One‐Step Multigram‐Scale Biomimetic Synthesis of Psiguadial B

A gram‐scale synthesis of psiguadial B, a purported inhibitor of human hepatoma cell growth, has been achieved in one step by a biomimetic three‐component coupling of caryophyllene, benzaldehyde, and diformylphloroglucinol. This cascade reaction is catalyzed by N,N′‐dimethylethylenediamine, and proceeds at ambient temperature to generate four stereocenters, two rings, one C−O bond, and three C−C bonds. Combined computational and experimental investigations suggest the biosynthesis of the natural product is non‐enzyme mediated, and is the result of a Michael addition between caryophyllene and a reactive ortho‐quinone methide, followed by two sequential intramolecular cationic cyclization events. A one‐step multigram‐scale synthesis of psiguadial B has been achieved using a biomimetic three‐component coupling, thus generating three C−C bonds, one C−O bond, two rings, and four stereocenters. Combined synthetic and computational experiments suggest the reaction proceeds by a Michael addition of caryophyllene to an in situ generated ortho‐quinone methide, followed by two sequential cationic cyclization events.