oxa-Michael Addition Research Articles

Oxa-Michael/Ugi-Smiles cascade reaction with α,β-unsaturated aldehydes

Use of α,β-unsaturated aldehydes as components in Ugi-Smiles couplings of 2-nitrophenol with alkyl isocyanides and primary amines provides ready access to γ-alkoxy substituted amides when performed in the presence of alcoholic solvents. The observed five component coupling forms these adducts via a cascade event involving an oxa-Michael conjugate addition and an Ugi-Smiles multicomponent reaction. Five bonds and two stereocenters are generated in this diastereoselective formation of γ-alkoxy substituted amides in moderate to good yields.

Synthesis of thermoresponsive nonconjugated fluorescent branched poly(ether amide)s via oxa-Michael addition polymerization

Novel thermoresponsive nonconjugated fluorescent branched poly(ether amide)s with tunable LCST via t-BuP2-catalyzed oxa-Michael addition polymerization of N,N′-methylenebis(acrylamide) with triols.

Towards understanding oxygen heterocycle-forming biocatalysts: a selectivity study of the pyran synthase PedPS7.

Intramolecular oxa-Michael addition-catalysing cyclases are widespread in polyketide biosynthetic pathways. Although they have significant potential in biotechnology and chemoenzymatic synthesis of chiral heterocycles, they have only scarcely been studied. Here, we present detailed investigations on the selectivity profile of the pyran synthase PedPS7 showing that it combines broad substrate tolerance with high selectivity for the formation of up to two new stereocentres and relaxed precursor stereoisomer discrimination. Two of the four possible tetrahydropyran stereoisomers are reliably accessible by this enzyme. The results indicate fundamental differences between the individual subtypes of intramolecular oxa-Michael addition-catalysing cyclases.

A stepwise lactol carbocyclisation to bridged ethers via a keto–acetal cascade

Lactol carbocyclisations provide a succinct method of constructing the oxabicyclo[3.2.1]octane scaffold, a motif present in various natural products of medicinal interest. Lactols containing an unsaturated ketone or ester were prepared by olefin cross-metathesis; an electrophilic alkene derived from methyl vinyl ketone underwent concomitant terminal α-methylenation and oxa-Michael addition to give a bridged lactol which then underwent oxygen-to-carbon transposition in the presence of titanium (IV) chloride giving the desired unsaturated carbocyclic seven-membered bridged ether via a novel dehydrative cascade considered to involve titanium enolates.

Unprecedented Biodegradable Cellulose-Derived Polyesters with Pendant Citronellol Moieties: From Monomer Synthesis to Enzymatic Degradation.

Levoglucosenone (LGO) is a cellulose-derived molecule that is present commercially on a multi-ton/year scale. Taking advantage of the α,β-conjugated ketone of LGO, a new citronellol-containing 5-membered lactone (HBO-citro) was synthesized through a one-pot two-step pathway involving oxa-Michael addition and Baeyer-Villiger oxidation. The solvent-free treatment of HBO-citro with NaBH4 at room temperature led to the full reduction of the lactone moiety which gave a novel fully renewable triol monomer having a citronellol side chain (Triol-citro). Noticeably, by simply changing the reducing agent, temperature and reaction duration, the partial reduction of HBO-citro can be achieved to yield a mixture of 5- and 6-membered Lactol-citro molecules. Triol-citro was chosen to prepare functional renewable polyesters having citronellol pendant chains via polycondensation reactions with diacyl chlorides having different chain lengths. Good thermal stability (Td5% up to 170 °C) and low glass transition temperatures (as low as −42 °C) were registered for the polyesters obtained. The polymers were then hydrolyzed using a commercial lipase from Thermomyces lanuginosus (Lipopan® 50 BG) to assess their biodegradability. A higher degradation profile was found for the polyesters prepared using co-monomers (acyl chlorides) having longer chain lengths. This is likely due to the decreased steric hindrance around the ester bonds which allowed enhanced accessibility of the enzyme.

