Intramolecular Michael Addition Research Articles

Diastereoselective Synthesis of Highly Functionalized γ-Lactams via Ugi Reaction/Michael Addition.

The γ-lactam ring is a prominent feature in medicinal chemistry, and its synthesis has garnered significant interest due to its valuable properties. Among the γ-lactams, 2-oxopyrrolidine-3-carbonitrile derivatives stand out as versatile synthons that can be readily transformed into a variety of other functional groups. In this work, we successfully synthesized highly functionalized 3-cyano-2-pyrrolidinones with moderate to good overall yields using the Ugi reaction followed by intramolecular Michael addition. The process demonstrated excellent diastereoselectivity and showed good tolerance to a range of isonitriles and carbonyl compounds.

L-DOPA Autoxidation: An Empirical Valence Bond Simulation of the Reactive Step.

L-DOPA, or levodopa, plays an important role in the treatment of Parkinson's disease, a debilitating neurological disorder. It acts as a precursor to dopamine, a neurotransmitter crucial for the regulation of motor functions. Administered orally, L-DOPA easily crosses the blood-brain barrier and converts into dopamine in the brain, relieving symptoms such as tremors and rigidity. However, its prolonged use can lead to complications. A significant concern with L-DOPA is its conversion to dopaquinone, a quinone metabolite that enters the redox cycle and continuously produces hydrogen peroxide. In addition, L-DOPA, which resembles tyrosine with an additional hydroxyl group, can randomly incorporate into the proteins of dopaminergic neurons and thus become an additional source of oxidative stress in Parkinson's patients. In this study, we scrutinized the rate-limiting step of L-DOPA autoxidation in aqueous solution. The reaction we studied is an intramolecular Michael addition concerted with a proton transfer from the amino group. Using the Empirical Valence Bond (EVB) method, we computed the free energy profiles of the reaction in water. The calculated barrier of 30.93 ± 1.12 kcal/mol is in reasonable agreement with the experimental barrier of 27.55 kcal/mol. This agreement confirms the validity of the studied mechanism and demonstrates the applicability of our simulation methodology for studying the autoxidation kinetics of L-DOPA within proteins.

Practical Access to Fused Carbazoles via Oxidative Benzannulation and their Photophysical Properties.

An aryne annulation strategy for the synthesis of fused carbazoles is developed using indolyl β-ketonitrile in a cascade manner. The reaction sequence involves aryne-mediated [2 + 2] cycloaddition cleavage and intramolecular Michael addition, followed by oxidation under transition-metal-free reaction conditions. Subsequently, conversion of benzo[b]carbazole-6-carbonitrile to carbazole quinone is observed upon prolongation of the reaction time. Furthermore, these materials exhibit high quantum efficiency, which promotes the light-emitting diode applications.

Difluorocarbene Enables Access to 2,2-Difluorohydrobenzofurans and 2-Fluorobenzofurans from ortho-Vinylphenols.

2-Fluorobenzofurans are the backbone structures of many drug molecules and have many potential therapeutic bioactivities. Despite the potential applications in medicinal chemistry, practical and efficient synthetic methods for the construction of 2-fluorobenzofuran are very limited. Herein, we report an efficient and general method for the construction of 2-fluorobenzofurans. Contrary to the previous functionalizations of the existing backbone of benzofuran, our strategy directly constructs benzofuran scaffolds alongside the incorporation of fluorine atom on C2 position in a formal [4 + 1] cyclization from readily accessible ortho-vinylphenols and difluorocarbene. In our strategy, ClCF2H decomposes into difluorocarbene in the presence of base, which is further captured by the oxygen anion from the hydroxy group in ortho-hydroxychalcones; subsequent intramolecular Michael addition to the α, β-unsaturated system leads to 2,2-difluorohydrobenzofurans, and further fluorine elimination renders 2-fluorobenzofurans by forming one C-O bond and one C-C double bond. Of note, various complex 2,2-difluorohydrobenzofurans and 2-fluorobenzofurans could be readily accessed through our protocol via the late-stage elaborations.

