Chemists frequently encounter problems associated with trace palladium in synthetic samples because palladium is widely used in synthetic organic chemistry. We previously reported a colorimetric method for trace palladium quantification, the only high-throughput method implemented in the pharmaceutical industry. However, slight changes from the published reaction conditions have caused reproducibility problems, with little understanding of underlying molecular mechanisms. In the current study, we took a combinatorial approach to investigate the method and found that excess NaOH was a culprit for the lack of reproducibility. We changed the reaction conditions and procedure accordingly, which substantially improved reproducibility. The reaction under current conditions followed Michaelis–Menten kinetics, allowing for predicting reaction rates on the basis of the substrate concentrations. The current method showed 57 and 72% average error, respectively, when drugs spiked with known amounts of palladium and synthetic samples with unknown amounts of palladium were analyzed. The trend of palladium concentrations determined by the current method boded well with actual palladium concentrations.
Meayamycin B is currently the most potent modulator of the splicing factor 3b subunit 1 and used by dozens of research groups. However, current supply for this natural product analogue is limited because of the lengthy synthetic scheme. Here, we report a more concise, more cost-effective, and greener synthesis of this compound by developing and employing a novel asymmetric reduction of a prochiral enone to afford an allylic alcohol with high enantioselectivity. In addition to this reaction, this synthesis highlights a scalable Mukaiyama aldol reaction, Nicolaou-type epoxide opening reaction, stereoselective Corey–Chaykovsky-type reaction, and a modified Horner–Wadsworth–Emmons Z-selective olefination. We also discuss a Z–E isomerization during the α,β-unsaturated amide formation. The new synthesis of meayamycin B consists of 11 steps in the longest linear sequence and 24 total steps.
The palladium-catalyzed Tsuji–Trost reaction has been extensively studied under synthetically relevant conditions (millimolar concentrations of substrates and catalyst, aprotic solvents, no additives). Despite the increasing use of the Tsuji–Trost reaction in other areas (e.g., chemical biology), the paucity of kinetic studies at micromolar concentrations of substrates in water has impeded progress. Herein, we show that a fluorescence-based high-throughput method provided massive Eyring plot data and revealed three kinetic regimes. The associated turnover-limiting steps (TLSs) were assigned as the oxidative addition (regime 1; ΔH ⧧ > 0), nucleophilic attack (regime 2; ΔH ⧧ ≈ 0), and association (regime 3; ΔH ⧧ < 0, inverse temperature dependence). A kinetic profile under particular conditions depended on the substrate concentration and reaction temperature. Density functional theory calculations supported these findings. This work indicates that a TLS under dilute conditions may be different from that under synthetically relevant conditions and may provide a path toward the development of faster and more reproducible Tsuji–Trost reactions for synthetic, analytical, and biological applications.
Hydrogen peroxide (H2O2) mediates the biology of wound healing, apoptosis, inflammation, etc. H2O2 has been fluorometrically imaged with protein‐ or small‐molecule‐based probes. However, only protein‐based probes have afforded temporal insights within seconds. Small‐molecule‐based electrophilic probes for H2O2 require many minutes for a sufficient response in biological systems. Here, we report a fluorogenic probe that selectively undergoes a [2,3]‐sigmatropic rearrangement (seleno‐Mislow‐Evans rearrangement) with H2O2, followed by acetal hydrolysis, to produce a green fluorescent molecule in seconds. Unlike other electrophilic probes, the current probe acts as a nucleophile. The fast kinetics enabled real‐time imaging of H2O2 produced in endothelial cells in 8 seconds (much earlier than previously shown) and H2O2 in a zebrafish wound healing model. This work may provide a platform for endogenous H2O2 detection in real time with chemical probes.
Hydrogen peroxide (H2O2) mediates the biology of wound healing, apoptosis, inflammation, etc. H2O2 has been fluorometrically imaged with protein‐ or small‐molecule‐based probes. However, only protein‐based probes have afforded temporal insights within seconds. Small‐molecule‐based electrophilic probes for H2O2 require many minutes for a sufficient response in biological systems. Here, we report a fluorogenic probe that selectively undergoes a [2,3]‐sigmatropic rearrangement (seleno‐Mislow‐Evans rearrangement) with H2O2, followed by acetal hydrolysis, to produce a green fluorescent molecule in seconds. Unlike other electrophilic probes, the current probe acts as a nucleophile. The fast kinetics enabled real‐time imaging of H2O2 produced in endothelial cells in 8 seconds (much earlier than previously shown) and H2O2 in a zebrafish wound healing model. This work may provide a platform for endogenous H2O2 detection in real time with chemical probes.
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