Total Synthesis of Hybridaphniphylline B

Hybridaphniphylline
B (1) is a Daphniphyllum alkaloid possessing 11 rings and 19 stereocenters. Here we report
the first total synthesis of 1 featuring a late-stage
intermolecular Diels–Alder reaction of a fully elaborated cyclopentadiene
and asperuloside tetraacetate. The diene was prepared on the basis
of a scalable route to daphnilongeranin B (4). Claisen
rearrangement of an allyl dienol ether was exploited as a key step;
the subtle variation of the substrate and use of protic solvents suppressed
the undesired Cope rearrangement. Daphniyunnine E (6)
and dehydrodaphnilongeranin B (7), two congeners of 4, were also synthesized. The dienophile arose from (+)-genipin
through glycosylation and lactonization. A one-pot protocol was developed
for the diene formation and Diels–Alder reaction; one of the
cycloadducts was converted into 1 through reductive desulfurization
and global deacetylation.