Regiodivergent synthesis of vinyl trifluoromethansulfonates γ/δ lactones: Via 1,6 addition/intramolecular one-pot annulation of 1,4-dihidropyridines derivated from pyridinyl propenones

We report a novel intramolecular 1,6 oxa-Michael addition on substituted dihydropyridines to obtain 5 and 6 member ring lactones in an one-pot reaction starting from activated pyridinyl propenones, without organic catalysis or presence of bulky groups in the Michael acceptor. A marked dependence on the regioselectivity of ring closure was found, dependent on the propenone used.

Enhancing the ionic conductivity and mechanical properties of zwitterionic polymer electrolytes by betaine-functionalized graphene oxide for high-performance and flexible supercapacitors

In this study, we demonstrate the betaine-functionalized graphene oxide (BFGO) as roles in reinforcement filler and dissociation enhancer, enhancing the mechanical properties and ionic conductivity of zwitterionic polymers electrolytes (ZPEs). BFGO was synthesized by grafting sulfobetaine methacrylate onto the graphene oxide via oxa-michael addition reaction. Then, BFGO-ZPs were prepared by random oxidative polymerization of equimolar Positive charged monomer (TMA) and negative charged monomer(AMPS) with PEGDA in aqueous dispersions of BFGO. BFGO-ZPE was simply prepared by 1 M Na 2 SO 4(aq) intake. BFGO enables a high water content of 86.4 wt% and swelling ratio of 625% in BFGO-ZPEs which also showed excellent mechanical properties, including the compressive strength of 84.4 kPa, compressive strain of 67%, compressive modulus of 14.2 kPa, and toughness of 1.16 Jm -3 . In addition, BFGO-ZPEs possess ultra-high ionic conductivity of 107 mScm −1 at 25 °C. Furthermore, the electrochemical performances of electrolytes were studied using carbon-based supercapacitors which were assembled with BFGO-ZPEs (SBGZ). Since BFGO-ZPEs possessed ultra-high ionic conductivity, SBGZ possessed the remarkable high energy density of 46.2 WhKg −1 and high power density of 8.2 kWKg −1 . Notably, SBGZ also possess 100% capacitance retention after bending to 90°, being potential application in flexible supercapacitors. • BFGO enhances the mechanical properties and ionic conductivity of ZPE. • BFGO-ZPE possesses ultra-high ionic conductivity. • SBGZ possesses the remarkable high energy density and high power density. • SBGZ retains 100% capacitance with vertical bending.

Convenient synthesis of flavanone derivatives via oxa-Michael addition using catalytic amount of aqueous cesium fluoride

A total of 36 flavanones, which included polycyclic aromatic and heterocyclic rings, were readily synthesized via oxa-Michael addition from the corresponding hydroxychalcones with a catalytic amount of aqueous cesium fluoride solution under mild conditions. This method could be applied to the scalable synthesis of eriodictyol as a known potent inhibitor of the SARS-CoV-2 spike protein.

Xylitol-Maleic Anhydride as Small-Molecule Binders for Silicon Anodes in Lithium-Ion Batteries

The theoretical capacity (∼4200 mAh g−1) of silicon (Si) electrode is almost tenfold higher than that of commercially available graphite. However, the cycle-life performance of the Si electrode is poor. Herein, small molecules, sugar alcohol (xylitol) and maleic anhydride, are used as an aqueous binder to obtain high-performance Si electrodes. The xylitol-maleic anhydride (X-MA) binder is in situ polymerized by esterification of maleic anhydride with xylitol and oxa-Michael addition of an α,β-unsaturated ester with hydroxyl groups of xylitol during the preparation of slurry and the drying of electrode. The X-MA binder is characterized by Fourier-transform infrared and solid-state 13C nuclear magnetic resonance spectroscopy, confirming that the esterification and oxa-Michael addition reactions occur during the fabrication of Si electrodes. The results of thermogravimetric analysis and differential scanning calorimetry show that X-MA has good thermal stability and is an elastomer. The 180° peeling test results indicate that the presence of hydroxyl groups in the xylitol moiety results in a strong interaction between the binder and Si nanoparticles, improving the mechanical properties of the Si electrode. Furthermore, the Si electrode with the X-MA binder exhibits a high energy capacity of 4012 mAh g−1 at 0.1 C, enhanced C-rate performance, and good cycle-life performance.

