High Enantioselectivity Research Articles

Peroxycarbenium-Mediated Asymmetric Synthesis of 1,2-Dioxanes and 1,2-Dioxolanes.

The endoperoxide scaffold is found in numerous natural products and synthetic substances of pharmaceutical interest. The main challenge to their synthetic access remains the preparation of chiral compounds due to the weakness of the peroxide bond, which limits the scope of available or applicable methods. Here, we demonstrate how peroxycarbenium species can be trapped by silylated nucleophiles with high enantioselectivities and diastereoselectivities when applicable, using a chiral imidophosphorimidate (IDPi) as a catalyst. The scope of the methodology is broad, encompassing a large variety of enoxysilanes and yielding 1,2-dioxanes or 1,2-dioxolanes. Peroxides can be converted into alcohols or trans-epoxides, and the methodology was applied in a key step of the total synthesis of ethyl plakortide Z, enhancing the selectivity compared to a conventional Lewis acid-catalyzed transformation. Kinetic studies have shown that the reaction necessitates an induction period, indicating the formation of a silylium species that behaves as a true catalyst.

A C-H Arylation-Based Enantioselective Synthesis of Planar Chiral Cyclophanes.

Despite the growing importance of planar chiral macrocyclophanes owing to their unique properties in different areas of chemistry, methods that are effective in controlling their planar chirality are restricted to certain molecular scaffolds. Herein, we report the first Pd(0)-catalyzed enantioselective intermolecular C-H arylation that induces planar chirality by installing bulky aryl groups through dynamic kinetic resolution (DKR). A computer-assisted approach allowed a fine-tuning of the structure of the employed chiral bifunctional phosphine-carboxylate ligands to achieve high enantioselectivities. A range of planar chiral macrocyclophanes were successfully synthesized from configurationally labile macrocyclic precursors via C-H arylation with various perfluoroarenes. Mechanistic investigations indicated that the reaction proceeds via reversible oxidative addition and enantiodetermining C-H activation. Selected macrocyclophane products showed interesting photophysical and chiroptical properties, which depended on both the nature of the ansa chains and the aromatic moieties.

Au(I)‐Catalyzed Regiodivergent Hydroarylation of Allenes for the Synthesis of Tetrahydrodiazepines or Tetrahydrodiazonines

Allenes tethered to pyrroles undergo Au(I)‐catalyzed hydroarylation leading to tetrahydrodiazepines or tetrahydrodiazonines. The regioselectivity of the reaction is governed by both the substitution pattern of the allene and the nature of the Au(I) ligand. Hence, alkyl‐gem‐disubstituted allenes preferentially lead to tetrahydrodiazepines via 7‐exo‐ cyclizations, while aryl‐substituted allenes preferentially lead to tetrahydrodiazonines via 9‐endo cyclization when a phosphite ligand is used. Enantioselective reactions have been developed with the SEGPHOS chiral ligand, leading to chiral heterocycles with high enantioselectivity (up to 96% ee). In addition, DFT calculations have streamlined the regioselectivity (7‐exo vs 9‐endo) of these gold(I)‐catalyzed cyclizations.

A Novel Enantioselective Synthesis of Cryptophycins Unit A from Rocher’s Ester

A novel synthesis of cryptophycin unit A in its enantiomerically pure form was achieved. In five steps, an enantiomeric mixture of unit A was initially prepared from trans-cinnamaldehyde. Subsequently, in its enantiomerically pure forms, unit A was prepared from Rocher’s ester in six steps, involving an essential aldehyde (2R,3E)-2-methyl-4-phenylbut-3-enal. The final step of this process involved two different approaches: a Reformatsky reaction of an essential aldehyde with tertbutyl 4-bromocrotonate and the vinylogous Mukaiyama aldol reaction with O,O-Silyl ketene acetal in the presence of isopropyl alcohol and L-tryptophane-based B-phenyloxazaborolidinone, thereby resulting in the desired products in good overall yields and high enantioselectivities.

Stereoselective Vinylogous Aza-Pummerer Reaction of β,β-Disubstituted Enesulfinamides.

