Anodic oxidation brings back some good memories

Here is an interesting electrocatalytic aziridination reaction just published by Dan Little of UCSB ( Reading this work was akin to a flashback, at least for me. My lab developed very similar chemistry about 13 years ago ( Our postulated mechanism was different, though, and I still think we were correct because we were able to show that iodosobenzene derivatives oxidized N-aminophthalimide in a similar manner to our anodic process. I have always liked the analogy between the hydroxylamine intermediate and mCPBA. Atkinson used to run these sorts of processes way before any of us, although he used super-stoichiometric amounts of lead tetraacetate, which is one nasty reagent. In his Org. Lett. paper, Dan postulates a radical mechanism and it very well may be operating in the present reincarnation of the nitrene transfer. I was really surprised to see that both cis and trans alkenes lead to the cis-aziridine isomer. Ordinarily, cis-epoxides and aziridines are less stable than their trans-counterparts, but N-aminophthalimide substituent is special… These peculiarities aside, it is too bad that N-aminophthalimide is more or less the only amine that reliably participates in these kinds of reactions. Why? There are many reasons, but the most obvious one is this: the amino terminus of N-aminophthalimide is fairly nucleophilic, yet sterically unencumbered. In addition, there are no hydrogens at the alpha position. Taken together, these features lead to oxidation reactions that are relatively free of by-products.


Boron baits

My lab’s interest in boron-containing compounds has led to a sustained exploration of electrophiles that engage nucleophilic residues in proteins. In contrast to aldehydes, acrylates and epoxides, which are widely used as “baits” for nucleophilic residues in active sites, small boron-containing electrophiles have received relatively little attention. This is mainly due to their lack of stability and relative difficulty of preparation, especially when it comes to molecules with C(sp3)-B bonds. Over the past year or so, we have been working together with Ben Cravatt of the Scripps Research Institute, trying to get off the ground a research program aimed at “borofragments”. Our first paper just came out in Chem. Comm. In it, we describe a reagent that enables straightforward linking of biologically relevant heterocycles with boron. The stability of our molecules depends on the MIDA group, which acts as a slow-release element under biological conditions. This group stabilizes borofragments against premature decomposition and is released under biological conditions to unmask an active boronic acid. Borofragments can be used to discover inhibitors of enzymes that use catalytic oxygen nucleophiles. We have resorted to Ben’s activity-based protein profiling and employed our method to identify inhibitors of ABHD10 and the predicted carboxypeptidase CPVL. This technique should be applicable to other classes of targets. Given the diversity of heterocycles that are either commercially available or exist in the historical collections of the pharmaceutical industry, our straightforward method of linking molecular recognition units with stabilized boron electrophiles should enable facile exploration of previously uncharted covalent inhibitor space. I really have to thank my Japanese co-worker, Dr. Shinya Adachi, for developing this useful chemistry.


New England travels

I visited Boehringer-Ingelheim (Connecticut) last Friday, where I was hosted by Dr. Nick Desroisiers. During my visit I gave a talk and had a chance to meet many people with both process and medicinal chemistry interests. This Ridgefield site is being superbly run by Dr. Chris Senanayake, Vice-President of Chemical Development. I came away impressed by the high quality of scientific publications that have been emerging from this organization over the past 10 years. This commitment to outstanding output is due to Chris’s leadership, which is why he has my utmost respect. I always learn a lot during these trips and, today, I want to comment on a scaleable carbamoyl anion addition process that has been practiced in several different forms at Boehringer-Ingelheim. Various types of amphoteric organolithium species have been generated on 100+ kg scale. I am particularly fond of the dipeptide synthesis using this technology.