Studies toward Pestalachloride B: Synthesis of the 6/7/6 Tricyclic Scaffold

TL;DR

Scientists synthesized a complex antibiotic compound, pestalachloride B, to develop new treatments for drug-resistant bacteria.

Contribution

The first synthetic approach to construct the 6/7/6 tricyclic scaffold of pestalachloride B is presented.

Findings

A key intramolecular Parham-type cyclization successfully formed the tricyclic scaffold in 74% yield.

A late-stage intermediate with the full pestalachloride B framework was achieved in 8% overall yield over 11 steps.

Abstract

Antibiotic therapy
is a critical part of modern healthcare, and
the discovery of antibiotics with novel mechanisms of action is needed
to combat the rise of antimicrobial resistance. Pestalachloride B,
isolated from Pestalotiopsis adusta, is a compound
belonging to the pestalone family of natural products which demonstrates
potent and selective antimicrobial activity against clinically relevant,
antimicrobial-resistant Gram-positive bacteria. Here, we report the
first synthetic studies focused specifically on pestalachloride B.
Two key disconnections were evaluated for the construction of the
rare 6/7/6 tricyclic scaffold, and a key intramolecular Parham-type
cyclization was found to afford the desired scaffold in 74% yield,
enabling us to obtain a late-stage intermediate bearing the complete
pestalachloride B framework in 8% overall yield over 11 steps.

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