Asymmetric Cyclization Research Articles

Stereodivergent Synthesis of Chiral Hydrobenzofuranpyrrolidines by Catalytic Asymmetric Dearomative Cyclization and Controlled Epimerization

AbstractA methodology to access stereoisomeric sets of products bearing multiple stereogenic centers is still a significant challenge in asymmetric catalysis. We present herein our experimental studies on the stereodivergent synthesis of chiral hydrobenzofuran‐fused pyrrolidines with three stereogenic centers via organocatalytic asymmetric dearomative cyclization and epimerization process. Chiral bifunctional thiourea catalyst could successfully promote the enantioselective dearomatization cyclization of 2‐nitrobenzofurans with o‐hydroxy aromatic aldimines, which enabled the synthesis of (3S,3aR,8bR)‐hydrobenzofuran[3.2]pyrrolidines in 79–92% yields with >20:1 stereoselectivities and 93–>99% enantio‐selectivities. While catalytic amount of DBU could induce the direct intramolecular epimerization of (3S,3aR,8bR)‐hydrobenzofuran[3.2] pyrrolidines to its diastereomers (3R,3aR,8bR)‐hydrobenzofuran[3.2] pyrrolidines in 72–87% yields without loss of stereoselectivities. The mechanistic pathways of the epimerization process were investigated by a series of control experiments study. This work provides an alternative and forward solution for the stereodivergent preparation of functionalized pyrrolidines with potential bioactivities.

The Catalytic Asymmetric Polyene Cyclization of Homofarnesol to Ambrox

The Catalytic Asymmetric Polyene Cyclization of Homofarnesol to Ambrox

Palladium-catalyzed difluorocarbene transfer enables access to enantioenriched chiral spirooxindoles

AbstractWe disclose herein an unprecedented Pd-catalyzed difluorocarbene transfer reaction, which assembles a series of structurally interesting chiral spiro ketones with generally over 90% ee. Commercially available BrCF2CO2K serves as the difluorocarbene precursor, which is harnessed as a user-friendly and safe carbonyl source in this transformation. Preliminary mechanistic studies exclude the formation of free CO in the reaction process, and importantly, we also find that BrCF2CO2K outcompete gaseous CO and several common CO surrogates in this asymmetric process. The reaction mechanism, including the in-situ progressive release of the difluorocarbene, the rapid migratory insertion of ArPd(II) = CF2 species, and subsequent defluorination hydrolysis by water to introduce the carbonyl group, accounts for the overall high efficiency and uniqueness. This work clearly showcases the advantage and potential of the difluorocarbene in synthesis and supplies a mechanistically distinct route for asymmetric carbonylative cyclization reactions.

Organocatalytic asymmetric cyclization of aminochalcones and azlactones: synthesis of 3,4-dihydroquinolinones

A novel and efficient reaction of aminochalcones and azlactones has been developed under the catalysis of bifunctional organocatalysts. The corresponding enantioenriched 3,4-dihydroquinolinones were efficiently assembled in moderate to excellent yield with excellent enantioselectivitiy. In this work, the synthons with tosylaminochalcones in an asymmetric approach were not confined to traditional unsaturated compounds via the aza-Michael/Michael addition pathway. Azlactones with highly nucleophilicity under a chiral base could promote the Michael addition to substituted 2-aminochalcones, followed by amide formation to deliver dihydroquinolinones in high enantiocontrol.

Nickel-Catalyzed Enantioselective Reductive N-Cyclization-Thiolation Reaction of Alkene-Tethered Oxime Esters and Disulfides.

Asymmetric aza-Heck cyclization and coupling reactions offer efficient access to enantioenriched N-heterocycles, yet the current studies focus primarily on sequential C-N and C-C bond formation. Herein, we report an enantioselective reductive aza-Heck cyclization followed by a C-S coupling sequence, ultimately yielding sulfide-containing enantioenriched pyrrolines. The reaction is conducted under mild conditions and tolerates broad functionalities including alkynes, phenols, anilines, amides, nitriles, and bromides.

Chiral Brønsted Acid-Catalyzed Asymmetric Reaction via Vinylidene Ortho-Quinone Methides.