Antifouling performance enhancement of PES membranes using hydrophilic nanoparticles of poly(dopamine-acrylate) for oil/water separation

Polydopamine-acrylate (P(A-D)x) nanoparticles were blended with polyethersulfone (PES) to fabricate a high-performance hybrid ultrafiltration (UF) membrane for the separation of water from oily wastewater. In tris-alkaline buffer solution at room temperature, P(A-D)x nanoparticles were synthesized by intramolecular Michael addition of dopamine with acrylic acid (AA) monomers. Hybrid PES membranes were prepared using P(A-D)x at 0.05–0.4 wt% and characterized using various assays including Field emission scanning electron microscopy (FESEM), Thermogravimetric analysis (TGA), atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FTIR), and water contact angle (WCA). The membranes showed a significant increase in hydrophilicity, water permeability, and oil rejection (R). The primary and secondary pure water fluxes of the membrane with 0.2 wt% P(A-D)0.25 were 45% and 110.78% higher than those of neat PES membrane, respectively. For 3300 ppm oil feed solution, water flux during water/oil separation increased by 107%, while the oil rejection (R) remained at 99.08%. The surface of membrane was markedly hydrophilic, with a WCA about 40°, much lower than that of the neat PES membrane (80.67°). UF hybrid membranes also showed a remarkable reduction in oil adhesion on the membrane surface as well as superior antifouling performance for membranes containing 0.2 wt% P(A-D)0.25, flux recovery ratio (FRR) = 84.88 ± 3.27%, reversible fouling (Rr) = 51.12 ± 1.09%, and irreversible fouling (Rir) = 15.12 ± 3.27%. In addition, the pure water flux was 446% higher than that of the unmodified membrane after five cycles (900 minutes).

Asymmetric total syntheses of sarglamides A, C, D, E, and F.

Sarglamides A-E were identified as a structurally new class of alkaloids with potential application for inflammation-associated diseases. Reported is the first asymmetric total synthesis of sarglamides A, C, D, E, and F within 7 steps, featuring an intermolecular Diels-Alder cycloaddition of (S)-phellandrene and 1,4-benzoquinone and intramolecular (aza-)Michael addition to construct the tetracyclic core of sarglamides. Importantly, our work demonstrated that the hypothetic Diels-Alder reaction of α-phellandrene with dienophile toussaintine C (or analogues) originally proposed as a biosynthetic pathway was not viable under non-enzymatic conditions. Additionally, we discovered novel and efficient double cyclization (cycloetherification and oxa-Michael cyclization) to construct the core framework of sarglamides E and D. Our concise synthetic strategy might allow rapid access to a library of sarglamide analogues for further evaluation of their bioactivity and mode of action.

Non-covalent interactions in the diastereoselective synthesis of cis-2,3-dihydrobenzofurans: experimental and computational studies.

The diastereoselective synthesis of 2,3-DHBs has been previously reported via an intramolecular Michael addition reaction using alkali bases such as Cs2CO3 and K2CO3. However, no systematic study has been performed to understand the possible role of bases in the mechanism of the reaction and factors behind the stereoselective outcome of the reaction. Herein, from experimental and theoretical points of view, we disclose the role of the cesium salt in the rate-determining step along the catalytic cycle and the key role of stabilizing non-covalent interactions in the stereoselective outcome of the reaction.

Visible light-induced cascade sulfonylation/annulation of ortho-allyloxy chalcones with sodium sulfinates for the synthesis of sulfonated chromane derivatives.

A visible-light-induced radical cascade reaction for the synthesis of structurally diverse sulfonated chromanes is described. The protocol involves the addition of sulfonyl radicals to ortho-allyloxy chalcones and intramolecular Michael addition reactions in the presence of eosin Y as a photocatalyst. Additionally, this protocol shows that it is also an effective method to construct seven-membered oxygen-containing heterocycles. The method features a wide substrate scope, the use of easily accessible materials and excellent functional group tolerance with high to excellent yields. Control experiments and mechanistic studies indicate that a visible light-induced radical cascade process is involved in the transformation.

DFT study on the mechanism of phosphine-catalyzed ring-opening reaction of cyclopropyl ketones.

