Asymmetric Synthesis Research Articles

Asymmetric one-carbon ring expansion of diverse N-heterocycles via copper-catalyzed diyne cyclization.

One-carbon ring expansion reaction of N-heterocycles has gained particular attention in the past decade because this method allows for the conversion of readily available N-heterocycles into potentially useful complex ring-expanded N-heterocycles, which are inaccessible by traditional methods. However, the catalytic asymmetric variant of this reaction has been rarely reported to date. Herein, we disclose an enantioselective one-carbon ring expansion reaction through chiral copper-catalyzed diyne cyclization, leading to the practical, atom-economic and divergent assembly of an array of valuable chiral N-heterocycles bearing a quaternary stereocenter in generally good to excellent yields with excellent enantioselectivities (up to >99% ee). This protocol represents the first example of asymmetric one-carbon ring expansion reaction of N-heterocycles based on alkynes.

Asymmetric Photoinduced Excited-State Nazarov Reaction.

We report herein the first asymmetric photoinduced excited-state Nazarov reaction of non-aromatic dicyclic divinyl ketones by using hydrogen-bonding catalysis. The enantioselectivity of photoinduced electrocyclization is highly dependent on the structural features of the substrate and its interaction with chiral catalysts. For the simple dicyclic divinyl ketone substrates, there is no discernible selectivity of the hydrogen bond coordination between the thiourea and carbonyl groups of the substrates in the ground state. However, we found that the direction of the electrocyclization was well controlled in each coordination model and the N,N'-dimethylamine motif acts as a base in the regioselective deprotonation process, which leads to the formation of two stereoisomers with high enantioselectivity. Photolysis of dicyclic divinyl ketones bearing a 1,3-dioxolane motif in the presence of bifunctional hybrid peptide-thiourea chiral catalysts gave the tricyclic cis-hydrofluorenones with good enantioselectivity. Mechanistic and DFT studies suggested that the amide and thiourea groups in the bifunctional chiral catalysts play a key role as H-bond donors, which coordinate with both the carbonyl group and the 1,3-dioxolane motif to provide a more favorable chiral species, and control the direction of the electrocyclization. Due to the presence of the rigid 1,3-dioxolane ring, the deprotonation/protonation process occurs regiospecifically with high driving force. This photo-electrocyclization is mild (room temperature and neutral solution), which results a broad reaction scope and functional group tolerance and demonstrates its synthetic potential in organic synthesis.

Development of biocatalysts for high-value-added compounds.

High-value-added compounds, such as monoterpenoids, are an important industrial targets because they are an essential group of compounds for pharmaceutical and industrial applications. Meanwhile, the depletion of natural resources and climate change demands sustainable production methods. In recent years, biocatalysis, which allows microbial bioproduction by regio- and stereo-selective reaction under mild conditions, has been attracted researchers' attention as a possible alternative to conventional methods. In this mini-review, we focus on the identification of biotransformation pathways in the non-model microorganism Acinetobacter sp. Tol 5 using geraniol, a representative monoterpenoid, and on the construction of an unconventional bioproduction method for high-value-added monoterpenoid (E)-geranic acid, which has great potential for industrial applications. This method offers a more environmentally friendly approach and insights contribute to optimizing biotransformation and bioproduction strategies for high-value-added compounds.

Multicomponent Cyanation of 2‐Amino‐3‐cyano‐4H‐chromenes in Aqueous Media

Chromenes represent a pivotal molecular structure found in a diverse range of biologically active compounds. Specifically, derivatives of 2‐amino‐3‐cyano‐4H‐chromene have demonstrated pharmacological applications, displaying potential antioxidant and anticancer activities. This has heightened interest in the exploration of new and more efficient methods for their synthesis. In recent years, few examples have emerged, focusing on the organocatalytic and enantioselective synthesis of 2‐amino‐3‐cyano‐4H‐chromene derivatives, although the overall number of works to date is limited. In this study, we present the results of the synthesis of 2‐amino‐4H‐chromen‐3,4‐dicarbonitriles through a Michael addition of cyanide to 2‐iminochromenes. To achieve this, we utilized a mild source of cyanide (acetone cyanohydrin), green solvents and catalytic conditions at room temperature, via a multicomponent approach. Furthermore, we initiated the enantioselective study of this process using chiral organocatalysts obtaining promising preliminary results.

