Development of a general strategy for the synthesis of daphnane diterpenes, including gnidimacrin, kirkinine, and synaptolepis factor K(7)

The daphnane diterpene family, which includes gnidimacrin, kirkinine, and synaptolepis factor K7 amongst its over one hundred members, comprises a diverse array of incredibly complex natural products possessing spectacularly potent biological activity in a wide variety of applications. Their promising therapeutic potential as antitumor, antihyperglycemic, inflammatory, and neurotrophic agents has garnered significant interest from the scientific community, although extensive research into the mechanisms of these intriguing behaviors has been severely limited by generally low isolation yields. Development of efficient synthetic routes to these targets offers an ideal solution to this obstacle, with the additional benefit that a truly flexible strategy will also allow for the design and facile synthesis of analogs to be used as molecular probes of the complex biological machinery that governs their impressive activities.; Progress towards the total synthesis of gnidimacrin via a macrolactonization-based strategy is presented, including a detailed discussion of the challenging scale-up effort of early intermediates to the key methyl triflate-initiated oxidopyrylium [5+2] cycloaddition, as well as some of the optimization and strategic improvements incorporated into the route's latter stages. Initial strategies directed towards a tigliane-derived daphnane analog of gnidimacrin have also been explored, resulting in the development of a daphnane-tigliane hybrid system possessing an unprecedented alkyl substitution pattern at the C1 position of the phorbol A-ring. Information gained from this and related synthetic work has since been applied to a general approach to the daphnane diterpenes, with a current focus on the syntheses of kirkinine and synaptolepis factor K7. Remarkable improvements in enantioselectivity, step count, and overall yield have been obtained through the identification of a latent element of C2 symmetry in the molecule, the development of a previously unreported type of diastereoselective Claisen rearrangement, and the discovery of a microwave-enhanced thermal oxidopyrylium [5+2] cycloaddition. The advancement of this route to a completed daphnane carbon skeleton is discussed, along with the conceptual "point of diversification" for this generalized strategy.