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
It's great. Thank you for sharing this and hope hear many more..