Conjugate Addition Reactions Research Articles

Divergent Total Syntheses of Napelline-Type C20-Diterpenoid Alkaloids: (-)-Napelline, (+)-Dehydronapelline, (-)-Songorine, (-)-Songoramine, (-)-Acoapetaldine D, and (-)-Liangshanone.

The napelline-type alkaloids possess an azabicyclo[3.2.1]octane moiety and an ent-kaurane-type tetracyclic skeleton (6/6/6/5) along with varied oxidation patterns embedded in the compact hexacyclic framework. Herein, we disclose a divergent entry to napelline-type alkaloids that hinges on convergent assembly of the ent-kaurane core using a diastereoselective intermolecular Cu-mediated conjugate addition and subsequent intramolecular Michael addition reaction as well as rapid construction of the azabicyclo[3.2.1]octane motif via an intramolecular Mannich cyclization. The power of this strategy has been demonstrated through efficient asymmetric total syntheses of eight napelline-type alkaloids, including (-)-napelline, (-)-12-epi-napelline, (+)-dehydronapelline, (+)-12-epi-dehydronapelline, (-)-songorine, (-)-songoramine, (-)-acoapetaldine D, and (-)-liangshanone.

Phytophenol Dimerization Reaction: From Basic Rules to Diastereoselectivity and Beyond.

Phytophenol dimerization, which is a radical-mediated coupling reaction, plays a critical role in many fields, including lignin biosynthesis. To understand the reaction, 2,2-diphenyl-1-picrylhydrazyl radical was used to initiate a series of phytophenol dimerization reactions in methanol. The products were identified using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-ESI-Q-TOF-MS/MS) analysis in situ. The identified products mainly included biphenols, magnolol, honokiol, gingerol 6,6′-dimers, 3,6-dimethoxylcatechol β,β′ dimer, euphorbetin, bis-eugenol, dehydrodiisoeugenol, trans-ε-viniferin, (+) pinoresinol, and (−) pinoresinol. Structure–function relationship analysis allowed four basic rules to be defined: meta-excluded, C–C bonding domination, ortho-diOH co-activation, and exocyclic C=C involvement. The exocyclic C=C involvement, however, required conjugation with the phenolic core and the para-site of the -OH group, to yield a furan-fused dimer with two chiral centers. Computational chemistry indicated that the entire process was completed via a radical coupling reaction and an intramolecular conjugate addition reaction. Similar results were also found for the horseradish peroxidase (HRP)-catalyzed coniferyl alcohol dimerization, which produced (+) and (−) pinoresinols (but no (−) epipinoresinol), suggesting that the HRP-catalyzed process was essentially an exocyclic C=C-involved phytophenol dimerization reaction. The reaction was highly diastereoselective. This was attributed to the intramolecular reaction, which prohibited Re-attack. The four basic rules and diastereoselectivity can explain and even predict the main products in various chemical and biological events, especially oxidase-catalyzed lignin cyclization.

Polymer-Supported Chiral Heterogeneous Copper Catalyst for Asymmetric Conjugate Addition of Ketones and Imines under Batch and Flow

Enantioselective conjugate addition reactions are powerful methods in synthesizing optically active molecules. Procedures that employ chiral homogeneous catalysts have been developed extensively, but ones that use chiral heterogeneous catalysts are less explored and remain a challenge. Here we report a polymer-supported chiral heterogeneous copper catalyst that demonstrated high reactivity and enantioselectivity in asymmetric conjugate addition reactions of both ketones and imines. It was found that reduced steric hindrance inside the micro catalytic environment and a 1:1 ligand to metal ratio was crucial for the high efficiency and reusability of the chiral heterogeneous catalyst. Various α,β-unsaturated carbonyl substrates, including pharmaceutical intermediates and natural products, could be transformed in high yields with high enantioselectivities. Successful application of this methodology in a continuous flow fashion further broadened its usage in dealing with sensitive organozinc reagents. In addition, production was successfully scaled up under the flow condition.

Synthesis of 2,3,6‐Trisubstituted β‐Carbolin‐1‐ones Utilizing 3‐Amino‐2‐pyridone Synthesis

AbstractSynthesis of 2,3,6‐triisubstituted β‐carbolin‐1‐ones is disclosed using palladium‐catalyzed intramolecular amination of 3‐amino‐4‐(2‐bromophenyl)‐2‐pyridones prepared by the conjugate addition reaction of diethyl 2‐aminomalonate having a bulkier ketimine moiety to alkynyl imines. The transformation of the synthesized 3‐amino‐4‐(2‐bromophenyl)‐2‐pyridones using palladium‐catalyzed intramolecular amination produced 2,3,6‐trisubstituted β‐carbolin‐1‐ones in good to high yields.

