Β-hydroxy Ketones Research Articles

Development and validation of a stability-indicating method, structural elucidation of new degradation products from misoprostol by LC-MS time-of-flight, and an ex vivo study of vaginal permeation.

Misoprostol (MSP) is commonly prescribed in obstetrics and gynecology clinical practice for labor induction, cervical ripening, first-trimester pregnancy termination, and the treatment of postpartum hemorrhage. Furthermore, there is a lack of comprehensive discussion evaluating how different commercially available formulations influence the overall efficacy of MSP, even though reports indicate issues with the quality of these formulations, particularly regarding stability and vaginal absorption processes. This study investigates the stability of MSP under acidic conditions and its in vitro permeation using swine vaginal mucosa. A forced degradation study was conducted using 0.2 M HCl, and a high-efficiency LC method was developed. Three degradation products were identified and characterized using electrospray ionization-high-resolution quadrupole-time-of-flight-MS, with respective m/z values of 391.2508, 405.2705, and 387.2259, respectively. These results suggest that the degradation mechanism involves dehydration of the β-hydroxy ketone moiety, followed by isomerization to its most resonance-stable form and de-esterification. Finally, the in vitro permeation study revealed that the esterified form of MSP was unable to permeate the mucosa and required prior degradation for any component to be detected in the receptor fluid.

A Proline-Based Artificial Enzyme That Favors Aldol Condensation Enables Facile Synthesis of Aliphatic Ketones via Tandem Catalysis.

A proline-based artificial enzyme is prepared by grafting the l-proline moieties onto the surface of bovine serum albumin (BSA) protein through atom transfer radical polymerization (ATRP). The artificial enzyme, the BSA-PolyProline conjugate, prefers to catalyze the formation of unsaturated ketones rather than β-hydroxy ketones in the reaction between acetone and aldehydes, which is difficult to achieve in free-proline catalysis. The altered reaction selectivity is ascribed to the locally concentrated l-proline moieties surrounding the BSA molecule, indicating a microenvironmental effect-induced switching of the reaction mechanism. Taking advantage of this selectivity, we used this artificial enzyme in conjunction with a natural enzyme, old yellow enzyme 1 (OYE1), to demonstrate a simple synthesis of different aliphatic ketones from acetone and aldehydes via tandem catalysis.

Ni-catalyzed enantioconvergent deoxygenative reductive cross-coupling of unactivated alkyl alcohols and aryl bromides

Transition metal-catalyzed enantioconvergent cross-coupling of an alkyl precursor presents a promising method for producing enantioenriched C(sp3) molecules. Because alkyl alcohol is a ubiquitous and abundant family of feedstock in nature, the direct reductive coupling of alkyl alcohol and aryl halide enables efficient access to valuable compounds. Although several strategies have been developed to overcome the high bond dissociation energy of the C − O bond, the asymmetric pattern remains unknown. In this report, we describe the realization of an enantioconvergent deoxygenative reductive cross-coupling of unactivated alkyl alcohol (β-hydroxy ketone) and aryl bromide in the presence of an NHC activating agent. The approach can accommodate substituents of various sizes and functional groups, and its synthetic potency is demonstrated through a gram scale reaction and derivatizations into other compound families. Finally, we apply our convergent method to the efficient asymmetric synthesis of four β-aryl ketones that are natural products or bioactive compounds.

Synthesis of the MN Ring of Caribbean Ciguatoxin C-CTX-1 via Desymmetrization by Acetal Formation.

The MN ring of Caribbean ciguatoxin C-CTX-1 was synthesized from a meso-syn-2,7-dimethyloxepane derivative corresponding to the M ring via desymmetrization by acetal formation with a camphor derivative, followed by construction of the N ring via the Horner-Wadsworth-Emmons reaction and acetal formation. The meso-syn-2,7-dimethyloxepane derivative was synthesized via photoinduced electrocyclization of a conjugated exo-diene under flow conditions, giving a cyclobutene derivative, followed by ring expansion via oxidative cleavage and diastereoselective reduction of a β-hydroxy ketone.

Nickel/Titanocene-Catalyzed Electrophilic Acylation Coupling of Styrene Oxides.

The cross-coupling of epoxides with acyl chlorides or anhydrides by a nickel/titanocene dual catalytic system is established. A variety of synthetically useful β-hydroxy ketones were obtained in good to high yields by using modified pyridine-oxazoline ligand. The reaction proceeds via the cooperation of titanocene-catalyzed ring-opening of epoxides and nickel-catalyzed acylation of the benzylic radical intermediate.

