Conjugate Addition Research Articles

From gem‐Dichlorocyclobutenones to Cyclobutenols: Unveiling a Ruthenium‐Catalyzed Allylic Reduction‐Asymmetric Transfer Hydrogenation Cascade

Cyclobutenones constitute an appealing class of substrates in catalytic asymmetric transformations leading to diversely substituted enantioenriched four‐membered carbocycles, which are eliciting a growing interest in medicinal chemistry. Whilst several synthetically useful enantioselective conjugate addition reactions have been reported, the catalytic enantioselective reduction of the carbonyl group of simple cyclobutenones remains an elusive transformation. Herein, we disclose the discovery of a novel allylic reduction‐asymmetric transfer hydrogenation cascade, catalyzed by a Noyori‐Ikariya ruthenium complex, from readily available gem‐dichlorocyclobutenones, leading to 2‐chlorocyclobutenols with high optical purities, which can be engaged in postfunctionalization reactions enabling access to substituted four‐membered rings.

N-Protection Dependent Phosphorylation of Dehydroamino Acids to Build Unusual Phosphono-Peptides.

An efficient Mn(III)-promoted phosphorylation of dehydroalanine (Dha) has been developed to give unusual α-amino acids bearing phosphonates/phosphine oxides and β-vinyl phosphonates/phosphinates depending on N-protection of amino acid. N,N-diprotected dehydroalanine reacted with H-phosphonates and H-phosphine oxides to give structurally diverse phosphorylated α-amino acids through conjugate addition of phosphorous radical generated by Mn(OAc)3.2H2O. Whereas, a highly Z-selective phosphorylation was observed in the case of mono N-Boc protected dehydroalanine via cross dehydrogenative coupling to give (Z)- β -vinyl phosphono amino acid. The method is successfully applied to short peptides to derive unusual phosphono-peptides under mild conditions.

Semisynthesis and DFT Study of New Michael Adducts using (E)-α-Atlantone, Isolated from Cedrus atlantica Essential Oil

This work is devoted to the synthesis of divers Michael adducts from (E)-α-atlantone as an α,β-unsaturated ketone isolated from Cedrus atlantica essential oil. The (E)-α-atlantone is subjected to ethyl cyanoacetate, phenylmagnesium bromide, and ethanol to produce the corresponding 1,4-Michael adducts in good yields. The conjugate addition of the appropriate reagents onto (E)-α-atlantone proceeds in a regiospecific manner, closely governed by the nucleophilicity of the reagents as well as their stereospecific blocking. The structure of the obtained Michael adducts is established using NMR (1H 13C) spectroscopy and elemental analysis. Likewise, the DFT method was utilized to comprehend the molecular properties, stability, and reactivity of the investigated compounds, as well as to explain the proposed mechanism. The computed outcomes are in good agreement with the experimental data.

N-Heterocyclic Carbene Catalyzed Reactions Involving Acetylenic Breslow and/or Acylazolium as Key Intermediates.

N-heterocyclic carbene (NHC) organocatalysis has been developed as a powerful tool in modern synthetic chemistry. NHC catalytic activation of ynals and alkynoic acid derivatives provided versatile reactions that involve acetylenic Breslow and/or acylazolium as key intermediates, and diverse transformations have been established for access to molecules with unique skeletons in efficient fashions. Herein we summarize the recent achievements in NHC-catalyzed reactions involving acetylenic Breslow and/or acylazolium intermediates. Different reactions belonging to three catalytic modes, including (1) conjugate additions to acetylenic Breslow derived α,β-unsaturated acylazolium intermediates, (2) β-umpolung of ynals via acetylenic Breslow intermediates, and (3) conjugate additions to acetylenic acylazolium intermediates, are emphasized with examples and plausible mechanisms cited to guide a better understanding.

Carbon-silicon-switch effect in enantioselective construction of silicon-stereogenic center from silacyclohexadienones

Carbon-silicon-switch strategy, replacing one specific carbon atom in organic molecules with a silicon, has garnered significant interest for developing new functional molecules. However, the influence of a reaction regarding its selectivity and reactivity by carbon-silicon-switch strategy has far less been investigated. Here we discover an unusual carbon-silicon-switch effect in the enantioselective construction of silicon-stereogenic center. It is found that there has been a significant change in the desymmetrization reaction of silacyclohexadienones using asymmetric conjugate addition or oxidative Heck reaction with aryl/alkyl nucleophiles when compared with their carbon analogues cyclohexadienones. Specifically, the carbon-silicon-switch leads to a reversal in enantioselectivity with arylzinc as the nucleophile by the same chiral catalyst, and results in totally different reactivity with arylboronic acid as the nucleophile. Control experiments and density functional theory (DFT) calculations have shown that the unusual carbon-silicon-switch effect comes from the unique stereoelectronic feature of silicon.