Treatment of multisubstituted NH-enesulfinamides with tosyl isocyanate (TsNCO) at room temperature results in the formation of α-tosylcarbamoyloxy N-sulfenyl ketimines with high enantioselectivity. This process is believed to proceed via a vinylogous aza-Pummerer-type reaction pathway in which the sulfinyl oxygen atom in the enesulfinamides undergoes nucleophilic attack on tosyl isocyanate, triggering the subsequent transformations that enable the transfer of chirality from sulfur to carbon.

Photoinduced Regiodivergent and Enantioselective Cross-Coupling of Glycine Derivatives with Hydrocarbon Feedstocks.

Regiodivergent asymmetric synthesis represents a transformative strategy for the efficient generation of structurally diverse chiral products from a single set of starting materials, significantly enriching their enantiomeric composition. However, the design of radical-mediated regiodivergent and enantioselective reactions that can accommodate a wide range of functional groups and substrates has posed significant challenges. The obstacles primarily lie in switching the regioselectivity and achieving high enantiodiscrimination, especially when dealing with high-energy intermediates. To address these issues, we have developed a new catalytic system that integrates photoinduced hydrogen atom transfer (HAT) and chiral copper catalysis, involving the fine-tuning of chiral ligands, additives, and other reaction parameters. The strategy facilitates regiodivergent and enantioselective cross-couplings between N-aryl glycine ester/amide derivatives and abundant hydrocarbon feedstocks through strong C(sp3)-H bond activation. This approach allows for the controlled and stereoselective formation of C(sp3)-C(sp3) and C(sp3)-N bonds, yielding a rich variety of C- or N-alkylated glycine esters and amides with commendable yields (up to 92% yield), exclusive regioselectivities (typically >20:1 rr), and high enantioselectivities (up to 96% ee). Our methodology not only provides a promising avenue for the stereoselective incorporation of alkyl functionalities onto specific sites of biologically significant molecules but also offers a practical approach for regioselectivity switching while simultaneously achieving high asymmetric induction within photochemical reactions.

A catalytic atroposelective Friedel–Crafts alkylation to access axially chiral C2-arylindoles via dynamic kinetic resolutions

An amine-catalyzed atroposelective FC alkylation of 2-arylindoles with α,β-unsaturated aldehydes via the DKR process has been developed. Various axially chiral 2-arylindoles were obtained in good yields with high enantioselectivities.

Asymmetric isochalcogenourea-catalysed (4 + 2)-cycloadditions of ortho-quinone methides and allenoates.

Chiral isochalcogenoureas (i.e. isothioureas and isoselenoureas) catalyse the asymmetric (4 + 2)-cycloaddition of various allenoates with ortho-quinone methides. This approach provides straightforward access to different chromane derivatives with high enantioselectivities, good yields, and control of the configuration of the exocyclic double bond. Furthermore, some of the novel ortho-quinone methides used herein were successfully integrated into the Mayr reactivity scale by determining their electrophilicity parameter.

Chiral ruthenium porphyrin-catalyzed asymmetric cyclopropanation of 1,3-dienes with tert-butyl 2-cyano-2-diazoacetate as the carbene source

With the chiral ruthenium porphyrin complex (S,R)-cmcpor-RuCO as a catalyst and tert-butyl 2-cyano-2-diazoacetate as the carbene source, a panel of substituted vinylcyclopropanes is readily prepared in good product yields and high enantioselectivity.

Development of chiral ferrocenyl P,P,N,N,O-ligands for ruthenium-catalyzed asymmetric hydrogenation of ketones.

A new type of ferrocenyl P,P,N,N,O-ligand has been developed through a one-step transformation. This represents a rare example of a ligand containing both chiral bisphosphine and diamine groups suitable for ruthenium-catalyzed asymmetric hydrogenation. Its ruthenium complex can be directly prepared by stirring the ligand and [Ru(benzene)Cl2]2 at 90 °C in DMF for 4 hours. The catalyst showed high reactivity and enantioselectivity in the hydrogenation (AH) of simple ketones and α,β-unsaturated ketones, providing the corresponding chiral aryl alkyl alcohols and chiral allyl alcohols with up to 99% yield and 96% ee.