Chemical Recycling of Polyhydroxybutyrate (PHB) into Bio-Based Solvents and Their Use in a Circular PHB Extraction

Two novel protocols for the chemical valorization of polyhydroxybutyrate (PHB) were developed, aiming at the production of two bio-based molecules: methyl 3-hydroxybutyrate (MHB) and methyl 3-methoxybutyrate (MMB). Optimized reaction conditions were applied to pure PHB and PHB inclusions inside bacterial cells as starting materials. MHB was synthesized through a single-step catalytic methanolysis, while MMB was synthesized through a three-step process: thermolytic distillation to give crotonic acid (CA), esterification to give methyl crotonate (MC), and oxa-Michael addition of MeOH. The obtained MHB and MMB were tested as solvents for the recovery of PHB itself both from freeze-dried single strain cultures (SSC) and mixed microbial cultures (MMC) with low to medium contents of PHB (22–57 wt %). High PHB recovery was achieved: up to 96 ± 1% through MHB and up to 98 ± 1% through MMB. Extraction from MMC slurry (with a PHB content of 39% on dry weight) was also performed, recovering 77 ± 2% using MHB and 92 ± 2% using MMB. High purities and excellent molecular weights and polydispersity indexes of extracted PHB were obtained with both MHB and MMB. Solubility in water, octanol/water partition coefficients (log Kow), and aerobic ready biodegradability of both solvents were also evaluated.

Electron-rich triarylphosphines as nucleophilic catalysts for oxa-Michael reactions.

Electron-rich triarylphosphines, namely 4-(methoxyphenyl)diphenylphosphine (MMTPP) and tris(4-trimethoxyphenyl)phosphine (TMTPP), outperform commonly used triphenylphosphine (TPP) in catalyzing oxa-Michael additions. A matrix consisting of three differently strong Michael acceptors and four alcohols of varying acidity was used to assess the activity of the three catalysts. All test reactions were performed with 1 mol % catalyst loading, under solvent-free conditions and at room temperature. The results reveal a decisive superiority of TMTPP for converting poor and intermediate Michael acceptors such as acrylamide and acrylonitrile and for converting less acidic alcohols like isopropanol. With stronger Michael acceptors and more acidic alcohols, the impact of the more electron-rich catalysts is less pronounced. The experimental activity trend was rationalized by calculating the Michael acceptor affinities of all phosphine–Michael acceptor combinations. Besides this parameter, the acidity of the alcohol has a strong impact on the reaction speed. The oxidation stability of the phosphines was also evaluated and the most electron-rich TMTPP was found to be only slightly more sensitive to oxidation than TPP. Finally, the catalysts were employed in the oxa-Michael polymerization of 2-hydroxyethyl acrylate. With TMTPP polymers characterized by number average molar masses of about 1200 g/mol at room temperature are accessible. Polymerizations carried out at 80 °C resulted in macromolecules containing a considerable share of Rauhut–Currier-type repeat units and consequently lower molar masses were obtained.

Asymmetric Synthesis of (−)-Atorvastatin Calcium by Tandem Catalysis

Abstract A seven-step synthesis of (−)-atorvastatin calcium, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, has been developed. The key transformations of the present synthesis are a tandem olefin cross-metathesis/hemiacetalization/intramolecular oxa-Michael addition and a subsequent regioselective Baeyer–Villiger oxidation for the stereocontrolled construction of the syn-3,5-dihydroxy carboxylic acid substructure.

Stereodivergent Synthesis of Enantioenriched 2,3-Disubstituted Dihydrobenzofurans via a One-Pot C-H Functionalization/Oxa-Michael Addition Cascade.

