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. 2014 Sep 24;136(38):13442-52.
doi: 10.1021/ja507740u. Epub 2014 Sep 12.

A Unified Strategy for the Synthesis of 7-membered-ring-containing Lycopodium Alkaloids


A Unified Strategy for the Synthesis of 7-membered-ring-containing Lycopodium Alkaloids

Amy S Lee et al. J Am Chem Soc. .


A unique subset of the Lycopodium alkaloid natural products share a 7-membered-ring substructure and may potentially arise from a common biosynthetic precursor. To both explore and exploit these structural relationships, we sought to develop a unified biosynthetically inspired strategy to efficiently access these complex polycyclic alkaloids through the use of a cascade sequence. In pursuit of these goals, the first total synthesis of (+)-fastigiatine (2) was accomplished via a series of cascade reactions; we describe herein a full account of our efforts. Insight from these endeavors led to critical modifications of our synthetic strategy, which enabled the first total syntheses of (-)-himeradine A (1), (-)-lycopecurine (3), and (-)-dehydrolycopecurine (4), as well as the syntheses of (+)-lyconadin A (5) and (-)-lyconadin B (6). Our approach features a diastereoselective one-pot sequence for constructing the common 7-membered-ring core system, followed by either a biomimetic transannular Mannich reaction to access himeradine A (1), lycopecurine (3), and dehydrolycopecurine (4) or an imine reduction for lyconadins A (5) and B (6). This strategy may potentially enable access to all 7-membered-ring-containing Lycopodium alkaloids and provides additional insight into their biosynthetic origin.

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