Excellent Enantioselectivities Research Articles

Enantiodivergent kinetic resolution of 4-substituted 1,2,3,4-tetrahydroquinolines employing amine oxidase

Optically pure 1,2,3,4-tetrahydroquinolines (THQs) represent a class of important motifs in many natural products and pharmaceutical agents. While recent advances on redox biocatalysis have demonstrated the great potential of amine oxidases, all the transformations focused on 2-substituted THQs. The corresponding biocatalytic method for the preparation of chiral 4-substituted THQs is still challenging due to the poor activity and stereoselectivity of the available enzyme. Herein, we developed a biocatalytic kinetic resolution approach for enantiodivergent synthesis of 4-phenyl- or alkyl-substituted THQs. Through structure-guided protein engineering of cyclohexylamine oxidase derived from Brevibacterium oxidans IH-35 A (CHAO), the variant of CHAO (Y215H/Y214S) displayed improved specific activity toward model substrate 4-phenyl substituted THQ (0.14 U/mg, 13-fold higher than wild-type CHAO) with superior (R)-stereoselectivity (E > 200). Molecular dynamics simulations show that CHAO Y215H/Y214S allows a suitable substrate positioning in the expanded binding pocket to be facilely accessed, enabling enhanced activity and stereoselectivity. Furthermore, a series of 4-alkyl-substituted THQs can be transformed by CHAO Y215H/Y214S, affording R-isomers with good yields (up to 50 %) and excellent enantioselectivity (up to ee > 99 %). Interestingly, the monoamine oxidase from Pseudomonas fluorescens Pf0–1 (PfMAO1) with opposite enantioselectivity was also mined. Together, this system enriches the kinetic resolution methods for the synthesis of chiral THQs.

Atroposelective Construction of Naphthylpyrazoles by Chiral Phosphoric Acid Catalyzed Enantioselective Cross‐Coupling of Pyrazoles with Naphthoquinone Esters

AbstractThe catalytic asymmetric reaction of 5‐aminopyrazoles with naphthoquinone esters has been established. A wide range of unprecedented axially chiral naphthylpyrazole derivatives (29 examples) have been synthesized in moderate to excellent yields (up to 99 % yield) with excellent enantioselectivities (up to 99 % ee) by utilizing chiral phosphoric acid as a catalyst. This protocol features mild reaction conditions, a broad substrate scope, good scalability and facile derivatization. Moreover, preliminary mechanistic investigation was conducted to elucidate the mechanism.

De novo Synthesis of Chiral 3,4‐DihydroquinazolinesviaOne‐Pot Enantioselective Ugi‐Azide/Cyclization Sequences†

Comprehensive SummaryHerein, we reported a precise de novo synthesis of chiral 3,4‐dihydroquinazoline frameworks via a one‐pot anionic stereogenic‐at‐cobalt(III) complex‐catalyzed enantioselective Ugi‐azide/Pd‐catalyzed cyclization sequence. This powerful protocol involves 5 components and 2 catalytic systems, delivering chiral 3,4‐dihydroquinazolines with excellent enantioselectivities (up to 94% ee). The preliminary antifungal experiments suggest that both Ugi‐adducts and 3,4‐dihydroquinazolines have great potential in inhibiting plant pathogens such as Trichoderma viride and Fusarium graminearum.

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.

Design of 3D-Printed Heterogeneous Reactor Systems To Overcome Incompatibility Hurdles when Combining Metal and Enzyme Catalysis in a One-Pot Process.

Combining chemo- and biocatalysis enables the design of novel economic and sustainable one-pot processes for the preparation of industrial chemicals, preferably proceeding in water. While a range of proofs-of-concept for the compatibility of such catalysts from these two different "worlds of catalysis" have recently been demonstrated, merging noncompatible chemo- and biocatalysts for joint applications within one reactor remained a challenge. A conceptual solution is compartmentalization of the catalytic moieties by heterogenization of critical catalyst components, thus "shielding" them from the complementary noncompatible catalyst, substrate or reagent. Exemplified for a one-pot process consisting of a metal-catalyzed Wacker oxidation and enzymatic reduction as noncompatible individual reactions steps, we demonstrate that making use of 3D printing of heterogeneous materials containing Cu as a critical metal component can overcome such incompatibility hurdles. The application of a 3D-printed Cu-ceramic device as metal catalyst component allows an efficient combination with the enzyme and the desired two-step transformation of styrene into the chiral alcohol product with high overall conversion and excellent enantioselectivity. This compartmentalization concept based on 3D printing of heterogenized metal catalysts represents a scalable methodology and opens up numerous perspectives to be used as a general tool also for other related chemoenzymatic research challenges.

Biocatalytic, Enantioenriched Primary Amination of Tertiary C-H Bonds.

