Straightening out natural products’ stereochemistry

When chemists at the University of Bristol set out to make a pair of natural products with antimicrobial activity, it seemed like a quick and easy way to highlight some synthetic methodology their lab had developed. But after finishing their 10-step syntheses of baulamycins A and B, the researchers noticed that the NMR spectra of the molecules they made didn’t match those originally reported for the natural material. It turns out that the stereochemistry of the natural compounds had been incorrectly assigned, and the Bristol team had been making the wrong molecules all along.

The team, led by Varinder K. Aggarwal, Eddie L. Myers, and Craig P. Butts, now reports a method to figure out the correct stereochemistry of baulamycins A and B and other complex molecules.

It’s not so easy, Aggarwal says. Baulamycins A and B have an open chain structure with seven stereocenters. “It was very daunting to think about which of the seven stereocenters was incorrect,” Aggarwal notes. There are, after all, 128 possible isomers.

The researchers used computational methods and NMR spectra of the natural material to determine the most likely configuration of the three contiguous stereocenters on one side of the molecule. They then made a mixture of four possible isomers of baulamycin A in predetermined unequal ratios, making it possible to quickly identify which compound’s spectra matched that of natural baulamycin A. The chemists finally synthesized the correct structure on its own (Nature 2017, DOI: 10.1038/nature23265).

“The method we’ve described could be very useful for the structural determination of other complex molecules,” Aggarwal says.

Rajib K. Goswami, a professor at the Indian Association for the Cultivation of Science who first reported that the structures of baulamycins A and B were incorrect, says the work highlights how total synthesis of natural products allows chemists to confirm the accuracy of proposed structures, something he says is “vital for any industry interested in developing new natural-product-based drugs.”