We have completed the asymmetric total synthesis of (-)-γ-Lycorane, a deoxygenated derivative of the natural product Lycorine, using an Iridium-catalyzed hydrogen-borrowing reaction to form a key carbon-carbon bond. To our knowledge, this is the first example of the use of C-C bond formation via hydrogen-borrowing in the total synthesis of a complex natural product derivative. Starting from cyclohexenone, an asymmetric aziridination utilising conditions developed by Hamada and co-workers furnished an enantiopure, Cbz protected aziridine. Upon reduction with NaBH4, we developed a tandem deprotection/reprotection sequence to give the desired hydrogen-borrowing starting alcohol as an inconsequential mixture of diastereomers. In accordance with previous methodology developed within our group, a [Cp*IrCl2]2 catalyzed hydrogen-borrowing alkylation using Ph* (pentamethylbenzene) methyl ketone gave us the desired all cis aziridine product. Upon treatment with Br2, we observed a tandem Ph* retro Friedel-Crafts type removal/lactam formation/aziridinium opening/bromination sequence to give a known intermediate on the path to (-)-γ-Lycorane. A number of known and novel methodologies were explored for the endgame, ranging from a radical cyclisation to a reductive Heck reaction onto an olefin on the core ring. Studies are still ongoing to optimise the overall reaction sequence, as well as to synthesise other related natural products.

Total synthesis of (-)-γ-lycorane

2019 Fall National Meeting

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