Just as Bizarro World is a place where expectations are confounded and processes are weirdly inverted, Bizarro Chemistry is a flipped version of traditional organic chemistry. Whereas organic chemistry focuses on the division between reactive, or functional, molecular bonds and inert, or nonfunctional carbon-carbon (C–C) and carbon-hydrogen (C–H) bonds, Bizarro Chemistry does the opposite. It bypasses the reactive groups, and it initiates synthetic work at inert C–H sites.

This unusual approach to chemistry promises to shorten synthetic roots, making it easier to generate derivatives of natural products. It is of particular interest to drug developers, who would like to enhance their capacity for late-stage diversification of candidate molecules. Yet Bizarro Chemistry, better known as C–H functionalization, is challenged by limited selectivity. C–H functionalization can be tricky in complex organic molecules, which typically contain many C–H bonds.

A selective application of C–H functionalization, however, has been described by researchers at Emory University and the Novartis Institutes for BioMedical Research. According to these researchers, C–H functionalization in their hands has demonstrated “remarkable chemoselectivty and predictable regioselectivty.”

The researchers gave an account of their work January 12 in Nature Communications, in an article entitled, “Late-stage C–H functionalization of complex alkaloids and drug molecules via intermolecular rhodium-carbenoid insertion.”

“In the realm of late-stage C–H functionalization, alkaloids remain a significant challenge due to the presence of the basic amine and a variety of other functional groups,” wrote the authors. “Herein we report the first examples of dirhodium(II)-catalysed intermolecular C–H insertion into complex natural products containing nucleophilic tertiary amines to generate a C–C bond.”

The study’s authors, who were part of a collaboration fostered by the National Science Foundation’s Center for Selective C–H Functionalization (CCHF), asserted that their work had attained “proof of concept” status. The CCHF’s director, Huw M.L. Davies, Ph.D., an organic chemist at Emory and a study co-author, said, “We've shown that C–H functionalization has reached the stage where it can readily be applied to derivatization of nitrogen-containing compounds, ubiquitous in the discovery and development of new medicines.”

“We had already demonstrated that we have a tool box of reagents and catalysts that allow us to control which sites in a molecule will undergo C–H functionalization,” Dr. Davies continued. “Novartis wanted to explore whether this chemistry was robust enough to be carried out on really complex compounds like alkaloids.”

On this point, the Nature Communications article optimistically noted, “The capacity for late-stage diversification is highlighted in the catalyst-controlled selective functionalizations of the alkaloid brucine. The remarkable selectivity observed, particularly for site-specific C–H insertion at N-methyl functionalities, offers utility in a range of applications where efficient installation of synthetic handles on complex alkaloids is desired.”

Alkaloids are a family of natural products produced by plants that have biological properties important to medicine. Morphine, codeine, and opioids are examples of alkaloids.

If libraries of alkaloid derivatives could be generated with ease, a few natural products could quickly yield groups of chemical compounds with small molecular differences. “These small differences could determine whether a compound is toxic or carries other liabilities, or has the right mix of properties to become a safe and effective therapeutic agent,” Dr. Davies added.