Organic chemist Yoshito Kishi dies at 85

Yoshito Kishi, emeritus professor of organic chemistry at Harvard University, died Jan. 9. He was 85.

“Kishi was a primary force in the modern era of synthetic organic chemistry, having the type of transformative effect seen by R. B. Woodward and E. J. Corey in earlier eras,” Stuart Schreiber, also an organic chemist at Harvard and one of Kishi’s former students, says in an email. “His pioneering work resulted in a new appreciation of the reach and power of this field.”

Kishi was known for developing total syntheses of very complicated natural products. Perhaps most famously, he achieved the total synthesis of palytoxin, a highly toxic vasoconstrictor found naturally in limu-make-o-Hana, a zoanthid coral that is native to Hawaii. The molecule has 64 stereocenters and 7 double bonds. Kishi and his research group are the only scientists who have ever synthesized the compound—widely considered the Mount Everest of total synthesis, says organic chemist Eric Jacobsen, one of Kishi’s colleagues at Harvard.

Although Kishi may be best known for that work, he also had an enormous impact in other areas of research, Jacobsen says. One of his most important contributions to organic chemistry was his development of acyclic stereocontrol. “That’s the idea of setting new stereocenters in molecules that are not cyclic, so they have the freedom to rotate,” he says. Kishi came up with principles for controlling stereochemistry in acyclic molecules that were based on his understanding of what shapes acyclic molecules adopt. “It really just changed the field of synthesis after that,” Jacobsen says.

Kishi used this idea to synthesize some of the most complex small-molecule natural products known. Those included the anticancer drug eribulin, an analog of the natural product halichondrin B, in 1992. “At the time, it was considered an impossibly complicated small molecule that nobody could ever imagine being synthesized in quantities that would be necessary to make them useful as a treatment,” Jacobsen says. “It’s actually one of the defining molecules in the history of cancer treatment.” Commercially called Halaven, eribulin was approved by the US Food and Drug Administration in 2010 for the treatment of metastatic breast cancer. “This extraordinary drug resulted from Kishi’s advances in organic synthesis, especially his catalytic diastereoselective chromium/nickel-mediated coupling reactions. . . . Its impact on Taxol-resistant cancers is substantial,” Schreiber says.

Scientists in the field of total synthesis have always tied their work to natural products because of the molecules’ biological activity and potential use as medicines, Jacobsen says, but very rarely are these syntheses used to make the compounds commercially. Such molecules are usually made via fermentation or other natural processes. “But here was a case where, through total synthesis, they were able to make a complex molecule that was unnatural but that maintained the properties of a more complicated natural product. Kishi is almost certainly the only person that could have done this work,” Jacobsen says.

Kishi was born in Nagoya, Japan, on April 13, 1937. He earned his undergraduate and doctoral degrees from Nagoya University, then was an instructor there until he left to pursue postdoctoral work with Woodward at Harvard. He returned to Nagoya to take a position as an associate professor but moved back to Harvard as a professor in 1974. He retired from teaching in 2002 but kept an active research group until his death. Schreiber called him a “crown jewel” in the Harvard chemistry department. “He was a steady, guiding force for the department for 50 years. He would have denied this, as part of his magic was his extreme modesty.”

Kishi would often say self-effacing things in a very genuine way, Jacobsen adds. “He didn’t speak much. But when he did speak, it was always something extremely deep and impactful.” Kishi had very high standards, which he mostly applied to himself, and had a wonderful sense of humor, Jacobsen says. “He was just someone who made everyone around him better. He was an amazing scientist and colleague. I miss him greatly.”