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Enantioselective N-heterocyclic carbene (NHC) catalysis via the dienyl acyl azolium
Angewandte Chemie International Edition
Abstract
Herein we report the enantioselective N‐heterocyclic carbene catalyzed (4+2) annulation of the dienyl acyl azolium with enolates. The reaction exploits readily accessible acyl fluorides and TMS enol ethers to give a range of highly enantio‐ and diastereo‐enriched cyclohexenes (most >97:3 er and >20:1 dr). The reaction was found to require high nucleophilicity NHC catalysts with mechanistic studies supporting a stepwise 1,6‐addition/β‐lactonization. 1,6‐Addition of enolates into the dienyl acyl azolium followed by β‐lactonization provides a diverse array of polycyclic β‐lactones. The reaction proceeds with high enantioselectivity, diastereoselectivity and good yields and represents the first example of enantioselective catalysis using the dienyl acyl azolium, the higher homologue of the α,β‐unsaturated acyl azolium.
... However, the differences between the Claisen reaction reported firstly in 1912 [80][81][82] As mentioned, one of the mechanistic fundamentals of the Claisen-type reactions is the generation of α,β-unsaturated acylazolium (Scheme 7). Formation of this intermediate is usually carried out via the reaction of NHCs with α,β-unsaturated enol esters or ethers [84][85][86], ynals [87][88][89][90], 2-bromoenals [91][92][93][94], or acyl fluorides [95,96]. Moreover, formation α,β-unsaturated acylazolium is possible via two-electron oxidation of Breslow intermediate [97][98][99][100][101][102][103]. ...
... As mentioned, one of the mechanistic fundamentals of the Claisen-type reactions is the generation of α,β-unsaturated acylazolium (Scheme 7). Formation of this intermediate is usually carried out via the reaction of NHCs with α,β-unsaturated enol esters or ethers [84][85][86], ynals [87][88][89][90], 2-bromoenals [91][92][93][94], or acyl fluorides [95,96]. Moreover, formation α,β-unsaturated acylazolium is possible via two-electron oxidation of Breslow intermediate [97][98][99][100][101][102][103]. ...
Giving reactions the names of their discoverers is an extraordinary tradition of organic chemistry. Nowadays, this phenomenon is much rarer, although already named historical reactions are still often developed. This is also true in the case of a broad branch of N‑heterocyclic carbenes catalysis. NHCs allow many unique synthetic paths, including commonly known name reactions. This article aims to gather this extensive knowledge and compare historical reactions with current developed processes. Furthermore, this review is a great opportunity to highlight some of the unique applications of these procedures in the total synthesis of biologically active compounds. Hence, this concise article may also be a source of knowledge for scientists just starting their adventure with N‑heterocyclic carbene chemistry.
... Lupton and coworkers [169] presented another protocol for δ-carbon activation via NHC catalysis. Substituted α,β-γ, δ-bisunsaturated acyl fluorides 186 were utilized as the precursor of α,β-γ,δ-bisunsaturated acyl azolium intermediate. ...
Enzymes are the core for biological transformations in nature. Their structures and functions have drawn enormous attention from biologists as well as chemists since last century. The large demand of bioactive molecules and the pursuit of efficiency and greenness of synthesis have spurred the rapid development of biomimetic chemistry in the past several decades. Biomimetic asymmetric catalysis, mimicking the structures and functions of enzymes, has been recognized as one of the most promising synthetic strategies for the synthesis of valuable chiral compounds. This review summarizes the evolution of asymmetric catalysis inspired by aldolases, vitamin B1/B6-dependent enzymes, NAD(P)H, flavin, hydrogenases, heme oxygenases, non-heme oxygenases, and dinuclear/multinuclear metalloenzymes in aspects of biomimetic design, catalyst development and related catalytic transformations. Those well-established synthetic approaches originating from biological reactions have demonstrated the unique prowess of biomimetic asymmetric catalysis in bridging the gap between bio-catalysis and chemical synthesis.
... In this context, normal order cycloadditions (cycloaddition that involves <6π-electron components) have been investigated in NHC catalysis in terms of in situ generated active enolate 13,14 or dienolate intermediates 15 (Fig. 1a). These pioneer works include [2 + 2] [16][17][18][19][20] , [2 + 3] [21][22][23] , [2 + 4] [24][25][26][27][28][29] , [4 + 2] [30][31][32][33][34][35] , etc. 36,37 . In 2008, Zhang et al. 18 and Duguet et al. 16 simultaneously realized an NHC-catalyzed [2 + 2] cycloaddition of enolates with imines, yielding versatile chiral βlactams. ...
Higher-order cycloadditions are a powerful strategy for the construction of polycycles in one step. However, an efficient and concise version for the induction of asymmetry is lacking. N-heterocyclic carbenes are widely used organocatalysts for asymmetric synthesis and could be an ideal choice for enantioselective higher-order cycloadditions. Here, we report an enantioselective [10 + 2] annulation between catalytically formed aza-benzofulvene intermediates and trifluoromethyl ketone derivatives. This protocol exhibits a wide scope, high yields, and good ee values, reflecting a robust and efficient higher-order cycloaddition. Density functional theory calculations provide an accurate prediction of the reaction enantioselectivity, and in-depth insight to the origins of stereocontrol.
A variety of structurally diverse spirocyclohexane oxindoles featuring a quaternary carbon centre have been successfully constructed through an N‐heterocyclic carbene‐catalyzed [4+2] annulation of isatin‐derived enals with α‐cyano‐β‐methylenones. This domino process exhibits a wide substrate tolerance, operates under mild conditions, and yields products with high enantioselectivities.
As a significant variant of the Michael reaction, the 1,6‐addition reaction has undergone considerable development over the past decade. This effective strategy enables the synthesis of a variety of novel and potentially bioactive functional molecules. In this review, we summarize the recent progress in NHC‐catalyzed 1,6‐addition reactions, highlighting their efficiency in the rapid synthesis of complex functional molecules. We also provide our perspectives on the future development of this dynamic and highly active research area.
Herein we report a catalytic enantioselective (3+2) annulation, in which a vinyl phosphonium intermediate serves as the 2‐carbon component. The reaction involves an α‐umpolung β‐umpolung coupling sequence, enabled by β‐haloacrylates and chiral enantioenriched phosphepine catalysts. The reaction shows good generality, providing access to an array of cyclopentenes, with mechanistic studies supporting stereospecific formation of the vinyl phosphonium intermediate which, then undergoes annulation with turn over limiting catalyst elimination. Beyond defining a new approach to cyclopentenes, these studies demonstrate that β‐haloacrylates can replace ynoates in reaction designs that require exclusive umpolung coupling at the α‐ and β‐positions.
Herein we report a catalytic enantioselective (3+2) annulation, in which a vinyl phosphonium intermediate serves as the 2‐carbon component. The reaction involves an α‐umpolung β‐umpolung coupling sequence, enabled by β‐haloacrylates and chiral enantioenriched phosphepine catalysts. The reaction shows good generality, providing access to an array of cyclopentenes, with mechanistic studies supporting stereospecific formation of the vinyl phosphonium intermediate which, then undergoes annulation with turn over limiting catalyst elimination. Beyond defining a new approach to cyclopentenes, these studies demonstrate that β‐haloacrylates can replace ynoates in reaction designs that require exclusive umpolung coupling at the α‐ and β‐positions.