The Chemistry of Cyclopropanes and New Insights into Organocatalyzed Asymmetric Cyclopropanation

AbstractCyclopropane structure has been the object of interest in multiple investigations due to its prevalence in different natural products. In addition, this structure has a particular reactivity, specifically the 1,1‐cyclopropanedicarboxylate compounds, which act as acceptor‐donor cyclopropanes. Its reactivity could be compared with that of an α,β‐unsaturated carbonyl, which undergoes conjugate addition reaction and depending on the nature of the nucleophile this can lead to a cycloaddition reaction. Therefore, cyclopropane can be transformed into several useful structures in organic synthesis. Different methods have been described to achieve cyclopropanes such as, Simmons‐Smith reaction, decomposition of diazoalkanes and Michael‐Initiated ring closure (MIRC). Due to the absence of metals, this last method has been applied to the asymmetric organocatalytic synthesis of cyclopropanes, where the substrates activation is through the imine‐enamine intermediates formation or by hydrogen bonds. The asymmetric reaction consists of a domino reaction composed of a conjugate addition reaction and a cyclization reaction via intramolecular nucleophilic substitution. In this review, different asymmetric organocatalytic syntheses of the last two decades until 2021 are presented. With the intention to facilitate the reading of the review, an example of each paper was selected with the optimal reaction conditions and with the best organocatalyst producing the best yield and high stereoselectivity.

Synthesis of 3,6‐Disubstituted 4‐Ethoxycarbonylpyranoindol‐1‐ones Utilizing 3‐Amino‐2‐pyrone Synthesis

AbstractSynthesis of 3,6‐disubstituted 4‐ethoxycarbonylpyranoindol‐1‐ones is developed using palladium‐catalyzed intramolecular amination of 3‐amino‐4‐(2‐bromophenyl)‐2‐pyrones prepared by the conjugate addition reaction of diethyl 2‐aminomalonate to alkynyl ketones. The transformation of the synthesized 3‐amino‐4‐(2‐bromophenyl)‐2‐pyrones via palladium‐catalyzed intramolecular amination afforded 3,6‐disubstituted 4‐ethoxycarbonylpyranoindol‐1‐ones.

Synthesis of Trifluoromethylated 4H‐1‐Benzopyran Derivatives via Photocatalytic Trifluoromethylation/Oxidation/Conjugate Addition, and Cyclization Sequences of Vinyl Phenols

AbstractThe objective of this study was to describe a cyclization reaction of photoredox generated ortho‐quinone methides using 1,3‐diketones for the synthesis of trifluoromethylated 4H‐1‐benzopyrans with moderate to high yields. This process resulted in in situ formation of trifluoromethylated ortho‐quinone methides from 2‐vinyl phenols with Umemoto's reagent, followed by conjugate addition and cyclization reaction of 1,3‐diketones.

Stereoselective Synthesis of Cyclohexane Derivatives: Tandem Lithium Iodide Mediated Intramolecular Conjugate Addition of Thiols to α,β-Bisenones

AbstractA tandem intramolecular conjugate addition reaction was conducted with α,β-bisenones as selected Michael acceptors which were converted into 1,2,3-trisubstituted six-membered rings in the presence of activated sulfur nucleophiles. The products were obtained in good to excellent yields (maximum yield: 99%). Various substituted α,β-bisenones and sulfur nucleophiles were examined to understand the substrate scope of the reaction. Only one diastereomer was isolated, as lithium iodide mediated enolate trapping reactions improve the stereoselectivity of reactions involving 1,2,3-trisubstituted cyclohexanes.

Double Addition Reactions Involving Vinyl-Substituted N-Heterocycles and Active Methylene Compounds.

A series of conjugate addition reactions have been performed with vinyl-substituted N-heterocycles in acid-catalyzed conversions. Using active methylene compounds, double conjugate addition reactions have been accomplished to provide dipyridyl and related heterocyclic products. These conversions have utilized 1,3-dicarbonyl compounds, cyano esters, a cyano sulfone, and malonyl nitrile as nucleophiles. The Michael accepting groups include vinyl-substituted pyridines, quinoline, and pyrazine. Double conjugate addition reactions have also been accomplished with 2,6-divinylpyridine and related systems.

