Sequential Michael Addition Research Articles

Total Synthesis of (-)-Cordycicadin D and 3,4-trans-Cordycicadins A and B: Entry to the 3,4-trans-Fused Cordycicadin Framework.

Lost in post-translation. Cordycicadins A-D are four C20polyketides, all containing ag-lactonefused to a 10-membered lactone. The proposed biosynthetic pathway for the cordycicadins anticipates the formation of two more natural products which are unknown. We report the total synthesis of (-)-cordycicadin D and the two anticipated natural products 3,4-trans-cordycicadins A and B. The targets were convergently assembled, in a biomimetic fashion,viaan efficient ketene trapping-intramolecular Michael addition sequence that delivered the requisite 3,4-trans-fused framework with high diastereoselectivity, enabled by the synthesis of complex dioxenones that serve asin situketene precursors. Recognition of the embedded polyketide symmetry enabled the use of a divergent-convergent syntheticstrategy, based on the use of two products from an early-stage enzymatic resolution. The synthetic routes afforded (-)-cordycicadin D in 14 steps and 3,4-trans-cordycicadins A and B in 13 steps (longest linear sequence). This work confirms the structure of (-)-cordycicadin D and the observed instability of the anticipated natural product 3,4-trans-cordycicadin B during purification may explain why it is yet to be isolated.

Three-Component Reaction of Cyclopropanols, DABSO, and N-(Sulfonyl)acrylamides: Preparation of Sulfone-Bridged 1,7-Dicarbonyl Compounds.

A cascade reaction of cyclopropyl alcohols, DABSO (1,4-diazoniabicyclo[2.2.2]octane-1,4-disulfinate), and N-(sulfonyl)acrylamides has been developed. This tandem process went through a cyclopropanol ring opening and Michael addition sequence. The γ-keto sulfinate generated from the reaction between cyclopropanol and DABSO serves as the nucleophilic reagent, and N-(sulfonyl)acrylamide is used as the Michael addition acceptor. By utilizing this strategy, multitudinous sulfone-bridged 1,7-dicarbonyl compounds that contain both a β-sulfonyl amide unit and γ-keto sulfone skeleton were conveniently synthesized.

Synthesis of 2,3-Dialkyl-5-hydroxybenzofurans via a One-pot, Three-step Reaction Sequence of 2-Monosubstituted 1,3-Diketones and 1,4-Benzoquinones.

An economical one-pot, three-step reaction sequence of readily available 2-monosubstituted 1,3-diketones and 1,4-benzoquinones has been explored for the facile access of 2,3-dialkyl-5-hydroxybenzofurans. By using cheap K2CO3 and conc. HCl as the reaction promoters, the reaction occurs smoothly via sequential Michael addition, aromatization, retro-Claisen, deacylation, hemiketalization, and dehydration processes under mild conditions in a practical manner. Additionally, an interesting phenomenon was observed during the derivatization studies, where the dihydroquinoline was converted into tetrahydroquinoline and quinoline products, respectively, via a disproportionation process.

Total Synthesis of Pallamolides A-E.

We have achieved the first total synthesis of pallamolides A-E. Of these compounds, pallamolides B-E possess intriguing tetracyclic skeletons with novel intramolecular transesterifications. Key transformations include highly diastereoselective sequential Michael addition reactions to construct the bicyclo[2.2.2]octane core with the simultaneous generation of two quaternary carbon centers, a one-pot SmI2-mediated intramolecular ketyl-enoate cyclization/ketone reduction to generate the key oxabicyclo[3.3.1]nonane moiety, and an acid-mediated deprotection/oxa-Michael addition/β-hydroxy elimination cascade sequence to assemble the tetracyclic pallamolide skeleton. Kinetic resolution of ketone 14 through Corey-Bakshi-Shibata reduction enabled the asymmetric synthesis of pallamolides A-E.

Total Synthesis of (+)- and (-)-Calycanthine by Means of Thio-Urea-Catalyzed Sequential Michael Reactions of Bis-oxindoles.

A unified catalytic asymmetric approach to naturally occurring piperidinoindoline and pyrrololidinoindoline alkaloids has been realized via the development of a thio-urea-catalyzed sequential Michael addition of bis-oxindole onto nitroethylene (up to 93% ee and >20:1 dr). This strategy offers the total syntheses of either enantiomers of naturally occurring calycanthine.

Total Synthesis of Pallamolides A‐E

We have achieved the first total synthesis of pallamolides A‐E, of which pallamolides B‐E possess intriguing tetracyclic skeletons with novel intramolecular transesterifications. Key transformations include highly diastereoselective sequential Michael additions to construct the bicyclo[2.2.2]octane core with simultaneous generation of two quaternary carbon centers, a one‐pot SmI2‐mediated intramolecular ketyl‐enoate cyclization/ketone reduction to generate the key oxabicyclo[3.3.1]nonane moiety, and an acid‐mediated deprotection/oxa‐Michael addition/β‐hydroxy elimination cascade sequence to assemble pallamolides tetracyclic skeletons. Kinetic resolution of ketone 14 via Corey‐Bakshi‐Shibata reduction enabled the asymmetric synthesis of pallamolides A‐E.