Both furan and 1,4‐dihydropyridine (1,4‐DHP) are key structural motifs in pharmaceuticals. Herein, we report the synthesis of 4‐(furan‐2‐ylmethyl)‐1,4‐dihydropyridines from pyridiniums and furfural derivatives under NHC catalysis. This reaction involves the generation of NHC‐bounded trienolates from furfural derivatives and following addition to the C‐4 position of N‐aryl pyridinium salts. This protocol features good yields (41–99%), and high levels of regioselectivity (>20:1 for all cases).
The reactivity of N‐Heterocyclic carbene (NHC)‐bound alkynyl acyl azoliums is underexplored in chemistry. We herein reported an NHC‐catalyzed [3+3] annulation of alkynyl acyl azoliums with β‐keto esters. The strategy features mild reaction conditions and exhibits broad substrates scope, delivering a wide range of tri‐substituted α‐pyrones in moderate to excellent yields (up to 95%). This approach extends the reactivity of alkynyl acyl azoliums to β‐keto esters binucleophiles.
Deuterium incorporation at selective sites of organic compounds has long attracted the interest of pharmaceutical industry. Here, we present a distal p-benzylic deuteration via N-heterocyclic carbene catalyzed ring-opening of cyclopropylbenzaldehydes...
N‐heterocyclic carbene (NHC)‐catalyzed enantioselective Mannich‐type reactions of the biomass‐derived platform compound 5‐(chloromethyl)furfural (CMF) with imines were developed. A series of high‐value‐added chiral amines were afforded in good to high yields with excellent regio‐ and enantioselectivities. The bifunctional NHC derived from ʟ‐pyroglutamic acid efficiently steered the remote addition of the trienolate intermediate to the imine in a highly stereocontrolled manner. This represents the first enantioselective reaction proceeding via an NHC‐bound trienolate intermediate.
N‐heterocyclic carbene (NHC)‐catalyzed enantioselective Mannich‐type reactions of the biomass‐derived platform compound 5‐(chloromethyl)furfural (CMF) with imines were developed. A series of high‐value‐added chiral amines were afforded in good to high yields with excellent regio‐ and enantioselectivities. The bifunctional NHC derived from ʟ‐pyroglutamic acid efficiently steered the remote addition of the trienolate intermediate to the imine in a highly stereocontrolled manner. This represents the first enantioselective reaction proceeding via an NHC‐bound trienolate intermediate.
Over the recent decades, due to the special electronic characteristics and diverse reactivities, N-heterocyclic carbene (NHC) has received significant interest in organocatalyzed reactions. The formation of Breslow intermediates by NHC can convert into acyl anion equivalent, enolates, homoenolate, acyl azolium, and vinyl enolate etc., and the cycloaddition reactions of these species has attracted lots of attention. In this review, we focus on the summry of the development of NHC-activation of carbonyl carbon (or imine carbon) in situ, α-, β-, γ-, and beyond, and the cycloaddition reaction of these species.
β-Lactones are common substructures in bioactive molecules. Herein, we developed an enantioselective N‑heterocyclic carbene (NHC)-catalyzed rearrangement of enol ε-lactones for the construction of bicyclic β-lactones. The reaction works well for...
N-heterocyclic carbene (NHC) has been widely used as an organocatalyst for both umpolung and non-umpolung chemistry. Previous works mainly focus on species including Breslow intermediate, azolium enolate intermediate, homoenolate intermediate, alkenyl acyl azolium intermediate, etc. Notably, the NHC-bound alkynyl acyl azolium has emerged as an effective intermediate to access functionalized cyclic molecular skeleton until very recently. In this review, we summarized the generation and reactivity of the NHC-bound alkynyl acyl azolium intermediates, which covers the efforts and advances in the synthesis of achiral and axially chiral cyclic scaffolds via the NHC-bound alkynyl acyl azolium intermediates. In particular, the mechanism related to this intermediate is discussed in detail.
The ε-benzylation of γ-alkenyl-γ-oxidized enals via dual photoredox and N-heterocyclic carbene catalysis has been developed, affording the corresponding ε-benzyl-α,β-γ,δ-bisunsaturated esters in moderate to good yields with exclusive regioselectivities. The reaction is proposed via the generation of benzyl radical under photocatalysis, followed by its addition to an NHC-bound trienolate intermediate.
Acyl fluorides show unique reactivity and stability, and the catalytic conversions using acyl fluorides as a divergent building block have recently attracted much attention and have been rapidly researched. Thus, a development of a new synthetic method of acyl fluorides is constantly demanded. Herein, we describe a phosphine‐catalyzed acyl‐group exchange reaction between carboxylic acids and an aroyl fluoride. A variety of acyl fluorides are directly obtained from carboxylic acids through a catalytic system composed of tricyclohexylphosphine (PCy3) and 2,6‐difluorobenzoyl fluoride. This report is the first example of utilizing an acyl fluoride as a deoxyfluorination reagent.
Developing reliable indexes for prediction of the actual chemical active site of substrates is one of the most challenging questions in chemistry field. Herein, we suggested a general method for...
Oxidative carbene organocatalysis, inspired from Vitamin B1 catalyzed oxidative activation from pyruvate to acetyl coenzyme A, have been developed as a versatile synthetic method. To date, the α-, β-, γ-, δ- and carbonyl carbons of (unsaturated)aldehydes have been successfully activated via oxidative N-heterocyclic carbene (NHC) organocatalysis. In comparison with chemical redox or photoredox methods, electroredox methods, although widely used in mechanistic study, were much less developed in NHC catalyzed organic synthesis. Herein, an iodide promoted electroredox NHC organocatalysis system was developed. This system provided general solutions for electrochemical single-electron-transfer (SET) oxidation of Breslow intermediate towards versatile transformations. Radical clock experiment and cyclic voltammetry results suggested an anodic radical coupling pathway. Oxidative carbene organocatalysis has been developed as a versatile synthetic method, but has been paired with electroredox chemistry in only limited examples. Herein, enantioenriched heterocycles are synthesized from racemic substrates via an iodide-promoted NHC organocatalysis system that is powered by electroredox chemistry.
Numerous studies on the activation of carbon–fluorine bonds have been reported in recent years. For example, acyl fluorides have been utilized as versatile reagents for acylation, arylation, and even fluorination. In this review, we focus on acyl fluorides as compounds with carbon–fluorine bonds, and highlight recent advances in strategies for the activation of their C–F bonds via transition-metal catalysis, N-heterocyclic carbene (NHCs) catalysis, organophosphine catalysis, and classical nucleophilic substitution reactions.
1 Introduction
2 Transition-Metal-Mediated C–F Bond Activation
2.1 Acylation (Carbonyl-Retentive) Coupling Reactions
2.2 Decarbonylative Reactions
2.3 C–F Bond Activation by Other Transition Metals
3 C–F Bond Activation by N-Heterocyclic Carbenes (NHCs)
3.1 NHC-Catalyzed Cycloaddition of Acyl Fluorides
3.2 NHC-Catalyzed Radical Functionalization of Acyl Fluorides
3.3 NHC-Catalyzed Nucleophilic Fluorination of (Hetero)aromatics
4 C–F Bond Activation by Phosphines
4.1 Phosphine-Catalyzed Direct Activation of the C–F Bond of Acyl Fluorides
4.2 Phosphine-Catalyzed Indirect Activation of the C–F Bond of Acyl Fluorides
5 C–F Bond Activation by Classical Nucleophilic Substitution
6 Miscellaneous Examples
7 Summary and Perspective
Oxidative carbene organocatalysis, inspired from Vitamin B1 catalyzed oxidative activation from pyruvate to acetyl coenzyme A, have been developed as a versatile synthetic method. To date, the α-, β-, γ-, δ- and carbonyl carbons of (unsaturated)aldehydes have been successfully activated via oxidative N-heterocyclic carbene (NHC) organocatalysis. In comparison with chemical redox or photoredox methods, electroredox methods, although widely used in mechanistic study, were much less studied in NHC catalyzed organic synthesis. Herein, an electroredox NHC organocatalysis system with iodine cocatalyst was developed. With the help of non-uniform distribution of electrolysis system, NHC and iodine, which was normally not compatible in chemical reaction, cooperated well in the electrochemical system. This cocatalyst system provided general solutions for electrochemical single-electron-transfer (SET) oxidation of Breslow intermediate towards versatile transformations. Radical clock experiment and cyclic voltammetry results suggested an anodic radical coupling pathway.
