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.