Rhodium(III)-Catalyzed Atroposelective Indolization to Access Planar-Chiral Macrocycles.

Macrocycles incorporating conformationally defined indoles are widely found in bioactive natural products. However, the catalytic enantioselective synthesis of planar-chiral indoles via indolization involving macrocyclization remains elusive. Herein, we present the first rhodium(III)-catalyzed atroposelective macrocyclization, which involves the C-H activation of aniline, and a subsequent oxidation [3 + 2] annulation reaction with an intramolecular alkyne. This protocol achieves the construction of indoles, macrocyclization, and planar chirality control in a single step. Importantly, this strategy produces macrocyclic atropisomers bearing full-carbon ansa chains, which represent challenging targets in organic synthesis. Thermodynamic experiments revealed that the rotational barrier of the full-carbon ansa chain-linked macrocyclic atropisomer was lower than that of the atropisomer bearing an oxa-ansa chain. The reaction mechanism was elucidated by computational studies, which revealed that the C-H activation and intramolecular alkyne insertion steps collectively determined the enantioselectivity.

Asymmetric phase-transfer catalysis.

Over the past three decades, chiral phase-transfer catalysts (PTCs) have emerged as highly successful organocatalysts in a diverse range of asymmetric reactions. A substantial number of chiral PTCs have now already been discovered and utilized in dependable routes to enantioenriched products. These extend beyond the classical cationic PTCs with the emergence of anionic phase-transfer catalysis and hydrogen-bonding phase-transfer catalysis providing new asymmetric synthetic approaches. Nevertheless, the application level of chiral PTCs in both academic and industrial processes is below our expectation. This Review highlights the notable advances in chiral PTCs, including challenges, limitations and efforts to overcome them. Following this, the potential for sustainable chiral PTCs is described with a focus on using photocatalysed, flow and electrochemical synthesis.

Gold(I)‐Catalyzed Desymmetrization of Homopropargylic Alcohols via Cycloisomerization: Enantioselective Synthesis of Cyclopentenes Featuring a Quaternary Chiral Center

AbstractCyclopentene rings possessing a chiral quaternary center are important structural motifs found in various natural products. In this work, we disclose expedient and efficient access to this class of synthetically valuable structures via highly enantioselective desymmetrization of prochiral propargylic alcohols. The efficient chirality induction in this asymmetric gold catalysis is achieved via two‐point bindings between a gold catalyst featuring a bifunctional phosphine ligand and the substrate homopropargylic alcohol moiety—an H‐bonding interaction between the substrate HO group and a ligand phosphine oxide moiety and the gold‐alkyne complexation. The propargylic alcohol substrates can be prepared readily via propargylation of enoate and ketone precursors. In addition to monocyclic cyclopentenes, spirocyclic and bicyclic ones are formed with additional neighboring chiral centers of flexible stereochemistry in addition to the quaternary center. This work represents rare gold‐catalyzed highly enantioselective cycloisomerization of 1,5‐enynes. Density functional theory (DFT) calculations support the chirality induction model and suggest that the rate acceleration enabled by the bifunctional ligand can be attributed to a facilitated protodeauration step at the end of the catalysis.

Diastereoselective Addition of Lithiated Allenyl Sulfones to Nonracemic Sulfinimines: Asymmetric Synthesis of Diverse Heterocycles.

The addition of lithiated allenyl sulfones to nonracemic sulfinimines furnished sulfinamides possessing the allenyl sulfonyl moiety with excellent diastereoselectivity. The formed products are transformed into different heterocycles, including the synthesis of pyrroline, pyran, and functionalized benzopyran.

