Corey Chaykovsky Research Articles

Recent Developments in Stereoselective Reactions of Sulfoxonium Ylides

This review probes the recent developments in stereoselective reactions within the area of sulfoxonium ylide chemistry since the early 2000s. An abundance of research has been applied to sulfoxonium ylide chemistry since its emergence in the early 1960s. There has been a continued effort since then with work in traditional areas, such as epoxidation, aziridination and cyclopropanation. Efforts have also been applied in novel areas, such as olefination and insertion reactions, to develop stereoselective methodologies using organocatalysis and transition metal catalysis. The growing research area of interrupted Johnson–Corey–Chaykovsky reactions is also described, whereby unexpected stereoselective cyclopropanation and epoxidation methodologies have been developed. In general, the most observed mechanistic pathway of sulfoxonium ylides is the formal cycloaddition: (2 + 1) (e.g., epoxides, cyclopropanes, aziridines), (3 + 1) (e.g., oxetanes, azetidines), (4 + 1) (e.g., indanones, indolines). This pathway involves the formation of a zwitterionic intermediate through nucleophilic addition of the carbanion to an electrophilic site. An intramolecular cyclization occurs, constructing the cyclic product. Insertion reactions of sulfoxonium ylides to X–H bonds (e.g., X = S, N or P) are also observed, whereby protonation of the carbanion is followed by a nucleophilic addition of X, to form the inserted product.

A Practical Approach to Cyclopropanation of Masked o‐Benzoquinones with Applications in Tropolone Derivative Synthesis

AbstractThe Corey–Chaykovsky cyclopropanation of readily available masked o‐benzoquinones (MOBs) has been investigated to generate functionalized bicyclo[4.1.0]heptane derivatives with regioselectivity. The resulting bicyclic products were subjected to a sequence of hydrolysis, BF₃ ⋅ Et₂O‐mediated ring‐opening, and then again hydrolysis to access various tropolone derivatives – a class of molecules with significant roles in synthetic, biological, and theoretical chemistry. Utilizing an improved approach based on established cyclopropanation and ring‐opening strategies, several bicyclo[4.1.0]heptanes, tropolone difluorides, and tropolones can be synthesized from readily available MOBs. Our efforts focused on modifying each step to make these reactions general and of considerable practical value.

Design and Synthesis of Out/Out, Out/In, and In/In Epoxides in Polycyclic Cage Frameworks

AbstractWe report a useful synthetic approach to assemble in/in epoxide, in/out epoxide, and out/out epoxide in cage systems using the Corey–Chaykovsky reaction and the Peterson olefination as key steps. In this regard, a variety of pentacycloundecane (PCUD) based cage compounds containing oxirane rings with diverse stereochemical disposition were synthesized via a simple synthetic sequence. Five cage diones were used for this purpose, and the starting cage diones were prepared with easily accessible starting materials such as 1,4-hydroquinone derivatives and cyclopentadiene. Here, we have used the Diels–Alder (DA) reaction, a [2+2] photocycloaddition, the Corey–Chaykovsky reaction, and the Peterson olefination as crucial steps to prepare the target molecules.

An α-chloroaldehyde-based formal synthesis of eribulin

Eribulin (Halaven) is the most structurally complex non-peptidic drug made by total synthesis and has challenged preconceptions of synthetic feasibility in drug discovery and development. However, despite decades of research, the synthesis and manufacture of eribulin remains a daunting task. Here, we report syntheses of the most complex fragment of eribulin (C14–C35) used in two distinct industrial routes to this important anticancer drug. Our convergent strategy relies on a doubly diastereoselective Corey–Chaykovsky reaction to affect the union of two tetrahydrofuran-containing subunits. Notably, this process relies exclusively on enantiomerically enriched α-chloroaldehydes as building blocks for constructing the three densely functionalized oxygen heterocycles found in the C14–C35 fragment and all associated stereocenters. Overall, eribulin can now be produced in a total of 52 steps, which is a significant reduction from that reported in both academic and industrial syntheses.

Synthesis of 2-[2-(Ethoxymethoxy)phenyl]spiro[cyclopropane-1,2′-indene]-1′,3′-dione

An 1,3-indanedione-derived donor–acceptor cyclopropane, bearing the ethoxymethyl-protected phenolic group at the ortho-position of the donor aryl substituent, has been synthesized using a reaction sequence involving the Knoevenagel condensation of 1,3-indanedione with the corresponding protected salicylaldehyde followed by the Corey–Chaykovsky cyclopropanation of the obtained adduct with dimethylsulfoxonium methylide. The structure of the synthesized cyclopropane was unambiguously proved by single-crystal X-ray diffraction data.

