Abstract

Gambierol, a representative of the marine ladder toxin family, consists of eight ether rings, 18 stereocenters, and two challenging pyranyl rings having methyl groups that are in a 1,3-diaxial orientation to one another. Herein we describe the generation of gambierol's A–C and F–H ring systems and demonstrate the versatility of the glycosyl anhydride, enol ether–olefin RCM strategy to fused polycyclic ethers. This work has both enabled us to generate sufficient quantities of the gambierol precursors and has enabled us to better understand the chemical transformations that were key to these efforts. Fundamental work included efforts to C-glycosides and C-ketosides, Claisen rearrangements, and enol ether–olefin RCM reactions.

The preceding manuscript detailed our synthesis of the gambierol A–C and F–H ring precursors. Reported herein is a description of the coupling of the two precursors and the conversion of the coupled material into gambierol. Coupling of the subunits involved ester formation, enol ether RCM, and mixed thioketal formation and reduction. By employing this strategy we were able to bring highly advanced subunits into the coupling and, as a result, we were able to minimize the number of post-coupling transformations required to complete gambierol. At the completion of the synthesis, we generated 7.5 mg (1.5 % overall yield) of (−)-gambierol in 44 steps (longest linear sequence).

Closing the ring: The cyclization of a 2-thioindole with an electrophilic substituent serves as the key transformation in a synthetic strategy for the generation of indole alkaloids of the perophoramidine and communesin class. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, Ms=methanesulfonyl chloride.