Biology inspires new route to himastatin

Himastatin, a natural product churned out by the bacterium Streptomyces himastatinicus, has an unusual dimeric structure built around a biaryl core. Chemists are interested in making the molecule because it has antibiotic activity, even though its structure doesn’t resemble other antibiotics. Seeking a route to build himastatin and provide quick access to diverse derivatives, chemists at the Massachusetts Institute of Technology developed a synthesis of the molecule that mimics nature’s biosynthesis. Instead of starting with the biaryl core and building outward, as other chemists have done when synthesizing himastatin, the MIT team, led by Mohammad Movassaghi and Bradley L. Pentelute, built the complex halves of the dimer and then used a one-electron oxidation to snap them together in the final stage of the synthesis. “All the work in this area concentrates on making that biaryl linkage at an early stage, but nature is doing it as the very last step. So it was natural for us to say, ‘Can we do the same thing?’ ” said Kyan A. D’Angelo, who recently completed his doctoral studies in Movassaghi’s lab and presented the work at ACS Spring 2022 last week. “This type of a late-stage, complex fragment assembly provides opportunities for rapid diversification,” Movassaghi told C&EN. The chemists use their synthetic approach to build derivatives of himastatin, including one with a fluorophore that could provide clues about himastatin’s antibiotic mechanism of action. The team recently published the synthesis in Science (2022, DOI: 10.1126/science.abm6509).