Diterpenoid alkaloids have long been recognized for their wide range of biological activities—from analgesics to anti-arrhythmic agents and potent toxins—many of which stem from differential interactions with ion channels. As a result of this interesting activity and the topological complexity of this family of natural products, our laboratory became interested in the total synthesis of these intriguing pseudoalkaloids. As part of this endeavor, we have previously reported strategies to synthesize several C18-, C19-, and C20-diterpenoid alkaloids. Although these approaches provided sufficient material for biological assays, the syntheses are relatively long and poorly suited for wide-ranging modification of oxidation patterns. In order to overcome these challenges, we investigated a synthesis approach to analogues of aconitine-type diterpenoid alkaloids in order to systematically introduce oxygenated substituents at key positions. We have developed a copper-mediated method for addition of oxygenated arenes into a complex vinyl nitrile using arylmagnesium bromides, which overcomes the limitations of a previously investigated rhodium-catalyzed method. The products of this conjugate addition were then advanced toward the synthesis of analogues of aconitine-type diterpenoid alkaloids. Systematic variation in oxygenation patterns on the arene coupling partner, introduced through the current conjugate addition approach, may ultimately contribute to elucidation of structure–activity relationships of the diterpenoid alkaloids.

Copper-mediated conjugate addition approach to aconitine analogues

2019 Spring National Meeting

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