Acid‐Mediated One‐Pot Three‐Component Tandem Cyclization: Access to Some New Series of Benzo[5,6]chromeno[2,3‐d]pyrimidine Derivatives

AbstractAn efficient one‐pot synthesis of some new series of benzo[5,6]chromeno[2,3‐d]pyrimidine derivatives is reported by the three‐component condensation reaction of 2,3‐dihydroxynaphthalene, 2‐thiobarbituric acid and aromatic aldehydes using sulfuric acid as the catalyst in glacial acetic acid under reflux condition. This transformation apparently proceeds through Michael addition, intra‐molecular heterocyclization and dehydration sequences. This protocol provides cleaner reaction profiles, good to high yields, operational simplicity, easy workup, readily accessible starting materials and not requires column chromatography for isolation of target products in pure form.

Stable Immobilization of DNA to Silica Surfaces by Sequential Michael Addition Reactions Developed with Insights from Confocal Raman Microscopy.

The immobilization of DNA to surfaces is required for numerous biosensing applications related to the capture of target DNA sequences, proteins, or small-molecule analytes from solution. For these applications to be successful, the chemistry of DNA immobilization should be efficient, reproducible, and stable and should allow the immobilized DNA to adopt a secondary structure required for association with its respective target molecule. To develop and characterize surface immobilization chemistry to meet this challenge, it is invaluable to have a quantitative, surface-sensitive method that can report the interfacial chemistry at each step, while also being capable of determining the structure, stability, and activity of the tethered DNA product. In this work, we develop a method to immobilize DNA to silica, glass, or other oxide surfaces by carrying out the reactions in porous silica particles. Due to the high specific surface area of porous silica, the local concentrations of surface-immobilized molecules within the particle are sufficiently high that interfacial chemistry can be monitored at each step of the process with confocal Raman microscopy, providing a unique capability to assess the molecular composition, structure, yield, and surface coverage of these reactions. We employ this methodology to investigate the steps for immobilizing thiolated-DNA to thiol-modified silica surfaces through sequential Michael addition reactions with the cross-linker 1,4-phenylene-bismaleimide. A key advantage of employing a phenyl-bismaleimide over a comparable alkyl coupling reagent is the efficient conversion of the initial phenyl-thiosuccinimide to a more stable succinamic acid thioether linkage. This transformation was confirmed by in situ Raman spectroscopy measurements, and the resulting succinamic acid thioether product exhibited greater than 95% retention of surface-immobilized DNA after 12 days at room temperature in aqueous buffer. Confocal Raman microscopy was also used to assess the conformational freedom of surface-immobilized DNA by comparing the structure of a 23-mer DNA hairpin sequence under duplex-forming and unfolding conditions. We find that the immobilized DNA hairpin can undergo reversible intramolecular duplex formation based on the changes in frequencies and intensities of the phosphate backbone and base-specific vibrational modes that are informative of the hybridization state of DNA.

Total synthesis of (−)-ribesin B and its structural revision

A highly symmetric dihydrofuran lignan, ribesin B (1), isolated from the leaves of Ribes nigrum, was synthesized via a process whereby the key step was a sequential Michael addition–carbocyclization. However, the NMR spectral features of the synthesized 1 were inconsistent with those of the natural product 1. Thus, the chemical synthesis of the isovanillin-moiety containing compound 2 from chiral propargyl alcohol was conducted through a process that included lipase-catalyzed kinetic resolution. The NMR spectrum of 2 was perfectly superimposable to that of naturally isolated ribesin B. Consequently, the structure of ribesin B was revised to be that of 2.

Sequential Base‐Promoted Formal [4+2] Allenoate Based Cycloaddition: Synthesis of Functionalized Acridines

AbstractBase‐promoted formal [4+2] cycloaddition reaction of (Z)‐2‐(2‐hydroxy‐2‐alkylvinyl)quinoline‐3‐carbaldehydes and allenoates represents an efficient method for the synthesis of functionalized acridines through a sequential Michael addition, aldol condensation, and isomerization process in a mild condition. This new approach tolerates a wide range of (Z)‐2‐(2‐hydroxy‐2‐alkylvinyl)quinoline‐3‐carbaldehydes and allenoates and affords the functionalized acridines in good to excellent yields. The exclusive selectivity, high atom economy, and high bond‐formation efficiency of this method makes it a valuable approach for the synthesis of acridine backbones.