Organocatalyzed Asymmetric Conjugate Addition of Cyclic β-Keto Esters to (E)-β-Nitroacrylate Derivatives.

A diaminomethylenemalononitrile organocatalyst efficiently promoted the asymmetric conjugate addition of cyclic β-keto esters to (E)-β-nitroacrylate derivatives, yielding the corresponding β-nitro esters derivatives with excellent enantioselectivities (up to >99% ee). This is the first successful example of highly stereoselective conjugate addition of cyclic β-keto esters to (E)-β-nitroacrylate derivatives to obtain anti-isomers.

Direct Catalytic Asymmetric Conjugate Addition of Benzofuran‐3(2H)‐Ones to α,β‐Unsaturated Thioamides: Stereodivergent Synthesis of Rocaglaol

AbstractRocaglaol, a representative flavagline, has attracted significant attention because of its unique chemical structure and biological activities. This paper reports a mild and scalable copper‐catalyzed enantioselective conjugate addition of benzofuran‐3(2H)‐ones to α,β‐unsaturated thioamides. This method allows for the concise synthesis of all possible stereoisomers of a key intermediate of rocaglaol and its derivatives in a highly diastereo‐ and enantioselective manner using different chiral phosphine ligands. Theoretical insights into the reaction mechanism and the origin of ligand‐dependent diastereodivergence were obtained using density functional theory calculations.

Direct Catalytic Asymmetric Conjugate Addition of Benzofuran-3(2H)-Ones to α,β-Unsaturated Thioamides: Stereodivergent Synthesis of Rocaglaol.

Rocaglaol, a representative flavagline, has attracted significant attention because of its unique chemical structure and biological activities. This paper reports a mild and scalable copper-catalyzed enantioselective conjugate addition of benzofuran-3(2H)-ones to α,β-unsaturated thioamides. This method allows for the concise synthesis of all possible stereoisomers of a key intermediate of rocaglaol and its derivatives in a highly diastereo- and enantioselective manner using different chiral phosphine ligands. Theoretical insights into the reaction mechanism and the origin of ligand-dependent diastereodivergence were obtained using density functional theory calculations.

Cascade Reactions of Alkynyl Ketones and Amides to Generate Unsaturated Oxacycles and Aromatic Carbocycles.

We describe novel amine-mediated transformation of alkynyl ketones and amides to generate 2-methylene-2H-pyrans, substituted 3-hydroxy-9H-fluoren-9-ones, and amine-incorporated arenes. These cascade processes are initiated by conjugate addition of secondary amine followed by hydrolysis of the enamine/vinylogous amide intermediates. The product distribution is highly sensitive to the steric and electronic effects of the substituents on both the alkyne moieties, the tether structure connecting them, and the nature of the amine. Alkynyl amide participates in the Alder-ene reaction favorably to generate more reactive allene amide that reacts with amine to generate amine-incorporated arene products. These metal-free cascade reactions are a useful synthetic method that can be exploited for the construction of various hetero- and carbocyclic systems.

Tetrasubstituted Chromanone Synthesis by a Tandem Oxa‐Michael/Michael Addition Reaction of 2‐Hydroxyacetophenones and Alkynyl Nitriles

AbstractAn efficient transition metal‐free approach for the synthesis of chroman‐4‐ones via double conjugate addition of 2‐hydroxyacetophenones on alkynyl nitriles utilizing NaH as a base has been realized. This operationally simple protocol offers library of 4‐chromanones in moderate to good yields.

Dipeptidic Proline Amide–Isothiouronium Salt Organocatalysts for Enantiodivergent Conjugate Addition Reactions Between Aldehydes and Nitroolefins

AbstractWe rationally designed and successfully developed novel dipeptidic proline amide–isothiouronium catalysts for asymmetric conjugate addition reactions between various aldehydes and nitroolefins, which generated 1,4‐addition products with up to 95% yields, 92:8 syn‐diastereoselectivity, and 96% enantiomeric excess. The catalysts, which were prepared via simple methylation of the corresponding thiourea, can provide the desired enantiomeric syn‐1,4‐adducts by exchanging the configuration of the N‐terminal proline moiety.

