Enamine Catalysis Research Articles

Light triggers select isomers to flip

Converting a mixture of mirror-image forms, or stereoisomers, of a molecule into a single isomer is a big deal in making pharmaceuticals, because usually only one isomer is useful as a drug. But current options for this process, called deracemization, are complicated and fiddly. Research by Sanzhong Luo and coworkers at Tsinghua University and the Haihe Laboratory of Sustainable Chemical Transformations has now made it as simple as turning on a light. The group used an iridium compound, an enamine, and violet light to transform a mixture of branched aldehyde isomers into a single one ( Science 2022, DOI: 10.1126/science.abl4922 ). The work combines two well-understood reactions: double-bond photoisomerization and enamine catalysis, which was recognized with the 2021 Nobel Prize in Chemistry . The group’s straightforward approach can be used to deracemize mixtures of many types of chiral aldehydes. The method works by transferring the chirality, or handed-ness, from the

Deracemization through photochemical E/Z isomerization of enamines.

Catalytic deracemization of α-branched aldehydes is a direct strategy to construct enantiopure α-tertiary carbonyls, which are essential to pharmaceutical applications. Here, we report a photochemical E/Z isomerization strategy for the deracemization of α-branched aldehydes by using simple aminocatalysts and readily available photosensitizers. A variety of racemic α-branched aldehydes could be directly transformed into either enantiomer with high selectivity. Rapid photodynamic E/Z isomerization and highly stereospecific iminium/enamine tautomerization are two key factors that underlie the enantioenrichment. This study presents a distinctive photochemical E/Z isomerization strategy for externally tuning enamine catalysis.

Bond Energies of Enamines.

Energetics of reactive intermediates underlies their reactivity. The availability of these data provides a rational basis for understanding and predicting a chemical reaction. We reported here a comprehensive computational study on the energetics of enamine intermediates that are fundamental in carbonyl chemistry. Accurate density functional theory (DFT) calculations were performed to determine the bond energies of enamines and their derived radical intermediates. These efforts led to the compilation of a database of enamine energetics including a thermodynamic index such as free-energy stability, bond dissociation energy (BDE), and acid dissociation constant (pKa) as well as a kinetic index such as nucleophilicity and electrophilicity. These data were validated by relating to experimentally determined parameters and their relevance and utility were discussed in the context of modern enamine catalysis. It was found that pKa values of enamine radical cations correlated well with redox potentials of their parent enamines, the former could be used to rationalize the proton-transfer behavior of enamine radical cations. An analysis of the BDE of enamine radical cations indicated that these species underwent facile β-C–H hydrogen transfer, in line with the known oxidative enamine catalysis. The enamine energetics offers the possibility of a systematic evaluation of the reactivities of enamines and related radicals, which would provide useful guidance in exploring new enamine transformations.

Domino Michael/Michael reaction catalyzed by switchable modularly designed organocatalysts.

The domino Michael/Michael reaction between (E)-7-aryl-7-oxohept-5-enals and trans-cinnamaldehydes was investigated by using modularly designed organocatalysts (MDOs). It was found that both the enamine and iminium catalytic modes of the MDOs are switchable and can be individually switched on and off by using appropriate combinations of the precatalyst modules and the reaction conditions. When both the enamine and iminium catalysis modes of the MDOs are switched on, the desired domino reaction products can be obtained in good yields and stereoselectivities under optimized conditions.

High trans‐2‐Decalones by Photoredox Catalyzed β‐Isomerization

AbstractThe synergistic combination of three catalytic processes – photoredox, enamine and hydrogen atom transfer (HAT) catalysis – enabled the β‐isomerization of 2‐decalones towards the thermodynamically most stable trans‐isomers. A library of iridium (III) complexes and organic dyes were screened in combination with cyclic amines and thiols which after optimization gave the desired trans‐2‐decalones with high trans/cis ratios of 60 : 40 up to 98 : 2.

Asymmetric Photocatalysis Enabled by Chiral Organocatalysts.

