Conjugate Addition Research Articles

Synthesis of Chiral β‐Trifluoromethyl‐β‐Amino Acid Derivatives in Aqueous Medium

A practical synthesis of chiral β‐trifluoromethyl‐β‐amino acids is reported by using water as a reaction medium to facilitate the diastereoselective aza‐Michael addition of aromatic amines to chiral β‐trifluoromethyl‐α,β‐unsaturated oxazolidinone. A variety of aromatic amines could serve as a suitable nucleophile that readily undergo nucleophilic conjugate addition at ambient temperature to provide the corresponding β‐trifluoromethyl‐β‐amino acid derivatives in excellent combined yields (up to 97%) with moderate to good diastereoselectivities (up to 3:1). Being complementary to the precedent methods, this work offers the advantages, e.g., a green and environmentally friendly reaction medium, a stable and readily synthesized chiral starting material, and a simple and practical operation providing enantioenriched β‐trifluoromethyl‐β‐amino acids which are found major applications in advanced organic synthesis and medicinal research field.

Synthetic Studies on Poecillastrin C: Synthesis of the C14-C35 Segment of the Macrolide Ring Model.

A synthesis of the C14-C35 segment of the macrolide ring model of poecillastrin C has been achieved. The C14-C23 segment was synthesized by the stereoselective Mukaiyama aldol reaction between ketene silyl N,O-acetal possessing chiral oxazolidinone auxiliary and O-acetyl lactol prepared by the stereoselective conjugate addition followed by iodolactonization. The C24-C35 segment was constructed by three stereoselective vinylogous Mukaiyama aldol reactions. Both segments were coupled by the aldol reaction followed by diisobutylaluminium hydride (DIBALH) reduction to produce the C14-C35 moiety of the macrocyclic model.

Highly Selective α-Addition and β-Conjugate Addition Products from Peptides Composed of α,β-Unsaturated γ-Amino Acids.

β-Addition products are common in conjugate addition reactions consisting of α,β-unsaturated carbonyl compounds. Here, we are reporting an uncommon α-addition product as a major product in the thioacetic acid conjugate addition reaction on a peptide consisting of (E)-α,β-unsaturated γ-amino acids. In addition, we observed highly diastereoselective β-addition products from the thiophenol and thioethanol conjugate addition reaction on peptides. In comparison, (E)-α,β-unsaturated γ-amino amides give both α- and β-addition products with thioacetic acid and only β-addition products in the thiophenol conjugate addition reaction. Further, the conformations of both α-addition and β-addition products were studied in single crystals as well as in solution. The peptide product with α-thioacetate addition (α,γ-disubstituted γ-amino acid) adopted a regular 12-helix conformation, whereas β-addition (β,γ-disubstituted γ-amino acid) products slightly distorted 12-helix conformation. A kink is observed at the site of β-addition in the 12-helix structures of all β-addition products. Overall, the uncommon and stereospecific conjugate addition reactions reported here can be explored to introduce diverse functional groups to the peptide backbone.

Visible Light-Mediated Decarboxylative Giese Addition Utilizing Thioxanthone or Thioxanthone-TfOH Complex as the Photocatalyst.

Synthetic photochemistry is an alternative, green and sustainable approach in organic synthesis, offering the possibility for the discovery of novel reactivities. Carboxylic acids are abundant and widely used as suitable radical precursors for light-mediated processes, providing access to products that are not accessible via conventional methods. Herein, we report a green, cheap, metal-free, photochemical decarboxylative protocol for the 1,4-radical conjugate addition (Giese reaction) using thioxanthone, a commercially available organic molecule, or a thioxanthone-triflic acid (TfOH) complex, as the photocatalyst, under LED 427 nm irradiation. A wide range of carboxylic acids, amino acids and Michael acceptors has been tested, affording the desired products in good to high yields.

Rhodium‐Catalyzed Enantioselective 1,4‐Addition of Arylboronic Acids to 2,3‐Dihydro‐4‐pyridones Using 4,8‐Substituted Bicyclo[3.3.1]nona‐2,6‐dienes as Ligands

AbstractC2‐symmetric 4,8‐substituted bicyclo[3.3.1]nona‐2,6‐dienes are efficient bidentate steering ligands for the rhodium‐catalyzed asymmetric conjugate addition of arylboronic acids to N‐Cbz‐2,3‐dihydro‐4‐pyridone. The arylation reactions proceed under mild conditions to provide corresponding 2‐aryl‐4‐piperidones in high yields along with excellent enantioselectivities (up to 99.8:0.2 er).

Total Syntheses of Bryostatins 1, 7, 9 and 9-N3.

