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Angewandte Chemie (International Ed. in... May 2024β-Phenethylamines are widely represented in biologically and pharmacologically active organic small molecules. Here, we introduce N-pyridinium aziridines as latent dual...
β-Phenethylamines are widely represented in biologically and pharmacologically active organic small molecules. Here, we introduce N-pyridinium aziridines as latent dual electrophiles for the synthesis of β-phenethylamines. Bromide-promoted ring opening generates β-halopyridinium amines. Selective Ni-catalyzed C-C cross-coupling between organozinc nucleophiles and the benzylic C-Br electrophile affords a diverse family of β-functionalized phenethylaminopyridinium salts, and coupling is stereoconvergent in the presence of chiral ligands. Subsequent Ni-catalyzed reductive N-N bond activation within the β-functionalized phenethylaminopyridinium salts furnishes the products of formal olefin carboamination. Other reductive N-N cleavage reactions are demonstrated to provide access to free primary amines, alkylated amines, heterocycles, and products derived from N-centered radical chemistry. The developed reaction sequence can be implemented in the context of complex molecules and natural product derivatives. Together, the described results provide a general and modular synthesis of β-phenethylamines and significantly expand the utility of N-pyridinium aziridines as linchpins in chemical synthesis.
PubMed: 38699820
DOI: 10.1002/anie.202406335 -
Journal of Inorganic Biochemistry Jul 2024The solvated iron(II) salt [Fe(NCMe)](BF) (Me = methyl) is shown to be a bifunctional catalyst with respect to aziridination of styrene. The salt serves as an active...
The solvated iron(II) salt [Fe(NCMe)](BF) (Me = methyl) is shown to be a bifunctional catalyst with respect to aziridination of styrene. The salt serves as an active catalyst for nitrene transfer from PhINTs to styrene to form 2-phenyl-N-tosylaziridine (Ph = phenyl; Ts = tosyl, -S{O}-p-CHMe). The iron(II) salt also acts as a Lewis acid in non-coordinating CHCl solution, to catalyze heterolytic CN bond cleavage of the aziridine and insertion of dipolarophiles. The 1,3-zwitterionic intermediate is presumably supported by interaction of the metal dication with the anion, and by resonance stabilization of the carbocation. Nucleophilic dipolarophiles then insert to give a five-membered heterocyclic ring. The result is a two-step cycloaddition, formally [2 + 1 + 2], that is typically regiospecific, but not stereospecific. This reaction mechanism was confirmed by conducting a series of one-step, [3 + 2] additions of unsaturated molecules into pre-formed 2-phenyl-N-tosylaziridine, also catalyzed by [Fe(NCMe)](BF). Relevant substrates include styrenes, carbonyl compounds and alkynes. These yield five-membered heterocylic rings, including pyrrolidines, oxazolidines and dihydropyrroles, respectively. The reaction scope appears limited only by the barrier to formation of the dipolar intermediate, and by the nucleophilicity of the captured dipolarophile. The bifunctionality of an inexpensive, earth-abundant and non-toxic catalyst suggests a general strategy for one-pot construction of heterocyclic rings, as demonstrated specifically for pyrrolidine ring formation.
Topics: Aziridines; Catalysis; Styrene; Ferrous Compounds; Heterocyclic Compounds; Cycloaddition Reaction; Imines
PubMed: 38678911
DOI: 10.1016/j.jinorgbio.2024.112551 -
Redox Biology Jun 2024Protein disulfide isomerases (PDIs) are involved in many intracellular and extracellular processes, including cell adhesion and cytoskeletal reorganisation, but their...