Visible-light photocatalysis has advanced as a versatile tool in organic synthesis. However, attaining precise stereocontrol in photocatalytic reactions has been a longstanding challenge due to undesired photochemical background reactions and the involvement of highly reactive radicals or radical ion intermediates generated under photocatalytic conditions. To address this problem and expand the synthetic utility of photocatalytic reactions, a number of innovative strategies, including mono- and dual-catalytic approaches, have recently emerged. Of these, exploiting chiral organocatalysis, such as enamine catalysis, iminium-ion catalysis, Brønsted acid/base catalysis, and N-heterocyclic carbene catalysis, to induce chirality transfer of photocatalytic reactions has been widely explored. This Review aims to provide a current, comprehensive overview of asymmetric photocatalytic reactions enabled by chiral organocatalysts published through June 2021. The substrate scope, advantages, limitations, and proposed reaction mechanisms of each reaction are discussed. This review should serve as a reference for the development of visible-light-induced asymmetric photocatalysis and promote the improvement of the chemical reactivity and stereoselectivity of these reactions.

Can Primary Arylamines Form Enamine? Evidence, α-Enaminone, and [3+3] Cycloaddition Reaction.

The formation of enamine from primary arylamines was detected and confirmed by nuclear magnetic resonance spectroscopy. The presence of a radical quencher, e.g., (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl, was found to be essential for the detection of enamine formation. A direct synthesis of α-enaminones from primary arylamines and ketones was also developed. Mechanistic investigation of α-enaminone formation suggests that an amine radical cation generated through O2 singlet energy transfer was involved in initiating α-enaminone formation. The reactivity and utility of α-enaminones were explored with a [3+3] cycloaddition reaction of enones affording dihydropyridines in good yields (58-85%). α-Enaminones displayed a set of reactivities that is different from that of enamines. The knowledge gained in this work advances our basic understanding of organic chemistry, providing insights and new opportunities in enamine catalysis.

Catalytic Asymmetric Disulfuration by a Chiral Bulky Three‐Component Lewis Acid‐Base

AbstractA three‐component Lewis acid–base (Lewis trio) involving a bulky chiral primary amine, B(C6F5)3 and a bulky tertiary amine has been developed as an effective enamine catalyst for enantioselective disulfuration reactions. The bulky tertiary amine was found to activate a bulky primary–tertiary diamine–borane Lewis pair for enamine catalysis via frustrated interaction. The resulted chiral bulky Lewis trio (BLT) allows for the construction of chiral disulfides via direct disulfuration with β‐ketocarbonyls or α‐branched aldehydes in a practical and highly stereocontrolled manner.

Catalytic Asymmetric Disulfuration by a Chiral Bulky Three-Component Lewis Acid-Base.

A three-component Lewis acid-base (Lewis trio) involving a bulky chiral primary amine, B(C6 F5 )3 and a bulky tertiary amine has been developed as an effective enamine catalyst for enantioselective disulfuration reactions. The bulky tertiary amine was found to activate a bulky primary-tertiary diamine-borane Lewis pair for enamine catalysis via frustrated interaction. The resulted chiral bulky Lewis trio (BLT) allows for the construction of chiral disulfides via direct disulfuration with β-ketocarbonyls or α-branched aldehydes in a practical and highly stereocontrolled manner.

Reactivity of steroidal 1-azadienes toward enamines: an approach to novel chiral penta- and hexacyclic steroids.

The chemical behavior of steroidal N-sulfonyl-1-azadienes toward carbonyl compounds, in the presence of pyrrolidine, is described. With aldehydes, these azadienes participate in hetero-Diels-Alder reactions with the in situ generated enamines. The stereoselectivity results from the approach of the dienophiles from the less hindered α-face of the steroid, with the pyrrolidine moiety endo and retention of the enamine trans geometry. This diastereoselective synthetic methodology led to a new class of chiral pentacyclic steroids. Interestingly, the studied steroidal scaffolds follow a different mechanistic pathway with cyclic ketones. They undergo a diastereoselective annulation reaction, under enamine catalysis, affording chiral hexacyclic steroids.