Biomimetic Catalytic Retro-Aldol Reaction Using a Cation-Binding Catalyst: A Promising Route to Axially Chiral Biaryl Aldehydes.

Here we describe a biomimetic catalytic retro-aldol reaction of racemic α-substituted β-hydroxy ketones utilizing a chiral oligoEG cation-binding catalyst as a type-II aldolase mimic. Our investigation of various aldol substrates has demonstrated that our biomimetic retro-aldol protocol enables rapid access to highly enantiomerically enriched aldols with a selectivity factor (s) of up to 70. Additionally, we have demonstrated the synthetic strategy's feasibility for accessing diverse and valuable axially chiral aldehydes.

Copper-Catalyzed Ligand-Controlled Selective Borocarbonylation of α-Substituted Styrenes Toward β-Boryl Aldehydes and Cyclopropyl Boronate Esters

Copper-Catalyzed Ligand-Controlled Selective Borocarbonylation of α-Substituted Styrenes Toward β-Boryl Aldehydes and Cyclopropyl Boronate Esters

Facile access to β-hydroxyl ketones via a cobalt-catalyzed ring-opening/hydroxylation cascade of cyclopropanols

A cobalt-catalyzed ring-opening/hydroxylation cascade of highly strained cyclopropanols has been developed for the first time. The reaction was conducted under open-air atmosphere to afford a broad series of structurally diverse β-hydroxy ketones in moderate to good yields with high regioselectivity. The protocol features mild reaction conditions, simple operation, high-functional-group tolerance, facile scalability, and heterocycle compatibility.

Development of Regio- and Face-selective [2 + 3] Cycloaddition Reactions of Readily Preparable Oxime-substituted Nitrile Oxides with Silicon-linked Allylic-alcohol Moieties for Intramolecular Reactions

Abstract Nitrile oxides are typically prepared in situ from nitroalkanes and converted to 2-isoxazoline heterocycles upon [2 + 3] cycloaddition with alkenes, providing synthetically useful intermediates such as β-hydroxy ketones and γ-amino alcohols. Herein, we prepared oxime-substituted nitrile oxides bound to allylic-alcohol derivatives through a silicon atom and demonstrated their intramolecular cycloaddition reactions. The desired cycloadducts were obtained as single regioisomers in good yields. Furthermore, face-selective cycloaddition reactions were achieved using α-substituted allylic-alcohol derivatives, affording the desired cycloadducts with high diastereoselectivity.

Development of regioselective [2 + 3] cycloaddition reactions of nitrile oxides with alkenes using intramolecular reactions through oxime groups [1

Nitrile oxides afford 2-isoxazoline heterocycles through [2 + 3] cycloaddition reactions with alkenes. These heterocycles can be converted to useful intermediates, such as β-hydroxy ketones and γ-amino alcohols, leading to pharmaceutical and agrochemical compounds. However, nitrile oxides directly connected to a carbonyl group show low reactivity owing to the decrease in energy of the dipole HOMO. Furthermore, when dissymmetric internal alkenes are used, regioselective control is difficult. Herein, we have designed nitrile oxides bound to alkenes through the oxime group and demonstrated their intramolecular [2 + 3] cycloaddition reactions. The desired cycloadducts were obtained in high yields and as single regioisomers. Furthermore, face-selective cycloaddition reactions were achieved by introducing a stereocenter into the linker moiety, affording the desired cycloadducts with good diastereoselectivity.

Synthesis, Biological Activities and Molecular Docking analysis of a Novel Series of 11H-Indeno[1,2-b]quinoxalin-11-one Derivatives

In this study, olefin adducts were synthesized from Wittig reactions on carbonyl group and stereo-identity of the alkene products. The reaction of 11H-Indeno[1,2-b]quinoxalin-11-one with few stabilized phosphonium ylides yielded a combination of the corresponding E and Z olefins in each case. On the other hand, the reaction of 11H-indeno[1,2-b]quinoxalin-11-one with dialkyl phosphites gave related phosphonates. The aldol condensation reaction of 11H-Indeno[1,2-b]quinoxalin-11-one with boiling dry acetone and/or 2-butanone in presence of aluminum oxide or anhydrous potassium carbonate as a catalyst led to the formation of the β-hydroxy ketones. The nucleophilic addition reaction of acetone and/or 2- butanone to (E)-alkyl 2-(11H-indeno[1,2-b]quinoxalin-11-ylidene)acetate in presence of aluminum oxide or anhydrous potassium carbonate as a catalyst led to the formation of the corresponding an addition products.Reaction mechanisms are taken into consideration and the structural assignments of the new compounds are based on the chemical and spectroscopic evidences. The cytotoxic activity of some new compounds had been evaluated against human hepatocellular carcinoma cell line (HePG2) and human Caucasian breast adenocarcinoma (MCF7). Compounds 6b,c showed higher cytotoxicity towards breast (MCF7) most cancers cellular line than the reference drug (Doxorubicin). The binding mode of phosphonates 6 changed into similarly tested by using molecular docking studies

