Asymmetric Synthesis of a CBI-Based Cyclic N-Acyl O-Amino Phenol Duocarmycin Prodrug

[Image: see text] A short, asymmetric synthesis of a cyclic N-acyl O-amino phenol duocarmycin prodrug subject to reductive activation based on the simplified 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) DNA alkylation subunit is described. A key element of the approach entailed treatment of iodo-epoxide 7, prepared by N-alkylation of 6 with (S)-glycidal 3-nosylate, with EtMgBr at room temperature to directly provide the optically pure alcohol 8 in 78% yield (99% ee) derived from an effective metal–halogen exchange and subsequent regioselective intramolecular 6-endo-tet cyclization. Following O-debenzylation, introduction of a protected N-methylhydroxamic acid, direct trannannular spirocyclization, and subsequent stereoelectronically controlled acid-catalyzed cleavage of the resulting cyclopropane (HCl), further improvements in a unique intramolecular cyclization with N–O bond formation originally introduced for formation of the reductively labile prodrug functionality are detailed.