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The reliable design and prediction of enzyme promiscuity to access transformations not observed in nature remains a long-standing challenge. Herein, we present the first example of an intramolecular stereoselective Stetter reaction catalyzed by benzaldehyde lyase, guided by the rational structure screening of various ThDP-dependent enzymes using molecular dynamics (MD) simulations. After optimization, high productivity (up to 99 %) and stereoselectivity (up to 99:1 e.r.) for this novel enzyme function was achieved.

The total synthesis of iheyamine A from readily available ethyl 2-aminocinnamate and 5-methoxyindole-2-carboxaldehyde is described. The cyanide-catalyzed imino-Stetter reaction of an aldimine derived from ethyl 2-aminocinnamate and 5-methoxyindole-2-carboxaldehyde provided the desired unsymmetrical 2,2'-bisindole-3-acetic acid derivative. The subsequent introduction of an amino group at the C-3' position, followed by the formation of the azepine ring, completed the total synthesis of iheyamine A.

A new protocol to access benzo[a]carbazole derivatives was developed, via the cyanide-catalyzed imino-Stetter reaction/Friedel–Crafts reaction sequence. The cyanide-catalyzed imino-Stetter reaction of aldimines derived from 2-aminochalcones and aromatic aldehydes provided the corresponding 2-aryl-3-arenacylindole derivatives, which could be converted to benzo[a]carbazoles via intramolecular Friedel–Crafts ractions. Various 2-aminochalcones and aldehydes were applicable to this protocol, affording the desired benzo[a]carbazoles in good to high yields. Furthermore, we also developed a sequential protocol for the construction of benzo[a]carbazoles from 2-aminochalcones and aldehydes, without isolating any intermediates.

Oxazolium salts were successfully employed for the first time as organocatalysts for benzoin, Stetter, and redox esterification reactions. An N-mesityl oxazolium salt catalyzed homobenzoin reaction of aromatic, heteroaromatic, and aliphatic aldehydes delivered α-hydroxy ketones in high yields. This new type of catalyst proved remarkably effective for the Stetter reaction of challenging substrates such as β-alkyl-α,β-unsaturated ketones and electron-rich aromatic aldehydes in comparison to common thiazolium and triazolium salts.

An intermolecular Stetter reaction of aromatic aldehydes with maleimides has been developed using thiazolylidene salt derived Isa‒NHC as an efficient organocatalyst. The synthesized Stetter products “3‒aroylsuccinimides” are important building blocks for the synthesis of natural products and bioactive compounds. The reaction conditions are mild, and various substituents on aromatic aldehyde and maleimide nitrogen were tolerated.

An N-heterocyclic carbene-catalyzed intermolecular Stetter reaction of aromatic aldehydes with N-substituted itaconimides has been developed. A delicate balance between the Stetter reaction and the competing isomerization of the itaconimide double bond has been achieved in this operationally simple reaction to afford valuable new succinimide derivatives containing 1,4 and 1,5 dicarbonyl scaffolds in good to excellent yields. The reaction tolerates variable substituents on both aldehydes and N-substituted itaconimides.

Highly concise total syntheses of paullone and kenpaullone were developed. Cyanide-catalyzed intramolecular imino-Stetter reaction of aldimines derived from methyl 2-aminocinnamate derivatives and 2-nitrobenzaldehyde provided 2-(2′-nitrophenyl)indole-3-acetic acid derivatives. Subsequent reduction of the nitro group with zinc under acidic conditions to an amino group followed by spontaneous lactam formation allowed for the total syntheses of paullone and kenpaullone to be completed in two steps starting from commercially available materials. The direct use of a nitro group as the precursor of an amino group present in the phenyl ring at the 2-position in the indole ring significantly streamlined the total syntheses of these target molecules.

A new strategy applicable to the synthesis of indoloquinolizine natural products has been developed. A cyanide-catalyzed intramolecular imino-Stetter reaction of aldimines, derived from 2-aminocinnamic acid derivatives and 2-pyridinecarboxaldehydes, provided indole-3-acetic acid derivatives bearing a pyridyl ring at the 2-position. Reduction of the carboxylic acid moiety to an alcohol followed by activation of the resulting alcohol with Tf2O or TsCl generated indoloquinolizinium salts, which were utilized as precursors for indoloquinolizine natural products. The advantage of this protocol was successfully demonstrated in the total syntheses of arborescidine A and nauclefidine.