Vinylidene ortho-quinone methides (VQMs) have been proven to be versatile and crucial intermediates in the catalytic asymmetric reaction in last decade, and thus have drawn considerable concentrations on account of the practical application in the construction of enantiomerically pure functional organic molecules. However, in comparison to the well established chiral Brønsted base-catalyzed asymmetric reaction via VQMs, chiral Brønsted acid-catalyzed reaction is rarely studied and there is no systematic summary to date. In this review, we summarize the recent advances in the chiral Brønsted acid-catalyzed asymmetric reaction via VQMs according to three types of reactions: a) intermolecular asymmetric nucleophilic addition to VQMs; b) intermolecular asymmetric cycloaddition of VQMs; c) intramolecular asymmetric cyclization of VQMs. Finally, we put forward the remained challenges and opportunities for potential breakthroughs in this area.

The catalytic asymmetric polyene cyclization of homofarnesol to ambrox

Polyene cyclizations are among the most complex and challenging transformations in biology. In a single reaction step, multiple carbon–carbon bonds, ring systems and stereogenic centres are constituted from simple, acyclic precursors1–3. Simultaneously achieving this kind of precise control over product distribution and stereochemistry poses a formidable task for chemists. In particular, the polyene cyclization of (3E,7E)-homofarnesol to the valuable naturally occurring ambergris odorant (−)-ambrox is recognized as a longstanding challenge in chemical synthesis1,4–7. Here we report a diastereoselective and enantioselective synthesis of (−)-ambrox and the sesquiterpene lactone natural product (+)-sclareolide by a catalytic asymmetric polyene cyclization by using a highly Brønsted-acidic and confined imidodiphosphorimidate catalyst in the presence of fluorinated alcohols. Several experiments, including deuterium-labelling studies, suggest that the reaction predominantly proceeds through a concerted pathway in line with the Stork–Eschenmoser hypothesis8–10. Mechanistic studies show the importance of the enzyme-like microenvironment of the imidodiphosphorimidate catalyst for attaining exceptionally high selectivities, previously thought to be achievable only in enzyme-catalysed polyene cyclizations.

Chiral Magnesium Complex-Catalyzed Asymmetric Cyclization of Vinyl Diazo Compounds with Phenol Derivatives via Noncarbene Pathways

Chiral Magnesium Complex-Catalyzed Asymmetric Cyclization of Vinyl Diazo Compounds with Phenol Derivatives via Noncarbene Pathways

Enantioselective Reductive Cyclization of Alkynyl-Tethered Cyclohexadienones Catalyzed by Rhodium Complexes.

Although various types of asymmetric cyclization reactions of 1,6-enynes have been established, simple asymmetric reductive cyclization remains underdeveloped. In this study, the enantioselective reductive cyclization of alkynyl-tethered cyclohexadienones (1,6-enynes) has been developed via a chiral pincer rhodium catalyst, affording cis-hydrobenzofurans and cis-hydroindoles with high enantioselectivities (90-99% ee). Furthermore, several synthetic applications and preliminary inhibitory activity studies against SARS-CoV-2 3CLpro are presented.

Nickel-catalyzed defluorinative asymmetric cyclization of Trifluoromethyl-substituted 1,6-Enynes: Insights from DFT calculations on the reaction mechanism and selectivity

Density functional theory (DFT) calculations were employed to elucidate the mechanism and selectivity of nickel-catalyzed defluorinative asymmetric cyclization reactions of trifluoromethyl-substituted 1,6-enynes. The results indicate that the product is formed via a stepwise addition cyclization mechanism, including sequential steps of ligand coordination, transmetalation, ligand exchange, alkyne insertion, olefin insertion, β-F elimination, another transmetalation, and a final ligand exchange. The regioselectivity is primarily governed by the alkyne insertion step, where electrostatic interactions strongly favor 1,2-insertion of the carbon-carbon triple bond over 2,1-insertion. The enantioselectivity is largely determined during the insertion step of the olefin insertion step, with the (S)-product forming preferentially over the (R)-product due to stronger non-covalent interactions between the ligand and the substrate, minimal catalyst conformational distortion, and enhanced electronic interactions between the catalyst and the substrate.

