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ACS Omega Jun 2023A divergent two-step process has provided access to optically pure enantiomers of MDMA and MDA, clinically relevant phenylisopropylamine entactogens. Target compounds...
A divergent two-step process has provided access to optically pure enantiomers of MDMA and MDA, clinically relevant phenylisopropylamine entactogens. Target compounds were synthesized from commercially available alanine-derived aziridines. Critical process parameters were identified, and the reactions were optimized to avoid chromatographic purifications toward gram-scale isolations, providing ()-(-)-MDMA, ()-(+)-MDMA, ()-(-)-MDA, and ()-(+)-MDA each in greater than 98% purity by UPLC, >99% enantiomeric excess, and net yields between 50 and 60% for the complete process.
PubMed: 37360440
DOI: 10.1021/acsomega.3c02358 -
Molecules (Basel, Switzerland) May 2023An unprecedented oxidative cyclodimerization reaction of 2-azirine-2-carboxylates to pyrimidine-4,6-dicarboxylates under heating with triethylamine in air is described....
An unprecedented oxidative cyclodimerization reaction of 2-azirine-2-carboxylates to pyrimidine-4,6-dicarboxylates under heating with triethylamine in air is described. In this reaction, one azirine molecule undergoes formal cleavage across the C-C bond and another across the C=N bond. According to the experimental study and DFT calculations, the key steps of the reaction mechanism include nucleophilic addition of ,-diethylhydroxylamine to an azirine to form an (aminooxy)aziridine, generation of an azomethine ylide, and its 1,3-dipolar cycloaddition to the second azirine molecule. The crucial condition for the synthesis of pyrimidines is generation of ,-diethylhydroxylamine in the reaction mixture in a very low concentration, which is ensured by the slow oxidation of triethylamine with air oxygen. Addition of a radical initiator accelerated the reaction and resulted in higher yields of the pyrimidines. Under these conditions, the scope of the pyrimidine formation was elucidated, and a series of pyrimidines was synthesized.
Topics: Azirines; Pyrimidines; Oxidative Stress
PubMed: 37298789
DOI: 10.3390/molecules28114315 -
The Journal of Organic Chemistry Jul 2023We have developed a highly stereospecific cyclization of aziridine silanols into 1'-amino-tetrahydrofurans. Our protocol of stirring a substrate with 10 mol % Sc (OTf)...
We have developed a highly stereospecific cyclization of aziridine silanols into 1'-amino-tetrahydrofurans. Our protocol of stirring a substrate with 10 mol % Sc (OTf) and 1 equivalent of NaHCO in CHCl is mild and compatible with a range of activating aziridine -substituents (including tosylates, mesylates, and carbamates) and functional groups on the alkyl chains (including substituted aryl rings, alkyl bromides, and alkyl ethers). In all cases examined, di-substituted aziridine silanols give products with an configuration; conversely, di-substituted aziridine silanols give products with a configuration. While literature syntheses of 1'-amino-tetrahydrofurans exist, only one example, contemporaneous with our work, uses a similar cyclization for their construction. Control experiments demonstrate that, for this transformation, the silanol is not particularly privileged, and a variety of protecting groups on the alcohol (including other silicon protecting groups, benzyl ethers, and MOM ethers) are compatible with product formation.
Topics: Furans; Stereoisomerism; Ethers; Aziridines
PubMed: 37253098
DOI: 10.1021/acs.joc.3c00763 -
Archiv Der Pharmazie Jul 2023The ubiquitin-proteasome pathway (UPP) represents the principal proteolytic apparatus in the cytosol and nucleus of all eukaryotic cells. Nowadays, proteasome inhibitors...
The ubiquitin-proteasome pathway (UPP) represents the principal proteolytic apparatus in the cytosol and nucleus of all eukaryotic cells. Nowadays, proteasome inhibitors (PIs) are well-known as anticancer agents. However, although three of them have been approved by the US Food and Drug Administration (FDA) for treating multiple myeloma and mantel cell lymphoma, they present several side effects and develop resistance. For these reasons, the development of new PIs with better pharmacological characteristics is needed. Recently, noncovalent inhibitors have gained much attention since they are less toxic as compared with covalent ones, providing an alternative mechanism for solid tumors. Herein, we describe a new class of bis-homologated chloromethyl(trifluoromethyl)aziridines as selective noncovalent PIs. In silico and in vitro studies were conducted to elucidate the mechanism of action of such compounds. Human gastrointestinal absorption (HIA) and blood-brain barrier (BBB) penetration were also considered together with absorption, distribution, metabolism, and excretion (ADMET) predictions.
