garsubellin-a and 7-epiclusianone

The polycyclic polyprenylated acylphloroglucinol (PPAP) family of natural products includes important compounds with notable biological activities, such as garsubellin A, hyperforin and clusianone. The synthesis of these complex, bridged, highly oxidized and substituted systems presents a formidable challenge to synthetic chemists. This feature article describes how the use of unconventional bridgehead substitution chemistry has enabled the synthesis of these natural products and their analogues.

Topics: Antineoplastic Agents; Benzophenones; Benzoquinones; Biological Products; Bridged Bicyclo Compounds; Catechin; Cell Line, Tumor; Humans; Phloroglucinol; Terpenes

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.

Topics: Acylation; Alkylation; Benzophenones; Benzoquinones; Bridged Bicyclo Compounds; Chlorine; Copper; Cyclization; Ether; Molecular Structure; Neoprene; Phloroglucinol; Silanes; Stereoisomerism; Terpenes