In the present study, the mechanism, origin of chemoselectivity, and substituent effects of the phosphine-catalyzed ring-opening reaction of cyclopropyl ketone have been investigated using the DFT method. Multiple pathways, including the formation of hydrofluorenone, the Cloke-Wilson product, and cyclopenta-fused product, were studied and compared. The computational results show that the pathway for the formation of hydrofluorenone is the most favorable one, which involves four processes: nucleophilic substitution to open the three-membered ring, an intramolecular Michael addition for the formation of an enolate intermediate, an intramolecular [1,5]-proton transfer to give ylide, and an intramolecular Wittig reaction to deliver the final product. For disclosing the origin of chemoselectivity, structural analysis and local reactivity index analysis were performed. Moreover, substituent effects were also considered using QTAIM analysis. The current study would provide useful insights for understanding phosphine-catalyzed chemoselective reactions.

β-Ketoallylic methylsulfones synthesis via inert C(sp3)–H bond activation by magnetic Ag–Cu MOF

Herein, the one-pot tandem synthesis of β-ketoallylic methylsulfones has been achieved from readily available dimethyl sulfoxide and acetophenones as coupling partners in one step. In this procedure, dimethyl sulfoxide serves as a triple role including solvent, dual synthon and as an oxidant agent. The use of magnetic Ag–Cu MOF as a bimetallic catalyst is the key to the progress of the reaction due to its accessible active sites. It provides facile access to various β-ketoallylic methylsulfone derivatives from direct C(sp3)–H bond activation and functionalization of aromatic methyl ketones especially acetophenones with electron-rich and electron-poor groups. Moreover, the present work offers a synthetically powerful strategy to form products in good to excellent yields (74–96%) with the atom, step, and pot economics. It has also delivered a new chromane-4-one derivative from 2-hydroxy acetophenone with intramolecular Michael-addition of related β-ketoallyl methylsulfone product. In the final step, the electronic properties of some products have been predicted with the theoretical studies.

Structure‐Unit‐Based Total Synthesis of (−)‐Sinulochmodin C

AbstractHerein we report a structure‐unit‐based asymmetric total synthesis of sinulochmodin C, a norcembranoid diterpenoid bearing a transannular strained ether bridge β‐keto tetrahydrofuran moiety. Our synthetic route features an intramolecular double Michael addition to construct stereospecifically the [7,6,5,5] tetracyclic skeleton, a vinylogous hydroxylation/oxidation procedure or a stereospecific epoxide opening/oxidation sequence to establish the γ‐keto enone intermediate, a Lewis acid/Brønsted acid mediated transannular oxa‐Michael addition to fuse the β‐keto tetrahydrofuran moiety, a Mukaiyama hydration/Pd−C hydrogenation to reverse the C1‐configuration of the isopropenyl unit, and a bioinspired transformation of sinulochmodin C into scabrolide A.

Structure-Unit-Based Total Synthesis of (-)-Sinulochmodin C.

Herein we report a structure-unit-based asymmetric total synthesis of sinulochmodin C, a norcembranoid diterpenoid bearing a transannular strained ether bridge β-keto tetrahydrofuran moiety. Our synthetic route features an intramolecular double Michael addition to construct stereospecifically the [7,6,5,5] tetracyclic skeleton, a vinylogous hydroxylation/oxidation procedure or a stereospecific epoxide opening/oxidation sequence to establish the γ-keto enone intermediate, a Lewis acid/Brønsted acid mediated transannular oxa-Michael addition to fuse the β-keto tetrahydrofuran moiety, a Mukaiyama hydration/Pd-C hydrogenation to reverse the C1-configuration of the isopropenyl unit, and a bioinspired transformation of sinulochmodin C into scabrolide A.

Stereoselective Approach to Multisubstituted Enolates from Unactivated Alkynes: Oxyalkylidenation of Alkynyl Ketone Enolates with Aldehydes.

The preparation of multisubstituted enolates with precise regio- and stereocontrol is a nontrivial task when conventional deprotonation methods are used on the corresponding carbonyl compounds. We describe herein an approach to preparing stereodefined enolates by leveraging the stereoselective oxyfunctionalization of unactivated alkynes, particularly in the context of the alkynylogous aldol reaction. trans-Iodo(III)acetoxylation of alkynes and subsequent Sonogashira coupling allow for the facile preparation of multisubstituted enynyl acetates, which can be deacetylated by MeLi into the corresponding enolates. The alkynyl enolates react with aldehydes to afford γ,δ-unsaturated β-diketones through a cascade of alkynylogous aldol addition, intramolecular Michael addition, and ring opening of the oxetene intermediate.