Facile access to chiral anti-1,2-diol derivatives via Ir-catalyzed asymmetric hydrogenation of α-alkoxy-β-ketoesters.

The iridium-catalyzed asymmetric hydrogenation of α-alkoxy-β-ketoesters via dynamic kinetic resolution has been achieved with high efficiency and enantioselectivity. This strategy allows for the synthesis of differentiated anti-1,2-diol derivatives in high yields, exhibiting excellent enantio- and diastereoselectivity (up to 99% yield, 99% ee, and 99 : 1 dr). Additionally, high turnover number (TON) experiments (up to 1000 TON) and gram-scale synthesis of a key fragment of the potential drug Tesaglitazar were successfully performed, highlighting the protocol's potential for broader applications.

Chiral iodine-catalyzed asymmetric oxyamination of unactivated olefins.

In this paper, chiral aryl iodides were used for the first time to catalyze the formation of C-O and C-N bonds of inactive olefins to obtain optically active aminolactone derivatives. The reaction is compatible with various substituted alkenyl carboxylic acid substrates. This method usually shows high activity and enantioselectivity, with a yield of up to 83% and an ee of up to 99%. It is recovery and reuse of chiral aryl iodide catalyst CIC4 showed almost no loss in product yield and enantioselectivity after 3 runs.

Asymmetric synthesis of atropisomers featuring cyclobutane boronic esters facilitated by ring-strained B-ate complexes

The strain-release-driven reactions of bicyclo[1.1.0]butanes (BCBs) have received significant attention from chemists. Notably, 1,2-migratory reactions enabled by BCB-derived B-ate complexes effectively complement the reactions initiated by common BCBs. The desired products are particularly valuable for late-stage transformations due to the presence of the C–B bond. However, asymmetric reactions mediated by BCB-derived boronate complexes have progressed slowly. In this study, we develop an asymmetric synthesis of atropisomers featuring cis-cyclobutane boronic esters facilitated by 1,2-carbon or boron migration of ring-strained B-ate complexes, achieving high enantioselectivity. The reaction is compatible with various aryl, alkenyl, alkyl boronic esters and B2pin2, and shows good compatibility with natural product derivatives. Mechanistic studies are conducted to understand stereoselective control in the dynamic kinetic asymmetric transformations (DYKATs). The target products can undergo a series of transformations, further demonstrating the practicality of this methodology.

Catalytic Asymmetric Desymmetrizing [4+2] Cycloaddition/Base-Mediated Oxidative Aromatization Sequence: De Novo Synthesis of Isobenzofuranone-Embedded Chiral Arenes.

Herein, an organocatalytic asymmetric desymmetrizing [4+2] cycloaddition/base-mediated oxidative aromatization reaction sequence has been developed between spirophthalide 2,5-cyclohexadienones and β-methyl cinnamaldehydes. The reaction proceeds through in situ chiral dienamine intermediate formation, and the densely functionalized spirocyclic isobenzofuranone-embedded chiral arenes were formed in high yields with excellent enantioselectivities. A 2-fold desymmetrization reaction was also performed, and the products were obtained in high enantioselectivities.

Regiodivergent Desymmetrization of meso-4,5-Epoxycyclohex-1-ene.

Herein, we report a regiodivergent desymmetrization of meso-4,5-epoxycyclohex-1-ene, which results in the formation of two enantioenriched structural isomers with high enantioselectivity from a single compound using a single chiral catalyst.

Enantioselective Synthesis of Isoindolinone by Sequential Palladium-Catalyzed Aza-Heck/Suzuki Coupling Reaction.

We present a tandem aza-Heck/Suzuki cross-coupling reaction of O-phenyl hydroxamic ethers with readily available arylboronic and alkenyl boronic acids. This protocol is enabled by a palladium catalyst paired with chiral phosphoramidite ligands, particularly under mild reaction conditions, yielding efficient and succinct synthetic routes to chiral isoindolinones with high enantioselectivity. Furthermore, this reaction exhibits excellent functional group compatibility and a rich diversity of subsequent transformations.