Synthesis of Bis(β‐Oximinoalkyl)malonates and Their Catalytic Reductive Cyclization to Piperidines

AbstractHitherto unknown bis(β‐oximinoalkyl)malonates were demonstrated to be convenient platforms for the synthesis of saturated N‐heterocycles. Upon heterogeneous catalytic hydrogenation, these dioximes undergo reductive cyclization to give substituted piperidine‐4,4’‐dicarboxylates, which are valuable building blocks in medicinal chemistry. By using dioximes bearing an additional ester group in the side chain, tandem piperidine/pyrrolidinone ring closure leading to indolizidinone framework was showcased in this work. A modular synthesis of initial bis(β‐oximinoalkyl)malonates (both symmetrically and unsymmetrically substituted) was accomplished via a sequential Michael addition of two nitrosoalkene molecules to malonic ester. The mechanism of the reductive cyclization of dioximes to piperidines was investigated by isotope scrambling experiments and isolation of intermediates.magnified image

Unified, Asymmetric Total Synthesis of the Asnovolins and Related Spiromeroterpenoids: A Fragment Coupling Approach.

3,5-Dimethylorsellinic acid (DMOA)-derived spiromeroterpenoids are a unique natural product family with attractive structures, unconventional stereochemistry, and potent biological activities. Herein, we report the first asymmetric total syntheses of the asnovolins, DMOA-derived spiromeroterpenoids. The spirocyclic skeleton was efficiently assembled through a sterically hindered bis-neopentyl 1,2-addition coupling/oxidative Michael addition sequence. The unusual axial C12-methyl stereochemistry was established via metal hydrogen atom transfer (MHAT) reduction involving a chair-to-boat conformational change. The mechanism of the HAT process was studied through both deuterium labeling and computational studies. Attempted late-stage alkene isomerization of an exocyclic enone proved to be challenging and resulted in hetero-Diels-Alder dimerization, which ultimately led to development of an alternative desaturation/coupling sequence. Endgame core modifications including orthogonal desaturation, Sc(III)-promoted regioselective Baeyer-Villiger oxidation, and Meerwein-Ponndorf-Verley reduction enabled collective syntheses of five asnovolin-related natural products. This study demonstrates the utility of anionic fragment coupling to assemble a sterically congested molecular framework and provides a foundation for the synthesis of spiromeroterpenoid congeners with higher oxidation states for biological studies.

Au Cluster-Cored Dendrimers Fabricated by Direct Synthesis and Post-functionalization Routes.

The use of dendrimers and dendrons as stabilizing agents for metal nanoparticles and nanoclusters has captured interest in both the biomedicine and catalysis fields. Herein, we describe the synthesis of Au cluster-cored dendrimers by either direct synthesis or multi-step functionalization pathways. Direct synthesis of Au cluster-cored dendrimers was performed by the Brust-Schiffrin method using cystamine core poly(amidoamine) (PAMAM) dendrons as capping agents. Alternatively, a divergent approach to make nanoclusters with dendritic branching groups by functionalizing glycine-cystamine Au clusters was also carried out. This synthesis involved sequential Michael addition reactions of methyl acrylate followed by a subsequent amide coupling reaction with ethylenediamine on amine-terminated Au nanoclusters to form dendritic architectures around the Au core. The chemical structure of the ligands was confirmed by proton nuclear magnetic resonance after each functionalization reaction, and the cluster size was characterized by transmission electron microscopy. Au cluster-cored dendrimers with amine or ester terminal groups on the surface were produced. The resulting amine- and ester-terminated Au cluster-cored dendrimers synthesized by the divergent method are stable in solution and in the presence of excess reducing agent. In contrast, amine-terminated Au cluster-cored dendrimers synthesized by direct synthesis undergo aggregation in solution over time as a result of the high reactivity of the surface, while ester-terminated Au cluster-cored dendrimers formed by direct synthesis have much larger core sizes than seen using the divergent approach. Finally, the catalytic activities of these clusters for 4-nitrophenol reductions have been investigated. Cluster-cored dendrimers formed by direct synthesis had larger core sizes and higher catalytic activities than those formed by the divergent approach, which is likely due to the poor passivation of the Au surface for the directly synthesized clusters. Furthermore, Au cluster-cored dendrimers with less sterically bulky dendrons showed higher catalytic activities.

Cyclic poly(β-amino ester)s with enhanced gene transfection activity synthesized through intra-molecular cyclization.

Topological structure plays a critical role in gene delivery of cationic polymers. Cyclic poly(β-amino ester)s (CPAEs) are successfully synthesized via sequential Michael addition and free radical initiating ring-closure reaction. The CPAEs exhibit superior gene transfection efficiency and safety profile compared to their linear counterparts.