Front Cover: Highly Efficient and Stereoselective Mukaiyama Aldol Reaction with Chiral Aziridine‐2‐carboxaldehyde and Its Synthetic Applications (Asian J. Org. Chem. 1/2022)

The straight forward and highly diastereoselective synthesis of β-(aziridin-2-yl)-β-hydroxy ketones was achieved by the Mukaiyama aldol reaction of optically pure 1-(α-methylbenzyl)-aziridine-2-carboxaldehyde and various enol-silanes in the presence of ZnCl2 via a chelation-controlled transition state (98:2 dr, and >82% yields). These β-(aziridin-2-yl)-β-hydroxy ketones were applied for the synthesis of various alkaloids including epiallo-isomuscarine, epi-enigmol, and epi-galantinic acid. More information can be found in the Full Paper by Nikhil Srivastava and Hyun-Joon Ha.

Enhancing β-hydroxy ketone selectivity in the aldol condensation of furfural and acetone over N–B–O sites in calcined boron nitride

Air-calcined BN can catalyze the aldol reaction of furfural and acetone while suppressing dehydration to afford β-hydroxy ketone. Two types of O-substituted N defect sites were identified and a B-centered Lewis acid-catalyzed mechanism was proposed.

Stereoselective total synthesis of (−)-hygrophorone A12 and 4-epi-2,3-dihydrohygrophorone H12

Stereoselective total synthesis of anti-fungal cyclopentenone (−)-hygrophorone A12 and cyclopentanone 4-epi-2,3-dihydrohygrophorone H12 were achieved in high overall yields from d-ribose. An aqueous KOH mediated diastereoselective formation of β-hydroxy ketone with three contiguous chiral centres served as a key step in this synthesis.

ASYMMETRIC ORGANOCATALYSIS

Dear Reader, Two basic reactions that were taught to us in the organic chemistry courses were the aldol condensation reaction and the Diels-Alder reaction. In aldol condensation, discovered by the French chemist Charles Wurtz in 1872, an enolate ion reacts with a carbonyl compound in the presence of an acid/ base catalyst to form a β-hydroxy aldehyde or a β-hydroxy ketone, usually followed by dehydration to give a conjugated enone. If the enolate ion and the carbonyl group are present in the same molecule, then the aldol reaction is intramolecular. It is an extremely useful carbon-carbon bond-forming reaction. The Diels-Alder reaction, discovered in 1928 by the German chemist Otto Diels and his student Kurt Alder, is the reaction between a conjugated diene and an alkene, a so-called dienophile, to form an unsaturated six-membered ring. It is called a cycloaddition reaction, since the reaction involves the formation of a cyclic product via a cyclic transition state. Uncatalysed Diels– Alder reactions usually require extended reaction times at elevated pressures and temperatures with the formation of by-products, hence various catalysts are employed. The Diels-Alder reaction also has great industrial relevance and the discoverers were crowned with the 1950 Nobel Prize in Chemistry. The aldol condensation reaction and the Diels-Alder reaction typically require catalysts, basically Brønsted acids, Brønsted bases, Lewis acids or Lewis bases. This triggered the minds of Dr. David MacMillan and Dr. Benjamin List for different reasons at different locations in USA around not so different times, more than twenty years ago, culminating in their being jointly awarded the Nobel Prize in Chemistry for this year.

Exploring polymerisation of 1,2-dicarbonyl compounds to decipher the formation of nitrogen-free substructures in melanoidins

• MGO or 3-DG can be reacted under different pH conditions to form polymers. • MW of the structural units of the polymers was mainly 54 ± 2 or 72 ± 2 Da. • Polymers can be cross-linked with gluten and dextran to form macromolecules. • Polymers are the nitrogen-free substructure in melanoidins. • Polymers can be used as candidate biomarkers. To decipher the formation mechanism of nitrogen-free substructures in melanoidins, methylglyoxal or 3-deoxyglucosone was used as a substrate to react by aldol reaction under different pH conditionst. The obtained products were characterised by chromatography, mass spectrometry, and spectroscopic methods. Overall, the molecular weights of the polymers structural units varied mainly within 54–56 and 72–74 Da, respectively, due to the different dehydration extent of β-hydroxy aldehyde or ketones, and uneven reduction by NaBH 4 . Moreover, the nitrogen-free substructures formed by this reaction can cross-link with gluten and dextran to form melanoidins. Therefore, the nitrogen-free substructures by this reaction to formed with units of 54–56 and 72–74 Da, which are similar as the typical polymers in food melanoidins. It is inferred that the typical polymers in food may also be formed by this pathway and which can be used as a detectable biomarker in melanoidins.

