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Synthesis

Streamlined Route To Hydroxylated Steroids

Method selectively adds hydroxyl groups to a steroid framework to make cardenolide heart-failure drug candidate

by Stephen K. Ritter
January 7, 2013 | APPEARED IN VOLUME 91, ISSUE 1

A strategy to install multiple hydroxyl groups on complex steroid frameworks has allowed chemists to streamline and scale up the synthesis of ouabagenin, a member of the cardenolide class of drugs used for treating congestive heart failure. Hans Renata, Qianghui Zhou, and Phil S. Baran of Scripps Research Institute in California anticipate that their approach will provide chemists with a versatile way to modify natural and synthetic steroid structures to lower toxicity and improve therapeutic properties (Science, DOI: 10.1126/science.1230631). Ouabagenin’s complex array of hydroxyl groups has made it difficult to synthesize: The previous best synthesis took 41 steps and had less than 1% overall yield. Starting with low-cost cortisone acetate, which has one hydroxyl group, Baran’s team used so-called relay reactions to transfer electronic and stereochemical properties from one carbon to another in the steroid framework. This facilitated C–H and C–C bond activation and C–O bond formation, achieving results similar to enzyme-mediated oxidations. They produced ouabagenin, which has six hydroxyl groups, on a gram scale in 21 steps. The work was funded by LEO Pharma, a company aiming to make new drugs based on polyhydroxylated steroids.


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