Hippadine and pratosine are lycorine-type pharmacologically active <i>Amaryllidaceae</i> alkaloids.  Although several total syntheses of these natural products have been developed, most of the routes require prohibitively expensive materials and/or give low overall yields.  Our current research involves the development of new synthetic methods starting with 6,7-disubstituted isoquinolines that should be suitable for preparing these alkaloids on a large scale using inexpensive materials.  The key step in the synthetic scheme centers around an intramolecular de Mayo photocyclization that uses the reaction of the alkene in an isocarbostyril with a 1,3-diketone contained within a six-carbon functionalized tether on nitrogen.  The resulting tricyclic system should contain a 1,5-diketone grouping, but these functions are actually masked in the form of a cyclic hemiketal.  Nevertheless, a base-catalyzed aldol addition reaction affords the ABCD-ring system present in hippadine and pratosine.  Dehydration of this product affords a β,γ-enone that can be transformed to a diene in two steps.  Oxidation of the diene with DDQ affords the target natural products after simple chromatographic purification.  This synthetic pathway circumvents the use of catalysts that are either expensive or contain metals such as palladium or iridium.  Moreover, our method allows for the syntheses of analogs in high yields by modifying the tether group on nitrogen.

Total synthesis of hippadine and pratosine: Intramolecular de Mayo photocyclization

255th National Meeting (2018)

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