title: A unified strategy for the synthesis of 7-membered-ring-containing Lycopodium alkaloids.
abstract: 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.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University , Cambridge, Massachusetts 02138, United States.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Lee
authors.forename: Brian B
authors.initials: BB
authors.lastname: Liau
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Shair
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry; D032502:Lycopodium / Q000737:chemistry*; D008958:Models, Molecular; D011083:Polycyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry; D011807:Quinolizines / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000470:Alkaloids; D006576:Heterocyclic Compounds, 4 or More Rings; D011083:Polycyclic Compounds; D011807:Quinolizines; C480481:himeradine A; C435307:lyconadin A; C514204:lyconadin B; C000602017:lycopecurine