Intermolecular functionalization of tertiary C-H bonds to construct fully substituted stereogenic carbon centers represents a formidable challenge: without the assistance of directing groups, state-of-the-art catalysts struggle to introduce chirality to racemic tertiary sp 3 -carbon centers. Direct asymmetric functionalization of such centers is a worthy reactivity and selectivity goal for modern biocatalysis. Here we present an engineered nitrene transferase (P411-TEA-5274), derived from a bacterial cytochrome P450, that is capable of aminating tertiary C-H bonds to provide chiral α-tertiary primary amines with high efficiency (up to 2300 total turnovers) and selectivity (up to >99% enantiomeric excess (e.e.)). The construction of fully substituted stereocenters with methyl and ethyl groups underscores the enzyme's remarkable selectivity. A comprehensive substrate scope study demonstrates the biocatalyst's compatibility with diverse functional groups and tertiary C-H bonds. Mechanistic studies elucidate how active-site residues distinguish between the enantiomers and enable the enzyme to perform this transformation with excellent enantioselectivity.

Design von 3D‐gedruckten heterogenen Reaktorsystemen zur Überwindung von Inkompatibilitätshürden bei der Kombination von Metall‐ und Enzym‐Katalyse in einem Eintopf‐Prozess

AbstractDie Kombination von Chemo‐ und Biokatalyse ermöglicht die Entwicklung neuartiger ökonomischer und nachhaltiger Eintopfverfahren für die Herstellung von Industriechemikalien, welche vorzugsweise in Wasser ablaufen. Während kürzlich anhand einer Reihe von Beispielen der Nachweis für die Kompatibilität solcher Katalysatoren aus diesen beiden unterschiedlichen “Welten der Katalyse” aufgezeigt wurde, blieb die Zusammenführung nicht kompatibler Chemo‐ und Biokatalysatoren für gemeinsame Anwendungen in einem Reaktor eine Herausforderung. Eine konzeptionelle Lösung besteht in der Kompartimentierung der katalytischen Einheiten durch Heterogenisierung kritischer Katalysatorkomponenten, wodurch diese von dem komplementären, nicht kompatiblen Katalysator, Substrat oder Reagenz “abgeschirmt” werden. Am Beispiel eines Eintopfverfahrens, das aus einer Metall‐katalysierten Wacker‐Oxidation und einer enzymatischen Reduktion als nicht‐kompatible Einzelreaktionsschritte besteht, zeigen wir, dass durch den Einsatz des 3D‐Drucks von heterogenen, die kritische Metallkomponente Kupfer enthaltenden Materialien solche Hürden der Inkompatibilität überwinden werden können. Der Einsatz eines 3D‐gedruckten Cu‐Keramikgerüsts als Metallkatalysator‐Komponente ermöglicht eine effiziente Kombination mit dem Enzym und die gewünschte zweistufige Umwandlung von Styrol in das chirale Alkoholprodukt mit hohem Gesamtumsatz und exzellenter Enantioselektivität. Dieses auf 3D‐Druck heterogenisierter Metallkatalysatoren basierende Konzept zur Kompartimentierung stellt eine skalierbare Methodik dar und eröffnet zahlreiche Perspektiven im Hinblick auf dessen Nutzung als allgemeiner Lösungsansatz auch für weitere verwandte chemoenzymatische Forschungsherausforderungen.

Asymmetric synthesis of allylic sulfonamides with axially and central chirality via palladium-catalyzed of atroposelective N-allylic alkylation

Axially chiral anilide compounds are an emerging but scarcely investigated class of stereogenic molecules with potential applications as chiral catalysts, biologically active scaffolds and functional materials. Compared to the C–C axially chiral molecules, the synthesis of axially chiral anilide compounds is a challenge owing to the lower rotation barriers. Herein, the construction of chiral allylic amine bearing axial chirality and central chirality via Pd-catalyzed atroposelective N-allylic alkylation reaction of cyclic vinyl carbonates and sulfonamides is reported. A diverse range of chiral sulfonamides bearing axial chirality and central chirality were synthesized in high yields and excellent enantioselectivities (up to 92 ​% yield and 99 ​% ee). In addition, the practical application of this protocol was also demonstrated by gram-scale synthesis and derivatives of the compound.

Enantioselective Tsuji-Trost α-Fluoroallylation of Amino Acid Esters with Gem-Difluorinated Cyclopropanes.

A novel enantioselective Tsuji-Trost-type cross coupling reaction between gem-difluorinated cyclopropanes and N-unprotected amino acid esters enabled by synergistic Pd/Ni/chiral aldehyde catalysis is presented herein. This transformation streamlined the diversity-oriented synthesis (DOS) of optically active α-quaternary α-amino acid esters bearing a linear 2-fluoroallylic motif, which served as an appealing platform for the construction of other valuable enantioenriched compounds. The key intermediates were confirmed by HRMS detection, while DFT calculations revealed that the excellent enantioselectivity was attributed to the stabilizing non-covalent interactions between the Pd(II)-π-fluoroallyl species and the Ni(II)-Schiff base complex.

