For Your Consideration...

A New, Improved 47-Step Synthesis of Shootmenowicene

Editor: We originally sent a 1600 x 1200
color abstract. Just picture a 15-member
macrolide, densely functionalized with
heterocycles, five stereocenters,
 and chelated iron.

Abstract: Shootmenowicene, a heterocycle-containing polyketide macrolide polyene siderophore, was originally isolated in 0.009% from immature sprouts of the Bungus bungus tree. We report herein a significantly shortened 47-step route to the natural product (down from 48), which we believe will allow for kilo-scale synthesis for future clinical trials.

Synthetic highlights include: extensive use of Yamamoto's "super-silyl" protecting group, a Sezen C-H arylation / macrocyclization, kilo-scale flash-vacuum pyrolysis (FVP), and enantioselective tributyltin hydride reduction. Efforts to adapt "green" chemical considerations have been made - the penultimate oxidation occurs by swirling flask in open air for three days over twenty equivalents iron oxide catalyst.

This streamlined route utilizes seventeen silica gel purifications, four alumina plugs, two resolutions: D(-)-tartaric acid and 1R(-)-10-camphorsulfonic acid (the expensive ones, sorry!), and a one-pot global HF / Hg / chromic acid deprotection protocol. Overall yield was 0.0008%, as a mixture of diastereomers (brsm).

Two medicinally active methylated analogues will be reported in due course.

Thanks to Derek for the initial inspiration, with a gentle nudge courtesy of Chemjobber.