Better heterocycles

What is the best heterocycle out there and how do we find it? This is a dumb question because it is not clear what the purpose of the query is. Let’s say we are talking about drug discovery. I really doubt that there are yet-to-be-discovered “silver bullets” that will beat everything else from the standpoint of ligand efficiency (I blogged about this concept in the past). It is actually quite amusing to talk to biologists, who expect that our heterocycle-containing inhibitors can be magically turned into something that is way better (by several log units – this is what they want) by some simple tweak that should be obvious to us based on our years of training… Something like this might become possible if we discover a handful of new elements on Mars, bring them down here, and plug them into pyridine. But not before… If we consider drug discovery a bit further, though, there are reasons to rank heterocycles in terms of their metabolic liability. In fact, there are efforts aimed at comparing heterocycles from the standpoint of binding to human serum albumin, CYP450 inhibition, etc. One recent study carried out at GlaxoSmithKline suggests that pyridazine is one of the most “developability”-friendly heterocycles as it presents the fewest downstream issues. This is quite interesting and you can read the details of analysis here:!divAbstract

As luck would have it, I got some interesting “pyridazine” insights today. Earlier I had a phone conversation with Dr. Herdewijn of Galapagos in Belgium. I am not at liberty to disclose the subject of our conversation at this point, but I went online to read about some chemistry developed at Galapagos and was excited to come across a really cool pyridazine construction that came out of their labs. The sequence that you see below is a fantastic way to these scaffolds; it employs a rarely used process – the diaza-Wittig reaction (not to be confused with the aza-Wittig reaction, which is a very well established way to make imines).


Forgotten tools of separation

First of all, you might say: “Forgotten by whom? Not by me!”… You might be right, I admit that it is rather presumptuous of me to come up with post titles boasting the words “forgotten”, “neglected”, etc. But I would still venture to say that, given the wealth of high tech machines a synthesis laboratory might have these days, the majority of us do not resort to the older, more obscure purification methods. Today I want to bring to life silver nitrate (SN) impregnated chromatography as a method par excellence in really tricky separations. Below you can see two pinene isomers that are rather difficult to separate using conventional silica gel chromatography, yet are differentiated by the delta Rf of 0.2 using SN chromatography. I am including an excellent review by Mander that goes into the details of this great method. Some of you wonder if this would work best on alkene-containing molecules and you are right (due to silver-alkene coordination), but the method is not limited to separating on this basis alone. In Mander’s review, you will notice some intriguing examples of heterocycles that have been successfully separated using SN chromatography. So let’s keep these old methods in our lore of separation tricks, ladies and gentlemen.


My recent visit to Alphora

I visited Alphora Research about 10 days ago. Alphora is a company that specializes in organic synthesis and leverages their tremendous process research expertise in projects that involve production of pharmaceuticals (under GMP standards). I think this is a great place to practice one’s synthetic skills because pretty much everything that is remotely interesting in the pharmaceutical process research is nowadays outsourced from places such as Pfizer (who are busy doing acquisitions) to smaller companies such as Alphora. As a result, students who are trained in synthesis may get jobs in such smaller companies and practice what they are passionate about – making molecules. I was really impressed with the kinds of projects Alphora scientists get to work on. They really solve important problems. For a representative recent example I direct you to a paper they put out earlier this year in Tetrahedron Letters (see the link below). The target of synthesis here is Eisai’s Eribulin molecule, which is a truncated version of the natural product Halichondrin B. I am amazed that molecules of this complexity (there are 15 chiral centers here!) have reached the market. The innovation in Alphora’s approach was to introduce nitrogen early in synthesis, which is something you typically want to avoid as the risks outweigh the benefits: according to conventional wisdom, one is better off introducing nitrogen atoms towards the end of synthesis. But, under the leadership of Dr. Boris Gorin, Alphora scientists took the risk of the “early nitrogen game plan” and, as a result, reaped the benefits of dealing with crystalline intermediates along the way.

There was something else during this trip that attracted my attention. It was one of those Chemtrix instruments that perform flow synthesis. I have seen a ton of flow synthesis machines in recent times at various venues, but Chemtrix really caught my eye. My beef with flow synthesis has always been about what happens next. It is ok to make a few mg’s really well. Or a gram. But what if you need to make 100 kg’s or 100 tons? Apparently, this Chemtrix instrument is a result of a ton of work on behalf of a very dedicated team of engineering geeks who promise linearity in scale-up. In other words, they have figured out an appropriate scaling algorithm that enables one to take the results of flow synthesis on a very small scale and have close to a guarantee that it will produce the same yield on a multi-kg or a multi-ton scale. All you need are fancier pumps and larger surface area in your tubes and reactors (which they produce and supply). None of this is random, but is calculated with utmost precision taking into account flow dynamics, mixing times, turbulence, etc. I need to buy one of these instruments one day.

Stereospecificity and protons

Recent efforts to chart novel classes of molecules beyond the co-called “rule of 5” space have consistently pointed at macrocycles as privileged scaffolds. A lot has been said about their conformation and capacity to hide hydrogen bonds. It is not easy to evaluate the significance of complex conformational ensembles, let alone extract useful rules that might have predictive power. I have been longing for a reductionist approach that could hopefully unambiguously demonstrate the effect of ONE hydrogen bond on lipophilicilty and other drug-like properties in a cyclic molecule. In fact, there is a recent study that does just that. In their J. Med. Chem. paper, Kihlberg and co-workers evaluate a diastereomeric series of T. cruzi growth 
inhibitors and showcase vastly different 
solubility, lipophilicity, pKa, and cell permeability for two sets
 of four stereoisomers. Intriguingly, all it takes is a switch in chirality of one of the stereocenters to improve the chances for intramolecular hydrogen 
bond and concomitant pKa difference. The authors carefully analyzed the conformations of their 8-membered rings by NMR, considered the differences in chemical shifts, their temperature dependencies, and obtained solid evidence pointing toward the formation of intramolecular hydrogen bond in the trans (not cis) diastereomer shown below. This is a very thought-provoking case as it highlights a fairly small perturbation that results in a substantial difference in properties. While I am impressed with the results, I keep reminding myself that obtaining this sort of data is not trivial and we are unlikely to see easy fixes as there are so many different scaffolds out there. The main reason there is a higher degree of difficulty in macrocycles compared to small molecules is that functional groups are much more interrelated through limited rotation (and the one you see isn’t even a macrocycle… it is a medium-sized model).