EnantioselectiveSynthesis ofspiro[indoline-3,4- pyrrolo [3,4-b]pyridines] via Organocatalysed Three-Component Cascade Reaction.

Asymmetric synthesis of spiro[indoline-3,4-pyrrolo [3,4-b]pyridines] derivatives was first developed through organocatalytic cascade Knoevenagel/Michael/cyclization reaction using a quinidine -derived squaramide. Under the optimized conditions, the three-component reaction of isatins, cyanoacetates, and 3-aminomaleimides yield the desired heterocycle-fused spirooxindoles in good yields (78-91%) with 53-99% enantiomer excess (ee). Notably, this reaction enabled a broad substrate scope under mild conditions, and provided a convenient method for enantioselective construction of diverse spirooxindoles combined with dihydropyridine and maleimide skeleton, which brought great potential to build new bioactive chemical entities.

Unraveling the Source of Self-Induced Diastereomeric Anisochronism in Chiral Dipeptides.

Mastering of analytical methods for accurate quantitative determinations of enantiomeric excess is a crucial aspect in asymmetric catalysis, chiral synthesis, and pharmaceutical applications. In this context, the phenomenon of Self-Induced Diastereomeric Anisochronism (SIDA) can be exploited in NMR spectroscopy for accurate determinations of enantiomeric composition, without using a chiral auxiliary that could interfere with the spectroscopic investigation. This phenomenon can be particularly useful for improving the quantitative analysis of mixtures with low enantiomeric excesses, where direct integration of signals can be tricky. Here, we describe a novel analysis protocol to correctly determine the enantiomeric composition of scalemic mixtures and investigate the thermodynamic and stereochemical features at the basis of SIDA. Dipeptide derivatives were chosen as substrates for this study, given their central role in drug design. By integrating the experiments with a conformational stochastic search that includes entropic contributions, we provide valuable information on the dimerization thermodynamics, the nature of non-covalent interactions leading to self-association, and the differences in the chemical environment responsible for the anisochronism, highlighting the importance of different stereochemical arrangement and tight association for the distinction between homochiral and heterochiral adducts. An important role played by the counterion was pointed out by computational studies.

Chiral Polar Bifunctional Polyimide Enantiomers for Asymmetric Photo- and Piezo-catalysis.

Chiral catalysts for asymmetric catalysis represent a crucial research focus in chemistry and materials science. However, a few cases about chiral-dependent photocatalysts primarily focus on plasmonic noble metals. Particularly, developing chiral nano-catalysts that can be driven by mechanical energy remains in the blank stage. Herein, organic polymer-based enantiomers, chiral polar polyimide (PI) microspheric nano-assembly are synthesized as novel bifunctional catalysts for asymmetric photocatalysis and piezocatalysis. The PI catalyst enantiomers present enantioselectivity towards left- and right-circularly polarized light, demonstrating chiral-dependent H2O2 photoproduction. Interestingly, enantioselectivity of the catalyst reverses under irradiation of different bands, presenting tunability in the interaction between chiral catalysts and circularly polarized light. For the first time, enantioselective piezocatalytic behavior is demonstrated by the chiral polar PI catalysts. They show remarkable chiral preference for asymmetric Diels-Alder reaction and enantioselective conversion of tyrosine substrates under ultrasonic vibration. The findings provide a new perspective into exploring metal-free chiral catalysts and their asymmetric catalysis applications across multiple energy forms.

Chiral Symmetry Breaking in Colloidal Metal Nanoparticle Solutions by Circularly Polarized Light.

