Accidental cracking at the bottom of a glass reactor vessel allowed silicone oil coolant to contaminate the reaction mixture of an N-terminal-free tripeptide intermediate (3) in the synthesis of a mid-sized cyclic peptide. Approximately 20 kg of silicone oil was leached from the reactor jacket and mixed with 35 kg of the reaction mixture. Our preliminary investigations showed that although the silicone oil and its degradation products could not be sufficiently removed by using heptane extraction from an acetonitrile solution of 3, these silicone-derived components could be successfully removed from an acidic aqueous solution of 3. Because 3 is an acid-sensitive N-alkylated peptide tert-butyl ester, it was essential to find an aqueous acidic solution that minimized decomposition while efficiently retaining 3 in solution. Using this approach, the silicone-derived components were reduced to a residual amount of 0.02 wt % relative to 3, with a 90% recovery of 3 from the contaminated reaction mixture.

A formal cyclopropylation of imines with cyclopropanols enables stereoselective access to cyclopropane-embedded γ-amino alcohols bearing three contiguous stereocenters. The transformation proceeds th...

In drug development, replacement of a skeletal carbon with a sulfur atom can result in analogs of bioactive compounds with improved properties. Currently, the sulfur analogs are almost exclusively pre...

Ambiguine P (5) is a synthetically challenging representative of the hapalindole-type natural products. Inspired by the biosynthesis of this indole terpenoid family, we developed a Cope/Prins/Friedel–...

Bifunctional methyltransferase–cyclases both transfer a methyl group to alkenes and induce cyclization—a process called methylcyclization. Now a non-enzymatic silver(I)-mediated electrophilic methylcy...

Quaternary stereocenters play a crucial role in shaping both the molecular topology of small molecules and the outcome of stereoselective transformations. While considerable progress has been achieved in constructing highly substituted carbon centers with varied substitution patterns, the stereoselective synthesis of quaternary carbon centers remains a significant challenge. Here we report a protocol for the precise manipulation of quaternary stereocenters through epimerization. The critical design element of our ketone α-epimerization process was developing a photoactive imine, which circumvents the numerous deleterious pathways of carbonyl photochemistry. Excitation of this imine with visible light in the presence of a photocatalyst enables reversible C–C bond cleavage and reformation to vary the stereochemistry of the quaternary center. This approach allows us to override intrinsic stereochemical outcomes of C–C bond construction, therefore providing novel tactics for retrosynthetic planning. The broad utility of this protocol was demonstrated by the topological alteration of various classes of carbocyclic scaffolds bearing diverse functional groups.

The introduction of a single C-atom into organic substrates typically results in the formation of flat molecules containing unsaturated C(sp)-centers. Adding a single C(sp3)-atom surrounded by four σ-...

It is commonly stated that alkyl groups exert an inductive electron-releasing effect when compared to hydrogen. This information has been given in numerous organic chemistry textbooks over the last 75...

The hydrolysis of glycosides is a biochemical transformation that occurs in all living organisms, catalyzed by a broad group of enzymes, including glycoside hydrolases. These enzymes cleave the glycosidic bond via a transition state with substantial oxocarbenium ion character, resulting in short-lived oxocarbenium ion-like species. While such transient species have been inferred through theoretical studies and kinetic isotope effect measurements, their direct spectroscopic characterization remains challenging. In this study, we exploit a superacid environment to generate, accumulate, and fully characterize nonprotected 2-deoxy glycosyl cations in the d-glucopyranose, d-galactopyranose, and l-arabinofuranose series using low-temperature NMR spectroscopy, supported by DFT calculations. Additionally, QM/MM MD simulations reveal that the properties of these glycosyl cations in superacid closely resemble those within the active sites of glycosidase enzymes, particularly in terms of conformation and anomeric charge distribution. These findings highlight a parallel between the stabilizing effect of counterions in superacid media and the network of multidentate noncovalent interactions within glycosidase active sites, which stabilize transition states with pronounced oxocarbenium ion character.