Organocatalytic Enantioselective Intramolecular Michael Addition by In Situ Generated Aminoisobenzofulvenes: Construction of Spiro Quaternary Carbon Stereocenters.

An unprecedented enantioselective organocatalytic spirocyclization strategy is presented by in situ generation of aminoisobezofulvenes. The reaction sequence involves a reductive Michael/aldol-condensation/Michael addition cascade by iminium-enamine catalysis. The key success of this spirocyclization was the formation of intermediatory nucleophilic aminoisobenzofuvenes accountable for intramolecular Michael addition. Benzospirononanes featuring an all carbon qauternary spirocenter were obtained using proline-derived amino-organocatalyst in moderate to good yields and excellent diastereo- and enantioselectivities (up to >20 : 1 dr, and 99 % ee). Post-methodological manipulation of benzospirononanes was also demonstrated.

Investigation of the Effect of Solvents on the Synthesis of Aza-flavanone from Aminochalcone Facilitated by Halogen Bonding.

It has been recognized that CBr4 can give rise to a noncovalent interaction known as halogen bond (XB). CBr4 was found to catalyze, in terms of XB formation, the transformation of 2'-aminochalcone to aza-flavanone through an intramolecular Michael addition reaction. The impact of XB and the resulting yield of aza-flavanone exhibited a pronounced dependence on the characteristics of the solvent. Notably, yields of 88% in ethanol and 33% in DMSO were achieved, while merely a trace amount of the product was detected in benzene. In this work, we use a computational modeling study to understand this variance in yield. The reaction is modeled at the level of density functional theory (based on the M06-2X exchange-correlation functional) with all-electron basis sets of triple-ζ quality. Grimme's dispersion correction is incorporated to account for the noncovalent interactions accurately. Harmonic frequency calculations are carried out to establish the character of the optimized structures (minimum or saddle point). Our calculations confirm the formation of an XB between CBr4 and the reacting species and its role in lowering the activation energy barrier. Stronger orbital interactions and significant lowering of the steric repulsion were found to be important in lowering the activation barrier. The negligible yield in the nonpolar solvent benzene may be attributed to the high activation energy as well as the inadequate stabilization of the zwitterionic intermediate. In ethanol, a protic solvent, additional H-bonding contributes to further lowering of the activation barrier and better stabilization of the zwitterionic intermediate. The combined effects of solvent polarity, XB, and H-bond are likely to give rise to an excellent yield of aza-flavanone in ethanol.

Approach to Seven-Membered Carbocycles via a Lewis Acid Catalyzed Intramolecular Michael Addition of Allenone.

A straightforward strategy for constructing seven-membered carbocycles by employing a Lewis acid catalyzed intramolecular Michael addition of allenones is reported. It offers atom-economic access to synthetically important furan-fused bi- or tricyclic frameworks containing seven-membered carbocycles, which are widely found in natural products possessing various bioactivities. A number of seven-membered carbocycle-containing polycyclic frameworks bearing diverse functional groups were prepared in good to excellent yields. Furthermore, the application potential of this strategy was exemplified by the construction of the key skeletons of Caribenol A and Frondosin B.

Discovery of myrsinane-type Euphorbia diterpene derivatives through a skeleton conversion strategy from lathyrane diterpene for the treatment of Alzheimer's disease

