The active ingredient in many drugs is what is known as a small molecule: larger than water, much smaller than an antibody, and composed primarily of carbon. However, it is difficult to produce these molecules if they require a quaternary carbon: a carbon atom bonded to four other carbon atoms. But now, scientists at Scripps Research have discovered a potentially cost-effective way to produce these complicated motifs.
In the new findings, which were published in Science On April 5, 2024, chemists at Scripps Research demonstrate that it is possible to convert chemical feedstocks to quaternary carbons using a single, inexpensive iron catalyst. This method could benefit drug developers by making molecules cheaper and easier to produce on small and large scales.
“Quaternary carbons are ubiquitous in diverse areas of research, from drug discovery to materials science,” says co-author Nathan Dao, a doctoral candidate at Scripps Research. “However, the synthesis of quaternary carbons is a long-standing challenge in the field of organic chemistry, typically requiring numerous steps and relying on harsh conditions or less accessible starting materials.”
In addition to Dao, co-authors of the study included Xu-Cheng Gan and Benxiang Zhang.
Catalysts are substances used to speed up the rate of a chemical reaction. Sometimes, several different catalysts are necessary to promote a given reaction and obtain the desired result: a real “soup of reactions.” But catalysts can be very expensive and don’t always react as expected, and the more catalysts used, the more waste is produced. But Scripps Research scientists determined that a single catalyst could perform multiple crucial functions.
“A difficult chemical reaction often requires many interacting components,” according to co-senior author Ryan Shenvi, PhD, a professor in the Department of Chemistry at Scripps Research. “A benefit of this work is that it is incredibly simple.”
The team identified simple conditions to convert carboxylic acids and olefins, two main classes of chemical feedstocks (or feedstocks that feed a machine or industrial process), into quaternary carbons using an inexpensive iron-based catalyst. Furthermore, these chemical raw materials are not only abundant, but also low-cost.
“Similar reactions have been gaining ground lately, so this discovery was inevitable,” Shenvi explains. “The pieces were already in literature, but no one had put them together before.”
Overall, the study, which was conducted in collaboration with the laboratory of co-senior author Phil Baran, PhD, the Dr. Richard A. Lerner Professor in the Department of Chemistry at Scripps Research, highlights the current role of chemistry in development. of modern technology and pharmaceutical products.
“This work is another striking demonstration of the power of the collaborative atmosphere at Scripps Research to discover new transformations that can have a dramatic impact on simplifying the practice of organic synthesis,” adds Baran.
This work and the researchers involved were supported by funding from the National Institutes of Health (grants GM122606 and GM118176), the National Science Foundation (CHE1955922), Nanjing King-Pharm Co., Ltd), Pfizer, and Biogen.