Shape symmetry breaking in the formation of inorganic nanostructures is of significant current interest. It was typically achieved through the growth of colloidal nanoparticles with adsorbed chiral molecules. Photochemical processes induced through asymmetric plasmon excitation by circularly polarized light in surface immobilized nanostructures also led to symmetry breaking. Here, we show that chiral symmetry breaking can be achieved by randomly rotating gold@silver core-shell nanobars in colloidal solution using circularly polarized illumination, where orientational averaging does not eliminate the symmetry breaking of an asymmetric plasmon-induced galvanic replacement reaction. Different morphological effects that are produced by circularly vs linearly polarized light illumination demonstrate the intricate effect of light polarization on the localized plasmonic-induced photochemical response. The essential features of this symmetry breaking, such as illumination wavelength dependence, were reproduced by simulations of circularly polarized light-excited-plasmon-induced hot-electron generation as the source for asymmetric metal deposition. The symmetry breaking becomes smaller in more symmetric geometrical shapes, such as triangular nanoprisms and nanocubes, and down to zero in spherical ones. The degree of symmetry breaking rises when the nanobars are immobilized on a substrate and illuminated from a single direction.

Highly Acidic Electron-Rich Brønsted Acids Accelerate Asymmetric Pictet-Spengler Reactions by Virtue of Stabilizing Cation-π Interactions.

Electron-rich heteroaromatic imidodiphosphorimidates (IDPis) catalyze the asymmetric Pictet-Spengler reaction of N-carbamoyl-β-arylethylamines with high stereochemical precision. This particular class of catalysts furthermore provides a vital rate enhancement compared to related Brønsted acids. Here we present experimental studies on the underlying reaction kinetics that shed light on the specific origins of rate acceleration. Analysis of Hammett plots, kinetic isotope effects, reaction orders, Eyring plots, and isotopic scrambling experiments, allowed us to gather insights into the molecular interactions between the chiral Brønsted acid and catalytically formed intermediates. Based on rigorously determined pKa values as well as the experimental evidence, we propose that attractive intermolecular forces offered by electron-rich π-surfaces of the chiral counteranion enthalpically stabilize cationic intermediates and transition states by way of cation-π interactions. This view is furthermore supported by in-depth density functional theory calculations. Our deepened understanding of the reaction mechanism allowed us to develop a method for accessing 1-aryltetrahydroisoquinolines from aromatic dimethyl acetals, a substrate class that was thus far inaccessible via catalytic asymmetric Pictet-Spengler reactions.

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.

Enantioselective Synthesis of Chiral 1,5-Benzodiazepin-2-ones by Pd-Catalyzed Asymmetric Hydrogenation and Reductive Amination.

The enantioselective synthesis of chiral 4-substituted 4,5-dihydro-1H-[1,5]benzodiazepin-2(3H)-ones via asymmetric hydrogenation catalyzed by the Pd/f-spiroPhos complex in the presence of hydrochloric acid as an additive has been developed, achieving excellent enantioselectivities and high turnover numbers, up to 99% ee and TON = 4600. More significantly, the asymmetric reductive amination of β-keto esters with 1,2-phenylenediamine has also been successfully realized to afford chiral 4-substituted 4,5-dihydro-1H-[1,5]benzodiazepin-2(3H)-ones with comparable enantioselectivities of up to 99% ee.

Asymmetric Synthesis of Benzofuranones with a C3 Quaternary Center via an Addition/Cyclization Cascade Using Noncovalent N-Heterocyclic Carbene Catalysis.

An asymmetric addition/cyclization cascade of amidoesters and iminoquinones is developed using noncovalent N-heterocyclic carbene (NHC) catalysis. The process enables access to various functionalized benzofuranones with an all-carbon quaternary stereocenter with high yields and ee values. The reaction displays a broad substrate scope. Via product modifications, enantioenriched synthesis of biologically relevant spirocyclic lactones and lactams is achieved. Substrate activation via noncovalent interaction with NHC is suggested for the process.

Stereoselective Synthesis of Chiral C2-Symmetric 1,3- and 1,5-Bis-Sulfoxides Guided by the Horeau Principle: Understanding the Influence of the Carbon Chain Nature in Its Ability for Metal Coordination.