Retraction of “Water-Mediated Intramolecular Cyclization/Oxidation of α-Carbonyl Sulfur Ylides: Synthesis of Corey–Chaykovsky Reagent Type Heterocycles”

ADVERTISEMENT RETURN TO ISSUEPREVRetractionNEXTORIGINAL ARTICLEThis notice is a retraction.Retraction of “Water-Mediated Intramolecular Cyclization/Oxidation of α-Carbonyl Sulfur Ylides: Synthesis of Corey–Chaykovsky Reagent Type Heterocycles”Xiaokang KangXiaokang KangMore by Xiaokang Kang, Xiayu LiangXiayu LiangMore by Xiayu Liang, and Qingle Zeng*Qingle ZengMore by Qingle Zenghttps://orcid.org/0000-0003-0750-540XCite this: Org. Lett. 2023, 25, 4, 714Publication Date (Web):January 20, 2023Publication History Received28 December 2022Published online20 January 2023Published inissue 3 February 2023https://doi.org/10.1021/acs.orglett.2c04347Copyright © 2023 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views2718Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (827 KB) Get e-Alerts Get e-Alerts

Opportunities for the Application and Advancement of the Corey–Chaykovsky Cyclopropanation

Opportunities for the Application and Advancement of the Corey–Chaykovsky Cyclopropanation

(3-Methylene-2,3-dihydronaphtho[2,3-b][1,4]dioxin-2-yl)methanol

(3-Methylene-2,3-dihydronaphtho[2,3-b][1,4]dioxin-2-yl)methanol was unexpectedly achieved as the main reaction product while applying a standard Johnson–Corey–Chaykovsky procedure to the 2,3-dihydronaphtho[2,3-b][1,4]dioxine-2-carbaldehyde, aiming at obtaining the corresponding epoxide. The structure of the recovered compound was confirmed through NMR and HRMS, the melting point was measured by DSC, and the organic purity was assessed using HPLC. We hypothesized the possible mechanism for the obtainment of this side product, which should involve the opening of the dioxane ring soon after the nucleophilic attack of the ylide to the carbonyl function. The consequent transfer of the negative charge allows the achievement of the phenolate function. The tautomer further rearranges, forming the unstable oxirane, which opening is favored by the acidic phenolic function, thus closing into the more stable six-membered ring compound. We confirmed the hypothesized reaction mechanism by applying the same reaction conditions while starting from the corresponding methyl ketone. This undesired compound, easily and quantitatively obtained by standard Johnson–Corey–Chaykovsky conditions, could pave the way to a new methodology for the obtainment of 2,3-disubstituted 1,4-naphthodioxanes, further derivatizable.

Reactions of Nitroarenes with Corey–Chaykovsky Reagents

AbstractElectrophilic and nucleophilic substitutions of aromatic substrates share common mechanistic pathways. In both scenarios reacting species attack rings at the unsubstituted (C–H) positions, giving cationic Wheland intermediates or anionic Meisenheimer complexes. However, the following step of rearomatization breaks the intrinsic symmetry, due to different leaving group ability of proton and hydride anion, respectively. In effect, electron-deficient arenes are prone to transformations unparalleled in electrophilic chemistry. In our article, we present transformations of anionic σH-adducts, formed between nitroarenes and carbanions of the Corey–Chaykovsky reagents. Depending on structure of the substrates and reaction conditions, the intermediates undergo cyclization to cyclopropanes (norcaradienes) or base-induced elimination to the alkylated products. Mechanistic studies reveal that order of the carbanions controls competition between the processes, due to steric hindrance developing at the β-elimination step.1 Introduction2 Cyclopropanation of Nitronaphthalenes3 Alkylation of Nitropyridines4 Mechanistic Studies5 Summary and Outlook

Extended Corey–Chaykovsky reactions: transformation of 2-hydroxychalcones to benzannulated 2,8-dioxabicyclo[3.2.1]octanes and 2,3-dihydrobenzofurans

We report the divergent synthesis of benzannulated 2,8-dioxabicyclo[3.2.1]octanes and 2,3-dihydrobenzofurans using the concept of extended Corey–Chaykovsky reactions.