Protein disulfide isomerases (PDIs) are involved in many intracellular and extracellular processes, including cell adhesion and cytoskeletal reorganisation, but their contribution to the regulation of fenestrations in liver sinusoidal endothelial cells (LSECs) remains unknown. Given that fenestrations are supported on a cytoskeleton scaffold, this study aimed to investigate whether endothelial PDIs regulate fenestration dynamics in primary mouse LSECs. PDIA3 and PDIA1 were found to be the most abundant among PDI isoforms in LSECs. Taking advantage of atomic force microscopy, the effects of PDIA1 or PDIA3 inhibition on the fenestrations in LSECs were investigated using a classic PDIA1 inhibitor (bepristat) and novel aromatic N-sulfonamides of aziridine-2-carboxylic acid derivatives as PDIA1 (C-3389) or PDIA3 (C-3399) inhibitors. The effect of PDIA1 inhibition on liver perfusion was studied in vivo using dynamic contrast-enhanced magnetic resonance imaging. Additionally, PDIA1 inhibitors were examined in vitro in LSECs for effects on adhesion, cytoskeleton organisation, bioenergetics, and viability. Inhibition of PDIA1 with bepristat or C-3389 significantly reduced the number of fenestrations in LSECs, while inhibition of PDIA3 with C-3399 had no effect. Moreover, the blocking of free thiols by the cell-penetrating N-ethylmaleimide, but not by the non-cell-penetrating 4-chloromercuribenzenesulfonate, resulted in LSEC defenestration. Inhibition of PDIA1 did not affect LSEC adhesion, viability, and bioenergetics, nor did it induce a clear-cut rearrangement of the cytoskeleton. However, PDIA1-dependent defenestration was reversed by cytochalasin B, a known fenestration stimulator, pointing to the preserved ability of LSECs to form new pores. Importantly, systemic inhibition of PDIA1 in vivo affected intra-parenchymal uptake of contrast agent in mice consistent with LSEC defenestration. These results revealed the role of intracellular PDIA1 in the regulation of fenestration dynamics in LSECs, and in maintaining hepatic sinusoid homeostasis.
Topics: Animals; Male; Mice; Cell Adhesion; Cells, Cultured; Cytoskeleton; Endothelial Cells; Enzyme Inhibitors; Liver; Protein Disulfide-Isomerases
PubMed: 38669864
DOI: 10.1016/j.redox.2024.103162 -
Organic Letters May 2024Lithiated 1,1-diborylalkanes have been used as nucleophilic coupling partners with a range of oxygen-based electrophiles, including esters, carbonyls, and epoxides....
Lithiated 1,1-diborylalkanes have been used as nucleophilic coupling partners with a range of oxygen-based electrophiles, including esters, carbonyls, and epoxides. However, their reactivity with nitrogen-based electrophiles, such as aziridines, has remained relatively understudied. Herein, we show that lithiated 1,1-diborylalkanes react with α-halo and α-tosyl aziridines to yield borylated (aminomethyl)cyclopropanes-a privileged scaffold within medicinal chemistry. The reaction displays high levels of diastereoselectivity, enabling careful control of up to three stereocenters within a single transformation. DFT studies provide insight into the reaction mechanism, which diverges from that observed with analogous epihalohydrin starting materials. Derivatization studies were also performed on the products to demonstrate the utility of the boron and amine handles.
PubMed: 38669565
DOI: 10.1021/acs.orglett.4c00987 -
The Journal of Organic Chemistry May 2024Herein, we presented a practical methodology for the intermolecular aziridination of alkenes, using HOSA as the aminating agent, alongside pyridine or piperidine as the...
Herein, we presented a practical methodology for the intermolecular aziridination of alkenes, using HOSA as the aminating agent, alongside pyridine or piperidine as the base, within HFIP solvent system. Notably, this approach showcases excellent reactivity, especially with nonactivated alkenes, and facilitates the transformation of various alkenes substrates, including mono-, di-, tri, and tetra-substituted alkenes, into aziridines with moderate to excellent yield. This method presents a promising avenue for synthesizing aziridines from a wide range of alkenes, featuring the benefits of straightforward operation, mild reaction conditions, extensive substrate compatibility, and scalability.
PubMed: 38652889
DOI: 10.1021/acs.joc.4c00253 -
Analytical Chemistry May 2024Unsaturated lipids constitute a significant portion of the lipidome, serving as players of multifaceted functions involving cellular signaling, membrane structure, and...
