First Divergent Total Synthesis of (±)-Nobilin D and Structurally Related Bibenzyl Natural Products

We report the first concise and efficient racemic total synthesis of (±)-Nobilin D, a bioactive bibenzyl natural product isolated from Dendrobium nobile. Our unified synthetic approach also provides access to (±)-Combretastatin, Moscatilin, and Erianin, all derived from a readily available bromoethyl-substituted norbornyl α-diketone precursor. The key steps involve a Grob fragmentation–aromatization sequence to yield a crucial aromatic ester intermediate, which is then subjected to Baeyer–Villiger oxidation, O-methylation, dehydrohalogenation, and epoxidation to generate highly substituted styrene epoxides. Subsequent regioselective aryl-organolithium epoxide opening, followed by Pd–C/H2 hydrogenolysis, enables the efficient assembly of all four target natural products. This work not only provides the first synthetic access to Nobilin D but also allows for unambiguous structure confirmation by X-ray crystallography. Furthermore, our strategy establishes a scalable platform for the preparation of pharmacologically relevant bibenzyl scaffolds, facilitating future structure–activity relationship (SAR) studies.