A urea with a pendant acetal has been reacted with nucleophilic aromatics to give a range of heterocyclic products. The acid‐catalyzed reaction has a complex mechanistic manifold, with the nature of the product dependent on the nucleophilicity of the arene and the strength of the acid. Catalytic glycosylations, with a particular focus on synthesis of oligosaccharides, are the subject of a comprehensive review. β‐Glucosyl fluoride has been used to identify the acid‐base catalytic residue of a glycosyltransferase enzyme. A computational study of fast pyrolysis of glucose has focused on four mechanisms of water loss; Maccoll elimination, pinacol ring contraction, cyclic Grob fragmentation, and alcohol condensation. Iridium‐catalyzed asymmetric hydrogenation of prochiral imines is very useful for preparing chiral amines. Aldehydes and ketones have been reacted with α‐nucleophiles such as hydrazines and alkoxy‐amines to give oximes and hydrazones using simple non‐toxic bifunctional buffers to both control pH and accelerate the reactions.
The formation of heterocyclic systems through a transient gold carbene has been detailed from mechanistic consideration to applications to total syntheses of complex natural and biologically relevant molecules. The nature of the nitrene precursor and mechanistic understanding are provided. Evidence for the generation of a ruthenium–carbene complex in the course of hydrogenation of propargylic derivatives has been established spectroscopically and is supported by density functional theory (DFT) calculation. Olefin metathesis probably represents the most iconic involvement of carbenes in coordination chemistry-driven organic transformations, as in many cases carbenes are present both as ligand and reactive center. The reaction mechanism of the ring-opening of cis-2,3-dimethylaziridine by singlet carbenes has been computationally investigated by means of ab initio and DFT calculations. Intramolecular Csp ³ –H insertion reactions of arynes bearing pendant alkyl groups have been achieved in the presence of boron trifluoride as a non-transition metal catalyst.
A theoretical study of the mechanism of the N-heterocyclic carbene (NHC)-catalyzed C-S bond cleavage and reconstruction reaction of unsaturated thioesters was conducted using density functional theory (DFT). The origin of stereoselectivity and the role of the NHC were also explored based on the established mechanism. The computational results showed that C-S bond cleavage was the rate-determining step, giving an α,β-unsaturated acyl azolium intermediate and sulfur anion species. Stereoselectivity can be generated by the sequential Michael addition process, preferentially generating an S-configured product. Topological analysis of the stereocontrolling transition states revealed that stronger weak interactions, such as π⋯π, C-H⋯O, LP⋯π and C-H⋯π interactions, were key for controlling the stereoselectivity. The key role of the NHC was also determined by electron localization function (ELF) analysis.
N-Heterocyclic carbene (NHC) organocatalysis has been recognized as a powerful synthetic strategy for the construction of a wide variety of medicinally and biologically important molecules. Although NHCs are known as the umpolung of aldehydes, NHC-based species involving non-umpolung processes have attracted considerable attention over the past decade because of their diverse reactivity and applicability to asymmetric reactions. Previous reviews focused mainly on the reactions of α, β-unsaturated acyl azoliums, while the current review focuses on the generation and application of other NHC-based intermediates including α, β-unsaturated alkynyl acyl azoliums, dienyl acyl azoliums, azolium enolates, azolium dienolates, azolium allenolates, and cumulenol in asymmetric transformations since 2010.
A highly stereoselective umpolung 1,4-addition of vinyl bromides to enals is enabled by NHC/palladium cooperative catalysis, generating various valuable γ,δ-unsaturated carbonyl derivatives in excellent yields (up to 90%). A detailed mechanism investigation indicates the NHC act as both organocatalyst and ligand for palladium during this system.
An approach to the α,β-unsaturated acyl azolium has been developed that exploits N-heterocyclic carbenes (NHCs) and acyl fluorides, without additional oxidants, bases, or preactivated coupling partners. These conditions have been applied in 4-classes of NHC catalyzed reaction. In all cases the expected products were produced with high yield and enantioselectivity, using two sets of closely related reaction conditions, without additional optimization
The higher-order cycloadditions are powerful strategies for construction of polycycles in one step, however an efficient and concise version for asymmetric induce is limited. N-heterocyclic carbenes are widely used organocatalysts for asymmetric synthesis and will be an ideal choice for enantioselective higher-order cycloadditions. Here we report an enantioselective [10+2] annulation between catalytically formed aza-benzofulvene intermediates and trifluoromethyl ketone derivatives. This protocol exhibits a wide scope, high yields and good ee values, reflecting a robust and efficient higher-order cycloaddition. Density functional theory (DFT) calculations provided an accurate prediction of the reaction enantioselectivity, and in-depth insight to the origins of stereocontrol.
In recent years, acyl fluorides have received a great deal of attention in organic chemistry. Among carboxylic acid derivatives, acyl fluorides display a good balance between stability and reactivity due to their moderate electrophilicity. They are easily prepared from the corresponding carboxylic acids and can be used without any special precautions against moisture. In this review, we describe the recent progress of transformation with acyl fluorides: Lewis base-assisted reactions and transition-metal-catalyzed reactions. The reactions with Lewis base proceeded well to provide a variety of acyl compounds such as lactones, and ketones, etc. In addition, transition-metal-catalyzed transformation gave the corresponding acyl compounds or decarbonylative compounds such as ketones and biaryls, etc.
N-Heterocyclic carbenes (NHC) catalyzing aza-Claisen rearrangement of α,β-unsaturated enals with cyclic vinylogous amides under oxidative condition generating potentially biologically active dihydropyridinone-fused uracils have been developed. This strategy represents an unique NHC-activation-based path with the use of 6-aminouracils as stable α,β-diEWG cyclic vinylogous amides for the efficient synthesis of bicyclic N-unprotected lactams similar to many useful drugs.
A NHC-promoted cascade reaction between β-methyl enal and dienone is developed for quick access to multicyclic lactone molecules bearing quaternary chiral carbon centers. Our study constitutes the first 1,6-addition of the acylazolium vinyl enolate γ-carbon via NHC catalysis and provides rapid access to complex lactone molecules that are otherwise difficult to prepare. The structurally sophisticated lactone products bearing up to four fused ring structures are afforded in up to quantitative yields with good to excellent enantioselectivities.
Eine carbenkatalysierte dynamische kinetische Racematspaltung wurde für die asymmetrische Acylierung und Modifizierung von Arznei- und Naturstoffen entwickelt, die Hydroxyphthalid- und Acetal/Ketal-Gruppierungen tragen. Die Reaktion beinhaltet die Bildung einer von einem Carbenkatalysator abgeleiteten chiralen Acylazolium-Zwischenstufe, die die beiden Enantiomere von racemischen Hydroxyphthaliden wirksam differenziert.