Unsaturated lipids constitute a significant portion of the lipidome, serving as players of multifaceted functions involving cellular signaling, membrane structure, and bioenergetics. While derivatization-assisted liquid chromatography tandem mass spectrometry (LC-MS/MS) remains the gold standard technique in lipidome, it mainly faces challenges in efficiently labeling the carbon-carbon double bond (C═C) and differentiating isomeric lipids in full dimension. This presents a need for new orthogonal methodologies. Herein, a metal- and additive-free aza-Prilezhaev aziridination (APA)-enabled ion mobility mass spectrometric method is developed for probing multiple levels of unsaturated lipid isomerization with high sensitivity. Both unsaturated polar and nonpolar lipids can be efficiently labeled in the form of N-H aziridine without significant side reactions. The signal intensity can be increased by up to 3 orders of magnitude, achieving the nM detection limit. Abundant site-specific fragmentation ions indicate C═C location and -position in MS/MS spectra. Better yet, a stable monoaziridination product is dominant, simplifying the spectrum for lipids with multiple double bonds. Coupled with a U-shaped mobility analyzer, identification of geometric isomers and separation of different lipid classes can be achieved. Additionally, a unique pseudo MS mode with UMA-QTOF MS boosts the sensitivity for generating diagnostic fragments. Overall, the current method provides a comprehensive solution for deep-profiling lipidomics, which is valuable for lipid marker discovery in disease monitoring and diagnosis.
Topics: Aziridines; Lipids; Isomerism; Tandem Mass Spectrometry; Ion Mobility Spectrometry
PubMed: 38648270
DOI: 10.1021/acs.analchem.4c00481 -
Physical Chemistry Chemical Physics :... May 2024Pentacycloundecanylidene was spectroscopically identified during the photolysis of the corresponding aziridine and its aerial oxidation results in the corresponding...
Pentacycloundecanylidene was spectroscopically identified during the photolysis of the corresponding aziridine and its aerial oxidation results in the corresponding ketone. Here we report the role of hyperconjugative interactions in stabilizing the singlet pentacycloundecanylidene and its corresponding ketone pentacycloundecanone. The pentacycloundecanylidene possesses a singlet ground state with two possible geometrical isomers based on the orientation of the carbene bridge (U1 and U2). The energy difference between U1 and U2 is minimal (0.9 kcal mol) and the triplet state is 5.6 kcal mol energetically higher than the more stable singlet state U1. The proximal C-C bonds of the carbene bridge in the singlet state are significantly elongated as compared to the distal C-C bonds. The bending of the carbene bridge in the triplet state and the carbonyl group in the ketone are minimal as compared to the parent pentacycloundecane. The molecular orbital (MO), natural bond orbital (NBO) and energy decomposition analysis (EDA) show that both Cieplak-type hyperconjugation donation of electrons from the proximal C-C σ bonds to the empty p-orbital on the carbene centre and Felkin-Anh type hyperconjugation donation of the lone pair of carbene carbon to the distal C-C σ* orbitals exist in carbene systems. The bending of the carbene bridge in singlet carbene is to enhance the Cieplak-type hyperconjugative interaction. The ketone is also stabilized by Cieplak-type hyperconjugative interaction but to a lower extent as compared to the singlet carbene. The reactivity study suggests that the singlet pentacycloundecanylidene is ambiphilic in nature.
PubMed: 38647394
DOI: 10.1039/d4cp01248h -
Angewandte Chemie (International Ed. in... Jun 2024The sulfolipid sulfoquinovosyl diacylglycerol (SQDG), produced by plants, algae, and cyanobacteria, constitutes a major sulfur reserve in the biosphere. Microbial...
