Structural Elucidation and Bioinspired Total Syntheses of Ascorbylated Diterpenoid Hongkonoids A–D

Hongkonoids A–D (1–4),
the first example of ascorbylated terpenoids featuring a unique 5,5,5-fused
tricyclic spiroketal butyrolactone moiety and diterpenoid-derived
long chain, were isolated from Dysoxylum hongkongense. Their structures were unambiguously assigned by a combination of
spectroscopic data, chemical degradation, X-ray crystallography, CD
analysis, and total synthesis. The total syntheses of compounds 1–4 were effectively accomplished by a
convergent strategy with the longest linear sequences of 12–14
steps and overall yields of 5.4–9.6%. Notably, we exploited
a bioinspired one-pot method to construct the key intermediate 14 from an easily made compound 12 by involving
the cascade reactions of an elaborate Claisen rearrangement, deprotections,
and a 5-exo-trig cyclization. The desired major epimer 14a was then transformed to the main building block 21. Assembly of 21 and the long chain vinyl iodide 7 was made by an NHK coupling reaction to furnish the framework
of 1–4. Some of the hongkonoids and/or
synthetic analogs showed significant to moderate inhibitory activities
against NF-κB, 11β-HSD1, and sterol synthesis. The most
active NF-κB inhibitor 34 exhibited distinct inhibition
on the LPS-induced inflammatory responses in RAW 246.7 and primary
BMDM cells.