December 11, 2019
12/12/2019
December 11, 2019
LA JOLLA, CA Chemists at Scripps Research have found a new and easy route for creating an enormous variety of organic molecules for use as potential drugs or other chemical products.
The researchers, who report their feat in Nature, developed a relatively simple method for modifying a broad category of compounds known as aliphatic acids to make new compounds that could have a variety of valuable properties, especially as medicines for cancers, heart disease, neurological diseases and potentially any other indication.
The particular type of modification the method enables is known as a -C-H functionalization. Modifying aliphatic acids in this way has long been viewed as a potential route to useful new molecules. However, until now, chemists haven't had a broadly applicable way of achieving it, and many molecules that in principle could be made this way were in practice out of reach.
The ease of the new technique and the low cost of ingredients mean that it should be suitable even for bulk production.
I am confident that this reaction will find very broad application at all scales, from drug discovery to ton-scale manufacturing, says principal investigator Jin-Quan Yu, PhD, professor in the Department of Chemistry at Scripps Research.
Yu and his laboratory are known for their development of innovative synthetic chemistry reactions that achieve what is known as a C-H functionalization. In this type of reaction, chemists replace a simple hydrogen atom from a starting compound's carbon-atom backbone with a more biologically active cluster of atoms.
C-H functionalizations of aliphatic acids at a position on these molecules known as the position have been relatively cumbersome, and narrow in scope; each requires a different reaction design. Overall, these reactions haven't come close to covering the chemical space that would be reachable by a general -C-H functionalizing method.
The Yu lab conceived the idea of the new method 17 years ago, but lacked a way to make the reaction adequately efficient. First author Zhe Zhuang, a graduate student in the Yu lab, found a solution: He developed a reaction-accelerating ligand molecule, derived from an amino acid, that did the trick.
The key step in the new method is the initial transformation of an aliphatic acid into a type of compound known as a -lactone. A transformation of this nature has never been achieved before by synthetic chemists. Since -lactone structures appear in some compounds made in the cells of plants and animals, chemists have even tried to no avail to find natural enzymes that can achieve such a one-step lactonization of aliphatic acids.
The value in this transformation comes from the fact that -lactones can themselves be modified relatively simply at the position to install alkyl, alkenyl, aryl, alkynyl, fluoro, hydroxyl, and amino groups. Thus, the method effectively provides a general shortcut for the easy -C-H functionalization of aliphatic acids. b-lactone also can be useful on its own as a structure within a drug molecule because of its high reactivity with some enzymes.
The new lactonization reaction has the further advantage that it works with relatively inexpensive and widely available reagents; they include a chemical called tert-butyl hydrogen peroxide (TBHP), which provides a necessary oxidant for the reaction and is suitable for use in large-scale production. The lactonization reaction also works so efficiently that it avoids the need for complicated and expensive methods of purifying the resulting -lactone product.
This reaction provides a one-for-all strategy for making a very large variety of molecules that were inaccessible via previous -C-H activation reactions, Yu says.
Yu and his lab are now continuing to develop the new lactonization-based method as a potential improvement over many other types of C-H activation reaction. In collaboration with pharmaceutical companies, they are also using it to generate b-lactone-based compounds as potential medicines.
Support for the research was provided by the National Institutes of Health (R01GM084019).
Chemistry Yu, Jin-Quan
LINK: | https://www.scripps.edu/news-and-events/press-room/2019/20191211-yu-la... |
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