Epoxides in dearomatization

I think most of us are aware of the delightful selectivity with which nature’s p450 enzymes turn benzene derivatives into dearomatized structures. For instance, p450’s are known for the conversion of aromatics into highly reactive monoepoxides, whereas the enzymes of pseudomonas putida take on aromatic compounds and convert them into cis-diols with exquisite selectivity.

I was looking at these reactions, noting that these oxidations affect two ring atoms at a time. What about turning an aromatic ring into an exocyclic epoxide structure in which one of the carbon atoms is outside the ring? There is in fact a great and purely synthetic way of running this transformation. I refer to the Adler-Becker reaction. It constitutes an enormously empowering, although not often used, process. The reaction does require a fairly electron-rich aromatic phenol, but the complexity generated in the course of the process is second to none. Professor Jon Njardarson of the University of Arizona used it in his approach to vinigrol and, although this was ultimately a failed route, the idea was really interesting. While in Colorado last week, I saw this process put to great use by Professor Derek Tan of the Sloan-Kettering Institute in New York City in an approach to medium-sized rings. What’s most interesting about Derek’s way is that he was later able to cleave the epoxide C-C bond, which is rather uncommon. I will discuss this nice work at some point.



On antibody-drug conjugates

While in Colorado, I had a chance to hear a remarkable talk by Dr. Peter Senter of Seattle Genetics. In recent years, this company has made quite a splash in the area of antibody/drug candidates (ADCs). One of their more recent accomplishments is FDA-approved brentuximab vedotin (Adcetris) for relapsed Hodgkin lymphoma and anaplastic large cell lymphoma.

If you have any interest in molecules that are toxic, the ADC concept is quite enabling. The idea is that the toxic “payload” is linked to an antibody, and thus specificity is “outsourced” as the antibody part is engineered to have high affinity for the target cell of interest. If a cancer cell is the target, the ADC binds to its cell surface, followed by internalization and payload release as the ADC undergoes degradation inside the cell. As you might imagine, a lot of effort goes into perfecting the payload/antibody conjugation chemistry. The corresponding reactions are fairly simple and typically rely on covalent cysteine modification. The key parameter is temporary stability of the conjugate as one does not want the toxic component to leak out prematurely. One of the recent Nature Biotechnology papers by Seattle Genetics describes a cool solution to the problem of undesired retro-Michael addition of payloads from antibody-drug conjugates. It turns out that planting an amine in the vicinity of the maleimide makes imide hydrolysis way faster. The retro-Michael reaction of the opened form is in turn significantly slower. I like this work because it is not often that I can trace back the inner workings of powerful technology to simple and teachable physical organic chemistry.



I have to note that I do not fully agree with the mechanistic statement made by the authors. They propose that the amine is there to catalyze water addition: “These results are consistent with an intramolecular catalysis mechanism in which the proximal amine promotes the attack of the succinimide carbonyl group by water”. In my view, this is almost certainly not the reason for the observed effect. Unless there is something unusual with the kinetics of imide hydrolysis, the more likely explanation is faster collapse of the tetrahedral intermediate when the amine is placed nearby.