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.
The synthetically challenging, diverse chemical skeletons and promising biological profiles of the Daphniphyllum alkaloids have generated intense interest from the synthetic chemistry community. Herein, the first and enantioselective total synthesis of (−)-caldaphnidine O, a complex bukittinggine-type Daphniphyllum alkaloid, is described. The key transformations in this concise approach included an intramolecular aza-Michael addition, a ring expansion reaction sequence, a Sm(II)/ Fe(III)-mediated Kagan−Molander coupling, and the rapid formation of the entire hexacyclic ring skeleton of the target molecule via a radical cyclization cascade reaction, which was inspired by an unexpected radical detosylation observed in our recent dapholdhamine B synthesis.
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