A general and efficient method for the synthesis of tricyclic spirocarbocycles is described. Various cyclic enal-enones were reacted with an N-heterocyclic carbene, and an intramolecular Stetter reaction proceeded smoothly to give various tricyclic spiro-1,4-diketones in 31–72% yields. The ring size of the spiro compounds can be easily controlled using different cyclic enals and enones or by altering the length of the carbon tether.

A general method to generate umpolung of aldimines with cyanide was developed via the addition of cyanide to aldimines followed by a proton transfer from the carbon atom to the nitrogen atom in the resulting cyanide adducts. This novel method was successfully applied to the first imino-Stetter reaction of aldimines obtained from 2-aminocinnamic acid derivatives and aromatic aldehydes with cyanide, affording 2-aryl-substituted indole-3-acetic acid derivatives. Furthermore, the usefulness of this method was successfully demonstrated by the synthesis of an FPTase inhibitor, one of the biologically important 2-arylindole-3-acetic acid derivatives.

An N-Heterocyclic Carbene (NHC) catalyzed biomimetic Stetter reaction was applied for the first time as a bioconjugation reaction to sensitive nucleoside-type biomolecules to provide original pyrrole linked nucleolipids. A versatile approach allowed the functionalization of thymidine at the three reactive positions (O-5′, O-3′ and N-3) providing a structural diversity oriented synthesis. This strategy was applied to the synthesis of an original glyconucleolipid amphiphile in the hope that the pyrrole aromatic moiety would induce additional self-assembling properties.

The use of multiple catalytic systems for cascade reactions has found widespread application in recent years. The combination of two important organocatalysts, chiral amines and N-heterocyclic carbenes (NHCs), is of extraordinary interest since they can both potentially mediate a variety of reactions with aldehyde derivatives. In this short review, we discuss the successful combination of asymmetric aminocatalysis and carbene catalysis in the efficient construction of complex chiral architectures, either in a relay or sequential manner. 1 Introduction 2 NHC-Catalyzed Redox Reaction Combined with Aminocatalysis 3 NHC-Catalyzed Benzoin Condensation Combined with Aminocatalysis 4 NHC-Catalyzed Stetter reaction Combined with Aminocatalysis 5 Miscellaneous NHC Catalysis Combined with Aminocatalysis 6 Summary

The functionalization of aliphatic and aromatic C-H bonds has remained a priority in transition-metal catalysis for the last few decades. N-heterocyclic carbenes (NHCs) have very recently been proven as an effective organocatalytic alternative toward site-selective sp(3) beta-C-H bond functionalization in aliphatic esters and related compounds. We have employed modern density functional theory computations to provide the first mechanistic insights into this entirely new form of reactivity of NHCs, leading to beta-C-H bond activation. NHC-catalyzed coupling between hydrazone and beta-phenyl propionate leading to a gamma-lactam bearing two chiral centers is reported. An interesting two-step mechanistic cascade that helps surmount the high bond dissociation energy of an otherwise inert beta-C-H bond is identified. An initial addition-elimination at the ester group installs the chiral triazolium NHC to the substrate. The deprotonation of the alpha-C-H by the departing phenoxide first furnishes an alpha-enolate intermediate. A concerted protonation at the enolate oxygen by the phenol and a beta-C-H deprotonation by the phenoxide leads to the vital nucleophilic beta-carbanion intermediate. The origin of enantioselectivity in the C-C bond formation between the si prochiral face of the nucleophilic beta-carbon and the re face of electrophilic hydrazone is traced to the differential in the C-H...pi, C-H...O and N-H...O interactions that exist in the transition states for the lower energy si,re and higher energy re,si modes in the Michael addition step. The computed enatio- and diastereoselectivities are in very good agreement with those in an earlier experimental report.

