Drawing inspiration from the world of biology, researchers have developed a novel approach to solving a long-standing problem in organic synthesis – regioselectivity.

The vast majority of drugs contain nitrogen, driving chemists to search for more efficient and selective methods to form new C-N bonds in substrate hydrocarbons. However, one of the most stubborn obstacles in the way of creating the desired compound is regioselectivity – the preference of a reaction to make or break bonds at particular sites of the substrate molecule over others.

This troublesome habit of nature often makes it very cumbersome to come up with a reaction mechanism that produces a desired molecular structure, at least with anything like a reasonable yield. The traditional approach would be to focus on the substrate molecule, modifying it in such a way as to make some particular carbon more likely to be that which forms the bond. Sometimes this means coming up with weird, exotic molecules that may be expensive or otherwise difficult to obtain.

Rather than manipulating the substrate, it would be much more desirable to have selectivity be determined by the catalyst. This way a chemist could produce different products from the same starting material simply by modifying the catalyst of the reaction.
Regioselectivity is determined by the enzyme catalyst.

Researchers at California Institute of Technology have come up with a way to accomplish just that. By engineering a natural biological enzyme, the team created two artificial variants which steer nitrogen atom transfer of a particular reaction in complementary directions. One enzyme favors ring-closing amination at the α-position of an alkyl substituent on a benzene sulfonyl azide. The other enzyme favors amination at the β-position. Simply by changing the catalyst, they have been able to switch the reaction to favor one product over the other by over 95%.

Synthetic biology may still seem like it belongs in the realm of science fiction to many, but the degree to which these enzymes have controlled the outcome of the reaction is difficult to ignore.

Considering the trouble these types of reactions have given scientists in the past, it may be reasonable to expect these new methods to gain favor in the future. The modification of enzymes for use in organic synthesis, according to the researchers, represents a promising platform for solving long-standing selectivity problems.




Source

Hyster, Todd K., Christopher C. Farwell, Andrew R. Buller, John A. McIntosh, and Frances H. Arnold. "Enzyme-Controlled Nitrogen-Atom Transfer Enables Regiodivergent C–H Amination." Journal of the American Chemical Society. N.p., 5 Nov. 2014. Web. 09 Nov. 2014, 136 (44), pp 15505–15508