Front Cover: Enantioselective Synthesis of Monosaccharide Analogues by Two‐Step Sequential Enamine Catalysis: Benzoyloxylation and Aldol Reaction (Eur. J. Org. Chem. 14/2020)

Front Cover: Enantioselective Synthesis of Monosaccharide Analogues by Two‐Step Sequential Enamine Catalysis: Benzoyloxylation and Aldol Reaction (Eur. J. Org. Chem. 14/2020)

Enantioselective Synthesis of Monosaccharide Analogues by Two‐Step Sequential Enamine Catalysis: Benzoyloxylation and Aldol Reaction

An efficient route to synthesize monosaccharide analogues in an enantio‐ and diastereoselective manner is described. Three contiguous stereocenters can be constructed via enantioselective benzoyloxylation of aldehydes using a chiral secondary amine catalyst and a subsequent aldol reaction of the resulting α‐benzoyloxyaldehydes with the protected dihydroxyacetones using chiral amino acid catalysts, and single diastereomers were obtained with excellent enantioselectivity.

Stereochemistry of the Reaction Intermediates of Prolinol Ether Catalyzed Reactions Characterized by Vibrational Circular Dichroism Spectroscopy.

Spectroscopic characterizations of key reaction intermediates are often considered the final confirmation of a reaction mechanism. This proof‐of‐principle study showcases the application of vibrational circular dichroism (VCD) spectroscopy for the characterization of in situ generated reaction intermediates using the key intermediates of enamine catalysis of Jørgensen–Hayashi‐type prolinol ether catalysts as model system. By comparison of experimental and computed spectra, the enamines are shown to preferentially adopt an anti‐conformation with E‐configured C=C bond. For the parent prolinol catalyst, the structure and stereochemistry of the oxazolidine side product is determined as well. This study thus demonstrates that VCD spectra can provide insights into structural preferences of organocatalysts that utilize a covalent activation mechanism. Thereby it outlines new fields of applications for VCD spectroscopy and finally adds the technique to the toolbox of physical organic chemistry for in‐depth mechanistic studies.

Asymmetric Reactions Enabled by Cooperative Enantioselective Amino- and Lewis Acid Catalysis.

Organocatalysis-the branch of catalysis featuring small organic molecules as the catalysts-has, in the last decade, become of central importance in the field of asymmetric catalysis, so much that it is now comparable to metal catalysis and biocatalysis. Organocatalysis is rationalized and classified by a number of so-called activation modes, based on the formation of a covalent or not-covalent intermediate between the organocatalyst and the organic substrate. Among all the organocatalytic activation modes, enamine and iminium catalysis are widely used for the practical preparation of valuable products and intermediates, both in academic and industrial contexts. In both cases, chiral amines are employed as catalysts. Enamine activation mode is generally employed in the reaction with electrophiles, while nucleophiles require the iminium activation mode. Commonly, in both modes, the reaction occurs through well-organized transitions states. A large variety of partners can react with enamines and iminium ions, due to their sufficient nucleophilicity and electrophilicity, respectively. However, despite the success, organocatalysis still suffers from narrow scopes and applications. Multicatalysis is a possible solution for these drawbacks because the two different catalysts can synergistically activate the substrates, with a simultaneous activation of the two different reaction partners. In particular, in this review we will summarize the reported processes featuring Lewis acid catalysis and organocatalytic activation modes synergically acting and not interfering with each other. We will focus our attention on the description of processes in which good results cannot be achieved independently by organocatalysis or Lewis acid catalysis. In these examples of cooperative dual catalysis, a number of new organic transformations have been developed. The review will focus on the possible strategies, the choice of the Lewis acid and the catalytic cycles involved in the effective reported combination. Additionally, some important key points regarding the rationale for the effective combinations will be also included. π-Activation of organic substrates by Lewis acids, via formation of electrophilic intermediates, and their reaction with enamines will be also discussed in this review.

Synthesis of Phenylcyclopropane-Based Secondary Amine Catalysts and Their Applications in Enamine Catalysis.