Recent developments in the N-heterocyclic carbene (NHC)-catalyzed umpolung of aldehydes followed by their interception with activated carbon–carbon double bonds, namely the Stetter reaction, are presented. Advances in the inter- and intramolecular versions of this reaction, enantioselective transformations as well as the use of unactivated olefins in this type of reaction are discussed. 1 Introduction 2 Proposed Mechanism of the Stetter Reaction 3 Intramolecular Stetter Reactions 4 Intermolecular Stetter Reactions 5 Hydroacylation Reactions 6 Applications in Total Synthesis 7 Conclusion

An NHC-catalyzed nitro-Stetter/elimination/Stetter reaction sequence employs nitroalkenes as latent 1,2-dication synthons providing a novel access to highly useful symmetrical and unsymmetrical 2-aryl substituted 1,4-diketone building blocks from commercially available aldehyde precursors. For less activated (aliphatic) aldehydes, a cooperative catalytic strategy has been developed via the merger of NHC and H-bonding catalysis. To further showcase the versatility of our approach, a great variety of these unprecedented 1,4-diketones are used to efficiently synthesize polysubstituted pyrroles—including those with hetaryl substituents—in good to excellent yields in a multicatalytic metal-free, four-step one-pot cascade reaction under mild, yet robust, conditions.

The intermolecular asymmetric Stetter reaction is a rarely found biocatalysts transformation. MenD, the second enzyme of the menaquinone biosynthetic pathway, catalyzes as a physiological reaction a Stetter-like addition of α-ketoglutarate to isochorismate. The substrate range of MenD for similar 1,4-additions is highly restricted. All other thiamine diphosphate dependent enzymes known to act as stetterases are members of the PigD enzyme subfamily, which accept aliphatic and aromatic α,β-unsaturated ketones and thioesters as Michael acceptor substrates. Here, we describe the unexpected activity of MenD with short-chain α,β-unsaturated acids and derivatives as substrates in Stetter reactions. MenD possesses a characteristic substrate range with respect to Michael acceptor substrates which is distinctly different from the classical stetterases. This provides biocatalytic access to new types of products which are not related to the products currently accessible by thiamine diphosphate dependent enzyme catalysis.

N,N-Dimethylbenzimidazolium iodide catalysed benzoin condensation and Stetter reaction in 1-butyl-3-methylimidazolium hydroxide (bmim)(OH) which acts as a basic catalyst as well as a solvent for the reactions are described. The recycled reaction media containing benzimidazolium salt can be reused for several times without significant loss of efficiency.

A novel synthesis of highly substituted pyrrole-N-acetic derivatives is described through the coupling of 1,4-diketones with amino acids following Paal-Knorr's approach. These pyrrole-N-acetic acid derivatives are found to exhibit potent anti-mycobacterial activity against Mycobacterium smegmatis and Mycobacterium tuberculosis strain H37Rv. In particular, 5n, 5q &5r are found to display excellent anti-mycobacterial activity against M. tuberculosis strain H37Rv with MIC values in the range of 2.97 μM. Conversely, these compounds showed low cytotoxicity (selectivity index: >16.83) against HEK-293T cell line.

The intermolecular asymmetric Stetter reaction is an almost unexplored transformation for biocatalysts. Previously reported thiamine diphosphate (ThDP)-dependent PigD from Serratia marcescens is the first enzyme identified to catalyze the Stetter reaction of α,β-unsaturated ketones (Michael acceptor substrates) and α-keto acids. PigD is involved in the biosynthesis of the potent cytotoxic agent prodigiosin. Here, we describe the investigation of two new ThDP-dependent enzymes, SeAAS from Saccharopolyspora erythraea and HapD from Hahella chejuensis. Both show a high degree of homology to the amino acid sequence of PigD (39 and 51 %, respectively). The new enzymes were heterologously overproduced in Escherichia coli, and the yield of soluble protein was enhanced by co-expression of the chaperone genes groEL/ES. SeAAS and HapD catalyze intermolecular Stetter reactions in vitro with high enantioselectivity. The enzymes possess a characteristic substrate range with respect to Michael acceptor substrates. This provides support for a new type of ThDP-dependent enzymatic activity, which is abundant in various species and not restricted to prodigiosin biosynthesis in different strains. Moreover, PigD, SeAAS, and HapD are also able to catalyze asymmetric carbon-carbon bond formation reactions of aldehydes and α-keto acids, resulting in 2-hydroxy ketones.

A five-step synthesis of the 6-6-6 tricyclic skeleton of the diterpene wickerol A is described. The synthesis features a diastereoselective d-proline-mediated Robinson annulation and N-heterocyclic carbene-catalyzed Stetter reaction as key transformations to give the tricyclic carbon skeleton of this promising anti-influenza A natural product.