Enantioselective Synthesis of 3-Hydroxy-2-Oxindoles via Ni-Catalyzed Asymmetric Addition of Aromatic Bromides to α-Ketoamides.

Nickel-catalyzed asymmetric intramolecular addition of aryl halides to α-ketoamides has been achieved to afford chiral 3-substituted-3-hydroxy-2-oxindoles in excellent yields and high enantioselectivities (up to 99 % yield and 98 % ee), which provides efficient access to valuable molecules containing 3-hydroxy-2-oxindole core. The gram-scale reaction proved the potential utility of the methodology.

Voltammetric sensors based on mesoporous graphitized carbon black and cyclopentadiene derivatives for determination and recognition of clopidogrel enantiomers

To recognize and determine the enantiomers of clopidogrel, a sensor system based on a glassy carbon electrode modified with Carbopack X mesoporous carbon black and cyclopentadiene derivatives – (1S)-2-cyclopenta-2,4-dien-1-yl-1,7,7-trimethylbicyclo[2.2.1]heptane; (1S, 2S, 4R)-2-cyclopenta-1,3-dien-1-yl-1-isopropyl-4-methylcyclohexane; 9-[(1S,2S,5R)-2-isopropyl-5-methylcyclohexyl]-9H-fluorene. Due to the unique properties of Carbopack X, such as large surface area and high conductivity, it was possible to obtain a mechanically stable and sensitive sensor layer that firmly retains chiral selector molecules on its surface. The morphological, electrochemical and analytical properties of the obtained sensors were studied by scanning electron microscopy, electrochemical impedance spectroscopy, cyclic and differential pulse voltammetry. The determination of clopidogrel enantiomers in biological fluids has been carried out; linear dependences of oxidation peak currents on their concentration in solution for all sensors are preserved in the concentration range from 1 × 10–6 to 5 × 10–4 M. The sensors are cross-sensitized, which allowed combining them into a sensor system with high enantioselectivity and sensitivity towards clopidogrel enantiomers. With the proposed sensor system, the probability of correctly recognizing samples increases compared to single sensors. In all cases, the content of R-clopidogrel in the mixture is correctly determined with a relative error not exceeding 9% and a degree of discovery ranging from 96 to 102%.

Highly Enantioselective Synthesis of 3,3-Diarylpropyl Amines and 4-Aryl Tetrahydroquinolines via Ir-Catalyzed Asymmetric Hydrogenation.

Chiral nitrogen-containing compounds are crucial for the chemical, pharmaceutical, and agrochemical industries. Nevertheless, the synthesis of certain valuable scaffolds remains underdeveloped due to the vast chemical space available. In this work, we present a diastereoselective methodology for synthesizing 3,3-diarylallyl phthalimides, which, following iridium-catalyzed asymmetric hydrogenation using Ir-UbaPHOX, yield 3,3-diarylpropyl amines with high enantioselectivity (98-99% ee). The importance of alkene purity to achieve high enantioselectivity is discussed. The synthetic utility of the chiral propylamines obtained is demonstrated through the preparation of medicinally useful bioactive compounds like the drugs tolterodine and tolpropamine and 4-aryl tetrahydroquinolines. This strategy enables the synthesis of these compounds with the highest enantioselectivity reported to date.

Enantioselective α-C(sp3)-H Borylation of Masked Primary Alcohols Enabled by Iridium Catalysis.

Functional group-directed site- and enantioselective C(sp3)-H functionalization of alcohols or masked alcohols represents a formidable challenge. We herein report the first example of iridium-catalyzed asymmetric α-C(sp3)-H borylation of primary alcohol-derived carbamates by the judicious choice of directing groups. A variety of chiral borylated carbamates were obtained with good to high enantioselectivities. We also demonstrated the synthetic utility by taking advantage of the highly transformable feature of C-B bonds and the leaving ability of carbamates.