus severely restricts the industrial application of HHDHs. In the present study, a novel selective conformation adjustment strategy was developed with an engineered HheCPS to regulate the kinetic parameters of the forward and reverse reactions, based on site saturation mutation and molecular simulation analysis. The HheCPS mutant E85P was constructed with a markable change in the conformation of (S)-ECH in the substrate pocket and a slight impact on the interaction between 1,3-DCP and the enzyme, which resulted in the kinetic deceleration of the reverse reactions. Compared with HheCPS, the catalytic efficiency (kcat(S)-ECH/Km(S)-ECH) of the reversed reaction dropped to 0.23-fold (from 0.13 to 0.03mM-1s-1), while the catalytic efficiency (kcat(1,3-DCP)/Km(1,3-DCP)) of the forward reaction only reduced from 0.83 to 0.71mM-1s-1. With 40mM 1,3-DCP as substrate, HheCPS E85P catalyzed the synthesis of (S)-ECH with the yield up to 55.35% and the e.e. increased from 92.54 to >99%. Our work provided an effective approach for understanding the stereoselective catalytic mechanism as well as the green manufacturing of chiral epoxides.

Asymmetric aza-Henry reaction toward trifluoromethyl β-nitroamines and biological investigation of their adamantane-type derivatives

Amino acid-derived quaternary ammonium salts were successfully applied in the asymmetric aza-Henry reaction of nitromethane to N-Boc trifluoromethyl ketimines. α-Trifluoromethyl β-nitroamines were synthesized in good to excellent yields with moderate to good enantioselectivities. This reaction is distinguished by its mild conditions, low catalyst loading (1 mol%), and catalytic base. It also proceeded on a gram scale without loss of enantioselectivity. The products were transformed to a series of adamantane-type compounds containing chiral trifluoromethylamine fragments. The potent anticancer activities of these compounds against liver cancer HepG2 and melanoma B16F10 were evaluated. Six promising compounds with notable efficacy have potential for further development.

Pd-catalyzed asymmetric Larock reaction for the atroposelective synthesis of N─N chiral indoles.

Atropisomeric indoles defined by a N─N axis are an important class of heterocycles in synthetic and medicinal chemistry and material sciences. However, they remain heavily underexplored due to limited synthetic methods and challenging stereocontrol over the short N─N bonds. Here, we report highly atroposelective access to N─N axially chiral indoles via the asymmetric Larock reaction. This protocol leveraged the powerful role of chiral phosphoramidite ligand to attenuate the common ligand dissociation in the original Larock reaction, forming N─N chiral indoles with excellent functional group tolerance and high enantioselectivity via palladium-catalyzed intermolecular annulation between readily available o-iodoaniline and alkynes. The multifunctionality in the prepared chiral indoles allowed diverse post-coupling synthetic transformations, affording a broad array of functionalized chiral indoles. Experimental and computational studies have been conducted to explore the reaction mechanism, elucidating the enantio-determining and rate-limiting steps.

Asymmetric Synthesis of SCF3‐Substituted Alkylboronates by Copper‐Catalyzed Hydroboration of 1‐Trifluoromethylthioalkenes

AbstractA synthetic method for preparation of optically active trifluoromethylthio (SCF3) compounds by a copper‐catalyzed regio‐ and enantioselective hydroboration of 1‐trifluoromethylthioalkenes with H‐Bpin has been developed. The enantioselective hydrocupration of an in situ generated CuH species and subsequent boration reaction generate a chiral SCF3‐containing alkylboronate, of which Bpin moiety can be further transformed to deliver various optically active SCF3 molecules. Computational studies suggest that the SCF3 group successfully controls the regioselectivity in the reaction.

