Asymmetric synthesis of substituted tetrahydro-gamma- carbolines and pyrrolo-[4,3,2 de]isochinolines by "Iso" Pictet-Spengler reactions with ciral silans as Lewis acids and biological testing of the novel N-heterocycles
Final Report Abstract
The goal of this project was to investigate Iso-Pictet-Spengler reactions using the chiral Silicon-Lewis acid invented in the Leighton lab. Inspired by the importance of these underexplored indole-structures in Medicinal Chemistry I developed Iso-Pictet-Spengler cyclizations to form pyrrolo [4,3,2-de] isoquinolines and tetrahydropyrazino[1,2-a]indoles in high yields and enantioselectivities using a simple and scaleable one pot procedure. For the first time this kind of compounds containing a quarternary stereocenter are accessible. To investigate their biological activity derivatives were synthesized and tested in CNS-cell lines. The methodology could be expanded to synthesize tetrahydroisoquinolines using electron-rich phenethylamines in place of indoles as substrate. I developed the first enantioselective Pictet- Spengler reaction for tetrahydroisoquinolines with a quarternary stereocenter. This can be an important reaction to streamline the synthesis of natural products containing this motive. Investigations are under way to showcase our new method in the total synthesis of Jasisoquinoline A. The chiral Silicon-Lewis acid allows us to get access to novel, chiral indole- and tetrahydroisoquinoline structures providing a very useful methodology for Medicinal Chemistry and natural product synthesis.
Publications
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Org. Lett. 2012, 14, 2610-2613
H. Schönherr, J. L. Leighton
