September 10, 2019 -- Researchers have developed a simple new method for the creation of hindered ether compounds, which are often important components of many drugs and commercial products. Hindered ethers have been traditionally difficult to manufacture, but scientists at Scripps Research have published a new electrochemistry technique in Nature on September 9, which allows these compounds to be produced faster and more efficiently.
Electrochemistry is the branch of chemistry which explores the interrelation of electrical and chemical changes that are caused by the passage of current. This process often generates key reactive components. "These are compounds that historically have required more than a dozen steps and more than a week of work to synthesize using standard methods," says Phil Baran, PhD, the Darlene Shiley Chair in Chemistry at Scripps Research and senior author of the study. "With our method, the compounds can be made in just a few steps--often in less than a day--and for that reason, drug companies that know of this new method already have started using it."
Hindered ethers are valuable to the pharmaceutical industry because they are naturally resistant to enzymatic degradation inside the human body. The traditional synthesis process utilized "Williamson ether synthesis," a process developed in 1850 and helped prove the structure of ethers. In this process, there is competition with base-catalyzed elimination of alkylating agents which can hinder the ether's reactivity.
When developing the new methodology, Baran and his team investigated using the Hofer-Moest reaction to synthesize hindered ethers. This method requires high electric current and an expensive setup involving the use of platinum electrodes. These factors have limited its use in chemistry laboratories. The team used this method as a foundation to build a more versatile system that uses a low electric current and cheap carbon electrodes.
The simple method for synthesis of hindered ethers, uses electrochemical oxidation to liberate high-energy carbocations. These carbocations can capture an alcohol donor under non-acidic conditions allowing for the formation of a range of ethers that would otherwise be difficult to create. Moreover, the researchers show that carbocations can be intercepted by simple nucleophiles to form hindered alcohols and alkyl fluorides.
The new methodology reported in the article suggests substantial reductions in the number of steps and the amount of labor required to create ether products. The researchers describe over 80 examples of hindered ethers that can be created with the method, some of which include:
Overall, the team found the new method allowed for an average yield of 43 percent, average step count of 1.5, and an average completion time of 9.8 hours. These compared to previous methods with 19 percent yield, 6.3 steps, and 100 hours.
Scientists see the applications of this new method ranging from small scale – exploratory chemistry for drug discovery – to large scale – chemical production. The method is particularly useful to researchers looking to build libraries of compounds that they can utilize during the candidate screening processes.
"Its ability to generate highly reactive carbocations under mild conditions suggests that we might be able to use it to make other classes of molecules that were previously inaccessible," Baran says.
Support for the research was provided by Pfizer Inc., the National Science Foundation (CCI Phase 1 grant 1740656) and the National Institutes of Health (GM-118176).
Do you have a unique perspective on your research related to medicinal chemistry and drug discovery? The Science Advisory Board wants to highlight your research. Contact the editor today to learn more.