N-to-S Acyl Transfer as an Enabling Strategy in Asymmetric and Chemoenzymatic Synthesis

<i>N</i>-to-<i>S</i> Acyl Transfer as an Enabling Strategy in Asymmetric and Chemoenzymatic Synthesis

Recent advances in catalytic asymmetric synthesis

Asymmetric catalysis stands at the forefront of modern chemistry, serving as a cornerstone for the efficient creation of enantiopure chiral molecules characterized by their high selectivity. In this review, we delve into the realm of asymmetric catalytic reactions, which spans various methodologies, each contributing to the broader landscape of the enantioselective synthesis of chiral molecules. Transition metals play a central role as catalysts for a wide range of transformations with chiral ligands such as phosphines, N-heterocyclic carbenes (NHCs), etc., facilitating the formation of chiral C-C and C-X bonds, enabling precise control over stereochemistry. Enantioselective photocatalytic reactions leverage the power of light as a driving force for the synthesis of chiral molecules. Asymmetric electrocatalysis has emerged as a sustainable approach, being both atom-efficient and environmentally friendly, while offering a versatile toolkit for enantioselective reductions and oxidations. Biocatalysis relies on nature’s most efficient catalysts, i.e., enzymes, to provide exquisite selectivity, as well as a high tolerance for diverse functional groups under mild conditions. Thus, enzymatic optical resolution, kinetic resolution and dynamic kinetic resolution have revolutionized the production of enantiopure compounds. Enantioselective organocatalysis uses metal-free organocatalysts, consisting of modular chiral phosphorus, sulfur and nitrogen components, facilitating remarkably efficient and diverse enantioselective transformations. Additionally, unlocking traditionally unreactive C-H bonds through selective functionalization has expanded the arsenal of catalytic asymmetric synthesis, enabling the efficient and atom-economical construction of enantiopure chiral molecules. Incorporating flow chemistry into asymmetric catalysis has been transformative, as continuous flow systems provide precise control over reaction conditions, enhancing the efficiency and facilitating optimization. Researchers are increasingly adopting hybrid approaches that combine multiple strategies synergistically to tackle complex synthetic challenges. This convergence holds great promise, propelling the field of asymmetric catalysis forward and facilitating the efficient construction of complex molecules in enantiopure form. As these methodologies evolve and complement one another, they push the boundaries of what can be accomplished in catalytic asymmetric synthesis, leading to the discovery of novel, highly selective transformations which may lead to groundbreaking applications across various industries.

Asymmetric Aldol Reactions Catalyzed by Polymeric Self-Assembly with Side-Chain Dipeptide Pendants.

To explore the role of proline amide moieties in polymer-supported organocatalysts, side-chain l-proline-l-alanine (Pro-Ala) dipeptide-containing block copolymers were synthesized, and their catalytic potential for the aldol reaction was explored. The dipeptide monomer (Boc-Pro-Ala-HEMA) was polymerized to prepare block copolymers in the presence of hydrophilic poly(poly(ethylene glycol) methyl ether methacrylate) (PPEGMA) and hydrophobic poly(methyl methacrylate) (PMMA) macro-chain transfer agents. Boc group expulsion from the block copolymers produced double hydrophilic PPEGMA-b-P(Pro-Ala-HEMA) (1b) and amphiphilic PMMA-b-P(Pro-Ala-HEMA) (1c) polymers. The solution behaviors of the polymers were studied by various physical techniques, which showed the formation of self-assembled aggregates of 1c in water and N,N-dimethylformamide (DMF)/water solvent mixtures. These polymers are used as organocatalysts during the aldol reaction of cyclohexanone and 4-nitrobenzaldehyde in different solvent polarities, catalyst loadings, temperatures, and reaction times. This work emphasizes superior catalytic activity of 1c at lower catalyst loadings (5%) while maintaining high conversion (95%) and enantioselectivity (94%) across multiple recycling cycles in DMF/water at a 3:1 ratio (v/v).

Concise Total Synthesis of (-)-Bipolarolide D.

Here we report the first and concise total synthesis of a complex ophiobolin-derived sesterterpene, bipolarolide D, which hinges on two strategic applications of pentafulvene: (1) enantioselective pentafulvene-involved [6+2] cycloaddition; (2) regioselective and diastereoselective pentafulvene-involved Heck cyclization. Late-stage selective allylic addition to the ketone moiety facilitates the successful installation of the side chain. This strategy enabled the accomplishment of its first enantioselective total synthesis through a modular approach. This synthesis will facilitate the investigation of relevant biological activities and provide a synthetic blueprint for utilizing fulvenes as versatile synthons in other complex natural product synthesis.

