Various total syntheses of the Lycorine-type pharmacologically active alkaloids hippadine and pratosine have been developed. However, most of these synthetic routes require prohibitively expensive materials and/or achieve yields that are subpar, making these schemes unlikely to be used in an industrial setting. Current research involves developing better synthetic methods for these two alkaloids starting with a 6,7-disubstituted isoquinoline. These syntheses are appealing since they utilize readily available starting materials and avoid expensive catalysts. The key step in the synthetic scheme centers around an intramolecular de Mayo photocyclization which involves a reaction between an alkene moiety in the isocarbostyril system and a 1,3-diketone (a functionalized tether on nitrogen), which forms a third ring in the structure of the molecule. Research on a model system (an isocarbostyril without the substituents at positions 6 and 7) for these natural products has been done in order to elucidate the optimal conditions for each step on the synthetic strategy. Initial attempts were made in order to synthesize the 6,7-disubstituted isocarbostyril with the 1,3-diketone tether so that the de Mayo photocyclization could be performed. However, the established synthetic strategy led to compounds along the synthetic route that had very undesirable solubility properties. To resolve this issue, the substituents were replaced with bulkier, more non-polar moieties in order to increase the solubility of the compound in ethyl ether.

Intramolecular de Mayo photocyclization: The total synthesis of hippadine and pratosine

253rd National Meeting (2017)

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