The sulfolipid sulfoquinovosyl diacylglycerol (SQDG), produced by plants, algae, and cyanobacteria, constitutes a major sulfur reserve in the biosphere. Microbial breakdown of SQDG is critical for the biological utilization of its sulfur. This commences through release of the parent sugar, sulfoquinovose (SQ), catalyzed by sulfoquinovosidases (SQases). These vanguard enzymes are encoded in gene clusters that code for diverse SQ catabolic pathways. To identify, visualize and isolate glycoside hydrolase CAZY-family 31 (GH31) SQases in complex biological environments, we introduce SQ cyclophellitol-aziridine activity-based probes (ABPs). These ABPs label the active site nucleophile of this enzyme family, consistent with specific recognition of the SQ cyclophellitol-aziridine in the active site, as evidenced in the 3D structure of Bacillus megaterium SQase. A fluorescent Cy5-probe enables visualization of SQases in crude cell lysates from bacteria harbouring different SQ breakdown pathways, whilst a biotin-probe enables SQase capture and identification by proteomics. The Cy5-probe facilitates monitoring of active SQase levels during different stages of bacterial growth which show great contrast to more traditional mRNA analysis obtained by RT-qPCR. Given the importance of SQases in global sulfur cycling and in human microbiota, these SQase ABPs provide a new tool with which to study SQase occurrence, activity and stability.
Topics: Fluorescent Dyes; Glycoside Hydrolases; Bacillus megaterium; Catalytic Domain; Models, Molecular; Methylglucosides
PubMed: 38647177
DOI: 10.1002/anie.202401358 -
Lipid Isobaric Mass Tagging for Enhanced Relative Quantification of Unsaturated -Positional Isomers.ACS Measurement Science Au Apr 2024Changes in the levels of lipid -positional isomers are associated with perturbation of the physiological environment within the biological system. Consequently, knowing...
Changes in the levels of lipid -positional isomers are associated with perturbation of the physiological environment within the biological system. Consequently, knowing the concentrations of these lipids holds significant importance for unraveling their involvement in disease diagnosis and pathological mechanisms. However, existing methods for lipid quantification often fall short in accuracy due to the structural diversity and isomeric forms of lipids. To address this challenge, we have developed an aziridine-based isobaric tag labeling strategy that allows (i) differentiation and (ii) enhanced relative quantification of lipid -positional isomers from distinct samples in a single run. The methodology enabled by aziridination, isobaric tag labeling, and lithiation has been applied to various phospholipids, enabling the determination of the -positions of fatty acyl chains and enhanced relative quantification. The analysis of lipid extracts demonstrated the enhanced determination of the concentration ratios of lipid isomers by measuring the intensity ratios of mass reporters released from -positional diagnostic ions. Moreover, we applied the method to the analysis of human colon cancer plasma. Intriguingly, 17 PC lipid -positional isomers were identified and quantified simultaneously, and among them, 7 showed significant abundance changes in the colon cancer plasma, which can be used as potential plasma markers for diagnosis of human colon cancer.
PubMed: 38645577
DOI: 10.1021/acsmeasuresciau.3c00062 -
Angewandte Chemie (International Ed. in... Jun 2024The one-pot synthesis of λ-dibenzothiophen-5-imino-N-dibenzothiophenium triflate (1) in multigram scale is reported. This compound reacts with Rh(esp)...
The one-pot synthesis of λ-dibenzothiophen-5-imino-N-dibenzothiophenium triflate (1) in multigram scale is reported. This compound reacts with Rh(esp) (esp=α,α,α',α'-tetramethyl-1,3-benzenedipropionic acid) generating a Rh-coordinated sulfonitrene species, which is able to transfer the electrophilic nitrene moiety to olefins. When indenes are used as substrates, isoquinolines are obtained in good yields. We assumed that after formation of the corresponding N-sulfonio aziridine, a ring expansion occurs via selective C-C bond cleavage and concomitant elimination of dibenzothiophene. Unexpectedly, a similar protocol transforms 1-arylcyclobutenes into 1-cyano-1-arylcyclopropanes. Our calculations indicate that aziridination is not favored in this case; instead, sulfilimine-substituted cyclobutyl carbocations are initially formed, and these evolve to the isolated cyclopropanes via ring contraction. Both procedures are operationally simple, tolerate a range of functional groups, including oxidation-sensitive alcohols and aldehydes, and enable the convenient preparation of valuable N-labelled products. These results demonstrate the potential of 1 to provide alternative pathways for the selective transfer of N-atoms in organic molecules.
PubMed: 38623698
DOI: 10.1002/anie.202403826