Enantioselective Tsuji‐Trost α‐Fluoroallylation of Amino Acid Esters with Gem‐Difluorinated Cyclopropanes

AbstractA novel enantioselective Tsuji–Trost‐type cross coupling reaction between gem‐difluorinated cyclopropanes and N‐unprotected amino acid esters enabled by synergistic Pd/Ni/chiral aldehyde catalysis is presented herein. This transformation streamlined the diversity‐oriented synthesis (DOS) of optically active α‐quaternary α‐amino acid esters bearing a linear 2‐fluoroallylic motif, which served as an appealing platform for the construction of other valuable enantioenriched compounds. The key intermediates were confirmed by HRMS detection, while DFT calculations revealed that the excellent enantioselectivity was attributed to the stabilizing non‐covalent interactions between the Pd(II)‐π‐fluoroallyl species and the Ni(II)‐Schiff base complex.

Pd-Catalyzed Asymmetric Intramolecular Dearomatizing Reductive Heck Reaction of Indoles.

An enantioselective Pd-catalyzed intramolecular dearomative reductive Heck reaction of N-(o-bromoaryl) indole-3-carboxamide is developed. By employing Pd(dba)2/SPINOL-based phosphoramidite as the chiral catalyst and HCO2Na as the hydride source, a series of enantioenriched spiro indolines bearing vicinal stereocenters were afforded in moderate to good yields with excellent enantioselectivities. The reductive Heck reaction of formal tetrasubstituted alkene bearing β-hydrogens is therefore realized by inhibiting β-H elimination.

Nickel-catalysed enantioselective alkene dicarbofunctionalization enabled by photochemical aliphatic C–H bond activation

The development of novel strategies to rapidly construct complex chiral molecules from readily available feedstocks is a long-term pursuit in the chemistry community. Radical-mediated alkene difunctionalizations represent an excellent platform towards this goal. However, asymmetric versions remain highly challenging, and more importantly, examples featuring simple hydrocarbons as reaction partners are elusive. Here we report an asymmetric three-component alkene dicarbofunctionalization capitalizing on the direct activation of C(sp3)–H bonds through the combination of photocatalysed hydrogen atom transfer and nickel catalysis. This protocol provides an efficient platform for installing two vicinal carbon–carbon bonds across alkenes in an atom-economic fashion, providing a wide array of high-value chiral α-aryl/alkenyl carbonyls and phosphonates, as well as 1,1-diarylalkanes from ubiquitous alkane, ether and alcohol feedstocks. This method exhibits operational simplicity, broad substrate scope and excellent regioselectivity, chemoselectivity and enantioselectivity. The compatibility with bioactive motifs and expedient synthesis of pharmaceutically relevant molecules highlight the synthetic potential of this protocol.

Protein engineering of lipase A from Candida antarctica to improve esterification of tertiary alcohols.

Chiral tertiary alcohols are important organic compounds in science as well as in industry. However, their preparation in enantiomerically pure form is still a challenge due to their complex structure and steric hindrances compared with primary and secondary alcohols, so kinetic resolution could be an attractive approach. Lipase A from Candida antarctica (CAL-A) has been shown to catalyze the enantioselective esterification of various tertiary alcohols with excellent enantioselectivity but low activity. Here we report a mutagenesis study by rational design to improve CAL-A activity against tertiary alcohols. Single mutants of CAL-A were selected, expressed, immobilized and screened for esterification of the tertiary alcohol 1,2,3,4-tetrahydronaphthalene-1-ol. A double mutant V278S+S429G showed a 1.5-fold higher reaction rate than that of the wild type CAL-A, while maintaining excellent enantioselectivity.

Y(OTf)3-Salazin-Catalyzed Asymmetric Aldol Condensation.

The chiral aziridine-containing vicinal iminophenol tridentate ligands (named salazins) are a class of readily prepared chiral ligands from enantiopure aziridines and salicylaldehydes. Their scandium and yttrium triflate complexes show excellent reactivity and enantioselectivities in the catalytic asymmetric aldol condensation of electron-deficient aromatic aldehydes and ketones, including acetone and cycloalkanones. The stereoselectivity is rationalized to the strong π-stacking interaction between aromatic aldehydes and the vicinal iminophenol group in the chiral ligands.

