EVENTS | VIEW CALENDAR
TSRI researchers develop versatile new way to build molecules
LA JOLLA, Calif.—Chemists at The Scripps Research Institute (TSRI) have devised a new, widely applicable technique for building potential drug molecules and other organic compounds.
The method, reported in Science, enables researchers to add clusters of atoms called carbon fragments or functional groups to certain organic molecules more efficiently, robustly and selectively. This opens up new possibilities for chemists to assemble novel compounds that can be tested for useful properties in the development of drugs and other products.
“We demonstrated this technique with two broad classes of compounds, aldehydes and ketones—the ‘bread and butter’ of modern chemical synthesis,” explains senior investigator Jin-Quan Yu, the Frank and Bertha Hupp Professor of Chemistry at TSRI.
Yu’s laboratory specializes in the development of techniques to improve the molecule-building process, particularly for chemists trying to devise potential new drugs. Their newest tool improves a basic molecule-building operation called C-H functionalization. When chemists 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 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.
The C-H functionalization process can be tricky, and chemists often have to employ special methods to make it work. Many of these methods involve helper molecules known as directing groups. Chemists attach a directing group to the initial molecule they want to modify; the directing group then guides a bond-breaking catalyst (often a metal such as palladium) to the carbon-hydrogen bond that needs to be broken to make way for the new functional group.
“This has proven to be a very reliable and broadly useful strategy,” notes Yu, “but it requires at least two additional steps—the installation of the directing group, and later its removal—and sometimes the directing group is incompatible with functional groups already present on the starting molecule.”
Yu and his team have found that amino acid molecules can work well as transient directing groups for ketone or aldehyde compounds. The amino acids attach themselves automatically to these starter compounds, and remove themselves automatically after the new functional group is attached. In effect the amino acids work catalytically, functionalizing one starter molecule after another, and they are continually reused, rather than consumed in the first reaction. “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,” explains Yu.
According to Yu, “The amino group in the amino acid is a perfect handle to transiently attach to ketones and aldehydes, which are main starting materials for making useful molecules; the carboxyl group in the amino acid is then used as a weakly coordinating and yet powerful director to guide the palladium (Pd) to insert into C-H bond and form a new bond. Simple amino acids such as glycine work, but chiral amino acids, such as valine and alanine, also work.”
A further advantage of the new technique is that it can, with the proper choice of chiral amino acid directing group (such as L-tert-leucine), preferentially generate chiral molecules that are functionalized just on 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.
“This method provides a new way to think about how to use readily available ketones and aldehydes. Certainly it will shorten the synthesis when ketones or aldehydes are used as starting materials,” Yu says, and notes he 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. “The same principle of using transient and weakly coordinating directors can be applied to amines and alcohols, and we will disclose those new designs shortly,” Yu tells DDNews.