Total Synthesis of (+)-Melicolone K Enabled by a Late-Stage Programmed C–H Functionalization

An asymmetric total synthesis of
(+)-melicolone K is
described
for the first time. The strategy features a late-stage programmed
C–H functionalization, which comprises a Rh(II)-catalyzed γ-C(sp3)–H amination and a newly formed cyclic sulfamate ester-directed
γ-C(sp3)–H prenylation through a formal (4
+ 2) cycloaddition/reductive ring-opening process. By incorporation
of a Sharpless asymmetric dihydroxylation, a Wolff ring contraction,
and a Ti(III)-mediated radical cyclization, our approach rendered
concise and efficient access to this flagship prenylated natural
product with good enantio- and diastereocontrol. The direct, single-step
prenylation protocol developed in this work paves the way for streamlined
syntheses of the prenylated natural products.