Dicarbonyl compounds 2 carrying a phosphonate group were obtained by utilizing a dually N-heterocyclic carbene (NHC) catalyzed domino reaction involving the intramolecular hydroacylation of salicyl alkynylphosphonates 1 and a subsequent intermolecular Stetter reaction with aromatic aldehyde at room temperature. In addition, 2 can also be applied for the synthesis of benzopyranopyrrole carrying a phosphonate group 4 in one pot and in moderate yield.

N-Heterocyclic carbene catalyzed desymmetrization of cyclohexadienones to construct tricyclic carbocycles via an intramolecular enantioselective Stetter reaction was realized. With 10 mol% of D-camphor-derived triazolium salt E and 10 mol% of KOAc, variou

A new method for the synthesis of 2-vinylindole-3-acetic acid derivatives from aldimines, which are derived from 2-aminocinnamic acid derivatives and α,β-unsaturated aldehydes, via a cyanide-catalyzed imino-Stetter reaction is described. Various types of 2-aminocinnamic acid derivatives and α,β-unsaturated aldehydes could be used in this protocol, and the desired 2-vinyl substituted indole-3-acetic acid derivatives were obtained in high yields. This cyanide-catalyzed imino-Stetter reaction was further extended to the preparation of indole-3-acetic acid derivatives bearing a carboxylic acid functionality at the 2-position, using aldimines obtained from glyoxylates and 2-aminocinnamic acid derivatives.

The use of multiple catalytic systems for cascade reactions has found widespread application in recent years. The combination of two important organocatalysts, chiral amines and N-heterocyclic carbenes (NHCs), is of extraordinary interest since they can both potentially mediate a variety of reactions with aldehyde derivatives. In this short review, we discuss the successful combination of asymmetric aminocatalysis and carbene catalysis in the efficient construction of complex chiral architectures, either in a relay or sequential manner. 1 Introduction 2 NHC-Catalyzed Redox Reaction Combined with Aminocatalysis 3 NHC-Catalyzed Benzoin Condensation Combined with Aminocatalysis 4 NHC-Catalyzed Stetter reaction Combined with Aminocatalysis 5 Miscellaneous NHC Catalysis Combined with Aminocatalysis 6 Summary

Functionalized 2,2-disubstituted benzofuran-3-(2H)-ones have been synthesized from simple aldehyde building blocks in a combined NHC- and base-catalyzed one-pot cascade reaction in moderate to excellent yields. This modular approach comprises a NHC-catalyzed hydroacylation/Stetter reaction sequence followed by a retro-Michael, 1,3-H shift and oxa-Michael cascade rearrangement promoted by strong bases.

A N-heterocyclic carbene/base-catalyzed cascade reaction leading to the formation of functionalized benzofuranones is reported. The reaction proceeds via an intramolecular hydroacylation of unactivated alkynes followed by an intermolecular Stetter reaction and a base-catalyzed chromanone to benzofuranone rearrangement.

A new approach has been developed for the synthesis of N-alkylpyrroles with a chiral substituent at the nitrogen atom by the Paal-Knorr reaction using esters of amino acids as the source of chirality.

An efficient method for the synthesis of 4,5-disubstituted 2-aminofuran-3-carbonitriles via a cascade Stetter―γ-ketonitrile cyclization reaction of aromatic aldehydes with acylidenemalononitriles, catalyzed by N-heterocyclic carbenes, has been developed. This procedure provides the corresponding products in moderate to high yields under mild conditions.

An organocatalytic intramolecular Stetter-type hydroacylation reaction between an aldehyde and an activated alkyne has been developed. This study induces salicylaldehyde-derived alkyne derivatives to assemble into a series of chromone derivatives using a catalytic amount of thiazolium-based carbene catalyst.

The inversion of the normal reactivity (umpolung) of aldehydes has been induced via N-heterocyclic carbenes (NHCs) thiazol-2-ylidenes 2a or 3a, generated by simple electrolyses of solutions containing thiazolium salt 2 or 3. Accordingly, 1,4-dicarbonyl compounds have been obtained, in mild conditions and in moderate to very high yields, via 1,4-addition of the Breslow intermediates to the suitable Michael acceptor. The procedure has been performed in classical organic solvents (VOCs) as well as in room temperature ionic liquids (RTILs). The different reactivity of aliphatic aldehydes vs the one of aromatic and heteroaromatic aldehydes has been emphasized.

