We have recently demonstrated a synthetic biology-enabled semi-synthesis of the potent neuroprotective compound, serofendic acid. An engineered bacterium produces ent-atis-16-en-19-oic acid, which has six of eight chiral carbons configured with the appropriate stereochemistry. Setting the configuration of the C15 hydroxyl group and C16 methylene is a critical step that occurs late in each published total or formal synthesis. Here we explore the use of alternative reducing reagents, stereochemical directing agents, reaction order, and product recycling to improve the diastereoselectivity of this step. We find that installing and oxidizing the C17 methylsulfide prior to reducing the C15 ketone provides the greatest yield of the desired C15,C16 diastereomer. This represents an improved total synthesis of serofendic acid.
Bibliographical noteFunding Information:
D. P. was supported by a grant through the University of Minnesota Biotechnology Institute. M. J. S. is supported by The Defense Advanced Research Projects Agency (grant number D17AP00028). The views, opinions, and/or findings contained in this article are those of the author and should not be interpreted as representing the official views or policies, either expressed or implied, of the Defense Advanced Research Projects Agency or the Department of Defense.
© 2019 The Royal Society of Chemistry.