TSRI tests new drug-making methods

Chemists devise simple method for making sought-after boronic acid-based drugs and other products

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LA JOLLA, Calif.—Chemists at The Scripps Research Institute (TSRI) have had a successful April—they have announced not just one, but two new methods for making drugs more easily. One team developed a method which will help to create boronic acids and other related compounds more easily. Another team created a new method called decarboxylative alkenylation, which turns carboxylic acids into alkenes (also called olefins). Both teams were led by Phil S. Baran, the Darlene Shiley Professor of Chemistry at TSRI and principal investigator for the work.
Decarboxylative borylation is a broad, easy method for synthesizing a class of molecules that have demonstrated value as pharmaceuticals. The difficulty of preparing these compounds—boronic acids and boronate esters—has greatly limited their use in the pharmaceutical industry, and to date there are only three FDA-approved drugs in this category.
With the new method, published recently in the journal Science, chemists can take carboxylic acids and convert them into similarly structured boronic acids and related compounds. Among the boronic acid-derived molecules Baran and his team made in demonstrating the method were several novel compounds now being investigated as potential treatments for COPD and other lung disorders.
The development of decarboxylative borylation follows a breakthrough made a year ago when Baran and his team were studying the amide bond-forming reaction. “We realized that the principles of amide bond formation, still the most utilized reaction in all of chemical synthesis, could be used to simplify a much broader set of molecule-building tasks,” Baran said.
This insight enables the transformation of virtually any carboxylic acid, whether simple or complex, using a single reaction step and inexpensive nickel catalysts. The new method essentially replaces a key carbon atom on a carboxylic acid with a boron atom. Baran noted, “Instead of devoting 95 percent of their effort to introducing a single boron atom, chemists can now easily install boron at any stage.”
Borylated versions of drug compounds should often have superior properties to their carboxylic acid counterparts. Decarboxylative borylation now makes it broadly practical for pharmaceutical chemists to create and investigate these borylated structures. To demonstrate, Baran and his team used the method to make boronic acid versions of several common drugs, including Lipitor (atorvastatin) and vancomycin.
Baran’s team and chemists from the California Institute for Biomedical Research (Calibr) collaborated and used the method to make boronic acid-based compounds that inhibit a human enzyme known as neutrophil elastase. Elastase is considered a major cause of the lung damage seen in COPD, cystic fibrosis and related respiratory ailments. Elastase inhibitors developed through other methods have shown limited effectiveness and/or significant side effects; so far none have been FDA-approved. However, the team found in initial lab-dish tests that their boronic acid-based compounds inhibit elastase more strongly than older elastase-inhibiting compounds. “We found that we could get a significant boost in potency by using a boronic acid group,” said study co-author Arnab Chatterjee, director of medicinal chemistry at Calibr.
These boronic acid-based compounds can bind very tightly to their target molecules but in a way that allows them to eventually detach, thus potentially reducing the impact of off-target interactions that cause unwanted side effects. “The next step is to see how well these compounds perform in animal models,” continued Chatterjee. “In general, this new method allows us in a practical way to get into this largely unexplored but promising chemical space of borylated compounds, and thus enables us to revisit old targets, such as elastase, that have largely resisted prior drug development efforts.”
Decarboxylative alkenylation, the second new method recently discovered at TSRI, turns carboxylic acids into alkenes (olefins), another large family of compounds commonly used for pharmaceuticals and other applications. “This method dramatically simplifies the syntheses of olefins; in fact, it has really changed the way I think about making molecules,” commented Baran.
The method, described in Nature, essentially supersedes reactions that have been in chemistry textbooks and in widespread industrial and academic use for decades. Chief among these is the Wittig reaction, which enables the making of many olefins from precursor compounds. Even though it tends to require a many-step process, chemists have continued to rely heavily on it up to the present.
“Organic chemists have endured this burdensome ‘analog’ process for decades with little complaint,” said Baran. “Now with this new method we’re bringing olefination into the digital era.” The new method originated with a breakthrough by Baran and his laboratory described a year ago in Journal of the American Chemical Society. “That advance opened the door to a lot of other possibilities, and since then we’ve been addressing as many of them as we can, starting with the most important.”
Decarboxylative alkenylation enables chemists to turn carboxylic acids into olefins in relatively few steps, using nickel or iron catalysts. Baran’s team produced sterol acetate from a standard precursor in two steps—whereas the traditional procedure using the Wittig reaction requires seven steps. To show the vast scope of the method, Baran’s team employed it to make nearly 70 diverse olefins with reactions that were greatly streamlined and simplified, compared to traditional methods.
The new method allows chemists much better control over the geometry of the resulting molecules, and simplifies the conceptual side of olefin synthesis. In one demonstration, the team synthesized the natural antibiotic cladospolide, which is otherwise hard to make, starting from tartaric acid. The paper includes 15 other total or near-total syntheses from cheap starting compounds of natural products that were previously difficult or impractical to synthesize, including prostaglandins, aureonitol and tocotrienols.  
Bristol-Myers Squibb, which has a research agreement with TSRI, works with the Baran Laboratory and is already using the new method in at least one of its drug development programs. Another collaborator, Asymchem, has also demonstrated the suitability of the new method for pharmaceutical manufacturing by scaling up a sample reaction to yields on the order of a kilogram.

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