The 1,3-Dipolar Cycloaddition Reactions of Nitrile Oxides in Water Media

The 1,3-dipolar Cycloadditions (DCs) of Nitrile Oxides (NOs) have been used as a powerful tool in synthetic organic chemistry. The cycloadducts arising from Cycloadditions (CAs) of NOs to alkenes and alkynes (2-isoxazolines and isoxazoles respectively) are valuable synthetic intermediates because, among others, their capacity to mask other functionalities including α, β -unsaturated ketones, β -hydroxy carbonyl compounds and 1,3- aminoalcohols. In particular, the β-hydroxy ketone functionality is an illustrative example, making the NOs alkenes CAs reactions a synthetically equivalent methodology of aldol reactions. The vast majority of these reactions are carried out in organic solvents. Nevertheless, the use of water as an alternative solvent has evident advantages on the “Green Chemistry” concept. The critical discussion on the use of water instead of “conventional” solvents in the 1,3-DCs reactions of NOs is the objective of the present review.

Catalytic Asymmetric Darzens-Type Epoxidation of Diazoesters: Highly Enantioselective Synthesis of Trisubstituted Epoxides.

Highly enantioselective Darzens-type epoxidation of diazoesters with glyoxal derivatives was accomplished using a chiral boron-Lewis acid catalyst, which facilitated asymmetric synthesis of trisubstituted α,β-epoxy esters. In the presence of a chiral oxazaborolidinium ion catalyst, the reaction proceeded in high yield (up to 99 %) with excellent enantio- and diastereoselectivity (up to >99 % ee and >20:1 dr, respectively). The synthetic potential of this method was illustrated by conversion of the products to various compounds such as epoxy γ-butyrolactone, tertiary β-hydroxy ketone and epoxy diester.

Design, synthesis and molecular modeling study of substituted indoline-2-ones and spiro[indole-heterocycles] with potential activity against Gram-positive bacteria.

Longstanding and firsthand infectious diseases are challenging community health threats. A new series of isatin derivatives bearing β-hydroxy ketone, chalcone, or spiro-heterocycle moiety, was synthesized in a good yield. Chemical structures of the synthesized compounds were elucidated using spectroscopic techniques and elemental analysis. Antibacterial activities of the compounds were then evaluated in vitro and by in silico modeling. The compounds were more active against Gram-positive bacteria, Staphylococcus aureus (MIC = 0.026-0.226 mmol L-1) and Bacillus subtilis (MIC = 0.348-1.723 mmol L-1) than against Gram-negative bacteria (MIC = 0.817-7.393 mmol L-1). Only 3-hydroxy-3-(2-(2,5-dimethylthiophen-3-yl)-2-oxoethyl)indolin-2-one (1b) was found as active as imipenem against S. aureus (MIC = 0.026 mmol L-1). In silico docking of the compounds in the binding sites of a homology modeled structure of S. aureus histidine kinase-Walk allowed us to shed light on the binding mode of these novel inhibitors. The highest antibacterial activity of 1b is consistent with its highest docking score values against S. aureus histidine kinase.

Generation of an Elusive Permanent Merocyanine via a Unique Mechanochemical Reaction Pathway.

We report the discovery of a 2H-naphtho[1,2-b]pyran mechanophore that produces a permanent merocyanine dye upon mechanochemical activation, in contrast to the reversible product generated photochemically. Experiments suggest that the irreversibility of the mechanically generated merocyanine is due to a unique reaction in which the scission of an ester C-O bond reveals a β-hydroxy ketone that locks the merocyanine through an intramolecular H-bonding interaction. In addition to demonstrating the reactivity using solution-phase ultrasonication, permanent merocyanine generation is also achieved in solid polymeric materials. The permanent coloration achieved with the naphthopyran mechanophore affords unique opportunities for sensing and force-recording applications as well as fundamental studies limited by the reversibility of typical colorimetric force probes.