Iminium-catalyzed cycloadditions are a hallmark of organocatalysis, a concept that David MacMillan famously coined as “LUMO-catalysis” when he and Benjamin List were awarded the Nobel Prize in Chemistry for their groundbreaking work. Now, the Houk and Tang research groups, in collaboration with their long-time collaborator structural biologist Jiahai Zhou, have discovered that Nature employs this same type of catalysis in the biosynthesis of sordarin, a fungal natural product with strong antifungal activities.
The work was recently published in Nature Catalysis. “We were intrigued to find that Nature synthesizes a norbornene ring in sordarin in the same way that synthetic chemists make norbornenes, by a Diels-Alder reaction,” Professor Yi Tang noted. “Zuodong Sun, a postdoctoral fellow in my group, was able to isolate the enzymes that catalyzes this reaction and probe the mechanism using mass spectrometry and mutagenesis studies; Jiahai and postdoctoral fellow Xin Zang obtained crystal structures of the enzyme in complex with the products; and Ken and Qingyang Zhou in his group determined how formation of the iminium from an enzymatic lysine and substrate aldehyde led to a more than ten-thousand times faster Diels-Alder reaction.”
The work establishes a new type of catalysis in the world of pericyclases, a class of enzymes named by the Tang and Houk groups. “Our ongoing collaborations have revealed many modes of catalysis for this class of enzymes, for which we received the RSC Horizon Prize in 2021,” Professor Ken Houk pointed out. ‘It is remarkable to think that very few pericyclases were identified until this decade. It is especially amazing that the Nobel Prize was awarded in 2021 for organocatalysis, and now we know that Nature has used exactly this type of catalysis in pericyclases for many millennia.”
For more information, contact Professor Ken Houk, houk@chem.ucla.edu.
