When I look at potently bioactive molecules, I can’t help but think of a “David vs Goliath” biblical analogy. An why not, especially when something that is rather miniscule (a small molecule) exerts a profound effect on a molecular entity that is orders of magnitude larger (a protein)? I particularly appreciate subtle aspects of molecular interactions, especially if there is a stereoelectronic effect that is linked to a biological outcome. In the past, I commented on such findings several times and will continue to do so because this is perhaps the main reason why organic chemistry is second to none in terms of pure intellectual delight.

David Fairlie of the University of Queensland was one of the speakers at the American Peptide Symposium I organized with Ved Srivastava this past June. In his lecture, David showed the following two molecules. The one on the left agonizes the C3a receptor (a G-protein coupled receptor), whereas the one on the left antagonizes the C3a target. Given the diametrically opposite effects of activating vs deactivating the receptor, a question arises about the underlying causes. In their JACS article, the Fairlie team provides convincing evidence that the observed effect is due to the preferred population of two different rotamers about the amide carbonyl and the heterocycle. This is a great example of how stereoelectronic effects in heterocycles dictate different dipole relationships, which in turn modulates molecular conformation and leads to different biological properties.

http://pubs.acs.org/doi/abs/10.1021/ja506518t

I really like reading Adam Nelson’s papers. The one I saw in Synlett today is noteworthy because of the kind of vignette that does not typically make it into a TOC (Table of Contents) graphic. I call it the “roadkill”, which is one of the most frustrating things in today’s world of science publishing. The published content seems to be ballooning out of hand. Not only do we have way too many journals, but the sheer volume of stuff is so enormous that it is impossible to do what was feasible even 15 years ago: flip through the contents of an issue and find roadside nuggets.

https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0034-1378704

Speaking of nuggets, the one I found in Adam’s paper is a mere afterthought to the main point of the manuscript, which happens to be construction of heterocycles by multicomponent reactions. As I was going through the paper, I noted how a TFA amide was converted into a cyclic urea. As someone who knows (or used to know) a thing or two about trifluromethylation (my Chemical Reviews paper with Prakash was influenced by the challenge of trifluoromethyl group transfer using organosilicon reagents: http://pubs.acs.org/doi/pdf/10.1021/cr9408991), I think there is something unique here. Can you name another case that involves a TFA amide losing its trifluoromethyl group in a reaction? I can’t. The authors did not make a big deal out of this, but they should have (in my opinion). While there have been cases in which metal catalysts had triggered fluoroalkyl group transfer from fluoroalkylated acid derivatives, the seemingly trivial afterthought in Adam’s paper is worthy of note. Trapping the resulting trifluoromethyl anion with electrophiles might be interesting in a different context. Again, I am assuming that TFA amides have not found any use in this capacity, which may not be the case. After all, I have not followed this area of inquiry for a number of years.

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.

http://www.sciencedirect.com/science/article/pii/S004040390900094X

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.

http://www.nature.com/nbt/journal/v32/n10/full/nbt.2968.html

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.

I am in Copper Mountain, Colorado, attending the annual meeting of the American Society of Pharmacognosy. Scott Lokey has put together a nice symposium on macrocycles, but a lot here is a bit beyond my expertise. The vast majority of researchers at this meeting are natural products isolation people, a crowd with its own jargon, rules, and ideas about what is cool and what is not.

There was a great talk by Jon Baell yesterday, in which he described molecules now referred to as PAINS, or pan-assay interfering compounds (http://pubs.acs.org/doi/pdf/10.1021/jm901137j). Essentially, anything that is an electrophile or a masked electrophile, is sure to cause trouble in assays. Looking out for structures that contain PAINS is not that tough if you are a trained chemist.

There were some real gems in the total synthesis section. I particularly liked the talk by Bill Maio of New Mexico State University. As someone who has been interested in new ways of making macrocycles, I really enjoyed his unconventional approach to making the amide bond of taumycin A. The allene intermediate shown below is generated by the base-induced decomposition of the corresponding beta-ketoester. I found this way of closing the ring to be very creative.

http://pubs.acs.org/doi/abs/10.1021/ol5025585

I was reading a maoecrystal V total synthesis paper by Regan J. Thomson and colleagues and kept telling myself: “Who would be crazy enough to do this sort of thing these days?”. And then cold sweat started pouring off my forehead… One of the co-authors on the paper was my former PhD student, Igor Dubovyk, who has been working in Regan’s lab over the last couple of years… Prior to going to Chicago, Igor was involved in some really neat palladium chemistry in my lab such that we still fondly remember his important contributions to our program. I reached over to Igor and asked him if he would be interested to sum up some elements of his approach to maoecrystal V. Here is what Igor had to say:

Ever since I purchased the 1^st volume of the “Classics in Total Synthesis” by K. C. Nicolaou from the U of T used bookstore for Andrei’s graduate class, I have developed an obsessive fascination with natural products. The idea of building something so complex from simple materials available from Aldrich was so mind-boggling; it was almost too good to be true. Of course, being a young rebellious mind that I was at the time, I had no appreciation for such important factors as funding or the tremendous risks involved in pursuing such long-term highly ambitious projects. These are very important factors in research, as any professor would tell you, which is why being a grad student or a postdoc is the carefree period of our careers. It is during these very periods when we find ourselves “vulnerable” to the “unfundable” ideas incepted in us by the top researches in the field, and therefore, are less likely to resist dreaming about bringing them to life. After defending my dissertation in the area of palladium-catalyzed allylic amination I had an opportunity to work in industry, which gave me more time to read books on strategies used to devise efficient routes for the syntheses of natural products. Reading this sort of literature had not satisfied my curiosity but, on the contrary, has left me with even more unanswered questions. It has become clear to me that I would never find piece unless I get directly involved in a total synthesis project. The opportunity has presented itself when professor Regan J. Thomson from the Northwestern University has agreed to offer me a postdoctoral position in the field of total synthesis of caged terpenes. I was put on the Maoecrystal V, an ongoing project in the group for several years. As I have learned, the molecule was subject of active pursuit not only due to its complex architecture, but also for its high toxicity towards human ovarian tumour HeLa cell line (IC₅₀ = 20 nM). By the time I joined, 3 groups have already accomplished a total synthesis of the racemate and numerous others have reported their ongoing efforts. My colleague Dr. Changwu Zheng has completed about 70% of the new synthetic route towards the racemate, which I was supposed to render enantioselective before helping him finish the synthesis. The route relied on several key steps, one of which was a highly diastereoselective Heck cyclization that furnished one of the quaternary centers and a new ring, while placing the alkene in the desired position (see the Scheme shown below). The precursor to the Heck reaction was allylic alcohol 1, which, in the synthesis of the racemate came from the corresponding enone 2. Switching LAH for the CBS reagent seemed like a no-brainer until the chiral HPLC confirmed the reproducible enantioselectivity of 30%. The result was not any better for the Midland reduction. We have reasoned that the chiral catalyst could not differentiate between the two bulky substituents on either side of the ketone. It became clear that at this point we had a choice to either spend another who-knows-how-long trying to optimize the system by screening solvents, additives etc. to improve the ee slightly or to take a more indirect approach by making something simple with high enantioselectivity and then find a way to convert that product to the compound of interest. In the course of our investigations we discovered that the required stereocenter could be correctly installed through the highly enantioselective Sharpless epoxidation of the starting allylic alcohol (see the Scheme shown below). After several months of experimentation, a scalable route to the desired Heck precursor was finally found. Coupling the Sharpless product 3 with trichloroacetimidate 4, followed by the reduction of the ketone with sodium borohydride gave a mixture of diastereomeric epoxy alcohols (Scheme 3). Transforming the alcohols into the corresponding iodides, and subjecting them to reductive conditions using zinc led to a stereoconvergent epoxide ring opening to give 25 g of alcohol 1 in 94% ee. The rest of the core of (–)-Maoecrystal V was assembled through an oxidative dearomatization made possible due to the proximity of the secondary alcohol to the phenol moiety, as well as an intermolecular Diels-Alder cycloaddition. The end game of the synthesis consisted of selective C–H oxidation reactions:

http://pubs.acs.org/doi/abs/10.1021/ja5109694

This aggressive approach not only resulted in the synthesis of (–)-Maoecrystal V, but also allowed us to gain access to the unnatural enantiomer of the molecule. Both enantiomers as well as the advanced synthetic intermediates leading to their formation were sent for biological studies against different tumour cell lines. Although the details of the complete synthetic study of (–)-Maoecrystal V will be released sometime in the future, I would like to admit that this project was an emotional rollercoaster, especially for my colleagues Changwu and Kiel. We owe a debt of gratitude to Kiel for his PhD-long synthetic investigations that have ultimately resulted in the undertaking of this particular route. In our group pressures to develop short practical total syntheses continue to uncover new reactivity and serve as an inspiration for the development of new methodologies.

It is not that often that I pick up an interesting purification trick from a chemical biology paper. Yet, this is exactly what happened to me while I was reading the ACS Chemical Biology manuscript by Bernat et al. This intriguing recent work documents the use of boronic acid probes of allosteric modulation of the chemokine CXCR3 receptor. Biological merits of the manuscript aside, I was drawn to the way the authors purified their boronic acid inhibitors. Their solution to the problem involves dry column flash chromatography, the description of which even made its way into the paper’s abstract. Given the focus of the journal, this probably means that the authors were really satisfied with the results. The technique consists of placing a dry bed of silica gel in a sintered glass funnel followed by fraction elution using suction. I have not attempted this methodology myself in the good old days when I was still doing somewhat meaningful research at the bench. I did a bit of digging and discovered a nice paper in the Journal of Chemical Education detailing this method. I actually think my students use this all the time, but I do not recall anything extraordinary about this tool. Now it turns out that it might be just what we need for some of our annoyingly polar boron-containing molecules. By the way, whenever there is something I want to learn in detail, I turn to the Journal of Chemical Education. Therein lies a treasure trove of information because the idea is to publish methods and procedures that are adaptable in undergraduate settings.

 http://pubs.acs.org/doi/abs/10.1021/cb500678c

http://pubs.acs.org/doi/abs/10.1021/ed074p1222

One more item of substance that relates to aliphatic boronic acids: during lyophilization, don’t go too crazy in your attempts to rigorously remove water from the purified compound. This is a bad idea as the Le-Chatelier principle will shift things in the direction of boraxine, which is notoriously sensitive to oxidative cleavage of the C-B bond. We like to keep our products somewhat wet. I picked up this tip from Professor Singaram while lecturing at University of California, Santa Cruz, last year.