Monday, September 9, 2019

Decarboxylative etherification

Our most recent work in electrochemistry was published today: A method to make hindered ether compounds from abundant carboxylic acids. Given the extensive information in the >400 pages of SI, we are not going through the details of the work in this blog post, but instead decided to present some details from behind the scenes.

As a project that required massive work, you might be wondering how it got started. Actually, Phil always got the consulting question that how to construct hindered ether bonds effectively from the pharmaceutical industry because they are quite important in drug discovery. It surprised us that in the 21st century, people still rely on acid promoted hydroalkoxylation to make such bonds, which often fails in the real-world cases due to a lack of chemoselectivity and sluggish reactivity. Being aware of this, we decided to tackle this problem.

By digging into the literature, we found an interesting reaction called the Hofer-Moest reaction which has a >100-year old history. This reaction enables generation of carbocations that can be intercepted by solvent quantities of alcohol to form the ether products. Without even understanding the details in the original paper published in 1902 (written in German), we started our journey towards the hindered ether synthesis. Carefully studying the follow up literature, we found this reaction is extremely limited in terms of the scope of both carboxylic acids and alcohols. In order to develop a practical method that can be used by the industry, we thought the key was to find a suitable solvent and electrolyte that enabled us avoiding use solvent amount of alcohol. After extensive evaluation (>1000 experiments), we identified a new set of conditions for this old chemistry. To make a long story short, here is an example of just how simplifying this chemistry is, in the context of synthesis of biologically active intermediates. Using compound 1 which is an intermediate of aurora kinase modulator as an example, previously, a multi-step route was employed requiring over 6 days of reaction time (<4% overall yield), wherein the key C–O bond-forming reaction—the treatment of methylenecyclobutane with BF3•Et2O—provides the ether in only 11% yield. Now with our electrochemical method, it can be accessed in only 2 steps, 51% yield and most impressively 15h.

While we think the step-count and time savings largely speak for themselves, our colleagues who are industrial process chemists are much more rigorous about efficiency characterization.

Process chemists tend to use “PMI,” or Process Mass Intensity, as a quantitative measure of a synthetic route’s efficiency. Our friends at BMS have conveniently developed an app, the “PMI Prediction Calculator” (Click here to play with the app yourself), that enables people quickly to know the efficiency and PMI of a certain process. We used this app to calculate the PMI of the old vs. new route to 1. The result: Our route to synthesis of compound 1 has a PMI of 252, versus 1304 for the previous one. This result clearly demonstrates the high efficiency, robustness and greenness of our new method.

Ideality is another way to quantify the parameters of efficiency for a synthetic sequence. We calculated the ideality% for the 12 real-word applications based on the definition published a few years ago (this paper). Amazingly, for 9 examples, the current methods have an ideality of 100% which are much higher than the reported routes.

Lastly, it is a tradition for our lab to showcase the limitations of the methodology that we have developed, to give the readers a better understanding of the reaction. Some of the limitations for the decarboxylative etherification and hydroxylation are shown below. In general, the secondary acids without any stabilizing effect such as benzyl or hetero atom will be problematic for this etherification reaction, due to the relatively instability of the corresponding carbocations. We hope this may be helpful for those who decide to try this reaction on similar substrates.

Let us know if you have any questions or comments regarding the work! Thanks for reading!

Ming, Jinbao and the etherification team