Building compounds less expensively

Rice team publishes simple aziridination method for synthesizing pharmaceutical building blocks

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HOUSTON—A team of researchers at Rice University has developed a one-step process for inexpensively synthesizing aziridines directly from olefins at room temperature, offering improved access to valuable pharmaceutical building blocks.
The group’s organic synthesis technique catalyzes the transfer of nitrogen atoms to olefins, also known as alkenes, which are critical to drug discovery. The team published their new aziridination method in Nature Catalysis earlier this year.
The process transfers nitrogen to unmodified olefins that have not already been functionalized. Unactivated olefins are commodity chemicals, but historically have been difficult to functionalize. The Rice process combines nitrogen, hydrogen and carbon atoms under operationally simple and mild conditions to obtain triangular aziridine products that are readily available to react with other agents. Nitrogen-containing small molecules are more easily converted into more complex molecules and are important chemical building blocks.
“The biggest improvement over existing methods is that our new process does not require expensive rhodium catalysts,” says Dr. László Kürti, an associate professor of chemistry at Rice University and head of the research team, adding that “The new process will be a lot less expensive as a result.” According to Kürti, as of mid-April 2020, the price of rhodium is around $5,800 per ounce, approximately three times the price of gold.
“Also, since pharmaceutical final products cannot tolerate the presence of residual rhodium, the use of traditional Rh-catalyzed methods is burdened with the costly removal of trace rhodium from the APIs [active pharmaceutical ingredients],” he notes.
The team expects that both small labs in academic and industrial discovery chemistry settings and large-scale industrial production labs can benefit from the operationally simple process of synthesizing aziridines.
“We anticipate that this cost-effective nitrogen-transfer process will be heavily used in pharmaceutical industry,” commented Dr. Zhe Zhou, a postdoctoral research associate at Rice University. “This new olefin organocatalytic aziridination allows for a drastically reduced cost of development and also improves the scalability of manufacturing.”
The primary disadvantage to the Rice process is that it is somewhat slower at producing aziridines compared to the rhodium-catalyzed process. The organic, room-temperature synthesis takes about six hours to complete using the new method, versus 10 to 30 minutes for the rhodium-catalyzed process. The team believes that many researchers will be willing to accept the trade-off, especially when producing large batches, of a somewhat slower process that is operationally simple and saves considerable cost.
The widespread adoption of this method of synthesizing aziridines can have far-reaching implications beyond simple cost savings. Researchers having ready access to these pharmaceutical building blocks using operationally simple processes that can be performed in mild conditions may open up new lines of study that might otherwise go unexamined.
“Aziridine functionalities have been shown to greatly improve the biological activities of APIs; however, due to the difficulties in their syntheses, these important functionalities are rarely explored,” explains Kürti. “We believe many new discoveries will be made as researchers can readily convert the ubiquitous olefins into the corresponding aziridines.”
Although confident that the current process should already be attractive to academic researchers and the pharmaceutical industry, the team continues to refine the process to control how the nitrogen attaches to the olefin and to control the essential chirality, or “handedness,” of the product early in the process in order to further conserve resources.
“We definitely want to make the process more enantioselective,” says Kürti. “Many compounds have chiral centers, and these are often obtained as racemates—a pair of enantiomers that are mirror images of each other and have very different biological activities—during the early manufacturing steps. However, most of the time the final API consists of only one of the enantiomers. This necessitates the sometimes costly separation of the two enantiomers in the final step. If we can selectively make only the desired enantiomers early in the synthetic route, it will save a lot of time and resources.”
According to Kürti, the team at Rice University has recently received new funding to continue its research program on the synthesis of amines. It has received funding support from the National Institutes of Health in the form of a Maximizing Investigators’ Research Award R35 grant, as well as from the Robert A. Welch Foundation.

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