Abstract
A catalytic dynamic kinetic resolution and asymmetric acylation reaction of hydroxyphthalides is developed. The reaction involves formation of a carbene catalyst derived chiral acyl azolium intermediate that effectively differentiates the two enantiomers of racemic hydroxyphthalides. The method allows quick access to enantiomerically enriched phthalidyl esters with proven applications in medicine. It also enables asymmetric modification of natural products and other functional molecules that contain acetal/ketal groups, such as corollosporine and fimbricalyxlactone C.
An unprecedented NHC-catalyzed generation of p-quinodimethanes via ε-umpolung of 4-(chloromethyl)benzaldehydes and the following ε-addition to active ketones was developed. A series of active ketones, such as trifluoromethyl ketones and 1,2-dicarbonyl compounds worked well for the reaction, giving the corresponding trifluoromethyl alcohols and α-hydroxyl carbonyl compounds in good yields.
A catalytic dynamic kinetic resolution and asymmetric acylation reaction of hydroxyphthalides is developed. The reaction involves formation of a carbene catalyst derived chiral acyl azolium intermediate that effectively differentiates the two enantiomers of racemic hydroxyphthalides. The method allows quick access to enantiomerically enriched phthalidyl esters with proven applications in medicine. It also enables asymmetric modification of natural products and other functional molecules that contain acetal/ketal groups, such as corollosporine and fimbricalyxlactone C.
The combination of light activation and N‐heterocyclic carbene (NHC) organocatalysis has enabled the use of acid fluorides as substrates in a UVA‐light‐mediated photochemical transformation previously observed only with aromatic aldehydes and ketones. Stoichiometric studies and TD‐DFT calculations support a mechanism involving the photoactivation of an ortho‐toluoyl azolium intermediate, which exhibits “ketone‐like” photochemical reactivity under UVA irradiation. Using this photo‐NHC catalysis approach, a novel photoenolization/Diels–Alder (PEDA) process was developed that leads to diverse isochroman‐1‐one derivatives.
Durch Photo‐NHC‐Katalyse lassen sich zuvor ungeeignete Carbonsäurederivate in photochemischen Umwandlungen von Aldehyden und Ketonen einsetzen. Dieser Ansatz ermöglicht eine NHC‐katalysierte Photoenolisierungs‐Diels‐Alder‐Reaktion von Säurefluoriden zu Isochroman‐1‐onen. Ein Mechanismus wird postuliert, bei dem das NHC als „transiente Arylgruppe” fungiert, die die photochemischen Eigenschaften des Carbonylsubstrats während des Katalysezyklus temporär verändert.
Abstract
Die Kombination aus Lichtaktivierung und NHC‐Organokatalyse ermöglichte eine UVA‐lichtvermittelte photochemische Umwandlung von Säurefluoriden, die zuvor nur mit aromatischen Aldehyden und Ketonen beobachtet wurde. Stöchiometrische Studien und TD‐DFT‐Rechnungen stützen einen Mechanismus, der die Photoaktivierung eines ortho‐Toluylazolium‐Intermediats umfasst, das unter UVA‐Strahlung eine “ketonartige” photochemische Reaktivität aufweist. Mithilfe dieses Photo‐NHC‐Katalyseansatzes wurde ein neuer Photoenolisierungs‐Diels‐Alder (PEDA)‐Prozess entwickelt, der zu verschiedenen Isochroman‐1‐on‐Derivaten führte.
An umpolung 1,4‐addition of aryl iodides to enals promoted by cooperative (terpy)Pd/NHC catalysis was developed that generates various bioactive β,β‐diaryl propanoate derivatives. This system is not only the first reported palladium‐catalyzed arylation of NHC‐bound homoenolates but also expands the scope of NHC‐induced umpolung transformations. A diverse array of functional groups such as esters, nitriles, alcohols, and heterocycles are tolerated under the mild conditions. This method also circumvents the use of moisture‐sensitive organometallic reagents.
Nimm zwei: Synergistische Katalyse zwischen NHC‐ und Pd‐Katalysatoren ermöglicht die konjugierte Addition von Aryliodiden an Enale unter redox‐neutralen Bedingungen. Diese Methode umgeht die Verwendung feuchtigkeitsempfindlicher metallorganischer Reagentien und ist verträglich mit zahlreichen Funktionen wie Estern, Nitrilen, Alkoholen und Heterocyclen.
Abstract
An umpolung 1,4‐addition of aryl iodides to enals promoted by cooperative (terpy)Pd/NHC catalysis was developed that generates various bioactive β,β‐diaryl propanoate derivatives. This system is not only the first reported palladium‐catalyzed arylation of NHC‐bound homoenolates but also expands the scope of NHC‐induced umpolung transformations. A diverse array of functional groups such as esters, nitriles, alcohols, and heterocycles are tolerated under the mild conditions. This method also circumvents the use of moisture‐sensitive organometallic reagents.
Atroposelective arene formation is an efficient method to build axially chiral molecules with multi‐substituted arenes. Reported here is an organocatalyzed atroposelective arene formation reaction by an N‐heterocyclic carbene (NHC) catalyzed formal [4+2] cycloaddition of conjugated dienals and α‐aryl ketones. This study expands the synthetic potential of NHC organocatalysis and provides a competitive pathway for the synthesis of axially chiral ligands, catalysts, and other functional molecules. Atropselektive [4+2]: Eine neue organokatalytische atropselektive Arenbildung verläuft über eine carbenkatalysierte formale [4+2]‐Cycloaddition von konjugierten Enalen und α‐Arylketonen. Die Studie erweitert das Synthesepotenzial der NHC‐Organokatalyse und bietet einen kompetitiven Weg für die Synthese von axial‐chiralen Liganden, Katalysatoren und anderen funktionellen Molekülen.
Atroposelective arene formation is an efficient method to build axially chiral molecules with multi‐substituted arenes. Reported here is an organocatalyzed atroposelective arene formation reaction by an N‐heterocyclic carbene (NHC) catalyzed formal [4+2] cycloaddition of conjugated dienals and α‐aryl ketones. This study expands the synthetic potential of NHC organocatalysis and provides a competitive pathway for the synthesis of axially chiral ligands, catalysts, and other functional molecules.
A remote stereocontrolled 1,8-conjugate addition of thiazolones to propargylic aza-p-quinone methides formed from propargylic alcohols has been developed with the aid of a chiral phosphoric acid, and this represents the first report on organocatalytic stereocontrolled 1,8-addition of propargylic aza-p-quinone methides. Notably, the remote stereocontrolled activation protocol enables the construction of vicinal sulfur-containing quaternary carbon stereocenters and axially chiral tetrasubstituted allenes and promotes the chemistry of chiral phosphoric acids.
Organocatalyzed asymmetric Friedel–Craft reactions have enabled the rapid construction of chiral molecules with highly enantioselectivity enriching the toolbox of chemists for producing complex substances. Here, we report N-heterocyclic carbene-catalyzed asymmetric indole Friedel–Crafts alkylation-annulation with α,β-unsaturated acyl azolium as the key intermediate, affording a large variety of indole-fused polycyclic alkaloids with excellent diastereo- and enantioselectivities. The reaction mechanism is also investigated, and the reaction products can be easily converted to highly functionalized indole frameworks with different core structures.
Oxotryptamines were firstly used as flexible four‐atom synthons in an NHC‐catalyzed formal [4+3] annulation, providing a novel enantioselective method to access structurally diverse spiro‐ϵ‐lactam oxindoles with excellent enantioselectivities. This metal‐free reaction features a broad substrate scope, excellent functional‐group tolerance and proceeds under mild reaction conditions. Importantly, enantiopure privileged hexahydropyrroloindoles could be easily constructed by a one‐pot process from the resulting spiro‐ϵ‐lactam oxindoles.