Chiral Lewis Base/Achiral Acid Co‐Catalyzed Atroposelective Sulfenylation of Pyrrole Derivatives: Construction of C—N Axially Chiral Sulfides

Comprehensive SummaryChiral BINAM‐derived selenide/achiral acid co‐catalyzed atroposelective electrophilic sulfenylation of pyrrole derivatives has been realized for the first time. A variety of C—N axially chiral sulfur‐containing pyrrole derivatives were readily obtained in moderate to good yields with moderate to excellent enantioselectivities. This catalytic system involves sequential desymmetrization and kinetic resolution.

Stereodivergent Synthesis of Spiroaminals via Chiral Bifunctional Hydrogen Bonding Organocatalysis

AbstractSpiroaminals represent novel structural motifs prevalent in diverse natural products and biologically active molecules. Achieving their enantioselective synthesis is a highly desirable and challenging task in synthetic endeavors due to their intricate molecular frameworks. Herein, we accomplished the first stereodivergent construction of spiroaminals using chiral bifunctional organocatalyzed intramolecular 1,2‐addition followed by an oxa‐Michael addition cascade in a high atom and step economical pathway. A proper modulation of the cinchona‐derived squaramide catalysts efficiently provided access to all the possible stereoisomers with high yield, diastereoselectivity, and excellent enantioselectivity while displaying a broad substrate tolerance. Additionally, we validated the scalability of the reaction and demonstrated the synthesis of variable spiroaminal scaffolds, confirming the viability of our protocol.

Stereodivergent Synthesis of Spiroaminals via Chiral Bifunctional Hydrogen Bonding Organocatalysis.

Spiroaminals represent novel structural motifs prevalent in diverse natural products and biologically active molecules. Achieving their enantioselective synthesis is a highly desirable and challenging task in synthetic endeavors due to their intricate molecular frameworks. Herein, we accomplished the first stereodivergent construction of spiroaminals using chiral bifunctional organocatalyzed intramolecular 1,2-addition followed by an oxa-Michael addition cascade in a high atom and step economical pathway. A proper modulation of the cinchona-derived squaramide catalysts efficiently provided access to all the possible stereoisomers with high yield, diastereoselectivity, and excellent enantioselectivity while displaying a broad substrate tolerance. Additionally, we validated the scalability of the reaction and demonstrated the synthesis of variable spiroaminal scaffolds, confirming the viability of our protocol.

Catalytic Asymmetric Construction of α,α-Diaryl Aldehydes via Oxo-Hydroarylation of Terminal Alkynes.

Chiral aldehydes containing a tertiary stereogenic center are versatile building blocks in organic chemistry. In particular, such structural motifs bearing an α,α-diaryl moiety are very challenging scaffolds and their efficient asymmetric synthesis is not reported. In this work, a phosphoric acid-catalyzed enantioselective synthesis of α,α-diaryl aldehydes from simple terminal alkynes is presented. This approach yields a wide range of highly enolizable α,α-diaryl aldehydes in good yields with excellent enantioselectivities. Facile transformations of the products, as well as an efficient synthesis of bioactive molecules, including an effective anti-smallpox agent and an FDA-approved antidepressant drug (+)-sertraline, are demonstrated.

Enantioselective Construction of Chiral THIQUINOL and Its Derivatives via Chiral Phosphoric Acid Catalysis.

The first catalytic enantioselective construction of chiral THIQUINOL and its derivatives has been accomplished through a chiral phosphoric-acid-catalyzed direct aza-Friedel-Crafts reaction of 3,4-dihydroisoquinolines with 2-naphthols/anthracen-2-ols/phenanthren-9-ol. This method offers a powerful and straightforward synthetic route toward chiral THIQUINOL derivatives with good to excellent yields and enantioselectivities. These structural motifs are crucial chiral components for further transformations into established or potential chiral ligands and catalysis.

Chiral Bisphosphine-Catalyzed Asymmetric Staudinger/aza-Wittig Reaction: An Enantioselective Desymmetrizing Approach to Crinine-Type Amaryllidaceae Alkaloids.

An unprecedented chiral bisphosphine-catalyzed asymmetric Staudinger/aza-Wittig reaction of 2,2-disubstituted cyclohexane-1,3-diones is reported, enabling the facile access of a broad range of cis-3a-arylhydroindoles in high yields with excellent enantioselectivities. The key to the success of this work relies on the first application of chiral bisphosphine DuanPhos to the asymmetric Staudinger/aza-Wittig reaction. An effective reductive system has been established to address the challenging PV═O/PIII redox cycle associated with the chiral bisphosphine catalyst. In addition, comprehensive experimental and computational investigations were carried out to elucidate the mechanism of the asymmetric reaction. Leveraging the newly developed chemistry, the enantioselective total syntheses of several crinine-type Amaryllidaceae alkaloids, including (+)-powelline, (+)-buphanamine, (+)-vittatine, and (+)-crinane, have been accomplished with remarkable conciseness and efficiency.