Topics: Humans; Proteasome Endopeptidase Complex; Structure-Activity Relationship; Antineoplastic Agents; Proteasome Inhibitors; Neoplasms
PubMed: 37119396
DOI: 10.1002/ardp.202300174 -
Energy & Fuels : An American Chemical... Apr 2023Carbon dioxide (CO) hydrates, which contain a relatively large amount of captured CO (almost 30 wt % of CO with the balance being water), represent a promising CO...
Carbon dioxide (CO) hydrates, which contain a relatively large amount of captured CO (almost 30 wt % of CO with the balance being water), represent a promising CO sequestration option for climate change mitigation. To facilitate CO storage via hydrates, using chemical additives during hydrate formation might help to expedite formation/growth rates, provided the additives do not reduce the storage capacity. Implementing atomistic molecular dynamics, we study the impact of aziridine, pyrrolidine, and tetrahydrofuran (THF) on the kinetics of CO hydrate growth/dissociation. Our simulations are validated via reproducing experimental data for CO and CO + THF hydrates at selected operating conditions. The simulated results show that both aziridine and pyrrolidine could perform as competent thermodynamic and kinetic promoters. Furthermore, aziridine seems to exceed pyrrolidine and THF in expediting the CO hydrate growth rates under the same conditions. Our analysis unveils direct correlations between the kinetics of CO hydrate growth and a combination of the free energy barrier for desorption of CO from the hydrate surface and the binding free energy of chemical additives adsorbed at the growing hydrate substrate. The detailed thermodynamic analysis conducted in both hydrate and aqueous phases reveals molecular-level mechanisms by which CO hydrate promoters are active, which could help to enable the implementation of CO sequestration in hydrate-bearing reservoirs.
PubMed: 37114945
DOI: 10.1021/acs.energyfuels.3c00472 -
Nature Communications Apr 2023Here, we report an asymmetric electrochemical organonickel-catalyzed reductive cross-coupling of aryl aziridines with aryl iodides in an undivided cell, affording...
Here, we report an asymmetric electrochemical organonickel-catalyzed reductive cross-coupling of aryl aziridines with aryl iodides in an undivided cell, affording β-phenethylamines in good to excellent enantioselectivity with broad functional group tolerance. The combination of cyclic voltammetry analysis of the catalyst reduction potential as well as an electrode potential study provides a convenient route for reaction optimization. Overall, the high efficiency of this method is credited to the electroreduction-mediated turnover of the nickel catalyst instead of a metal reductant-mediated turnover. Mechanistic studies suggest a radical pathway is involved in the ring opening of aziridines. The statistical analysis serves to compare the different design requirements for photochemically and electrochemically mediated reactions under this type of mechanistic manifold.
PubMed: 37087477
DOI: 10.1038/s41467-023-37965-0 -
Journal of Enzyme Inhibition and... Dec 2023In this study, we report a series of newly synthesised sulphonamides of aziridine-2-carboxylic acid (Az-COOH) ester and amide analogues as potent protein disulphide...
In this study, we report a series of newly synthesised sulphonamides of aziridine-2-carboxylic acid (Az-COOH) ester and amide analogues as potent protein disulphide isomerase (PDI, EC 5.3.4.1) inhibitors. The inhibitory activity on PDI was determined against recombinant human PDIA1 and PDIA3 proteins using an insulin reduction assay. These compounds in low micromolar to low nanomolar concentrations showed the effective inhibitory properties of PDIA1 with weaker effects on PDIA3. Complexes of N- and N,C- uniformly labelled recombinant human PDIA1a with two PDIA1 inhibitors were produced and investigated by a protein nuclear magnetic resonance (NMR) spectroscopy. It was found that both C53 and C56 of the PDIA1 enzyme were involved in covalent binding. Finally, in a range of pharmacological studies, we demonstrated that investigated compounds displayed anti-cancer and anti-thrombotic activity. These findings demonstrate that sulphonamides of Az-COOH derivatives are promising candidates for the development of novel anti-cancer and anti-thrombotic agents.
