Pactamycin and Its Derivatives: Improved Synthesis Route

Stereoselective construction of the cyclopentane core 21 of pactamycin (1) was achieved from symmetric cyclohexadiene 7. Our synthetic strategy features catalytic Rh-mediated desymmetric aziridination of the cyclohexadiene derivative, selective ring-opening reaction at the C2 position of sulfonylaziridine with NaN3, ring-contraction of cyclohexene 9 by ozonolysis followed by intramolecular aldol reaction via enamine intermediate 11, and construction of the two consecutive tetra-substituted carbon centers by stereoselective epoxidation of the exo-methylene moiety of 14c with DMDO, followed by methylation reaction. Introduction of the urea unit on tetra-substituted carbon of 16 was achieved by amidation and subsequent Hofmann rearrangement.