Synthetic studies toward the total syntheses of scholarisine A and phomoidride D.


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Isolated in 2008 from a leaf extract of an Alstonia scholaris variant, scholarisine A contains a unique pentacyclic architecture that makes it a challenging target for total synthesis. Our approach toward the molecule’s polycyclic core consists of a nucleophilic olefin addition into an activated isonitrile with subsequent addition of an adjacent ester into the resultant carbocation to produce a polycyclic imine. The feasibility of this proposed cascade cycloaddition was explored in a model system that presented an analogous array of functionality within a similar, but not identical, carbon framework. Although we were delighted to find that the model substrate was capable of undergoing the desired cyclization process, it occurred in low yield and only when using an acyl group as an activating agent, the product of which is not suited as an intermediate en route to scholarisine A. Our efforts to access an advanced isonitrile-containing intermediate was met with only limited success and concerns regarding overall efficiency led us to eventually abandon the scholarisine A effort. Phomoidrides A and B were isolated in 1996 from an unidentified fungus, believed to be a steril Phoma variant. Phomoidrides C and D were later isolated from the same fungus and were shown to be epimeric at the C7 stereocenter. The synthetic challenges inherent to the phomoidrides have inspired many creative synthetic approaches that have culminated in four completed total syntheses of members of the phomoidride family. Our unique approach consist of a phenolic oxidation Diels-Alder sequence and eventual radical cascade cyclization to produce a functionalized isotwistane intermediate that undergoes a Grob-type fragmentation to produce the bicyclo[4.3.1]decadiene core of the phomoidrides. Attempts to install the maleic anhydride and complete the synthesis from a diester precursor failed. Subsequent model studies determined the maleic anhydride can be accessed from a β-keto ester functionality. In our current third-generation approach toward phomoidride D, we have achieved fragmentation to produce the phomoidride core and attempts to install the maleic anhydride and complete the total synthesis are currently underway.



Total Synthesis. Phomoidrides. Phomoidride D. Scholarisines. Scholarisine A. Organic Synthesis.