Topics: Humans; Aziridines; Protein Disulfide-Isomerases; Sulfonamides
PubMed: 37070480
DOI: 10.1080/14756366.2022.2158187 -
ACS Omega Apr 2023Protonation of cyclopropanes and aziridines is well-studied, but reactions of phosphiranes with acids are rare and have not been reported to result in ring opening....
Protonation of cyclopropanes and aziridines is well-studied, but reactions of phosphiranes with acids are rare and have not been reported to result in ring opening. Treatment of -Mes*PCHCHR (Mes* = 2,4,6-(-Bu)CH, R = Me or Ph, --) or -Mes*PCHCHPh (-) with triflic acid resulted in regiospecific -Markovnikov C-protonation with ring opening and cyclophosphination of a Mes* --Bu group to yield the phospholanium cations [PH(CHCHR)(4,6-(-Bu)-2-CMeCHCH)][OTf] (R = Me or Ph, -), which were deprotonated with NEt to give phospholanes -. Enantioenriched or racemic - both gave racemic . The byproduct [Mes*PH(CHCHMe)(OH)][OTf] () was formed from - and HOTf in the presence of water. Density functional theory calculations suggested that P-protonation followed by ring opening and hydride migration to C yields the phosphenium ion, [Mes*P(CHCHMe)][OTf], which undergoes C-H oxidative addition of an --Bu methyl group. This work established a new reactivity pattern for phosphiranes.
PubMed: 37033828
DOI: 10.1021/acsomega.3c00885 -
Substrate-Directed Enantioselective Aziridination of Alkenyl Alcohols Controlled by a Chiral Cation.Journal of the American Chemical Society Apr 2023Alkene aziridination is a highly versatile transformation for the construction of chiral nitrogen-containing compounds. Inspired by the success of analogous...
Alkene aziridination is a highly versatile transformation for the construction of chiral nitrogen-containing compounds. Inspired by the success of analogous substrate-directed epoxidations, we report an enantioselective aziridination of alkenyl alcohols, which enables asymmetric nitrene transfer to alkenes with varied substitution patterns, including those not covered by the current protocols. We believe that our method is effective because it is substrate-directed, exploiting a network of attractive non-covalent interactions between the substrate, an achiral dianionic rhodium(II,II) tetracarboxylate dimer, and its two associated cinchona alkaloid-derived cations. It is these cations that provide a defined chiral pocket in which the aziridination can occur. In addition to a thorough evaluation of compatible alkene classes, we advance a practical mnemonic to predict reaction outcome and disclose a range of post-functionalization protocols that highlight the unique synthetic potential of the enantioenriched aziridine-alcohol products.
PubMed: 36961353
DOI: 10.1021/jacs.3c00693 -
Molecules (Basel, Switzerland) Mar 2023Density functional calculations SMD(chloroform)//B3LYP/6-311+G(2d,p) were employed in the computational study of 1,3-dipolar cycloadditions of azides with guanidine. The...
Density functional calculations SMD(chloroform)//B3LYP/6-311+G(2d,p) were employed in the computational study of 1,3-dipolar cycloadditions of azides with guanidine. The formation of two regioisomeric tetrazoles and their rearrangement to cyclic aziridines and open-chain guanidine products were modeled. The results suggest the feasibility of an uncatalyzed reaction under very drastic conditions since the thermodynamically preferred reaction path (a), which involves cycloaddition by binding the carbon atom from guanidine to the terminal azide nitrogen atom, and the guanidine imino nitrogen with the inner N atom from the azide, has an energy barrier higher than 50 kcal mol. The formation of the other regioisomeric tetrazole (imino nitrogen interacts with terminal N atom of azide) in direction (b) can be more favorable and proceed under milder conditions if alternative activation of the nitrogen molecule releases (e.g., photochemical activation), or deamination could be achieved because these processes have the highest barrier in the less favorable (b) branch of the mechanism. The introduction of substituents should favorably affect the cycloaddition reactivity of the azides, with the greatest effects expected for the benzyl and perfluorophenyl groups.
PubMed: 36903588
DOI: 10.3390/molecules28052342