Synthesis of Dimeric Pyrrole-Imidazole Alkaloids




Wang, Xiao

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Dimeric pyrrole-imidazole alkaloids, also known as oroidin family of alkaloids, are a class of marine natural products with unique structural diversity and complexity. Focusing on the synthesis of the higher order dimeric pyrrole-imidazole alkaloids, my graduate work comprises two components: a synthetic study of massadine and the total synthesis of ageliferin, as describe herein. These highly nitrogenated marine natural products possess a densely functionalized [3+2] or [4+2] dimerization core skeleton, which present significant synthetic challenges. A manganese(III)-mediated oxidative radical cyclization has been developed to construct the core skeleton of these pyrrole-imidazole dimers and its mechanism is investigated by the methods of computational chemistry. Ent-15-epi-5,11-dioxomassadine has been synthesized by using a biomimetic oxidative ring contraction converting ageliferin skeleton to massadine skeleton with stereochemical control, followed by an oxidative cyclization to construct the oxo-bridge. An asymmetric total synthesis of ageliferin is described, featuring an early installation of 2-azidoimidazole for the oxidative radical cyclization and a phosphorus imide group as a novel protecting group for 2-aminoimidazole. These synthetic studies support the possibility that a single-electron transfer (SET) reaction and a pinacol-type rearrangement may be used in nature as a way to produce ageliferin and massadine.

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