Recent Advances in the Synthesis of Diverse Libraries of Small-Molecule Building Blocks in Ionic Liquids (ILs)

AbstractThe Account describes recent advances, from the authors’ laboratories, in the synthesis of diverse libraries of small-molecule building blocks employing ionic liquids (ILs). The ability of ILs to act as catalysts/promoters/solvents for electrophilic and onium ion chemistry, as well as in metal-mediated cross-coupling reactions, and the potential to sequence/hyphenate these methods, have opened up new opportunities for facile assembly of functional small molecules with increased complexity from readily available precursors. While Brønsted acidic IL/IL solvent mixtures are suitable media for carbocation and onium ion chemistry, piperidine-appended IL/IL solvent mixtures can successfully catalyze a variety of base-catalyzed reactions. Several widely practiced transformations including ‘name reactions’ were adapted and performed efficiently in ILs.1 Introduction2 Aryldiazonium Salts and Aryltriazenes as Coupling Partners in Metal-Mediated C–C Cross-Coupling Reactions in ILs3 Expanding the Scope of Metal-Mediated Cross-Coupling Reactions in ILs4 Application of ILs in Synthesis and Functionalization of Hetero­cycles5 Expanding the Scope of Amide Synthesis in ILs6 Generation and Chemistry of ‘Tamed’ Propargylic Cations in ILs7 Newer Nitration Methods for Arenes and Heteroarenes in ILs8 Halofunctionalization in ILs9 ‘Name Reactions’and Other Widely Practiced Synthetic Transformations in ILs9.1 The Biginelli Reaction9.2 Nitrile Synthesis by the Schmidt Reaction9.3 Rupe Rearrangement9.4 Synthesis of 1,3-Dioxanes via Prins Reaction in [BMIM(SO3H)][OTf]9.5 Synthesis of Cyclopropanes and Oxiranes by the Corey–Chaykovsky (CC) Reaction10 Conclusions and Closing Remarks

Asymmetric Sequential Corey-Chaykovsky Cyclopropanation/Cloke-Wilson Rearrangement for the Synthesis of 2,3-Dihydrofurans.

The first sequential Corey-Chaykovsky cyclopropanation/Cloke-Wilson rearrangement between propargyl sulfonium salts and acrylonitrile derivatives has been developed, affording the tetra-substituted 2,3-dihydrofurans in generally excellent yields (57-98%) with good diastereoselectivities (7:1-18:1). In addition, chiral propargyl sulfonium salt is also suitable for this strategy, giving the optically active 2,3-dihydrofurans with good enantioselectivities. This reaction sequence was designed upon in situ generated 10π-conjugated structures from the dearomatization of indole fragments and subsequent intramolecular 1,6-addition.

Water-Mediated Intramolecular Cyclization/Oxidation of α-Carbonyl Sulfur Ylides: Synthesis of Corey-Chaykovsky Reagent Type Heterocycles.

A new class of Corey-Chaykovsky reagent type five-membered heterocycles with an oxosulfonium ylide moiety has been synthesized by the water-mediated intramolecular cyclization/oxidation of α-carbonyl sulfur ylides generated in situ from sulfonium salts under mild conditions.

Comparison of synthetic routes for fully substituted (1H-1,2,3-triazol-4-yl)acetic acids

The new fully substituted (1H-1,2,3-triazol-4-yl)acetic acids were synthesized from available precursors (1H-1,2,3-triazol-4-yl)ethanones and 1Н-1,2,3-triazole-4-carboxylic acids, which are easily prepared by the Dimroth reaction from azides and 1,3-dicarbonyl compounds. The practical methods of homologization (the Arndt–Eistert reaction and homologization as a result of nucleophilic substitution by cyanide anion) and the Willgerodt-Kindler reaction were compared. The Willgerodt-Kindler method starting from (5-methyl-1H-1,2,3-triazol-4-yl)ethanones was selected as the most convenient method for the synthesis of 2-(1-aryl-5-methyl-1H-1,2,3-triazol-4-yl)acetic acids, which are promising building blocks for drug discovery. Additionally, (1H-1,2,3-triazol-4-yl)ethanones were studied for the synthesis of alcohols, amines and in the Johnson–Corey–Chaykovsky reaction.

Synthesis of (Het)aryl 2-(2-hydroxyaryl)cyclopropyl Ketones.

A simple general method for the synthesis of 1-acyl-2-(ortho-hydroxyaryl)cyclopropanes, which belong to the donor–acceptor cyclopropane family, has been developed. This method, based on the Corey–Chaykovsky cyclopropanation of 2-hydroxychalcones, allows for the preparation of a large diversity of hydroxy-substituted cyclopropanes, which can serve as promising building blocks for the synthesis of various bioactive compounds.