Peptide-Catalyzed Stereoselective Conjugate Addition Reaction of Aldehydes to C-Substituted Maleimides.

Catalytic stereoselective additions with maleimides are useful one‐step reactions to yield chiral succinimides, molecules that are widespread among therapeutically active compounds but challenging to prepare when the maleimide is C‐substituted. We present the tripeptide H‐Pro‐Pro‐Asp‐NHC12H25 as a catalyst for conjugate addition reactions between aldehydes and C‐substituted maleimides to form succinimides with three contiguous stereogenic centers in high yields and stereoselectivities. The peptidic catalyst is so chemoselective that no protecting group is needed at the imide nitrogen of the maleimides. Derivatization of the succinimides was straightforward and provided access to chiral pyrrolidines, lactones, and lactams. Kinetic studies, including a Hammett plot, provided detailed insight into the reaction mechanism.

Application of Proline-Derived (Thio)squaramide Organocatalysts in Asymmetric Diels–Alder and Conjugate Addition Reactions

AbstractThe synthesis of chiral proline-derived squaramide and thiosquaramide organocatalysts, which are capable of the dual activation in asymmetric reactions is reported. The (thio)squaramide moiety can form hydrogen bonds to activate the substrates and to stereocontrol the reaction, while the pyrrolidine unit can form enamines to activate carbonyl compounds via aminocatalysis. Comparing the performance of thiosquaramide to squaramide, the Diels–Alder reaction of (anthracen-9-yl)acetaldehyde and trans-β-nitrostyrene was examined, which has been investigated in the literature using quantum chemical calculations. Both squaramide and thiosquaramide gave excellent yields (up to 99%) and enantiomeric excess values (up to 98%). Moreover, their catalytic performance was compared in conjugate addition of lawsone to β,γ-unsaturated α-keto ester.

Divergent Synthesis of Decahydroquinoline‐Type Poison‐Frog Alkaloids

AbstractThe divergent synthesis of cis‐, 4a‐epi‐cis‐, 2‐epi‐cis‐, and trans‐decahydroquinoline‐type poison‐frog alkaloids was achieved from the known chiral acetate 5 using a stereoselective Michael‐type conjugate addition reaction and an intramolecular aldol‐type cyclization with epimerization. The conformational control was achieved on the basis of the A1,3 strain in the starting material and the stereoelectronic effect. More specifically, the synthesis of cis‐251 A, cis‐209 J‐1, cis‐223F‐1, 4a‐epi‐cis‐251 A, 2‐epi‐cis‐251 A, and trans‐251 A bearing a seven‐carbon chain at the α‐position of the nitrogen atom on the piperidine nucleus was also realized. These compounds are expected to show selective and potent inhibitory activities toward nicotinic acetylcholine receptors.

Cinchona Derivatives as Bifunctional H‐bonding Organocatalysts in Asymmetric Vinylogous Conjugate Addition Reactions

AbstractAsymmetric vinylogous conjugate addition reactions constitute an essential class of enantioselective C−C bond‐forming transformations characterized by remote functionalization of substrates and the construction of distal stereocenters. After the renaissance of organocatalysis in 2000, vinylogous addition methodologies have seen new horizons of development. Cinchona alkaloids and some of their derivatives have appeared as efficient chiral catalysts in several organic transformations. Their non‐toxicity, low cost, availability in pseudo‐enantiomeric forms, and “open flask” reaction procedures have been the main reasons behind their success in asymmetric synthesis. These organocatalysts have also shown remarkable applications in vinylogous chemistry. This mini‐review covers the developments of asymmetric vinylogous conjugate addition (VCA) reactions under bifunctional cinchona alkaloids/derivatives catalysis.

Direct decarboxylative Giese reactions.

The quest to find milder and more sustainable methods to generate highly reactive, carbon-centred intermediates has led to a resurgence of interest in radical chemistry. In particular, carboxylic acids are seen as attractive radical precursors due their availability, low cost, diversity, and sustainability. Moreover, the corresponding nucleophilic carbon-radical can be easily accessed through a favourable radical decarboxylation process, extruding CO2 as a traceless by-product. This review summarizes the recent progress on using carboxylic acids directly as convenient radical precursors for the formation of carbon-carbon bonds via the 1,4-radical conjugate addition (Giese) reaction.

Stereoselective peptide catalysis in complex environments - from river water to cell lysates.

