Colton Johnson

Recovery of a Peptide Intermediate from a Reaction Mixture Contaminated with a Large Quantity of Silicone Oil Coolant 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.

I can't imagine the stress after finding cracks in the reactor during a GMP run. Overall, a cool lesson in removing silicone oil derived impurities and contaminant purging.

pubs.acs.org/doi/10.1021/...

Formal Cyclopropylation of Imines with Cyclopropanols: Stereocontrolled Access to Conformationally Constrained γ‐Amino Alcohols A formal cyclopropylation of imines with cyclopropanols enables stereoselective access to cyclopropane-embedded γ-amino alcohols bearing three contiguous stereocenters. The transformation proceeds th...

Perhaps I'm a bit biased being at UofT, but cyclopropanols are pretty sweet. Yoshikai's report of cylopropyl anion equivalents beautifully expands the known reactivity of this versatile C3 synthon! Definitely worth a read!

onlinelibrary.wiley.com/doi/10.1002/...

Come check out my talk at #CSC2025 where I’ll discuss about my strategy towards hexacyclic diterpenoid alkaloids. If you want to see cool pericyclic reactions and how to troubleshoot a Mitsunobu reaction it’s the lecture for you! Come say hi!

Carbonyl-to-sulfur swap enabled by sequential double carbon-carbon bond activation 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...

Out First Release in @science.org today, Zining Zhang in @donglab.bsky.social swaps out ketones for sulfur in saturated carbon rings through two modes of radical trapping www.science.org/doi/10.1126/...

Concise Total Synthesis of Ambiguine P 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–...

Ang Li does it again! I'm always impressed with his syntheses; the Cope-Prins-FC Alkylation cascade just blows me away.

pubs.acs.org/doi/10.1021/...

Non-enzymatic methylcyclization of alkenes - Nature Chemistry 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...

There are a lot of reactions in nature that we take for granted and analogous "simple" chemical solutions don't exist; this leaves some beautiful problems to solve with creative solutions.
Magauer's work on methylcyclization directly addresses one of these; I love it!

www.nature.com/articles/s41...

Photocatalyzed Epimerization of Quaternary Stereocenters 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.

Beautiful work from the Schuppe group! This is a huge improvement to Zard and Schaffner's early work on these type of quaternary epimerizations.

pubs.acs.org/doi/10.1021/...

Spiro-C(sp3)-atom transfer: Creating rigid three-dimensional structures with Ph2SCN2 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-...

Also in @science.org this week, Max Hansmann’s group return with yet another convenient C-atom transfer agent. This time, a diazo/sulfur ylide hybrid favors spiro-type sp3 products from olefins

chemsky 🧪

www.science.org/doi/10.1126/...

Hi, I’d love to be included on this list!

Alkyl groups in organic molecules are NOT inductively electron-releasing 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...

First post on here for #chemsky you’ve always been told that alkyl groups are inductively electron donating. I’m afraid that’s not actually true! There’s a fair bit of evidence that they are electron withdrawing and we’ve just added to that!

pubs.rsc.org/en/content/a...

iirc it’s from a Swern byproduct, I think the authors tried other amines and didn’t see this byproduct, so perhaps one of the latter steps also affects it.

Glycosylium Ions in Superacid Mimic the Transition State of Enzyme Reactions 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.

I've always found Olah's work (among others) on the structure of carbocations to be fascinating. This work highlights our ability to design systems that come close to mimicking transformations nature has been doing for eons. Some absolutely beautiful research!

pubs.acs.org/doi/10.1021/...