Bryostatins are a family of marine natural products that have garnered significant interests, as evidenced by over 40 clinical trials. However, their extremely low natural abundance has severely limited further research. Despite significant efforts, which have led to the total synthesis of seven bryostatin members by eight independent research groups, these complex molecules present persistent challenges for stereocontrolled, large-scale, and especially divergent synthesis. Here, we report the divergent total syntheses of bryostatins 1, 7, 9 and 9-N3. Notably, 1.5 g of bryostatin 1 was obtained in a single sequence of the final three steps. Key transformations include Ni-catalyzed reductive cross-coupling to rapidly assemble the northern fragment, the flow chemistry-assisted visible light-induced alkyl radical conjugate addition to convergently construct the southern fragment, and an intramolecular geminal bis(silyl) Prins cyclization to establish the cis-Z selectivity on the B-ring. The syntheses consist of 20-22 steps in the longest linear sequence and 33-35 total steps, with overall yields ranging from 3.3 % to 4.5 %.

Manganese(I)-Catalyzed Enantioselective Alkylation To Access P-Stereogenic Phosphines.

This work introduces a novel Mn(I)-catalyzed enantioselective alkylation methodology that efficiently produces a wide array of P-chiral phosphines with outstanding yields and enantioselectivities. Notably, the exceptional reactivity of Mn(I) complexes in these reactions is demonstrated by their effective catalysis with both typically reactive alkyl iodides and bromides, as well as with less reactive alkyl chlorides. This approach broadens the accessibility to various P-chiral phosphines and simplifies the synthesis of chiral tridentate pincer phosphines to a concise 1-2 step process, contrary to conventional, labor-intensive multistep procedures. Importantly, the development significantly expands the applicability of earth-abundant Mn(I)-based complexes beyond their recently established roles in catalytic hydrogenative and conjugate addition reactions, emphasizing the catalytic potential of Mn(I) complexes as a viable alternative to noble metal chemistry and, in some cases, even surpassing their performance.

Diastereodivergent Construction of Octahydrophenanthridinone and Octahydrophenanthridine Cores.

Diastereodivergent synthesis of octahydrophenanthridinone and octahydrophenanthridine skeletons, structural motifs often found in biologically active natural products, is described. We previously reported a total synthesis of a pancratistatin analog using novel octahydrophenanthridinone construction. In this study, we examined the generality of our method and its extension to octahydrophenanthridine formation. Conjugate addition of diarylcuprates to nitrosocyclohexenes, which were generated in situ from 2-chlorocyclohexanone oximes, provided 2-arylcyclohexanone oximes. Subsequent reduction of the oxime moiety gave cis- and trans-configured amines. Both amines were separately converted into the corresponding octahydrophenanthridinones and octahydrophenanthridines via hexahydrophenanthridine intermediates.

Dual Activation Modes Enable Bifunctional Catalysis of Aldol Reactions by Flexible Dihydrazides.

Hydrazides are known to catalyze reactions of α,β-unsaturated aldehydes via transient iminium formation. The iminium intermediate displays enhanced electrophilicity, which facilitates conjugate additions and cycloadditions. We observed that a hydrazide embedded in a seven-membered ring catalyzes homoaldol condensation of a simple aldehyde in a process that displays an approximate second-order dependence on the hydrazide. This finding suggests a dual activation mechanism involving both iminium and enamine intermediates. The unexpected nucleophilic activation mode led us to examine a series of simple dihydrazides for bifunctional catalysis of the aldol condensation. The two cyclic hydrazide units were connected via linear polymethylene linkers, which are inherently flexible. Substantial increases in initial reaction rate, relative to a monohydrazide, were observed for polymethylene linkers of sufficient length, with a maximum at 10 methylenes. Reactions promoted by this dihydrazide displayed an approximate first-order dependence on catalyst concentration, which suggested a bifunctional catalytic mechanism. Even for a dihydrazide with an 18-methylene linker, a substantial increase in relative initial rate was observed. These observations show that significant coordination can be achieved between two catalytically active moieties even when these moieties are connected via many flexible bonds.

Preparation of mesoporous Cu₂O nanospheres for green synthesis in the enantioselective boron conjugate addition of α,β‐unsaturated chiral compounds in aqueous phase

Chiral organoboron compounds are essential intermediates in various significant reactions. However, there are still few efficient catalysts for their synthesis. This paper reports a novel catalytic material for chiral asymmetric boron conjugate addition reactions: mesoporous Cu₂O nanospheres (M‐Cu₂O). M‐Cu₂O is approximately 0.55 μm, exhibiting dense and uniformly distributed worm‐like pores. It features a specific surface area of 15.7 m²/g and an average pore size of 14.3 nm. Under the conditions of Toluene:H2O = 9:1, with a chiral ligand amount of 3.6 mol% and no additional base, it achieves a high yield (98% yield) and impressive enantioselectivity (98% ee ) for the template substrate chalcone using only 3.0 mol% of the catalyst. Notably, the catalyst can be easily recovered and maintains robust catalytic performance after seven cycles, yielding 92% and an ee value of 90%. This work presents a mild and effective method for synthesizing chiral boron compounds in an aqueous phase, significantly enhancing the application potential of mesoporous copper oxide nanospheres.

Diastereodivergence in catalytic asymmetric conjugate addition of carbon nucleophiles.