Asymmetric ε-regioselective conjugate addition of 2-furfuryl ketones to nitroalkenes using a thiourea organocatalyst

The asymmetric ε-regioselective conjugate addition of 2-furfuryl ketones to nitroalkenes using a pyrrolidine–thiourea organocatalyst yielded ε-regioselective addition products in high yields with high enantioselectivities. This work represents the first example of asymmetric ε-regioselective conjugate addition of 2-furfuryl ketones to nitroalkenes.

Two-Step Synthesis of Enantiomerically Pure Morphans from (R)-Carvone.

Enantiomerically pure 4-hydroxymorphan-7-ones were prepared in two steps from the natural product (R)-carvone. At first, the isopropenyl moiety of (R)-carvone was converted into the epoxide 7. A Domino reaction consisting of epoxide opening with primary amines followed by intramolecular conjugate addition of the resulting secondary amines at the α,β-unsaturated ketone established the morphan scaffold. This novel morphan synthesis allowed the modification of the bicyclic system at three positions resulting in 26 diverse morphans. Various primary amines led to morphans 8-13 with different N-substituents. Acylation or water elimination followed by hydrogenation led to esters 15 and 16 or the morphan 18 without a hydroxy moiety. The benzylidenemorphans 25a and 26a were prepared by condensation of the ketones 11a and 12a with benzaldehyde. Finally, the α-methylene ketone of 11a and 12a was exploited to obtain indolomorphans, quinolinomorphans, pyrimidinomorphans and pyrazolomorphans. Affinity of the novel morphans at opioid receptors MOR, DOR and KOR could not be detected. However, the indolomorphan 19 and the quinolinomorphan 22 showed nanomolar σ1 receptor affinity (Ki=58 nM and 20 nM).

Comparative Study of Catalysis Strategies: Friedel-Crafts Alkylation Vs. Michael's Addition of Indoles to Nitroalkenes

Indoles are critical in natural amalgamation for their flexible jobs in drugs, regular items, and material science, exhibiting huge pharmacological and compound reactivity. Due to their versatility and high reactivity, nitroalkenes are essential electrophilic partners in organic synthesis. While indoles and nitroalkenes are used in both Michael addition and Friedel-Crafts alkylation for producing carbon-carbon bonds, the catalyst types and reactions involved are different. Michael addition employs conjugate addition, whereas Friedel-Crafts alkylation employs electrophilic aromatic substitution. Each technique has a different level of selectivity and distinct synthetic applications. This review examines the advancements and persistent challenges in catalysis, focusing on the comparative methodologies of Friedel-Crafts alkylation and Michael addition involving indoles and nitroalkenes. Emphasizing green chemistry principles, it discusses the potential for sustainable and efficient synthetic processes through the use of innovative catalysts, including photocatalysis and biocatalysis. The integration of computational studies and interdisciplinary collaboration is essential for developing economically viable and environmentally responsible chemical synthesis, ultimately contributing to the creation of advanced materials and pharmaceuticals.

Electron donor-acceptor complex enabled photocascade strategy for the synthesis of trans-dihydrofuro[3,2-c]chromen-4-one scaffolds via radical conjugate addition of pyridinium ylide.

A visible-light-induced photocascade strategy is disclosed for the synthesis of trans-dihydrofuro[3,2-c]chromen-4-one scaffolds. The photocascade consists of electron donor-acceptor (EDA) complex enabled formation of arylidene coumarinone, followed by 1,4-radical conjugate addition (1,4-RCA) of an in situ generated pyridinium ylide radical (PyYR) towards diastereoselective formation of the trans-dihydrofuro[3,2-c]chromen-4-one scaffold in good to excellent yield. Thorough mechanistic investigations comprising photophysical, spectroscopic, electrochemical and DFT studies provide further insights into the reaction mechanism.