Nature utilizes simple C2 and C3 building blocks, such as dihydroxyacetone phosphate (DHAP), phosphoenolpyruvate (PEP), and the "active aldehyde" in various enzyme-catalyzed carbon-carbon bond formations to efficiently build up complex organic molecules. In this Perspective, we describe the transition from using enantiopure chemical synthetic equivalents of these building blocks, employing our SAMP/RAMP hydrazone methodology and metalated chiral alpha-amino nitriles, to the asymmetric organocatalytic versions developed in our laboratory. Following this biomimetic strategy, the DHAP equivalent 2,2-dimethyl-1,3-dioxan-5-one (dioxanone) has been used in the proline-catalyzed synthesis of carbohydrates, aminosugars, carbasugars, polyoxamic acid, and various sphingosines. Proline-catalyzed aldol reactions involving a PEP-like equivalent have also allowed for the asymmetric synthesis of ulosonic acid precursors. By mimicking the "active aldehyde" nucleophilic acylations in Nature catalyzed by the thiamine-dependent enzyme, transketolase, enantioselective N-heterocyclic carbene-catalyzed benzoin and Stetter reactions have been developed. Finally, based on Nature's use of domino reactions to convert simple building blocks into complex and highly functionalized molecules, we report on our development of biomimetic asymmetric multicomponent domino reactions which couple enamine and iminium catalysis.

An intramolecular Stetter reaction of vinylphosphine oxides and vinylphosphonates has been developed. Treatment of an aldehyde with a nucleophilic N-heterocyclic carbene catalyst allows for addition of an acyl anion equivalent into a vinylphosphine oxide or vinylphosphonate Michael acceptor in yields up to 99% and ee values up to 96%.

The development of a family of chiral bicyclic triazolium salts is described. Treatment of these salts with base provides a nucleophilic carbene which may be used as an organic catalyst for asymmet...

Recent developments in the N-heterocyclic carbene (NHC)-catalyzed umpolung of aldehydes followed by their interception with activated carbon–carbon double bonds, namely the Stetter reaction, are presented. Advances in the inter- and intramolecular versions of this reaction, enantioselective transformations as well as the use of unactivated olefins in this type of reaction are discussed. 1 Introduction 2 Proposed Mechanism of the Stetter Reaction 3 Intramolecular Stetter Reactions 4 Intermolecular Stetter Reactions 5 Hydroacylation Reactions 6 Applications in Total Synthesis 7 Conclusion

The atom-economic and practical N-heterocyclic carbene (NHC) catalyzed Stetter reaction for the synthesis of γ-ketophosphonates by the reaction of aromatic aldehydes with vinylphosphonates is reported. The NHC derived from N-mesitylimidazolium salt (IMes) was an effective catalyst for this transformation, and the products were formed in moderate to good yields.

We developed an efficient method for the synthesis of 3-substituted 2,3-dihydroquinolin-4-ones using a one-pot sequential multi-catalytic process: Pd-catalyzed allylic amination–thiazolium salt-catalyzed Stetter reaction cascade. Measurement of the initial rate of the developed sequential process revealed a significant increase in the reaction rate of the Stetter reaction in the presence of Pd(OAc)2 and AcOH·i-Pr2NEt, the constituents of the first Pd catalysis.

A highly enantio- and diastereoselective intramolecular Stetter reaction has been developed. Subjection of alpha,alpha-disubstituted Michael acceptors to an asymmetric intramolecular Stetter reaction results in a highly enantioselective conjugate addition and a diastereoselective proton transfer. Available evidence suggests the diastereoselective protonation occurs via intramolecular delivery to the sterically more hindered face of the enolate. The scope of the trisubstituted Michael acceptors has been examined and found to be broad with respect to the size of the alpha-substituent and nature of the Michael acceptor. Aliphatic and aromatic aldehydes were examined and found to afford the desired product in good overall yield with high enantio- and diastereoselectivity.

