Total synthesis of ent-plagiochianin B and development of a metathesis approach to aleutianamine.


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Isolated in 2018 from the Chinese liverwort Plagiochila duthiana, plagiochianin B features a novel 6/7/3 tricyclic core. The total synthesis of ent-plagiochianin B was achieved in 9 synthetic steps from a known cycloheptenone and 13 steps overall starting from (+)-3-carene. As anticipated, the inherent stereochemistry found in (+)-3-carene led to production of material that was enantiomeric to the natural product. Key features of the synthesis include the utilization of a 6p-azatriene electrocyclization and the subsequent discovery of a palladium catalyzed oxidative cleavage of a terminal olefin. The strained and heavily bridged pyrroloiminoquinone alkaloid aleutianamine was isolated in 2019 from the North Pacific sponge Latrunculia (Latrunculia) austini Samaai, Kelly & Gibbons, 2006 and exhibits cytotoxicity against a number of cancer cell lines. Noteworthy is aleutianamine’s IC 50 value of 25 nM against pancreatic cancer. Synthetic challenges posed by this natural product include the pyrroloiminoquinone core, an N,S-acetal, vinyl bromide containing 1,3-diene, and an iminium ion. Efforts to provide synthetic access to this biologically interesting alkaloid have been fruitful and several key checkpoints have been reached, including: the development of a scalable Larock-type indole synthesis for construction of the iminoquinone region, a model system study has validated the viability of a tandem metathesis reaction to forge a bromotetrahydrobenzo[b] thiophene moiety, and preparation of an intermediate that contains all necessary carbons for the natural product and is structurally poised for synthesis completion. The challenges, victories, and outlook of this synthetic campaign are herein described.