A series of novel myrsinane-type Euphorbia diterpene derivatives (1–37) were synthesized from the abundant natural lathyrane-type Euphorbia factor L3, using a multi-step chemical process guided by a bioinspired skeleton conversion strategy, with the aim of discovering potential anti-Alzheimer's disease (AD) bioactive lead compounds. The synthesis process involved a concise reductive olefin coupling reaction through an intramolecular Michael addition with a free radical, followed by a visible-light-triggered regioselective cyclopropane ring-opening. The cholinesterase inhibitory and neuroprotective activities of the synthesized myrsinane derivatives were evaluated. Most of the compounds showed moderate to strong potency, highlighting the importance of ester groups in Euphorbia diterpene. In particular, derivative 37 displayed the most potent acetylcholinesterase (AChE) inhibition, with an IC50 value of 8.3 μM, surpassing that of the positive control, tacrine. Additionally, 37 also showed excellent neuroprotective effect against H2O2-induced injury in SH-SY5Y cells, with a cell viability rate of 124.2% at 50 μM, which was significantly higher than that of the model group (viability rate 52.1%). Molecular docking, reactive oxygen species (ROS) analysis, immunofluorescence, and immunoblotting were performed to investigate the mechanism of action of myrsinane derivative 37. The results indicated that derivative 37 may be a promising myrsinane-type multi-functional lead compound for the treatment of Alzheimer's disease. Furthermore, a preliminary SAR analysis was performed to study the acetylcholinesterase inhibitory and neuroprotective activities of these diterpenes.

Collective Total Synthesis of Mavacuran Alkaloids through Intermolecular 1,4‐Addition of an Organolithium Reagent**

AbstractWe report a synthetic endeavor towards the highly strained pentacyclic caged framework of the mavacuran alkaloids which culminated with the concise total synthesis of C‐fluorocurine, C‐profluorocurine, C‐mavacurine, normavacurine, 16‐epi‐pleiocarpamine and taberdivarine H. We designed a strategy involving late‐stage construction of the D ring by Michael addition of a vinylic nucleophile to a 2‐indolyl acrylate moiety. While the intramolecular Michael addition did not succeed, we were able to perform a diastereoselective unusual intermolecular 1,4‐addition of a functionalized vinyl lithium reagent to a readily accessible Michael acceptor with the assistance of the piperidine nitrogen atom through the formation of a complex as suggested by DFT computations. Final cyclization was achieved by nucleophilic substitution to form an ammonium intermediate. The first total syntheses of C‐profluorocurine and C‐fluorocurine were finalized by the dihydroxylation of C‐mavacurine and a pinacol rearrangement, respectively.

Collective Total Synthesis of Mavacuran Alkaloids through Intermolecular 1,4-Addition of an Organolithium Reagent.

We report a synthetic endeavor towards the highly strained pentacyclic caged framework of the mavacuran alkaloids which culminated with the concise total synthesis of C-fluorocurine, C-profluorocurine, C-mavacurine, normavacurine, 16-epi-pleiocarpamine and taberdivarine H. We designed a strategy involving late-stage construction of the D ring by Michael addition of a vinylic nucleophile to a 2-indolyl acrylate moiety. While the intramolecular Michael addition did not succeed, we were able to perform a diastereoselective unusual intermolecular 1,4-addition of a functionalized vinyl lithium reagent to a readily accessible Michael acceptor with the assistance of the piperidine nitrogen atom through the formation of a complex as suggested by DFT computations. Final cyclization was achieved by nucleophilic substitution to form an ammonium intermediate. The first total syntheses of C-profluorocurine and C-fluorocurine were finalized by the dihydroxylation of C-mavacurine and a pinacol rearrangement, respectively.

Organocatalytic Desymmetric Conjugate Addition to Cyclobutanone: An Enantio- and Diastereoselective Synthesis of [6,5,4]-Fused Carbocycles.

The first organocatalytic, non-destructive desymmetrisation of 3-substituted cyclobutanone followed by intramolecular cyclisation is described. Owing to the slow activation of the pronucleophile by the weak Brønsted base, the α-functionalization of ketones with tertiary-amine-derived Brønsted base catalysis has been chemically challenging in asymmetric transformations. Herein, we demonstrate that the cinchona-derived squaramide catalyst works effectively for the intramolecular Michael addition of cyclobutanone to enones and affords the architecturally fascinating [6,5,4]-fused carbocyclic skeleton in good yields and excellent diastereo- and enantioselectivities (up to >20 : 1 dr and 96 % ee). Furthermore, as a synthetic application, this method provides an alternative pathway to enantioenriched high-value products like γ-lactones and indan-2-ol derivatives.