The stereoselective synthesis of two distinct types of C2-symmetric chiral bis-sulfoxides, 1,3- and 1,5-bis(sulfinyl) derivatives, has been achieved based on the DAG methodology. The 1,5-bis(sulfinyl) derivatives constitute a new family of tridentate chiral ligands thanks to the presence of an additional sulfenyl or sulfinyl group in the carbon chain acting as a bridge. A systematic development and optimization of two synthetic routes, one for each ligand family, have been undertaken, highlighting the strategic utilization of Horeau's law to enhance enantioselectivity. Additionally, palladium (Pd) and ruthenium (Ru) complexes derived from the synthesized bis-sulfoxides were prepared, and their structures were elucidated through spectroscopic analysis. Isolation of Pd(II) complexes involving 1,3-bis-sulfoxides was exclusively achieved using trifluoroacetates as coligands. In the case of Ru(II) complexes, the trans geometry could be determined for 1,3-bis-sulfoxides. The introduction of a third sulfur atom as a coordinating element in the 1,5-bis(sulfinyl) derivatives facilitates the formation of two distinct tricoordinated Ru(II) complexes. The structure of these complexes is intricately influenced by the oxidation state adopted by the central sulfur on the chain, whether as a thioether or as a sulfoxide.

Evolution of the Short Enantioselective Total Synthesis of the Unique Marine Myxobacteria Polyketide Salimabromide

Comprehensive SummarySalimabromide, a unique and scarce marine tetracyclic polyketide, was synthesized in both racemic and optically active forms. A novel carboxylic acid‐directed method for tandem oxidative difunctionalization of olefins was developed, whereby the formation of bridged butyrolactone and enone moieties occurs concurrently. Density functional theory (DFT) calculations indicate that this reaction follows a [3+2] process rather than the [2+2] process. In the meantime, the distinctive benzo‐fused [4.3.1] carbon skeleton and highly hindered vicinal quaternary stereocenters were simultaneously constructed through a challenging intramolecular Giese‐Baran radical cyclization. Furthermore, deuterium kinetic isotopic effects were utilized to enhance the efficacy of this pivotal step. This represents a new illustration of the application of kinetic isotope effects in natural product synthesis. Then, the short asymmetric synthesis of (+)‐salimabromide (13 or 15 steps) was accomplished by combing this method with rhodium‐catalyzed enantioselective hydrogenation of a cycloheptenone derivative (97% ee) or conjugate addition of an aryl boronic acid with 2‐cyclohepten‐1‐one (> 99% ee).

Cationic Foldamer‐Catalyzed Asymmetric Synthesis of Inherently Chiral Cages

AbstractThe stereochemistry of shape‐persistent molecular cages, particularly those resembling prisms, exerts significant influence on their application‐specific functionalities. Although methods exist for fabricating inherently chiral prism‐like cages, strategies for catalytic asymmetric synthesis of these structures in a diversity‐oriented fashion remain unexplored. Herein, we introduce an unprecedented organocatalytic desymmetrization approach for the generation of inherently chiral prism‐like cages via phosphonium‐containing foldamer‐catalyzed SNAr reactions. This methodology establishes a topological connection, enabling the facile assembly of a wide range of versatile stereogenic‐at‐cage building blocks possessing two highly modifiable groups. Furthermore, subsequent stereospecific transformations of the remaining chlorides and/or ethers afford convenient access to numerous functionally relevant chiral‐at‐cage molecules.

Conditions for enhancement of gas phase chemical reactions inside a dark microwave cavity

The ability to slow down or enhance chemical reactions, by a seemingly simple setup of reactions inside a cavity made of two parallel mirrors is fascinating. Unfortunately, currently, theory and experiment have not yet fully converged. Since theory and experiment perfectly match for atom/molecular collisions in gas phase the enhancing chemical reactions in gas phase through its coupling to quantized electromagnetic modes in a dark cavity is investigated. Here the conditions and guidelines for selecting the proper type of reactions that can be enhanced by a dark cavity are provided. Showing that the asymmetric reaction rates of O + D2 → [ODD]# → OD + D and H + ArCl → [ArHCl]# → H + Ar + Cl can be enhanced by a dark cavity. On the other hand, an effect of the dark cavity on the symmetric reaction of hydrogen exchange in methane is predicted to be negligible. Notice that the theory is not limited to microwave cavities only.