Catalytic asymmetric conjugate additions of carbon nucleophiles have emerged as a potent tool for constructing multi-stereogenic molecules with precise stereochemical control. This review explores the concept of diastereodivergence in such reactions, focusing on strategies to achieve selective access to diverse diastereomeric products upon carbon-carbon bond formation. Drawing from a rich array of examples, we delve into key approaches for controlling the stereochemical outcome of these transformations, including alteration of alkene geometry, fine-tuning of reaction parameters, synergistic catalysis, and isomerization of conjugate adducts. Additionally, we highlight the iterative strategies for conjugate additions, showcasing their potential for diastereodivergent synthesis of methyl-branched stereocenters in 1,3-relationships. By presenting a concentrated overview of this significant topic, this review aims to provide valuable insights into the design and execution of stereodivergent catalytic conjugate additions, offering new avenues for advancing stereoselective synthesis and structural diversity in organic synthesis.

Asymmetric desymmetrization of 2,5-cyclohexadienones initiated by organocatalytic conjugate addition to 4-nitro-5-styrylisoxazoles.

A highly regio-, enantio- and diastereo-selective strategy involving initial enantioselective conjugate addition to 4-nitro-5-styrylisoxazoles serves as a key step for the desymmetrization of 2,5-cyclohexadienones has been disclosed. We have designed a new class of 2,5-cyclohexadienones appended with 4-nitro-5-styrylisoxazoles to undergo organocatalytic asymmetric double or triple conjugate addition in a domino sequence depending on the substrate type leading to desymmetrization of the 2,5-cyclohexadienone core. The developed protocol allows the construction of a valuable hydrophenanthrene core or a unique bridged scaffold bearing multiple chiral centers with excellent enantio- (up to >99.5 : 0.5 er) and diastereo-control for diverse substrates.

Enantioselective nickel-catalyzed electrochemical reductive conjugate alkenylation of α,β-unsaturated ketones.

Catalytic electrochemical asymmetric catalysis is emerging as a promising strategy for the synthesis of chiral compounds. Herein, we report an asymmetric electrochemical nickel-catalysed reductive conjugate addition of alkenyl bromides/aryl iodides to α,β-unsaturated ketones in an undivided cell, leading to addition products with high yields and excellent enantioselectivities (up to 96% yield and 96% ee).

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

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

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

AbstractCyclobutenones 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.

REAKCJA RAUHUTA-CURRIER – OD KLASYCZNYCH METOD DO NOWOCZESNYCH ROZWIĄZAŃ

The formation of carbon-carbon bonds is a fundamental aspect of organic synthesis, serving as a key step in the construction of complex molecules with biological and pharmaceutical significance. In recent years, chemists have focused on developing new methods that not only expand the scope of available reactions but also enable control over stereoselectivity, which is particularly important in the context of asymmetric synthesis. One reaction that has gained increasing attention in this field is the Rauhut-Currier (RC) reaction. The RC reaction, based on conjugate addition, allows the creation of new carbon- carbon bonds through the reaction between α,β-unsaturated compounds containing carbonyl groups. Although its mechanism was described several decades ago, modern research is centered on discovering new catalysts, both organic and metallic, that enable the reaction to proceed more efficiently and selectively. The development of organocatalysis plays a crucial role here, as it allows the reaction to be conducted under milder conditions, while simultaneously increasing the yield and enantioselectivity. This review presents the latest advancements in the field of the Rauhut-Currier reaction, with a particular focus on the development of enantioselective variants of the reaction and the research into new catalysts. Furthermore, its application in the synthesis of natural products and pharmaceutically important compounds is discussed, highlighting the growing role of this reaction in modern organic synthesis

Synthesis of Functionalized Benzo[f]chromanes and Hydroxyalkyl Naphthols: Catalytic Coupling of Naphthols and Allylic Alcohols

AbstractCatalytic dearomatization of arenols is an uphill task that can serve as a powerful method to construct C−C bonds with unsaturated coupling partners. Herein, a simple and efficient strategy for coupling naphthols with allylic alcohols is reported. A single Ru(II) pincer catalyzed coupling of naphthols with primary allylic alcohols led to the formation of benzo(f)chromanes, whereas the use of secondary alcohols delivered the hydroxyalkyl naphthols. Broad substrate scope and good functional group tolerance are demonstrated. Notably, a high diastereoselectivity is attained on chromanes. Hydroxyalkyl naphthols are synthetically transformed into spiroethers, and dearomative bromination is achieved on chromanes. Mechanistic studies revealed the involvement of tandem reactions, a formal O−H bond activation of allylic alcohols by an active catalyst via amine‐amide metal‐ligand cooperation provided α‐β, unsaturated carbonyl intermediates, which further underwent 1,4 conjugate addition with dearomatized naphthols. One of the crucial intermediates, naphthyl radical, is elucidated by EPR studies and trapped using a radical scavenger. Liberated hydrogen and water molecules are the only byproducts in these transformations.

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.