Synthesis Strategy Goes Online

When constructing complex polycyclic natural products from simple molecules, chemists must first develop a bond-building strategy. There are many possible ways to attack that problem: One approach is to mimic nature’s biosynthetic pathway; another is to tackle the most complex region of the molecule’s ring system—a method known as network analysis. Chemists led by University of California, Berkeley, chemistry professor Richmond Sarpong used the latter in their total syntheses of weisaconitine D and liljestrandinine, but the chemists also added an Internet-age twist: They’ve created a website that anyone can use to apply network analysis to their molecules.

Created in partnership with Cadre Research Labs, the website—cadrerl.com/maxbridge—will perform network analysis on certain types of structure files, free of charge, to help chemists plan their synthetic strategies (Nature 2015, DOI: 10.1038/nature16440).

Previous approaches to computer-assisted design of syntheses weren’t easy to use and just spat out a proposed synthetic route, which chemists often disagreed with.

The new website, Sarpong says, provides a starting point. Everything else is up to the chemist’s imagination. “There is this human element where one can make quantum leaps in terms of how we make molecules,” he says.

Sarpong says his group’s network analysis approach to weisaconitine D and liljestrandinine was inspired by two giants in the field of natural product synthesis: Harvard University’s E. J. Corey and UC Berkeley’s Clayton Heathcock. “These are people who have taught the community about how to think about topologically complex molecules,” Sarpong says.

Weisaconitine D and liljestrandinine are both inhibitors of voltage-gated sodium and calcium channels—important targets for pain relief and cardiac health. The Sarpong synthesis strategy opens the door to making analogs of this family of diterpenoid alkaloids for drug discovery.

The Sarpong group’s synthesis is “a forceful reminder that unique strategies can be just as important as new methods in complex molecule total synthesis,” comments Phil S. Baran, an organic synthesis expert at Scripps Research Institute California.