One-Pot Synthesis of γ-Azidobutyronitriles and Their Intramolecular Cycloadditions

Efficient gram-scale, one-pot approaches to azidocyanobutyrates and their amidated or decarboxylated derivatives have been developed, starting from commercially available aldehydes and cyanoacetates. These techniques combine (1) Knoevenagel condensation, (2) Corey–Chaykovsky cyclopropanation and (3) nucleophilic ring opening of donor-acceptor cyclopropanes with the azide ion, as well as (4) Krapcho decarboxylation or (4′) amidation. The synthetic utility of the resulting γ-azidonitriles was demonstrated by their transformation into tetrazoles via intramolecular (3+2)-cycloaddition. A condition-dependent activation effect of the α-substituent was revealed in that case. Thermally activated azide–nitrile interaction did not differentiate the presence of an α-electron-withdrawing substituent in γ-azidonitriles, whereas the Lewis acid mediated (SnCl4 or TiCl4) reaction proceeded much easier for azidocyanobutyrates. This allowed us to develop an efficient procedure for converting azidocyanobutyrates into the corresponding tetrazoles.

Synthetic Approaches to Contemporary Drugs that Contain the Cyclopropyl Moiety

The U.S. Food and Drug Administration approved 18 new drugs that incorporate the cyclopropyl structural motif in the time frame from 2012 to 2018. This review provides an overview of synthetic approaches to these drugs with emphasis on the construction of the cyclopropyl moiety or its incorporation into the key building blocks for assembly of the highlighted drugs. Based on the structural diversity of these drugs, synthetic approaches for the construction and introduction of the cyclopropyl moiety into their structure are diverse and include: cycloalkylation (double alkylation) of CH-acids, catalytic cyclopropanation of alkenes with diazo compounds, the Simmons–Smith reaction, the Corey–Chaykovsky reaction, the Kulinkovich reaction, the Horner–Wadsworth–Emmons reaction, and cycloaddition. In addition, the cyclopropyl structure was also introduced into the drug substance intermediates via simple cyclopropyl-moiety-containing building blocks, such as cyclopropylamine, cyclopropanesulfonamide, cyclopropanecarbonyl chloride, and cyclopropylmagnesium bromide.1 Introduction2 Synthesis of Recently Approved Cyclopropyl-Moiety-Containing Drugs2.1 Cabozantinib2.2 Trametinib2.3 Simeprevir2.4 Ledipasvir2.5 Olaparib2.6 Tasimelteon2.7 Finafloxacin2.8 Paritaprevir2.9 Lenvatinib2.10 Lumacaftor2.11 Lesinurad2.12 Grazoprevir2.13 Glecaprevir2.14 Ozenoxacin2.15 Voxilaprevir2.16 Naldemedine2.17 Tezacaftor2.18 Tecovirimat3 Conclusion

Synthesis of the β2-Agonist Tulobuterol and Its Metabolite 4-Hydroxytulobuterol

Alternative methods have been developed for the synthesis of the β2-agonist tulobuterol and its metabolite 4-hydroxytulobuterol with a similar activity. The proposed procedures utilize available reagents, and the key stage in the synthesis is the formation of intermediate oxirane according to the Corey–Chaykovsky reaction, followed by opening of the oxirane ring by the action of excess tert-butylamine. In the synthesis of 4-hydroxytulobuterol, the hydroxy group was protected by benzylation, and the protecting group was removed in the final stage by hydrogenation over carbon-supported palladium.

Johnson-Corey-Chaykovsky fluorocyclopropanation of double activated alkenes: scope and limitations.

Johnson-Corey-Chaykovsky fluorocyclopropanation of double activated alkenes utilizing S-monofluoromethyl-S-phenyl-2,3,4,5-tetramethylphenylsulfonium tetrafluoroborate is an efficient approach to obtain a range of monofluorocyclopropane derivatives. So far, fluoromethylsulfonium salts have displayed the broadest scope for direct fluoromethylene transfer. In contrast to more commonly used fluorohalomethanes or freon derivatives, diarylfluoromethylsulfonium salts are bench stable, easy-to use reagents useful for the direct transfer of a fluoromethylene group to alkenes giving access to the challenging products - fluorocyclopropane derivatives. Interplay between the reactivity of the starting materials and stability of the fluorocyclopropanes formed determines the outcome of the process.

Synthesis of Epoxides from Alkyl Bromides and Alcohols with in Situ Generation of Dimethyl Sulfonium Ylide in DMSO Oxidations.

Direct conversion of the readily available alkyl bromides and alcohols to value-added epoxides using dimethyl sulfoxide (DMSO) under mild reaction conditions has been developed. Benzyl and allyl bromides, and activated and unactivated alcohols all proceeded smoothly to give epoxides in high to excellent yield. Dimethyl sulfide, generated by DMSO oxidations, was in situ elaborated to form the substituted dimethyl sulfonium ylide species that participates in the Corey-Chaykovsky epoxidation in a domino and one-pot fashion, respectively.