A one-pot rhodium-catalyzed C-H functionalization/organocatalyzed oxa-Michael addition cascade reaction has been developed. This methodology enables the stereodivergent synthesis of diverse 2,3-disubstituted dihydrobenzofurans with broad functional group compatibility in good yields with high levels of stereoselectivity under exceptionally mild conditions. The full complement of stereoisomers of chiral 2,3-disubstituted dihydrobenzofurans and 3,4-disubstituted isochromans could be accessed at will by appropriate permutations of the two chiral catalysts. The current work provides a rare example of two chiral catalysts independently controlling two contiguous stereogenic centers subsequently via a two-step reaction in a single operation.

Stereoselective Synthesis of the Southern Hemisphere Acyclic Domain of Neaumycin B.

A stereocontrolled synthetic entry to the southern hemisphere C3-C17 acyclic domain of neaumycin B, a highly potent cytotoxic macrolide natural product, has been developed. The present synthesis is based on (i) a tandem olefin cross-metathesis/hemiacetalization/intramolecular oxa-Michael addition, (ii) a regioselective reductive acetal opening for differential protection of the C14 hydroxy group, (iii) a Horner-Wadsworth-Emmons reaction for the stereoselective formation of the C8-C9 olefin, and (iv) a Corey-Bakshi-Shibata asymmetric reduction to create the C7 stereogenic center.

Synthetic Approaches for Building Tricyclic Cage-like Motifs Found in Indoxamycins

Indoxamycins A-F, a novel class of polyketides, were isolated from the saline culture of marine-derived actinomyces by Sato et al. in 2009. Intriguing stereochemical complexity involving tricyclic [5.5.6] cage-like structures with six consecutive chiral centers challenged many organic chemists. Chemical ingenuity, implementation of pioneered reactions along with fine chemical transformations allowed not only the rapid construction of the central core but also allowed minor structural revision and paved the information to delineate the absolute stereostructures of these complex polyketide marine natural products. To achieve the central core structure in indoxamycins A-F, reactions like the Ireland-Claisen rearrangement, an enantioselective 1,6-enyne reductive cyclization, and one-pot cascade reactions of 1,2- addition/oxa-Michael/methylenation were employed. Using the chiral pool approach, the readily available R-carvone was employed as a cost-effective starting material to achieve the concise total syntheses of (-)-indoxamycins A and B, in which Pauson-Khand, Cu-catalyzed Michael addition and tandem retro-oxa-Michael addition/1,2-addition/oxa-Michael addition reactions were employed. The antipodes, (+)-indoxamycins can be easily accessed by simply switching to S-carvone as the starting material. Synthetically prepared indoxamycins A-F are devoid of antiproliferative properties, which disagree with the work reported by Sato and co-workers for (-)- indoxamycins A and F. Nevertheless, ready access to such complex natural products allows probing the untapped potential biological activities of these polyketides including cytotoxicity. A concise overview of interesting, key chemical transformations including named reactions in establishing the architecture of indoxamycins was compiled to inspire organic chemists and help reinvigorate novel strategies for the asymmetric synthesis as well as the development of novel derivatives of indoxamycins with unique physicochemical and biological properties.

An intramolecular oxa-Michael addition on prebuilt β-lactam tethered α, β-unsaturated ester: A remarkable synthesis of a unique scaffold of 2,3-fused β-lactam-1,4-dioxepane

An expeditious base assisted highly diastereoselective intramolecular oxy-Michael addition reaction in the synthesis of enantiomerically pure 1,4-dioxepane fused β-lactam has been described. This present study has been portrayed a rapid intramolecular 7-exo-trig oxy-Michael reaction involving chemoselective nucleophilic addition of 20 alcohol of the vic-diols to an α β-unsaturated ester. Furthermore, the developed methodology elaborates an extremely atom-economical approach in constructing the C–O bond in stereoselective fashion under mild reaction conditions.

