Total Synthesis of Dapholdhamine B and Dapholdhamine B Lactone

The intriguing structural
complexity and bioactivities of the Daphniphyllum alkaloids have long attracted much attention.
Herein, we report the first and enantioselective total synthesis of Daphniphyllum alkaloid dapholdhamine B and its lactone derivative.
The chemical structure of dapholdhamine B contains a unique aza-adamantane
core skeleton and eight contiguous stereocenters, including three
contiguous fully substituted stereocenters, which present a formidable
synthetic challenge. This concise approach used to achieve the first
synthesis of an aza-adamantane natural product features a vinylogous
Mannich reaction, an optimized α-bromo-α,β-unsaturated
ketone synthesis, a substrate-dependent intramolecular aza-Michael
addition, a key annulation via amide activation, an SN2′-type
lactonization, and a facile Horner–Wadsworth–Emmons
reaction that converts the hemiacetal moiety to the corresponding
homologated carboxylic acid.