Rapid Access to the Heterocyclic Core of the Calyciphylline A and Daphnicyclidin A‑Type Daphniphyllum Alkaloids via Tandem Cyclization of a Neutral Aminyl Radical

ABSTRACT: A streamlined approach to the tertiary amine-containing core of the calyciphylline A and daphnicyclidin A-type Daphniphyllum alkaloids is presented. A known carvone derivative is converted into the core structure in only four synthetic operations, and it is well poised for further elaboration. The key enabling methodology is a radical cyclization cascade beginning with addition of a secondary, neutral aminyl radical to the β-position of an enone, followed by trapping with a pendant alkyne. The Daphniphyllum alkaloids are a structurally alluringfamily of plant alkaloids isolated from trees of the genus Daphniphyllum.1 Biosynthetic proposals from Kobayashi suggest that they are derived from rearrangements of secodaphnane,1a which in turn, arises via cyclization and condensation of squalene.2 Members of this family of alkaloids exhibit cytotoxicity against murine leukemia (L1210, P-388, and A-549 cell lines), demonstrate antioxidant activity against PC12 cells, show vasorelaxant effects in the rat aorta, and increase mRNA expression of nerve growth factor.1a Despite these promising bioactivities, the biological role of the vast majority of Daphniphyllum alkaloids has not been determined. The rang