Radicals as Chiral Catalysts for Asymmetric Radical Cyclization Reactions

AbstractDue to the innate highly reactive properties and short life‐time, organic free radicals can often serve as promoters or intermediates to engage in various radical transformations, which are often otherwise difficult to access by ionic pathway‐based mechanisms. With the evolvement of radical chemistry, chiral radical catalyzed‐transformations have recently emerged as an attractive and robust platform for synthesis of chiral molecules of interest. Herein, we highlight several creative and strategic advances in chiral radical catalyst design, cyclization reaction achievements, and future challenges. Key ScientistsIn the 1980s, some pioneering studies by Feldman and Oshima revealed that the thiyl radical could catalyze cyclization of vinylcyclopropane with alkenes, providing access to racemic cyclopentanes. In 1996, Brian P. Roberts reported an interesting enantioselective hydrosilylation of prochiral alkenes by using thioglucose‐derived chiral thiyl radical catalysts. Since then, chiral radical catalysis has become an emerging and promising catalytic strategy in organic synthesis. However, this field has not been extensively explored further until the Maruoka group in 2014 achieved the asymmetric C—C bond formation by employing a newly designed indanol core‐based chiral thiyl radical catalyst. In this protocol, an enantioselective radical cyclization of vinylcyclopropanes with electron‐rich alkenes was developed. In 2020, Chen and Xiao disclosed a nitrogen radical‐catalyzed version of this reaction. Later, this strategy was further expanded to metalloradical catalyzed asymmetric radical cascade cyclization reactions by Zhang in 2021. Later on, Wang, Fu and Zhang et al. described a novel class of boryl radical‐catalyzed asymmetric radical cycloisomerization reactions, further showcasing enormous synthetic potential of chiral radical catalysis. This Emerging Topic has focused on asymmetric radical cyclization reactions involving diverse chiral radical catalysts.

Lewis Acid-Driven Inverse Hydride Shuttle Catalysis.

Inverse hydride shuttle catalysis provides a multicomponent platform for the highly efficient synthesis of alkaloid frameworks with exquisite diastereoselectivity. However, a number of limitations hinder this method, primarily the strict requirement for highly electron-deficient acceptors. Herein, we present a general Lewis acid-driven approach to address this constraint, and have developed two broad strategies enabling the modular synthesis of complex azabicycles that were entirely unattainable using the previous method. The enhanced synthetic flexibility facilitates a streamlined asymmetric cyclization, leading to a concise total synthesis of the alkaloid (-)-tashiromine.

Lewis Säure‐Getriebene Inverse Hydrid‐Shuttle Katalyse

AbstractInverse Hydrid‐Shuttle Katalyse bildet eine Plattform für die hocheffiziente und diastereoselektive Synthese von Alkaloidstrukturen durch Multikomponentenreaktionen. Mehrere Einschränkungen hindern jedoch die breite Anwendbarkeit dieses Ansatzes, darunter vor allem die Notwendigkeit nach besonders elektronenarmen Akzeptoren. Hier präsentieren wir einen allgemeinen, durch Lewis Säuren getriebenen Ansatz, um diese Einschränkung anzugehen, und haben zwei Strategien entwickelt, die die modulare Synthese komplexer azabicyclischer Systeme ermöglichen, die mit der früheren Methode unerreichbar waren. Die so gewonnene synthetische Flexibilität führt zu einer verbesserten asymmetrischen Cyclisierung, die eine kurze Totalsynthese des Alkaloids (−)‐Tashiromin ermöglicht hat.

Asymmetric Construction of Bis‐Spirocyclic Pyrazolones Bearing Vicinal Quaternary Carbon Centers

AbstractA catalytic asymmetric (3+2) cyclization of pyrazolone‐based MBH adducts with alkylidenyl isoxazolones was presented by using DMAP‐derived chiral catalyst, affording bis‐spirocyclic pyrazolones bearing vicinal all‐carbon quaternary stereocenters within an imbedded cyclopentene ring scaffold in good yields with excellent stereoselectivities under mild conditions.

Phosphonium-Catalyzed Monoreduction of Bisphosphine Dioxides: Origin of Selectivity and Synthetic Applications.

Controlling product selectivity in successive reactions of the same type is challenging owing to the comparable thermodynamic and kinetic properties of the reactions involved. Here, the synergistic interaction of the two phosphoryl groups in bisphosphine dioxides (BPDOs) with a bromo-phosphonium cation was studied experimentally to provide a practical tool for substrate-catalyst recognition. As the eventual result, we have developed a phosphonium-catalyzed monoreduction of chiral BPDOs to access an array of synthetically useful bisphosphine monoxides (BPMOs) with axial, spiro, and planar chirality, which are otherwise challenging to synthesize before. The reaction features excellent selectivity and impressive reactivity. It proceeds under mild conditions, avoiding the use of superstoichiometric amounts of additives and metal catalysts to simplify the synthetic procedure. The accessibility and scalability of the reaction allowed for the rapid construction of a ligand library for optimization of asymmetric Heck-type cyclization, laying the foundation for a broad range of applications of chiral BPMOs in catalysis.

