Synthesis of the Antimalarial Flindersial Alkaloids



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The concept of mimicking nature to synthesize natural compounds has been successfully demonstrated in the synthesis of all the anti-malarial Flindersia alkaloids. Previous work on the biosynthesis of the related natural products borreverine and isoborreverine inspired us to synthesize racemic flinderoles A, B, and C in as few as three synthetic steps from simple and readily available materials. The development of reaction conditions for the dimerization of borrerine in the presence of acid is discussed in detail. The progress toward the enantioselective total synthesis of flinderoles A, B, and C is also presented. The retrosynthetic plan was inspired by the biomimetic synthesis of the flinderoles, in which an acid mediated amino cyclization would form the flinderole framework. Tryptamine and 3-butyn-2-one undergo a vinylogous Pictet-Spengler reaction to give a β-carboline, which opens to a 2-enone tryptamine in the presence of base. A BINOL catalyzed enantioselective conjugate addition of a vinyl boronic acid to the 2-enone tryptamine has been achieved. A pyrrolo[a]indole unit could be connected to another indole unit by a Sonagashira coupling reaction in a convergent manner.



Flinderoles, antimalarial, Biomimetic Synthesis, Organocatalysis


Portions of this document appear in: Vallakati, Ravikrishna, and Jeremy A. May. "Biomimetic synthesis of the antimalarial flindersial alkaloids." Journal of the American Chemical Society 134, no. 16 (2012): 6936-6939. And in: Vallakati, Ravikrishna, Brian J. Lundy, Santa Jansone‐Popova, and Jeremy A. May. "Biomimetic synthesis and studies toward enantioselective synthesis of flindersial alkaloids." Chirality 27, no. 1 (2015): 14-17. And in: Vallakati, Ravikrishna, and Jeremy A. May. "Biomimetic syntheses of the flindersial alkaloids." Synlett 23, no. 18 (2012): 2577-2581. And in: Smuts, Jonathan P., Yun-Cheol Na, Ravikrishna Vallakati, Adam Přibylka, Jeremy A. May, and Daniel W. Armstrong. "Enantioseparation of flinderoles and borreverines by HPLC on Chirobiotic V and V2 stationary phases and by CE using cyclodextrin selectors." Analytical and bioanalytical chemistry 405, no. 28 (2013): 9169-9177. And in: Vallakati, Ravikrishna, Jonathan P. Smuts, Daniel W. Armstrong, and Jeremy A. May. "On the biosynthesis and optical activity of the flinderoles." Tetrahedron Letters 54, no. 44 (2013): 5892-5894.