Synthesis and Molecular Docking Studies of N,N-Dimethyl Arylpyranopyrimidinedione Derivatives

AbstractThe synthesis of N,N-dimethyl arylpyranopyrimidinedione derivatives from aromatic aldehydes, N-methyl-1-(methylthio)-2-nitroethamine (NMSM) and 1,3-dimethyl barbituric acid, in the presence of piperidine as a catalyst, is reported. The reaction mechanism involves a Knoevenagel condensation, followed by Michael addition and intramolecular O-cyclization reaction sequence. The synthesized compounds were docked with human kinesin Eg5 protein to calculate binding energy, inhibition constant and H-bond interaction. All the compounds show good binding affinity towards the protein, with significant docking score.

Concise total syntheses of bis(cyclotryptamine) alkaloids via thio-urea catalyzed one-pot sequential Michael addition.

Naturally occurring bis(cyclotryptamine) alkaloids feature vicinal all-carbon quaternary stereocenters with an elongated labile C-3a-C-3a' Sigma bond with impressive biological activities. In this report, we have developed a thio-urea catalyzed one-pot sequential Michael addition of bis-oxindole onto selenone to access enantioenriched dimeric 2-oxindoles with vicinal quaternary stereogenic centers at the pseudobenzylic position (up to 96% ee and >20 : 1 dr). This strategy has been successfully applied for the total syntheses of either enantiomers of chimonanthine, folicanthine, and calycanthine.

Synthesis of 4-Aryldihydrocoumarins via a Sequential Michael Addition- Lactonization Route

Background: Coumarin and its derivatives have attracted the attention of synthetic chemists due to their importance in pharmaceutical and medicinal chemistry. The acid-catalyzed cyclization route constitutes the method of choice to access these important compounds. Objective: In this paper, we have discussed the synthesis of 4-aryldihydrocoumarins via a one-pot p-sulfonic acid calix[4]arene catalyzed reaction. Methods: The easily prepared calix[4]arene derivative catalyzes a sequential reaction involving Michael addition followed by intramolecular lactonization to afford the title compound in effective yield. Results: The described methodology is devoid of any metal salt, thus making it a very appealing protocol to safely produce dihydrocoumarins of pharmacological importance. Conclusion: The easy recovery, non-toxicity, and reusability of the catalytic system are some of the other advantages of our procedure. In addition, the catalyst efficiency is not compromised after its successive use in reactions.

Convenient Construction of Spiro[pyrazole‐4,1′‐pyrido[2,1‐a]isoquinoline] and Spiro[pyrazole‐4,4′‐pyrido[1,2‐a]quinoline] via Three‐Component Reaction

AbstractThe three‐component reaction of isoquinoline, dialkyl but‐2‐ynedioate and 4‐arylidene‐5‐methyl‐2‐phenylpyrazol‐3‐ones in acetonitrile at room temperature gave functionalized spiro[pyrazole‐4,1′‐pyrido[2,1‐a]isoquinolines] in satisfactory yields with cis/cis‐diastereoisomer as major product. On the other hand, the similar three‐component reaction with quinoline afforded both cis/cis‐ and cis/trans‐isomeric spiro[pyrazole‐4,4′‐pyrido[1,2‐a]quinolines] in nearly comparable yields. The reaction was finished with in situ generation of Huisgen’ 1,4‐dipole, sequential Michael addition and annulation reaction process.

Asymmetric Sequential Michael Addition and Cyclization Reactions of 2-(2-Nitrovinyl)phenols Catalyzed by Bifunctional Amino-Squaramides

AbstractIn this work, we describe the Michael addition–cyclization reaction of 2-(2-nitrovinyl)phenol with two different reactive Michael donors, which lead to chiral benzopyran derivatives. Specifically, bifunctional amino-squaramides with one or two chiral units in the side chains were evaluated as catalysts in these transformations. Furthermore, the utility of selected green solvents as reaction media for these processes was also tested. The best result was achieved with methyl-cyclopentanone-2-carboxylate as the Michael donor in ethyl (–)-l-lactate with quinine-based amino-squaramide as catalyst (yield 72%, dr >99:1, ee 99%).

Au-Catalyzed Formal Allylation of Diazo(thio)oxindoles: Application to Tandem Asymmetric Synthesis of Quaternary Stereocenters.

We report an efficient Au(I)-catalyzed formal allylation of diazo(thio)oxindoles using allyltrimethylsilane to give 3-allyl (thio)oxindoles, which are difficult to access by using traditional alkylation methods under basic conditions. The approach enables a highly stereoselective synthesis of quaternary (thio)oxindoles via a formal allylation-asymmetric Michael addition sequence. These adducts are versatile synthons for spirocyclic (thio)oxindoles. Initial biological studies reveal that chiral thiooxindoles show promising antiproliferation activity that is better than that of the corresponding oxindoles.