Total Synthesis of (−)-Psathyrin A Enabled by Radical Cyclization

We report herein an enantioselective total synthesis of (−)-psathyrin A, an antibacterial diterpene natural product possessing a unique 6/4/5/5 tetracyclic carbon skeleton and seven contiguous stereocenters, including three adjacent all-carbon quaternary centers. Our synthesis begins with commercially available 2-methyl-2-cyclopenten-1-one, which was subjected to an enantioselective copper/NHC-catalyzed conjugate addition, followed by trapping the resulting enolate with 1-bromo-2-butyne to set up the first two stereocenters, including one all-carbon quaternary center. A Suzuki–Miyaura cross coupling introduces an aromatic ring as the six-membered ring precursor, and a gold(I)-catalyzed Conia-ene reaction constructs the 5/5-fused bicyclic ring system and the second all-carbon quaternary center. Following Birch reduction of the aromatic ring, hydrolysis, and double bond isomerization, a Baran reductive olefin coupling, namely, MHAT-initiated olefin-enone radical cyclization, was employed to construct the four-membered ring and establish the third all-carbon quaternary center. This enabling radical cyclization completed the tetracyclic carbon framework for subsequent peripheral decorations, achieving the first total synthesis of (−)-psathyrin A in 19 steps.