A novel chiral motif based on a phenylcyclopropane scaffold has been designed, and a facile synthetic route to the key intermediate for the synthesis of phenylcyclopropane-based chiral secondary amines has been developed. Newly synthesized chiral amines function as effective catalysts for several asymmetric reactions through enamine intermediates.

Redox Property of Enamines.

Enamines are electron-rich compounds bearing intriguing redox properties. Herein, a series of secondary enamines condensed from primary amine and β-ketocarbonyls were synthesized and their electrochemical oxidation properties were systematically studied by cyclic voltammetry. Furthermore, theoretical calculation of oxidation potentials of enamines, particularly those catalytic intermediates, was also conducted to further broaden the scope investigated. Possible structural factors on oxidation and the nature of the resulted radical cation intermediates were revealed and discussed. Correlation of redox potentials with molecular properties such as highest occupied molecular orbital energies and natural population analysis charge were explored, and there appears no simple linear correlation. On the other hand, a good correlation with Mayr's nucleophilicity parameter N was noted among a range of catalytically relevant enamines. Spin population analysis disclosed that enamine radical cations mainly exhibit the carbon-center free radical feature. Taking experimental and computation data together, a comprehensive picture about the redox property of enamines is presented, which would provide guidance in the development of oxidative enamine catalysis and transformations.

Ugi reaction-derived prolyl peptide catalysts grafted on the renewable polymer polyfurfuryl alcohol for applications in heterogeneous enamine catalysis.

The multicomponent synthesis of prolyl pseudo-peptide catalysts using the Ugi reaction with furfurylamines or isocyanides is described. The incorporation of such a polymerizable furan handle enabled the subsequent polymerization of the peptide catalyst with furfuryl alcohol, thus rendering polyfurfuryl alcohol-supported catalysts for applications in heterogeneous enamine catalysis. The utilization of the polymer-supported catalysts in both batch and continuous-flow organocatalytic procedures proved moderate catalytic efficacy and enantioselectivity, but excellent diastereoselectivity in the asymmetric Michael addition of n-butanal to β-nitrostyrene that was used as a model reaction. This work supports the potential of multicomponent reactions towards the assembly of catalysts and their simultaneous functionalization for immobilization.

Prospect of Thiazole-based γ-Peptide Foldamers in Enamine Catalysis: Exploration of the Nitro-Michael Addition.

As three-dimensional folding is prerequisite to biopolymer activity, complex functions may also be achieved through foldamer science. Because of the diversity of sizes, shapes and folding available with synthetic monomers, foldamer frameworks enable a numerous opportunities for designing new generations of catalysts. We herein demonstrate that heterocyclic γ-peptide scaffolds represent a versatile platform for enamine catalysis. One central feature was to determine how the catalytic activity and the transfer of chiral information might be under the control of the conformational behaviours of the oligomer.

Prevalence of Diarylprolinol Silyl Ethers as Catalysts in Total Synthesis and Patents

Diarylprolinol silyl ethers are among the most utilized stereoselective organocatalysts for the construction of complex molecules. With their debut in 2005, these catalysts have been applied in numerous method developments primarily leveraging enamine and iminium-ion catalysis. These strategies have extended into the preparation of complex molecules in both academic and industrial settings. This Review intends to give an overview of the application of the diarylprolinol silyl ether catalysts in total synthesis. Furthermore, integration of these catalysts in patent literature is also disclosed highlighting the versatility of the catalytic system.

Synergistic palladium/enamine catalysis for asymmetric hydrocarbon functionalization of unactivated alkenes with ketones.

Synergistic palladium and enamine catalysis was explored to promote ketone addition to unactivated olefins. A secondary amine-based organocatalyst was identified as the optimal co-catalyst for the directed Pd-catalyzed alkene activation. Furthermore, asymmetric hydrocarbon functionalization of unactivated alkenes was also achieved with good to excellent yield (up to 96% yields) and stereoselectivity (up to 96% ee). This strategy presented an efficient approach to prepare α-branched ketone derivatives under mild conditions.