“Greener” chemical modification of cellulose nanocrystals via oxa-Michael addition with N-Benzylmaleimide

Surface modification of cellulose nanocrystals (CNCs) was conducted by an oxa-Michael addition of primary hydroxyl groups on the CNC surface with N-Benzylmaleimide (BnM). Six principles of green chemistry were used to obtain the hydrophobized CNC. Two catalytic approaches were used, a self-catalyzed reaction where alkyl sulfuric acid on the surface of the CNC was the catalyst, and a base-catalyzed approach using triethylamine (TEA). DMSO was chosen as reaction solvent due to its low cost, low toxicity and ability to disperse native CNC compared to other polar diprotic solvents. NMR and FTIR studies confirmed the successful modification of CNCs in both reaction routes. The TEA-catalyzed reaction showed a higher BnM conversion at 70 ​°C after 72 ​h (46 ​± ​2%) compared to the self-catalyzed reaction at 100 ​°C (24 ​± ​2%). Since BnM was added at a two-fold excess compared to superficial primary –OH groups, these had estimated conversions of 92% and 48%, for the base catalyzed and acid catalyzed routes, respectively. Zeta potential measurements suggest, the sulfate groups were retained after the modification reaction. AFM demonstrated no change in particle morphology after modification. Modified CNCs degraded at a higher temperature (390 ​± ​8 ​°C) when the reaction was catalyzed by TEA compared to native CNCs and the self-catalyzed product (220 ​± ​10 ​°C). Contact angle measurements demonstrated the increased hydrophobicity of the modified nanoparticles. Visual inspection and UV–vis spectroscopy demonstrated the modified CNCs had an increased affinity towards organic solvents like acetone, acetonitrile and toluene.

A facile one-pot synthesis of microgels and nanogels of laminarin for biomedical applications

HypothesisLaminarin (LAM) as a nontoxic, biodegradable, and biocompatible marine polysaccharide, has been reported for its ingenious bioactivities such as antioxidant, antitumor antiapoptotic anti-inflammatory, immunomodulatory and dietary fiber activities, and distinct physicochemical structure possess a remarkably promising potential in biomaterial science. Synthesis of LAM-based microgels and bulk hydrogels have been reported in two stages: modification of LAM polysaccharide with polymerizable functional groups and subsequent crosslinking reaction. Therefore, here an easier and more effortless methods to prepare poly(laminarin) (p(LAM)) particles were tackled. ExperimentalA direct and facile single step fabrication of micro/nanogels of p(LAM) for the first time by means of reverse micelle microemulsion system were illustrated. Preparation of p(LAM) particles were achieved by the well-known Oxa-Michael addition reaction mechanism using divinyl sulfone as the crosslinker. FindingsP(LAM) particles in 0.3–10 µm size range in spherical morphologies were prepared with 93 ± 7% yield and functionalized with chlorosulfonic acid (CSA) demonstrating their chemical modifiability for variety of agents e.g., targeting ligands. The bare and modified p(LAM) particles showed excellent blood compatibility with hemolytic indices of <1% and blood clotting indices higher than 90%. The reported p(LAM) particles hold great promise as natural alternative surrogates in biomedical applications including drug delivery.

Total synthesis of (+)-diospongin A

Enantioselective total synthesis of 2,4,6-trisubstituted pyran natural product diospongin A is accomplished from benzaldehyde in 5 steps. Key reaction in the synthesis is the addition of a silyl enol ether derived from vinylogous aryl methyl ketone to chiral β-alkoxy aldehyde and subsequent oxa -Michael addition. • Short one-pot reaction conditions for the synthesis of diospongin A. • Involves the vinylogous Mukaiyama Aldol reaction, Silyl deprotection and Oxa-Michael reaction in one-pot. • 25% overall yield from benzaldehyde.

Unified Total Synthesis of (-)-Enigmazole A and (-)-15-O-Methylenigmazole A.

The total synthesis of cytotoxic marine phosphomacrolides, (-)-enigmazole A and (-)-15-O-methylenigmazole A, is described in detail. The 2,6-cis-substituted tetrahydropyran ring was efficiently elaborated by using a tandem olefin cross-metathesis/intramolecular oxa-Michael addition reaction. The 18-membered macrolactone skeleton was forged via a Au-catalyzed propargylic benzoate rearrangement/macrocyclic ring-closing metathesis sequence. Late-stage diversification of a common intermediate enabled unified total synthesis of (-)-enigmazole A and (-)-15-O-methylenigmazole A.