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Total Synthesis of the Galbulimima Alkaloids Himandravine and GB17 Using Biomimetic Diels–Alder Reactions of Double Diene Precursors

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posted on 2015-09-02, 00:00 authored by Reed T. Larson, Ryan P. Pemberton, Jenna M. Franke, Dean J. Tantillo, Regan J. Thomson
The enantioselective total syntheses of himandravine and GB17 were completed through a common biomimetic strategy involving Diels–Alder reactions of unusual double diene containing linear precursors. The double diene precursors, containing or lacking a C12 substituent as required to produce GB17 or himandravine, respectively, were found to undergo Diels–Alder reactions to afford mixtures of regioisomeric cycloadducts that map onto the alternative carbocyclic frameworks of both himandravine and GB17. Computational investigations revealed that these Diels–Alder reactions proceed via transition state structures of similar energy that have a high degree of bispericyclic character and that the low levels of regioselectivity observed in the reactions are a consequence of competing orbital interaction and distortion energies. The combined experimental and computational results provide valuable insights into the biosynthesis of the Galbulimima alkaloids.