The synthesis of a drug candidate is often a kind of molecule improvement project in which even a modest expansion can involve an inordinate amount of scaffold building, tearing down, and reconstruction. Ideally, drug developers would be able to tack prefabricated units onto a starter molecule at will without having to worry about damaging preexisting structural elements.

To bring “at-will” construction closer to drug development reality, researchers based at The Scripps Research Institute (TSRI) have introduced a lighter approach to the use of directing groups. Typically, these groups are attached to a starter molecule in order to attract metal catalysts to the part of the molecule that needs to be modified. Because directing groups tend to be attached fairly firmly, removing them once the desired change has been made can be a project all by itself—one that can even defeat the purpose of the build-out altogether.

The directing groups proposed by the TSRI researchers, however, are different. They are, as the researchers say, “transient.” They do not have to be attached and detached in separate steps.

Even more conveniently, the transient directing groups are amino acids. They attach themselves automatically to starter compounds and remove themselves automatically after a new functional group is attached. In effect, the amino acids work “catalytically,” functionalizing one starter molecule after another and continually being reused, rather than being consumed in their first reaction. This further streamlines the process and reduces the overall quantity of reagents that are needed.

The approach was detailed January 15 in the journal Science, in an article entitled, “Functionalization of C(sp3)–H bonds using a transient directing group.”

“Here we report the development of an amino acid reagent that reversibly reacts with aldehydes and ketones in situ via imine formation to serve as a transient directing group for activation of inert C–H bonds,” wrote the authors. “Arylation of a wide range of aldehydes and ketones at the β or γ positions proceeds in the presence of a palladium catalyst and a catalytic amount of amino acid.”

Essentially, the approach described by the TSRI researchers improves a basic molecule-building operation called C-H functionalization. When chemists set out to build a candidate drug molecule, they often start with a simple organic compound whose central structure contains more inert carbon hydrogen bonds than reactive carbon heteroatom bonds. Turning such a starter molecule into a useful drug typically means replacing at least one of the hydrogen atoms with a more complex cluster of atoms called a functional group.

“In principle, all amino acids can be used as catalytic directing groups for such reactions,” said the study’s leader, Jin-Quan Yu, Ph.D. “The availability of diverse amino acids makes it possible to find different reagents to suit different substrates or transformations.”

Another advantage of the new approach is that it can, with the proper choice of chiral amino acid directing group, preferentially generate “chiral” molecules that are functionalized on just one side. C-H functionalization reactions typically generate a roughly even mix of molecules functionalized on one side plus mirror-image molecules functionalized on the other side—yet the desirable biological activity of a drug often comes exclusively from its “right-handed” or “left-handed” chiral form.

“The fact that we can do this using a simple amino acid as the directing group and ligand is phenomenal, considering the usual difficulty of such reactions,” asserted Kai Hong, a postdoctoral research associate in the Yu Laborator.

“Essentially with this new method we're improving functionalizations by cutting out two steps in the functionalization process—by using a directing group that is catalytic, and by employing, if needed, a chiral directing group to generate chirally pure compounds,” concluded Dr. Yu.

Dr. Yu and his team are now working to extend the applicability of the new method to other broad classes of medicinal chemistry compounds such as amines and alcohols.

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