Synthesis of chiral Cu(II) complexes from pro-chiral Schiff base ligand and investigation of their catalytic activity in the asymmetric synthesis of 1,2,3-triazoles

A pro-chiral Schiff base ligand (HL) was synthesized by the reaction of 2-amino-2-ethyl-1,3-propanediol and pyridine-2-carbaldehyde in methanol. The reaction of HL with CuCl2·2H2O and CuBr2 in methanol gave neutral mononuclear Cu(II) complexes with general formula of [Cu(HL)Cl2] (1) and [Cu(HL)Br2] (2), respectively. By slow evaporation of the methanolic solutions of 1 and 2, their enantiomers were isolated in crystalline format. The formation of pure chiral crystals in the racemic mixture was amply authenticated by single crystal X-ray analysis, which indicated that S-[Cu(HL)Cl2], R-[Cu(HL)Cl2], and S-[Cu(HL)Br2] are crystallized in chiral P212121 space group of orthorhombic system. Preferential crystallization was used to isolate the R and S enantiomers as single crystals and the isolated compounds were also studied by CD analysis. Structural studies indicated that the origin of the chirality in these compounds is related to the coordination mode of the employed pro-chiral ligand (HL) because one of its carbon atoms has been converted to a chiral center in the synthesized complexes. Subsequently, these complexes were used in click synthesis of a β-hydroxy-1,2,3-triazole and the results of catalytic studies indicated that 1 and 2 can act as enantioselective catalysts for the asymmetric synthesis of β-hydroxy-1,2,3-triazole product under mild condition. This study illustrates the significant capacity of the use of pro-chiral ligands in preparing chiral catalysts based on complexes which can also be considered as an effective approach to cheap chiral catalysts from achiral reagents.

Enantioselective construction of stereogenic-at-sulfur(IV) centres via catalytic acyl transfer sulfinylation.

Chiral sulfur pharmacophores are crucial for drug discovery in bioscience and medicinal chemistry. While the catalytic asymmetric synthesis of sulfoxides and sulfinate esters with stereogenic-at-sulfur(IV) centres is well developed, the synthesis of chiral sulfinamides remains challenging, which has primarily been attributed to the high nucleophilicity and competing reactions of amines. In this study, we have developed an efficient methodology for the catalytic asymmetric synthesis of chiral sulfinamides and sulfinate esters by the sulfinylation of diverse nucleophiles, including aromatic amines and alcohols, using our bifunctional chiral 4-arylpyridine N-oxides as catalysts. The remarkable results are a testament to the efficiency, versatility and broad applicability of the developed synthetic approach, serving as a valuable tool for the synthesis of sulfur pharmacophores. Mechanistic experiments and density functional theory calculations revealed that the initiation and stereocontrol of this reaction are induced by an acyl transfer catalyst. Our research provides an efficient approach for the construction of optically pure sulfur(IV) centres.

Sparteine Thiourea: The Synthesis of an N Chiral Bispidine-Quinolizidine-Derived Organocatalyst and Applications in Asymmetric Synthesis of Dihydropyrano[c]chromenes.

Bispidine, a bridged bicyclic diamine, has been widely utilized as a rigid scaffold in chiral chelating ligands in asymmetric synthesis. In particular, a chiral bispidine-quinolizidine hybrid, such as sparteine, was utilized in asymmetric synthesis involving a metal, exhibiting superior catalytic activity. In this study, we report the design and synthesis of a series of sparteine-derived organocatalysts and the utilization of these catalysts in tandem Michael addition-cyclization reactions. These catalysts have shown excellent catalytic reactivity and enantioselectivity, and the corresponding dihydropyrano[c]chromenes have been prepared in ≤99% yield and ≤99% ee with a low catalyst loading. The recycled catalysts maintain a good catalytic performance even after four cycles, and a gram-scale reaction with a 1% catalyst loading is also performed, providing the product in 96% yield and 98% ee.

