Bioinspired Total Synthesis of Hyperireflexolides A and B

Hyperireflexolides A and B have been synthesized in six steps using a strategy based on the dearomatization and fragmentation of a simple acylphloroglucinol starting material. The dearomatized acylphloroglucinol undergoes a sequence of oxidative radical cyclization, retro-Dieckmann fragmentation, stereodivergent intramolecular carbonyl-ene reactions and final α-hydroxy-β-diketone rearrangements to give the target natural products. This sequence is based on a biosynthetic proposal that claims the hyperireflexolides as highly rearranged polycyclic polyprenylated acylphloroglucinols (PPAPs), which is supported by a biosynthetically anticipated structure revision of hyperireflexolide B. In addition, hyperireflexolides A and B were synthesized using a convergent, non-biomimetic strategy that diastereoselectively constructs five C–C bonds onto a 2-cyclopentenone core.