The Evolution of a Strategy for the Total Synthesis of Hirsutellone B

Abstract

The hirsutellone family of natural products consists of six bioactive polyketides that were isolated from an insect pathogenic fungus in 2005. The intriguing polycyclic structures of the hirsutellones feature a strained 12 or 13-membered paracyclophane aryl ether and a trans-fused decahydrofluorene ring system with seven contiguous stereocenters. The degree of structural complexity exhibited by these natural products combined with their reported antitubercular activity make the hirsutellones attractive targets for total synthesis.

Our original strategy towards hirsutellone B was inspired by the proposed biosynthetic hypothesis and featured a cascade of cyclizations. Although we synthesized a model system to test the key hetero-Michael / SNi' / IMDA cascade, we were unable to form the desired cyclophane-containing product.

An alternative approach to hirsutellone B featured a key dioxinone intermediate that would enable a tandem intramolecular acylketene trapping / IMDA cascade. Our initial model system incorporated solvolytic capture of the acylketene intermediate to rapidly produce the decahydrofluorene core of hirsutellone B. We were later able to achieve the full tandem reaction sequence, forming three rings, three bonds, and four contiguous stereocenters in a single step. The advanced macrolactam and macrolactone intermediates produced via this sequence possess most key features of the hirsutellone framework, including the challenging cyclophane ring. However, attempts to complete the carbon skeleton of hirsutellone B via transannular carbon-carbon bond formation were unsuccessful due to competing O-alkylation.