Synthesis of Polyprenylated Acylphloroglucinols Using Bridgehead Lithiation: The Total Synthesis of Racemic Clusianone and a Formal Synthesis of Racemic Garsubellin A

The synthesis of polyprenylated phloroglucinol natural products, including clusianone, nemorosone, and
garsubellin A, was pursued by a strategy involving construction of a core bicyclo[3.3.1]nonanetrione
structure and subsequent elaboration via organolithium intermediates. Appropriate bridged core structures
were obtained through the cyclization of a suitably substituted cyclohexanone enol ether or enol silane
with malonyl dichloride. Additional substituents were then introduced by means of regioselective lithiation
reactions, including the generation of bridgehead enolates, thus enabling the total synthesis of clusianone
and also of an advanced intermediate toward nemorosone. In the case of garsubellin A, an additional
THF-like ring was elaborated by a biomimetic 5-exo-tet cyclization of an enol ether (or enol) with a
side-chain epoxide. This enabled a formal synthesis of racemic garsubellin A by accessing one of the
late intermediates in the Danishefsky synthesis.