The diterpenoid alkaloids are a diverse class of complex caged natural products whose pharmacological profiles are equally as diverse: biological activities include anti-inflammatory, anticancer, and antibacterial effects in addition to toxicity-associated interactions with ion channels. Due to the structural complexity, low natural abundance, and myriad biological activities of the diterpenoid alkaloids, concise divergent synthetic strategies towards these natural products are particularly valuable. A de novo synthesis of natural and unnatural analogues could not only grant greater delineation of the potential pharmaceutical utility of these fascinating natural products, but could also be an enabling technology for studies of ion channel biology (e.g., activity-based protein profiling). Our overall synthetic strategy is predicated on first forming the [2.2.2] bicycle (bold in 3  ) as found in the C20-diterpenoid alkaloids, and then, upon further functionalization, accessing the [3.2.1] bicycle (bold in 2  ) found in the majority of C18- and C19-diterpenoid alkaloids. We have successfully utilized a highly versatile hydrindanone intermediate (4  ), an uncommon conjugate addition of a functionalized arene to a vinyl nitrile, an intramolecular Diels�Alder reaction to generate the [2.2.2] bicycle (3  ), and a subsequent facile rearrangement to the [3.2.1] bicycle (2  ) to furnish the entire carbon core of the C18-diterpenoid alkaloids. Current progress and challenges will be discussed during the presentation.

Divergent strategy to the diterpenoid alkaloid family of natural products

248th National Meeting (2014)

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