Total Synthesis of Paxdaphnine A and Daphlongamine B via an Aza-Prins Cyclization Strategy

Paxdaphnine A (1) and daphlongamine B (2) are two heptacyclic Daphniphyllum alkaloids, each containing eight consecutive stereogenic centers. We achieved the first synthesis of these molecules in racemic form by using a biomimetic aza-Prins cyclization strategy. Paxdaphnine B (3), a putative biogenetic precursor of 1 and 2, was also obtained in the synthesis. A pentacyclic analogue of 3 was prepared in a scalable manner and served as a common intermediate. The sterically congested cyclopentane moiety of this intermediate was constructed via a nitrone-olefin cycloaddition reaction, and the assembly of its diquinane motif relied on an intramolecular Pauson-Khand reaction. Despite the unsatisfactory outcome of the initial biomimetic aza-Prins reaction of 3 with HCHO, we utilized the N-cyanomethyl derivative of 3 as an alternative substrate in combination with AgTFA as a promoter to rescue the biomimetic route to 1. On the basis of a similar strategy, an aza-Prins cyclization-lactonization cascade, involving a different terminating nucleophile, was developed for the synthesis of 2.