Brønsted Acid Catalyzed Dehydroxylative Cyanation of Benzylic Alcohols with Trimethylsilyl Cyanide Using 1,1,1,3,3,3‐Hexafluoro‐2‐propanol as a Solvent

A concise and direct cyanation of secondary and tertiary benzylic and allylic alcohols catalyzed by Brønsted acid has been developed using trimethylsilyl cyanide (TMSCN) as a cyanide source and 1,1,1,3,3,3‐hexafluoro‐2‐propanol (HFIP) as a solvent. The present transition metal‐free catalytic process is operationally simple to perform under “open‐flask” conditions and it is applicable to the preparation of a number of α‐arylacetonitriles as well as late‐stage material transformations. The effectiveness of the present protocol was further demonstrated by the first enantioselective synthesis and determination of the absolute configuration of verimol F.

Stereoselective Synthesis of 2‐Deoxy‐α‐N‐Glycosides from Glycals with 1,4,2‐Dioxazol‐5‐ones

Comprehensive SummaryThe synthesis of N‐glycosides has received significant attention due to their crucial role in carbohydrate chemistry. Despite considerable advancements developed in the construction of N‐glycosides, methods for the stereoselective construction of 2‐deoxy‐α‐N‐glycosides are still limited. Herein, we disclosed a nickel‐catalyzed hydroamination of glycals under mild conditions. This transformation could allow for the stereoselective synthesis of an array of 2‐deoxy‐α‐N‐glycosides with excellent α‐stereoselectivity. Nickel‐catalyzed glycosylation reactions, particularly those involving anomeric C(sp3)‐metal bond formation, have proven to be an effective and stereoselective strategy for producing various N‐glycosides. Additionally, with highlight of the application of this reaction, γ‐sugar amino acid derivatives were synthesized.

Enantioselective Synthesis of Tetra-substituted 3-Hydroxyphthalide Esters by Isothiourea-Catalysed Acylative Dynamic Kinetic Resolution.

A general and highly enantioselective method for the preparation of tetra-substituted 3-hydroxyphthalide esters via isothiourea-catalysed acylative dynamic kinetic resolution (DKR) is reported. Using (2S,3R)-HyperBTM (5 mol%) as the catalyst, the scope and limitations of this methodology have been extensively probed, with high enantioselectivity and good to excellent yields observed (>40 examples, up to 99%, 99:1 er). Substitution of the aromatic core within the 3-hydroxyphthalide skeleton, as well as aliphatic and aromatic substitution at C(3)-, is readily tolerated. A diverse range of anhydrides, including those from bioactive and pharmaceutically relevant acids, can also be used. The high enantioselectivity observed in this DKR process has been probed computation, with a key substrate heteroatom donor O•••acyl-isothiouronium interaction identified through DFT analysis as necessary for enantiodiscrimination.

Engineered Phenylalanine Ammonia‐Lyases for the Enantioselective Synthesis of Aspartic Acid Derivatives

Biocatalytic hydroamination of alkenes is an efficient and selective method to synthesize natural and unnatural amino acids. Phenylalanine ammonia‐lyases (PALs) have been previously engineered to access a range of substituted phenylalanines and heteroarylalanines, but their substrate scope remains limited, typically including only arylacrylic acids. Moreover, the enantioselectivity in the hydroamination of electron‐deficient substrates is often poor. Here, we report the structure‐based engineering of PAL from Planctomycesbrasiliensis (PbPAL), enabling preparative‐scale enantioselective hydroaminations of previously inaccessible yet synthetically useful substrates, such as amide‐ and ester‐containing fumaric acid derivatives. Through the elucidation of cryo‐electron microscopy (cryo‐EM) PbPAL structure and screening of the structure‐based mutagenesis library, we identified the key active site residue L205 as pivotal for dramatically enhancing the enantioselectivity of hydroamination reactions involving electron‐deficient substrates. Our engineered PALs demonstrated exclusive a‐regioselectivity, high enantioselectivity, and broad substrate scope. The potential utility of the developed biocatalysts was further demonstrated by a preparative‐scale hydroamination yielding tert‐butyl protected l‐aspartic acid, widely used as intermediate in peptide solid‐phase synthesis.