The pressure effect is examined in thiazolium salt catalyzed addition reactions of aldehydes (Stetter reaction and acyloin condensation). Both reactions are not affected by pressure when they involve unhindered substrates. Their response to pressure, however, is strongly enhanced with increasing bulkiness of the reactants. The result is in line with the general pressure effect on sterically congested reactions.

Using solid- and solution-phase synthesis, a library of 2,5-disubstituted pyrrole compounds was constructed. This is the first report that Stetter reaction was applied to the solid-phase synthesis for C-C bond formation. Some of 2,5-disubstituted pyrrole compounds showed the inhibitory activity of LPS-induced mouse B-lymphocyte proliferation.

The reaction of arylaldehydes 1 and N , N -dimethylacrylamide in the presence of tributylphosphine afforded N , N -dimethyl-3-aroylpropionamides 2 in moderate yields. The reaction might involve the formation of α-oxo ylide A .

The atom-economic and practical N-heterocyclic carbene (NHC) catalyzed Stetter reaction for the synthesis of γ-ketophosphonates by the reaction of aromatic aldehydes with vinylphosphonates is reported. The NHC derived from N-mesitylimidazolium salt (IMes) was an effective catalyst for this transformation, and the products were formed in moderate to good yields.

A large set of tetrahydro-2-benzazepines with an α-hydroxy or α-(aryl)alkoxy substituted benzyl moiety in the 5-position was prepared according to the recently reported C6C1 + C3N synthetic strategy. The Heck reaction of 2-iodobenzaldehyde acetal 4 and the subsequent Stetter reaction led to the ketone 7, which was reduced diastereoselectively to form the like-configured alcohol 8. The diastereomeric unlike-configured alcohol 9 was obtained by a Mitsunobu inversion of 8. Alkylation and reductive cyclization of the diastereomeric alcohols 8 and 9 provided like- and unlike-configured 2-benzazepines 13 and 23, which allowed the introduction of various substituents at the N-atom. Analysis of the relationship between the structure and the σ1 affinity revealed that large substituents such as the butyl, benzyl or 4-phenylbutyl moiety at the benzazepine N-atom resulted in high affinity ligands. A p-methoxybenzyl ether is less tolerated by the σ1 receptor than a methyl ether or an alcohol. The unlike-configured alcohols 25d and 27d show slightly higher σ1 affinity than their like-configured diastereomers 15d and 17d. With respect to the σ1 affinity, σ1/σ2 selectivity and lipophilic ligand efficiency, like- and unlike-configured alcohols 15d and 25d represent the most promising σ1 ligands of this series. Interactions of the novel 2-benzazepines with various binding sites of the NMDA receptor were not observed.

The 1,4-dicarbonyl motif is present in a large variety of natural products and active pharmaceutical ingredients. Compounds featuring this motif are also useful synthetic intermediates, such as in the synthesis of heterocycles. Consequently, a number of reactions have been developed to access this important structural pattern. Among them, the Stetter reaction stands as a powerful approach in which a new carbon–carbon bond is formed through the catalysis of a variety of azolium salts. The availability of a wide range of azolium salts, including chiral ones, makes the Stetter reaction a useful tool in enantioselective synthesis. This chapter provides a review of intra- and intermolecular Stetter reactions with an emphasis on recent enantioselective variants and on their application to total synthesis. Related processes utilizing aldehyde surrogates or unactivated alkenes are also covered in this chapter.

Optimized conditions including a polycyclic chiral triazole catalyst allow the conversion of cyclohexadienones into optically active tricycles with enantioselectivities up to 89%.

The asymmetric intramolecular Stetter reaction of aromatic aldehydes of type (I) is optimized to proceed in the presence of a chiral triazolium salt as the catalyst.

The first asymmetric intramolecular Stetter reaction is reported, using the chiral triazolium salt 1 as catalyst. Starting from the easily accessible 4-(2-formylphenoxy)but-2-enoates 2, this protocol opens up an enantioselective pathway to the benzo-annulated pyran-4-ones (chroman-4-ones) 3a–h with good yields and enantiomeric excesses of up to 74%.

The effect of different Michael acceptors was evaluated in the catalytic asymmetric intramolecular Stetter reaction. Utilizing a readily prepared chiral triazolium salt as a nucleophilic carbene precursor, the reactivity and selectivity of substrates containing different electron-deficient double bonds was shown to vary significantly under identical reaction conditions.