In this review, we summarize the current state‐of‐the‐art regarding late transition‐metal‐catalyzed reactions of acyl fluorides, including their synthesis and transformations. In organic reactions, the relationship between stability and reactivity of the starting substrates is usually characterized by a “trade‐off”. Yet, acyl fluorides display a very good balance between these properties, which is mostly due to their moderate electrophilicity. Thus, acyl fluorides (RCOF) can be used as versatile building blocks in transition‐metal‐catalyzed reactions, e.g. as an “RCO” source in acyl coupling reactions, as an “R” source in decarbonylative coupling reactions, and as an “F” source in fluorination reactions. Starting from the cleavage of the acyl C–F bond in acyl fluorides, various transformations are accessible, including C–C, C–H, C–B, and C–F bond‐forming reactions, which are catalyzed by transition‐metal catalysts that contain the group 9–11 metals Co, Rh, Ir, Ni, Pd, or Cu.
In this Review, we summarize the current state of the art in late‐transition‐metal‐catalyzed reactions of acyl fluorides, covering both their synthesis and further transformations. In organic reactions, the relationship between stability and reactivity of the starting substrates is usually characterized by a trade‐off. Yet, acyl fluorides display a very good balance between these properties, which is mostly due to their moderate electrophilicity. Thus, acyl fluorides (RCOF) can be used as versatile building blocks in transition‐metal‐catalyzed reactions, for example, as an “RCO” source in acyl coupling reactions, as an “R” source in decarbonylative coupling reactions, and as an “F” source in fluorination reactions. Starting from the cleavage of the acyl C−F bond in acyl fluorides, various transformations are accessible, including C−C, C−H, C−B, and C−F bond‐forming reactions that are catalyzed by transition‐metal catalysts that contain the Group 9–11 metals Co, Rh, Ir, Ni, Pd, or Cu.
An unprecedented Fe(III)-catalyzed Friedel-Crafts alkylation-hemiketalization-lactonization cascade of electron-rich hydroxy arenes and distinctively functionalized unsaturated 4-keto esters is developed for the construction of polycyclic bridged 2-chromanol lactones. Following this simple and facile protocol, a broad range of products was prepared in good to excellent yields as a single diastereomer. An unusual conglomerate (enantiomerically pure polymorph) of 3ac is reported along with the absolute stereochemistry, and the remaining products were rigorously confirmed by single-crystal X-ray analysis and analogy.
A new carbene-catalyzed [4 + 2] annulation of 2 H-azirine-2-carbaldehydes with ketones was developed, thus providing the 2,3-dihydro-6 H-1,3-oxazin-6-one core structures with broad scope and good to excellent yields. Notably, the azolium aza-dienolates generated from the addition of NHCs to 2 H-azirines are first uncovered.
N-Heterocyclic carbenes (NHCs) have emerged as a powerful class of organocatalysts that mediate a variety of organic transformations. The Benzoin reaction constitutes one of the earliest known carbon-carbon bond-forming reactions catalysed by NHCs. The rapid growth of NHC catalysis in general has resulted in the development of a variety of benzoin and benzoin-type reactions. An overview of such NHC-catalysed benzoin reactions is presented.
Highly enantioselective NHC-organocatalyzed synthesis of functionalized cyclopentenes proceeding via α,β-unsaturated acyl azolium intermediates is reported. The organocascade reaction of modified enals with malonic ester derivatives having a γ-benzoyl group involves the Michael-intramolecular aldol-β-lactonization-decarboxylation sequence to deliver cyclopentenes in good yields and excellent ee values.
First reported less than a decade ago the α,β−unsaturated acyl azolium has emerged as a intermediate central to reaction discovery using N-heterocyclic carbene catalysis. In this perspective an introduction to the four main reactivity patterns accessible from this intermediate is provided. The perspective is handled in a largely chronological fashions with an emphasis on new approaches to the key intermediate and new reaction cascades. Finally a brief introduction to the related chemistry of the α,β-unsaturated acyl ammonium intermediate is provided, along with insights into emerging trends. While not exhaustive the perspective provides an overview of this active area of research and will serve as a guide for future investigations.
An enantioselective β-carbon amination for enals is disclosed. The nitrogen atom from a protected hydrazine with suitable electronic properties readily behaves as a nucleophile. Addition of the nitrogen nucleophile to a catalytically generated N-heterocyclic-carbene-bound α,β-unsaturated acyl azolium intermediate constructs a new carbon–nitrogen bond asymmetrically. The pyrazolidinone products from our catalytic reactions are common scaffolds in bioactive molecules, and can be easily transformed into useful compounds such as β3-amino-acid derivatives.
An enantioselective β-carbon amination for enals is disclosed. The nitrogen atom from a protected hydrazine with suitable electronic properties readily behaves as a nucleophile. Addition of the nitrogen nucleophile to a catalytically generated N-heterocyclic-carbene-bound α,β-unsaturated acyl azolium intermediate constructs a new carbon-nitrogen bond asymmetrically. The pyrazolidinone products from our catalytic reactions are common scaffolds in bioactive molecules, and can be easily transformed into useful compounds such as β(3) -amino-acid derivatives.
The ability to modulate the nucleophilicity and Lewis basicity of N-heterocyclic carbenes is pivotal to their application as organocatalysts. Herein we examine the impact of the N-substituent on the nucleophilicity and Lewis basicity. Four N-substituents popular in NHC organocatalysis, namely, the N-2,6-(CH3O)2C6H3, N-Mes, N-4-CH3OC6H4, and N-tert-butyl groups, have been examined and found to strongly affect the nucleophilicity. Thus, the N-2,6-(CH3O)2C6H3 group provides the most nucleophilic imidazolylidene NHC reported and the N-tert-butyl group one of the least. This difference in nucleophilicity is reflected in the catalyst efficiency, as observed with a recently reported trienyl ester rearrangement.
The enantioselective synthesis of pyrazolone-fused spirocyclohexadienones was demonstrated by the reaction of α,β-unsaturated aldehydes with α-arylidene pyrazolinones under oxidative N-heterocyclic carbene (NHC)catalysis. This atom-economic and formal [3+3] annulation reaction proceeds through a vinylogous Michael addition/spiroannulation/dehydrogenation cascade to afford spirocyclic compounds with an all-carbon quaternary stereocenter in moderate to good yields and excellent ee values. Key to the success of the reaction is the cooperative NHC-catalyzed generation of chiral α,β-unsaturated acyl azoliums from enals, and base-mediated tandem generation of dienolate/enolate intermediates from pyrazolinones.
Efficient construction of complex cylcopentane- or cyclohexane-fused δ-lactones employing redox activation of enals using a chiral N-heterocyclic carbene and LiCl as cooperative catalysts is described. The organocascade proceeds with excellent diastereo- (>99:1) and enantioselectivity (up to >99% ee) and comprises the formation of three bonds with three contiguous stereocenters.
The N-heterocyclic carbene-catalyzed cascade reaction of enals with malonates to give bicyclic δ-lactones was developed. The cyclopentane- and cyclohexane-fused δ-lactones with three continued stereocenters were obtained in high yields with excellent diastereo- and high enantioselectivities.