Enantioselective Synthesis of Tetra‐substituted 3‐Hydroxyphthalide Esters by Isothiourea‐Catalysed Acylative Dynamic Kinetic Resolution

A general and highly enantioselective method for the preparation of tetra‐substituted 3‐hydroxyphthalide esters via isothiourea‐catalysed acylative dynamic kinetic resolution (DKR) is reported. Using (2S,3R)‐HyperBTM (5 mol%) as the catalyst, the scope and limitations of this methodology have been extensively probed, with high enantioselectivity and good to excellent yields observed (&gt;40 examples, up to 99%, 99:1 er). Substitution of the aromatic core within the 3‐hydroxyphthalide skeleton, as well as aliphatic and aromatic substitution at C(3)‐, is readily tolerated. A diverse range of anhydrides, including those from bioactive and pharmaceutically relevant acids, can also be used. The high enantioselectivity observed in this DKR process has been probed computation, with a key substrate heteroatom donor O•••acyl‐isothiouronium interaction identified through DFT analysis as necessary for enantiodiscrimination.

Engineered Phenylalanine Ammonia-Lyases for the Enantioselective Synthesis of Aspartic Acid Derivatives.

Biocatalytic hydroamination of alkenes is an efficient and selective method to synthesize natural and unnatural amino acids. Phenylalanine ammonia-lyases (PALs) have been previously engineered to access a range of substituted phenylalanines and heteroarylalanines, but their substrate scope remains limited, typically including only arylacrylic acids. Moreover, the enantioselectivity in the hydroamination of electron-deficient substrates is often poor. Here, we report the structure-based engineering of PAL from Planctomycesbrasiliensis (PbPAL), enabling preparative-scale enantioselective hydroaminations of previously inaccessible yet synthetically useful substrates, such as amide- and ester-containing fumaric acid derivatives. Through the elucidation of cryo-electron microscopy (cryo-EM) PbPAL structure and screening of the structure-based mutagenesis library, we identified the key active site residue L205 as pivotal for dramatically enhancing the enantioselectivity of hydroamination reactions involving electron-deficient substrates. Our engineered PALs demonstrated exclusive a-regioselectivity, high enantioselectivity, and broad substrate scope. The potential utility of the developed biocatalysts was further demonstrated by a preparative-scale hydroamination yielding tert-butyl protected l-aspartic acid, widely used as intermediate in peptide solid-phase synthesis.

Enantioselective synthesis of chiral α,α-dialkyl indoles and related azoles by cobalt-catalyzed hydroalkylation and regioselectivity switch

General, catalytic and enantioselective construction of chiral α,α-dialkyl indoles represents an important yet challenging objective to be developed. Herein we describe a cobalt catalyzed enantioselective anti-Markovnikov alkene hydroalkylation via the remote stereocontrol for the synthesis of α,α-dialkyl indoles and other N-heterocycles. This asymmetric C(sp3)−C(sp3) coupling features high flexibility in introducing a diverse set of alkyl groups at the α-position of chiral N-heterocycles. The utility of this methodology has been demonstrated by late-stage functionalization of drug molecules, asymmetric synthesis of bioactive molecules, natural products and functional materials, and identification of a class of molecules exhibiting anti-apoptosis activities in UVB-irradiated HaCaT cells. Ligands play a vital role in controlling the reaction regioselectivity. Changing the ligand from bi-dentate L6 to tridentate L12 enables CoH-catalyzed Markovnikov hydroalkylation. Mechanistic studies disclose that the anti-Markovnikov hydroalkylation involves a migratory insertion process while the Markovnikov hydroalkylation involves a MHAT process.