Asymmetric Rh-Catalyzed Reductive Enyne Cyclization Using a Continuous-Flow Setup

Asymmetric Rh-Catalyzed Reductive Enyne Cyclization Using a Continuous-Flow Setup

Kinetic Resolution of Sulfoximines via Asymmetric Organocatalyzed Formation of Benzothiadiazine-1-oxides.

A catalytic kinetic resolution of sulfoximines has been developed through chiral phosphoric acid-catalyzed intramolecular dehydrative cyclizations. A variety of racemic sulfoximines bearing an ortho-amidophenyl moiety underwent asymmetric dehydrative cyclizations using this method, yielding both the recovered sulfoximines and benzothiadiazine-1-oxide products with good to high enantioselectivities (with s-factor up to 61). The diverse derivatizations of the chiral products into a wide range of S-stereogenic center-containing S,N-heterocycles have demonstrated the value of this method.

Asymmetric cyclization catalyzed by a chiral phosphoric acid–gold(I) hybrid complex as a multifunctional catalyst

Abstract We herein report the development of a novel hybrid complex containing gold(I) and a chiral phosphoric acid moiety to generate a multifunctional catalyst. While the use of chiral phosphoric acid as a bifunctional catalyst is a common strategy in asymmetric organic synthesis, chiral phosphoric acid–transition metal hybrid complexes as multifunctional catalysts have not been investigated. Thus, we designed and synthesized a novel gold(I) hybrid complex as a multifunctional catalyst that promotes asymmetric catalytic reactions through multipoint nonclassical noncovalent interactions in substrates that lack classical hydrogen-bond donors. In addition, we demonstrate its usefulness as a multifunctional catalyst by successfully developing the first catalytic asymmetric synthesis of dihydrocyclohepta[b]indoles. Experimental and theoretical studies revealed that this asymmetric catalytic reaction involves the kinetic resolution of the reaction intermediate, and that the favored diastereomeric transition state for yielding enantiomeric products is formed through multipoint nonclassical noncovalent interactions originating from the acid–base nature of the chiral phosphoric acid moiety.

Nickel-catalyzed electrophiles-controlled enantioselective reductive arylative cyclization and enantiospecific reductive alkylative cyclization of 1,6-enynes.

Transition metal-catalyzed asymmetric cyclization of 1,6-enynes is a powerful tool for the construction of chiral nitrogen-containing heterocycles. Despite notable achievements, these transformations have been largely limited to the use of aryl or alkenyl metal reagents, and stereoselective or stereospecific alkylative cyclization of 1,6-enynes remains unexploited. Herein, we report Ni-catalyzed enantioselective reductive anti-arylative cyclization of 1,6-enynes with aryl iodides, providing enantioenriched six-membered carbo- and heterocycles in good yields with excellent enantioselectivities. Additionally, we have realized Ni-catalyzed enantiospecific reductive cis-alkylative cyclization of 1,6-enynes with alkyl bromides, furnishing chiral five-membered heterocycles with high regioselectivity and stereochemical fidelity. Mechanistic studies reveal that the arylative cyclization of 1,6-enynes is initiated by the oxidative addition of Ni(0) to aryl halides and the alkylative cyclization is triggered by the oxidative addition of Ni(0) to allylic acetates. The utility of this strategy is further demonstrated in the enantioselective synthesis of the antiepileptic drug Brivaracetam.

Rhodium-Catalyzed Tandem Asymmetric Allylic Decarboxylative Addition and Cyclization of Vinylethylene Carbonates with N-Nosylimines.

A enantioselective tandem transformation, concerning asymmetric allylic decarboxylative addition and cyclization of N-nosylimines with vinylethylene carbonates (VECs), in the presence of [Rh(C2H4)2Cl]2, chiral sulfoxide-N-olefin tridentate ligand has been developed. The reaction of VECs with various substituted N-nosylimines proceeded smoothly under mild conditions, providing highly functionalized oxazolidine frameworks in good to high yields with good to excellent enantioselectivity.