N-heterocyclic carbenes (NHC) have had a broad impact on the field of organic chemistry, often allowing for the mild construction of complex molecules from simple starting materials. The most widely used approach for the synthesis of imidazolium and imidazolinium salts is the introduction of the precarbenic carbon in the cyclization step. Using this strategy, imidazoliums have been generated from a variety of 1,1-biselectrophiles, including diiodomethane, Weiss' reagent, chloromethyl ethers, and chloromethyl pivalates. Knight and Leeper first introduced chiral bicyclic triazolium salts in 1998, using a three-step sequence from the chiral morpholinone or γlactam. Since many NHC-catalyzed reactions generate the active carbene in situ by deprotonation of the corresponding azolium a discussion of the acidity of these precatalysts is important. Suzuki and colleagues reported the intramolecular heterocoupling of aldehydes and ketones in 2003, synthesizing preanthraquinones in high yields. A Michael addition-intramolecular benzoin cascade reaction strategy was developed by Rovis and co-workers to synthesize highly functionalized cyclopentanones with high enantioselectivity.
An N-heterocyclic carbene (NHC) catalyzed domino reaction triggered by a δ-LUMO activation of α,β-γ,δ-diunsaturatedenal has been developed for the formal [4+2] construction of multi-substituted arenes and 3-ylidenephthalide. These two products, formed in a highly chemo- and regio-selective manner, were obtained via different catalytic pathways due to a simple change of the substrate. The activation of the remote δ-carbon of unsaturated aldehydes expands the synthetic potentials of NHC organocatalysis.
The benzene unit, in its substituted forms, is a most common scaffold in natural products, bioactive molecules and polymer materials. Nearly 80% of the 200 best selling small molecule drugs contain at least one benzene moiety. Not surprisingly, the synthesis of substituted benzenes receives constant attentions. At present, the dominant methods use pre-existing benzene framework to install substituents by using conventional functional group manipulations or transition metal-catalyzed carbon-hydrogen bond activations. These otherwise impressive approaches require multiple synthetic steps and are ineffective from both economic and environmental perspectives. Here we report an efficient method for the synthesis of substituted benzene molecules. Instead of relying on pre-existing aromatic rings, here we construct the benzene core through a carbene-catalyzed formal [3+3] reaction. Given the simplicity and high efficiency, we expect this strategy to be of wide use especially for large scale preparation of biomedicals and functional materials.
The enantioselective vinylogous Michael/aldol cascade is an underdeveloped approach to cyclohexenes. Herein we describe a highly enantio- (most ≥98:2 er) and diastereoselective (all ≥15:1 dr) N heterocyclic carbene catalyzed cycloisomerization of acyclic ester dienolates to cyclohexyl β-lactones. Derivatizations avail various cyclohexenes bearing 4-contiguous stereogenic centers while mechanistic studies support olefin isomerization prior to cyclization.
Höher, schneller, weiter! Eine neu entwickelte Familie von elektronenreichen 2,6-Dimethoxyphenyl-substituierten NHCs katalysiert die diastereo- und enantioselektive Titelreaktion, die strukturell wertvolle Acylcyclopropanen liefert. Erste kinetische Untersuchungen zeigen die Überlegenheit der neuen Katalysatoren über bisher bekannte NHCs in dieser anspruchsvollen Reaktion.
Katalytische Umwandlungen mit N-heterocyclischen Carbenen (NHCs) haben sich als effiziente Ansätze zum Aufbau komplexer Moleküle erwiesen. Seit der Veröffentlichung von Stetter 1975 zur Totalsynthese von cis-Jasmon und Dihydrojasmon durch Carbenkatalyse hat sich die Anwendung von NHCs in der Totalsynthese, insbesondere in den letzten zehn Jahren, schnell verbreitet. Dieser Aufschwung ist zweifellos die Folge neuerer Entwicklungen bei NHC-katalysierten Reaktionen, einschließlich der neuen Benzoin-, Stetter-, Homoenolat- und Aroylierungsprozesse. Die Umwandlungen ermöglichen ebenso typische wie auf Umpolung beruhende Bindungsbildungen und sind bereits als Schlüsselschritte in mehreren neuen Totalsynthesen aufgetreten. Dieser Kurzaufsatz beschreibt diese neuen Arbeiten und zeigt die verstärkten Einsatzmöglichkeiten der Carbenkatalyse in der Totalsynthese auf.
Oxidative Carbenkatalyse kehrt über zwei aufeinanderfolgende Umpolungsreaktionen die Reaktivität der β-Position in α,β-ungesättigten Aldehyden um: von der typischen elektrophilen zur nukleophilen und wieder zur elektrophilen. Die redoxaktivierten Michael-Akzeptoren sind in β-Position reaktiver als die Aldehyde. Mit β-Dicarbonylverbindungen entstehen unter milden Bedingungen Dihydropyranone in guten bis exzellenten Ausbeuten.
Während sich die organokatalytischen Dominoreaktionen (auch Organokaskadenkatalysen genannt) im letzten Jahrzehnt zu einem wichtigen Hilfsmittel in der Synthesechemie entwickelt haben, fand die Anwendung von N-heterocyclischen Carbenen (NHCs) als Katalysatoren in Dominoreaktionen erst in den letzten drei Jahren zunehmend Beachtung. Unter Berücksichtigung der besonderen Aktivierungsmodi der Substrate durch die NHC-Katalysatoren ist eine Unterscheidung zwischen einer einzelnen chemischen Transformation und einer sequenziellen Eintopfreaktion schwierig. Das Ziel dieses Kurzaufsatzes besteht darin, die Domino-, Kaskaden- und Tandemkatalyse in Gegenwart von NHC-Katalysatoren kritisch zu betrachten und jüngste Publikationen auf diesem Gebiet vorzustellen.
The reaction of enals with β-diketones, β-ketoesters, and malonates bearing a β-oxyalkyl substituent at the α-position by oxidative NHC catalysis to provide highly substituted β-lactones is described. Reactions occur with excellent diastereo- and enantioselectivity. The organo cascade comprises two CC bond formations and one CO bond formation. Up to four contiguous stereogenic centers including two fully substituted stereocenters are formed in the cascade.
The reaction of enals with β-diketones, β-ketoesters, and malonates bearing a β-oxyalkyl substituent at the α-position by oxidative NHC catalysis to provide highly substituted β-lactones is described. Reactions occur with excellent diastereo- and enantioselectivity. The organo cascade comprises two C-C bond formations and one C-O bond formation. Up to four contiguous stereogenic centers including two fully substituted stereocenters are formed in the cascade. Highly substituted β-lactones are generated by NHC catalysis of enals with β-diketones, β-ketoesters, and malonates bearing a β-oxyalkyl substituent at the α-position. LiCl acts as cooperative Lewis acid. The organocascade comprises two C-C bond formations and one C-O bond formation. Up to four contiguous stereogenic centers including two fully substituted stereocenters are formed with high diastereo- and enantioselectivity.
The successful isolation and characterization of an N-heterocyclic carbene in 1991 opened up a new class of organic compounds for investigation. From these beginnings as academic curiosities, N-heterocyclic carbenes today rank among the most powerful tools in organic chemistry, with numerous applications in commercially important processes. Here we provide a concise overview of N-heterocyclic carbenes in modern chemistry, summarizing their general properties and uses and highlighting how these features are being exploited in a selection of pioneering recent studies.
Neue Hydroacylierungs‐Katalysatoren: Die Verwendung von elektronenreichen N‐heterocyclischen Carbenen ermöglicht die intermolekulare Hydroacylierung von ungespannten Olefinen. Diese bisher beispiellose organokatalytische Kupplung verknüpft einfache und universelle Aldehyde und Styrole, um so wertvolle Keton‐Produkte zu erhalten. EWG=elektronenziehende Gruppe, EDG=elektronenschiebende Gruppe.
