Abstract
Over 80 unique polycyclic polyprenylated acylphloroglucinols (PPAPs) have been isolated from the family Guttiferae and related plants Fascinating chemical structures and intriguing biological activities are closely related with this class of natural products. The PPAPs, represented by hyperforin (1), feature a highly oxygenated and densely substituted bicycle[3.3.1]nonane-2,4,9-trione core with prenyl, geranyl, benzoyl, and isobutyryl side chains. Relevant to neurodegenerative diseases such as Alzhiemer's the natural product garsubellin A (2) has been shown to enhances choline acetyltransferase (ChAT) activity by 154% in P10 rat septal neurons, relative to a controls. Nemorosone (3) alternatively has displayed in vitro cytotoxicity against cancer cells over normal cell lines and possesses activity against drug resistant cancer cell lines. Clusianone (4) an anti-HIV agent displaying activity against HIV infection of C8166 human T lymphoblastoid cells additionally has promise as a potential therapeutic agent. Due to these intriguing biological activities we envisioned that the preparation of several members of this class of natural products could allow additional syntheses and provide the required materials for further pharmacological testing as well as provide access to edited structures, that may elucidate the structure activity relationships of these important natural products. The concise synthesis of garsubellin A (2) and nemorosone (3) are described. Starting from 3,5-dimethoxyphenol, the synthesis has provided garsubellin A (2) in an 18-step sequence and nemorosone (3) in a 14-step sequence. Notable transformations include dearomative allylation, diastereoselective vinylogous lactonization, iodocarbocyclization, and bridgehead functionalization reactions to construct and functionalize of the bicyclo[3.3.1] nonane carbon skeleton of the PPAP natural products garsubellin A (2) and nemorosone (3).