Recent Advances in Organocatalytic Enantioselective Reactions of α‐Functionalized Propargylic Alcohols

AbstractOwing to their unique properties, propargylic alcohols have been recognized as one of the most attractive synthons in the field of organic synthesis. Particularly, with the aid of auxiliary group, the α‐functionalized propargylic alcohols have been frequently involved in the organocatalytic enantioselective substitutions, conjugate additions, annulations and related reactions in recent years. Accordingly, the present review highlights recent advancements in the application of α‐functionalized propargylic alcohols in the field of asymmetric organocatalysis, which is organized according to the type of auxiliary group.

Comparative Study on Catalysis Strategies: Friedel-Crafts Alkylation vs. Michael Addition of Indoles to Nitroalkenes

Indoles are critical in natural amalgamation for their flexible jobs in drugs, regular items, and material science, exhibiting huge pharmacological and compound reactivity. Due to their versatility and high reactivity, nitroalkenes are essential electrophilic partners in organic synthesis. While indoles and nitroalkenes are used in both Michael addition and Friedel-Crafts alkylation for producing carbon-carbon bonds, the catalyst types and reactions involved are different. Michael addition employs conjugate addition, whereas Friedel-Crafts alkylation employs electrophilic aromatic substitution. Each technique has a different level of selectivity and distinct synthetic applications. This review aims to examine the advancements and persistent challenges in catalysis, focusing on the comparative methodologies of Friedel-Crafts alkylation and Michael addition involving indoles and nitroalkenes. Emphasizing green chemistry principles, it discusses the potential for sustainable and efficient synthetic processes through the use of innovative catalysts, including photocatalysis and biocatalysis. The integration of computational studies and interdisciplinary collaboration is essential for developing economically viable and environmentally responsible chemical synthesis, ultimately contributing to the creation of advanced materials and pharmaceuticals.

Catalytic Asymmetric Conjugate Addition and Allylic Substitution of Cyclobutenones with Arylzinc Halides

Comprehensive SummaryConjugate addition and allylic substitution are two essential chemical transformations, and they could be competitive for substrates with multiple reactive sites. Herein, we report the diversified enantioselective synthesis of cyclobutenes via the functionalization of cyclobutenones. The conjugate addition of cyclobutenones with arylzinc halides provided enantioenriched cyclobutenes with all‐carbon quaternary centers. On the other hand, when cyclobutenones with gem‐dichloro groups were employed, a chemo‐ and enantioselective allylic substitution occurred. Further synthetic utility was demonstrated for synthesizing versatile cyclobutane derivatives, together with ring‐opening and expansion products.

An Optically Active 4‐Aryl‐3,4‐dihydroisocoumarin‐3‐carboxylate

AbstractA four step sequence for the preparation of optically active (R,R)‐ethyl 4‐phenyl‐3,4‐dihydroisocoumarin‐3‐carboxylate is reported. In the first step the first stereocenter was installed by palladium catalyzed asymmetric conjugate addition of PhB(OH)2 to indenone (88 % ee). After deprotonation, the ester moiety was introduced with Mander's reagent. The α‐hydroxylation of the resulting β‐oxoester was then achieved with cerium‐catalysis under an air atmosphere. Key transformation was the cyanide‐catalyzed ring transformation of α‐hydroxy‐β‐oxoester furnishing the δ‐lactone moiety of the target compound, which was formed as a mixture of separable cis‐ and trans‐diastereoisomers, both with 88 % ee. The cis‐isomer could be epimerized to the trans‐compound. The relative trans and the absolute (R,R)‐configuration of the target compound was established by X‐ray single crystal structure analysis.

Catalytic prenyl conjugate additions for synthesis of enantiomerically enriched PPAPs.

Polycyclic polyprenylated acylphloroglucinols (PPAPs) are a class of >400 natural products with a broad spectrum of bioactivity, ranging from antidepressant and antimicrobial to anti-obesity and anticancer activity. Here, we present a scalable, regio-, site-, and enantioselective catalytic method for synthesis of cyclic β-prenyl ketones, compounds that can be used for efficient syntheses of many PPAPs in high enantiomeric purity. The transformation is prenyl conjugate addition to cyclic β-ketoesters promoted by a readily accessible chiral copper catalyst and involving an easy-to-prepare and isolable organoborate reagent. Reactions reach completion in just a few minutes at room temperature. The importance of this advance is highlighted by the enantioselective preparation of intermediates previously used to generate racemic PPAPs. We also present the enantioselective synthesis of nemorosonol (14 steps, 20% yield) and its one-step conversion to another PPAP, garcibracteatone (52% yield).