Ester – was sonst! Eine neue Strategie in der NHC‐Organokatalyse (NHC=N‐heterocyclisches Carben) ermöglicht die α‐, β‐ und γ‐Aktivierung gesättigter und ungesättigter Ester (siehe Schema). Die entstehenden Acylazolium‐Intermediate gehen effizient Dominoreaktionen mit geeigneten Substraten ein, wodurch Carbo‐ und Heterocyclen mit sehr guten Diastereo‐ und Enantioselektivitäten gebildet werden.
Aktivierung aromatischer Aldehyde: Die oxidative Aktivierung von 2‐Methylindol‐3‐carboxaldehyd (I) durch ein N‐heterocyclisches Carben (NHC) führt zur Bildung eines heterocyclischen ortho‐Chinodimethan‐Derivats (II) als Schlüsselintermediat. Dieses reagiert in einer formalen [4+2]‐Cycloaddition mit Trifluormethylketonen oder Isatin, wodurch Lactone mit einem quartären Stereozentrum aufgebaut werden.
The addition of an N-heterocyclic carbene to the carbonyl group of an α,β,γ,δ-unsaturated enol ester affords a hemiacetal azolium intermediate that enables a cascade olefin isomerization/Diels-Alder reaction, for which mechanistic studies implicate Lewis base catalysis. Preliminary studies into the utility of the products have been undertaken with reductive and oxidative cleavage, giving materials for potential use in complex-target synthesis. NHC-catalyzed cascade: The addition of an N-heterocyclic carbene (NHC) to the carbonyl group of an α,β,γ, δ-unsaturated enol ester affords a hemiacetal azolium intermediate that enables a cascade olefin isomerization/Diels-Alder reaction. Preliminary studies into the utility of the products using reductive and oxidative cleavage gave substrates for potential use in the synthesis of complex targets.
The addition of an N-heterocyclic carbene to the carbonyl group of an α,β,γ,δ-unsaturated enol ester affords a hemiacetal azolium intermediate that enables a cascade olefin isomerization/Diels–Alder reaction, for which mechanistic studies implicate Lewis base catalysis. Preliminary studies into the utility of the products have been undertaken with reductive and oxidative cleavage, giving materials for potential use in complex-target synthesis.
Esters-what else! A new strategy in NHC organocatalysis allows the α-, β- and γ-activation of saturated and unsaturated esters. The resulting acyl azolium intermediates efficiently participate in domino reactions with suitable substrates to generate synthetically valuable carbo- and heterocycles with very good diastereo- and excellent enantioselectivities.
The first N-heterocyclic carbene (NHC)-catalyzed [3+4] cycloaddition of azomethine imines and enals is disclosed. Oxidative catalytic remote activation of enals affords 1,4-dipoloarphile intermediates that react with 1,3-dipolar azomethine imines to generate dinitrogen-fused seven-membered heterocyclic products with high optical purities. Our approach also provides effective kinetic resolution of azomethine imines, in which the substrate chiral center that is remote from the NHC catalyst can be well resolved.
Control freaks: Chiral amine catalysts prove to be highly proficient mediators in the asymmetric, polyconjugate addition of C‐, N‐, and S‐based nucleophiles to acyclic dienals and cyclic dienones. For high 1,6‐selectivities, the stereo spatial matching of the molecular orbitals and ionic charges of the reacting species are key. But can we widen the scope and how far can we go with remote, iminium‐stereocontrol?
Aryl aldehyde activation: Oxidative activation of 2-methylindole-3-carboxaldehyde (I) through N-heterocyclic carbene organocatalysis generates heterocyclic ortho-quinodimethane (II) as a key intermediate. This intermediate then undergoes formal [4+2] cycloaddition with trifluoromethyl ketones or isatins to form polycyclic lactones containing a quaternary carbon center.
The in situ observation, isolation and reversible formation of intermediate 3-(hydroxybenzyl)azolium salts derived from NHC addition to a range of substituted benzaldehydes is probed. Equilibrium constants for the formation of these 3-(hydroxybenzyl)azolium salts, as well as rate constants of hydrogen–deuterium exchange (kex) at C(α) of these intermediates for a range of N-aryl triazolinylidenes is reported. These combined studies give insight into the preference of N-pentafluorophenyl NHCs to participate in benzoin and Stetter reaction processes.
Stereoselective methods for the synthesis of β-lactones involving a Lewis base-promoted (nucleophile-promoted) aldol-lactonization manifold have continued to expand since the initial reports of Bormann and Wegler in the late 1960's and later by Wynberg and Staring in the early 1980's. This review will cover these developments including enantioselective versions of these processes. Cinchona alkaloids and various pyridine derivatives have been used most extensively to expand the repertoire of β-lactones accessible by this process. Furthermore, recent advances in the development of a3-d3-ümpolung pathways using N-heterocyclic carbenes have also enabled access to previously unattainable manifolds for the stereoselective synthesis of both β- and γ-lactones via aldol-lactonization pathways. This review covers literature in this area in the period from 1967- June 2008.1Introduction2Lewis Bases as Chiral Nucleophilic Promoters2.1Cinchona Alkaloid Catalysts2.2Cinchona Alkaloid/Lewis Acid Combinations3N-Heterocyclic Carbenes (NHC)3.1Bicyclic β-Lactones via Aldol-Lactonizations3.2Bicyclic γ-Butyrolactones via Aldol-Lactonizations4Pyridine Derivatives5Applications in Natural/Unnatural Product Synthesis6Summary and Outlook. © 2008 The Japan Institute of Heterocyclic Chemistry All rights reserved.
β-Lactones are versatile intermediates in organic synthesis yet their use has been limited by the lack of concise and general methods for their asymmetric synthesis. A survey of asymmetric methods reported up to 1998 is provided in this Report. Applications of these strategies to natural and unnatural product synthesis are cited. A summary of the most concise and general procedures reported to date and an outlook of this field is given.
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Owing to their highly strained ring system and interesting functional group, β-lactones possess significant synthetic potential. Recently, novel methods have been developed to synthesize these valuable building blocks very efficiently by catalytic, enantioselective reactions, such as [2+2] cycloadditions, starting from simple precursors. These processes also offer an attractive alternative for the synthesis of optically active β-hydroxy and β-amino acids (see scheme).
Aliphatische 1,2-Diketone (I) können mit Cyanmethylentriphenylphosphoran (II) entweder stufenweise über die α,β-ungesättigten Ketone (III) oder direkt mit zwei Äquivalenten Phosphoran (II) in Muconsäurenitrile (V) und (VI) umgewandelt werden.
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Without detours: Oxidative catalysis mediated by N-heterocyclic carbenes (NHCs) enables the direct β-carbon functionalization of saturated aldehydes. The reaction proceeds through two sequential oxidative steps to generate α,β-unsaturated triazolium ester equivalents as Michael acceptors, which react with 1,3-diketones and β-ketone esters in an enantioselective manner.
Organocatalysis is shown to expand the classical reactivity pattern for conjugate addition reactions. It is demonstrated that the site-selectivity can be extended from 1,4- to 1,6-additions for the enantioselective vinylogous additions of methyl-substituted vinylogous lactones to enals and 2,4-dienals. This novel reactivity is demonstrated for methyl-substituted olefinic azlactones and butyrolactones. Their synthetic potential is first highlighted by the development of the organocatalytic regioselective vinylogous 1,4-addition to enals which proceeds with a very high level of double bond geometry control and excellent enantioselectivity. The concept is developed further for the unprecedented intermolecular enantioselective organocatalyzed vinylogous 1,6-addition to linear 2,4-dienals, by which the site-selectivity of the process is extended from the -position to the remote -position of the 2,4-dienal. The organocatalyst controls the newly generated stereocenter six bonds away from the stereocenter of the catalyst with a high level of enantiocontrol and the products are obtained with full control of double bonds configuration. The scope of these new reaction concepts is demonstrated for a series of aliphatic and aryl-substituted enals and 2,4-dienals undergoing enantioselective vinylogous reactions with methyl-substituted olefinic azlactones and butyrolactones. Furthermore, mechanistic considerations are presented which can account for the change from 1,4- to 1,6-selectivity. Finally, a number of different transformation of the optically active 1,4- and 1,6-addition products are demonstrated.
