Divergent Synthesis of Natural Derivatives of (+)-Saxitoxin Including 11-Saxitoxinethanoic Acid

  • Angew Chem Int Ed Engl. 2019 Feb 4;58(6):1689-1693. doi: 10.1002/anie.201811717.
James R Walker  1 ,  Jeffrey E Merit  2 ,  Rhiannon Thomas-Tran  3 ,  Doris T Y Tang  4 ,  J Du Bois  4
Affiliations
  • 1. SAFC, Inc., 645 Science Dr., Madison, WI, 53711, USA.
  • 2. Gilead Sciences, 333 Lakeside Dr., Foster City, CA, 94404, USA.
  • 3. Arcus Biosciences, Inc., 3928 Point Eden Way, Hayward, CA, 94545, USA.
  • 4. Department of Chemistry, Stanford University, Stanford, CA, 94305, USA.
PMID: 30488599 DOI: 10.1002/anie.201811717
Abstract

The bis-guanidinium toxins are a collection of natural products that display nanomolar potency against select isoforms of eukaryotic voltage-gated Na+ ion channels. We describe a synthetic strategy that enables access to four of these poisons, namely 11-saxitoxinethanoic acid, C13-acetoxy saxitoxin, decarbamoyl saxitoxin, and saxitoxin. Highlights of this work include an unusual Mislow-Evans rearrangement and a late-stage Stille ketene acetal coupling. The IC50 value of 11-saxitoxinethanoic acid was measured against rat NaV 1.4, and found to be 17.0 nm, similar to those of the sulfated toxins gonyautoxin II and III.

Keywords
Stille coupling; guanidinium toxins; rearrangement; sodium channels; sulfoxide.
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