Many stereoselective peptide catalysts have been established. They consist, like nature's catalysts, of amino acids but have significantly lower molecular weights than enzymes. Whereas enzymes operate with exquisite chemoselectivity in complex biological environments, peptide catalysts are used in pure organic solvents and at higher concentrations. Can a peptide catalyst exhibit chemoselectivity reminiscent of enzymes? Here, we investigated the properties of tripeptide catalysts in complex mixtures in hydrophobic and aqueous solvents. We challenged the catalysts with biomolecules bearing functional groups that could interfere by coordination or reaction with the peptide, the substrates, or intermediates. H-dPro-αMePro-Glu-NHC12H15 emerged through tailoring of the trans/cis ratio of the tertiary amide as a conformationally well-defined tripeptide that catalyzes C–C bond formations with high reactivity and stereoselectivity – regardless of the solvent and compound composition. The chemoselectivity of the tripeptide is so high that it even catalyzes reactions in cell lysates. The findings provoke the question of the potential role of peptide catalysis in nature and during the evolution of enzymes.

Carbon dioxide enhances sulphur-selective conjugate addition reactions.

Sulphur-selective conjugate addition reactions play a central role in synthetic chemistry and chemical biology. A general tool for conjugate addition reactions should provide high selectivity in the presence of competing nucleophilic functional groups, namely nitrogen nucleophiles. We report CO2-mediated chemoselective S-Michael addition reactions where CO2 can reversibly control the reaction pHs, thus providing practical reaction conditions. The increased chemoselectivity for sulphur-alkylation products was ascribed to CO2 as a temporary and traceless protecting group for nitrogen nucleophiles, while CO2 efficiently provide higher conversion and selectivity sulphur nucleophiles on peptides and human serum albumin (HSA) with various electrophiles. This method offers simple reaction conditions for cysteine modification reactions when high chemoselectivity is required.

Convergent access to mono-fluoroalkene-based peptidomimetics.

The convergent and selective preparation of (Z)-monofluoroalkene-based dipeptide isosteres from functionalized fluorosulfones as a cornerstone is described. In this approach, the N-terminal amino group is introduced by a conjugate addition reaction of phthalimide onto fluorinated vinylsulfones containing α-amino-acid side chains while the C-terminal motif is linked to the fluorovinylic peptide bond mimic via the Julia-Kocienski reaction between fluorosulfones and substituted aldehydes bearing α-amino-acid side chains.

L-(+)-Tryptophan methyl ester derived polymeric microbeads as an efficient heterogeneous catalyst for green synthesis of 2-amino-4-(nitromethyl)-4H-chromene-3-carbonitriles.

The cross-linked microbeads with average diameter of 106-300 μm, [poly(EGDMA-MATrp)], were obtained by copolymerization reaction of N-methacryloyl-L-(+)-tryptophan methyl ester (MATrp) with ethylene glycol dimethacrylate (EGDMA) and successfully applied as a heterogeneous catalyst in conjugate addition reaction of nitromethane to substituted 2-iminochromenes in aqueous media. A variety of 2-amino-4-(nitromethyl)-4H-chromene-3-carbonitriles has been synthesized in good yields. Polymeric microbeads were very durable and reused 5 times without a significant loss of activity. DFT calculations and experimental results revealed the significant role of π-π interactions as well as hydrogen bonding in the reaction mechanism.

Advances in Synthesis of Enantioenriched Chiral Sulfones by Enantioselective Conjugate Addition Reactions

AbstractChiral sulfones, a class of organic compounds with broad application prospects in organic synthesis and pharmaceutical chemistry, are an important part of building bioactive molecules or functional materials. In this paper, the advances and the state of synthesizing chiral sulfones by addition reactions are reviewed. The methods described in the manuscript are classified according to the types of reaction. Moreover, each chapter is arranged in chronological order.

Stereoselective Aldol and Conjugate Addition Reactions Mediated by Proline‐Based Catalysts and Its Analogues: A Concise Review

AbstractThe application of amino acids and small peptides as asymmetric organocatalysts in the aldol and conjugate addition reactions is a significant breakthrough in the past decade. The desired stereoselectivity in these reactions can be attained through tunable elements of diversity present in the amino acids/peptides. On this note, the current review highlights the organocatalytic aldol and conjugate addition by proline or its analogous in the form of amide/peptide derivatives. The wide‐ranging works of literature are classified based on the use of single amino acid or peptides as a catalyst. The designing of the aforementioned amide/amino acid/peptide catalyst, including their recent applications, is also detailed. Moreover, the analogous catalysts are also discussed, embedding other hetero‐organic functionalities that mimic the catalytic activity of proline in aldol/conjugate additions.