Remote control: The title reaction facilitates the synthesis of complex chiral molecules while selectively forging multiple stereocenters at distant positions, namely five and six bond lengths away from the catalyst chiral fragment (see scheme; Boc=tert-butoxycarbonyl). The potential of the strategy is demonstrated through the one-step preparation of spirocyclopentane oxindoles having four contiguous stereocenters.
This Concept article discusses the potential of oxidative carbene catalysis in synthesis and comprehensively covers pioneering studies as well as recent developments. Oxidative carbene catalysis can be conducted by using inorganic and organic oxidants. Applications in cascade processes, in enantioselective catalysis, and also in natural product synthesis are discussed. Cascading down: Reaction of an aldehyde with an NHC provides the corresponding Breslow intermediate A, which can be readily oxidized with various organic and inorganic oxidants to give the acylazolium ion B (see scheme). Intermediate B can react with various nucleophiles either at the 2 or 4-position. With enals as starting aldehydes, elegant cascade processes have been developed using oxidative carbene catalysis.
Reaction discovery using N-heterocyclic carbene organocatalysis has been dominated by the chemistry of acyl anion equivalents. Recent studies demonstrate that NHCs are far more diverse catalysts, with a variety of reactions discovered that proceed without acyl anion equivalent formation. In this tutorial review selected examples of acyl anion free NHC catalysis using carbonyl compounds are presented.
New hydroacylation catalysts: Highly electron-rich N-heterocyclic carbenes (NHCs) facilitate the intermolecular hydroacylation of unstrained olefins. This unprecedented organocatalytic coupling joins simple and abundant aldehydes and styrenes to yield valuable ketone products. EWG=electron-withdrawing group, EDG=electron-donating group.
The concise collective total synthesis of englerin A and B, orientalol E and F, and oxyphyllol has been accomplished in 10-15 steps, with the total synthesis of orientalol E and oxyphyllol being achieved for the first time. The success obtained was enabled by the realization of the [4+3] cycloaddition reaction of 9 and 10. Other features of the synthesis include 1) the intramolecular Heck reaction to access the azulene core, 2) the epoxidation-S(N) 2' reduction sequence to access the allylic alcohol, 3) the efficient regioselective and stereoselective formal hydration of the bridging CC bond in the synthesis of englerins, and 4) the late-stage chemo- and stereoselective CH oxidation in the synthesis of orientalol E. The total synthesis of these natural products has enabled the structural revision of oxyphyllol and established the absolute stereochemical features of the organocatalytic [4+3] cycloaddition reaction. The identification of 5 as the natural product oxyphyllol, the success in converting 5 to orientalol E, along with the fact that englerins and oxyphyllol were isolated from plants of the same genus Phyllanthus gives support to our proposed biosynthetic pathways. This work may enable detailed biological evaluations of these natural products and their analogues and derivatives, especially of their potential in the fight against renal cell carcinoma (RCC).
The NHC-catalyzed Claisen rearrangement of hybrid Ireland Coates structures has been achieved allowing (3 + 2) annulation between donor-acceptor cyclopropanes and α,β-unsaturated acyl fluorides. The reaction proceeds with high diastereoselectivity (>20:1) affording a diverse range of β-lactone fused cyclopentanes. Mechanistic studies are detailed.
Smooth as isatin! A straightforward synthesis of spirocyclic oxindole-dihydropyranones through an N-heterocyclic-carbene-catalyzed [4+2] annulation of α-bromo-α,β-unsaturated aldehydes or α,β-dibromoaldehyde bearing γ-H with isatin derivatives under mild reaction conditions is disclosed. The concise construction, ready availability of the starting materials, avoidance of external oxidants, and the potential utilization value of final products in molecular biology and pharmacy makes this approach particularly attractive.
N-Heterocyclic carbene (NHC) catalyzed transformations have emerged as powerful tactics for the construction of complex molecules. Since Stetter's report in 1975 of the total synthesis of cis-jasmon and dihydrojasmon by using carbene catalysis, the use of NHCs in total synthesis has grown rapidly, particularly over the last decade. This renaissance is undoubtedly due to the recent developments in NHC-catalyzed reactions, including new benzoin, Stetter, homoenolate, and aroylation processes. These transformations employ typical as well as Umpolung types of bond disconnections and have served as the key step in several new total syntheses. This Minireview highlights these reports and captures the excitement and emerging synthetic utility of carbene catalysis in total synthesis.
Im Jahre 1935 formulierte R. C. Fuson das Prinzip der Vinylogie, um zu erklären, wie sich der Einfluss einer funktionellen Gruppe an einer entfernten Position im Molekül bemerkbar macht, wenn diese über konjugierte Doppelbindungen mit der Gruppe verbunden ist. In polaren Reaktionen ermöglicht dieses Konzept die Erweiterung des elektrophilen oder nucleophilen Charakters einer funktionellen Gruppe über das π-System einer Kohlenstoff-Kohlenstoff-Doppelbindung. Diese vinyloge Erweiterung führt im Fall der Aldolreaktion zum Einsatz “erweiterter” Dienolether, die von γ-enolisierbaren α,β-ungesättigten Carbonylverbindungen abgeleitet sind. Seit 1994 sind einige Methoden für die katalytische enantioselektive vinyloge Aldolreaktion beschrieben worden, mit denen man unterschiedliche Regio- (Orts-), Enantio- und Diastereoselektivitäten erzielen kann. In diesem Aufsatz werden die Bandbreite und die Einschränkungen dieser Transformation sowie ihre Anwendung in der Naturstoffsynthese diskutiert.
An oxidative γ-functionalization of enals under N-heterocyclic carbene (NHC) catalysis to give unsaturated δ-lactones is disclosed. Enantioselectivity control involving the relatively remote enal γ-carbon was achieved via Lewis acid [Sc(OTf)(3) or combined Sc(OTf)(3)/Mg(OTf)(2)] and NHC cooperative catalysis.
The umpolung strategy encompasses all the methods that make organic molecules react in an inverse manner compared to their innate polarity-driven reactivity. This concept entered the field of organocatalysis when it was recognized that N-heterocyclic carbenes (NHCs) can provide catalytic access to acyl anion equivalents. Since then, tremendous efforts have followed to develop a broad variety of NHC-catalyzed reactions. In addition to this, more recent research developments have shown that other families of organocatalysts are also able to mediate transformations in which inversion of polarity is involved. This tutorial review aims at offering a didactic overview of organocatalytic umpolung and should serve as an inspiration for further progress in this field.
The N-heterocyclic carbene catalyzed (4 + 2) cycloaddition between α,β-unsaturated acid fluorides and TMS dienol ethers provides cyclohexene fused β-lactone intermediates stable below -20 °C. These can be intercepted reductively or with organolithium reagents to produce diastereomerically pure cyclohexenes (>20:1 dr) with up to four contiguous stereocenters. The mechanism has been investigated using theoretical calculations and by examining secondary kinetic isotope effects. Together these studies implicate the formation of a diastereomerically pure β-lactone intermediate by a stepwise (4 + 2) cycloaddition involving Michael addition, aldol cyclization, and lactonization.