title: Asymmetric synthesis of a CBI-based cyclic N-acyl O-amino phenol duocarmycin prodrug.
abstract: 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.
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Mika
authors.initials: M
authors.lastname: Uematsu
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D000478:Alkylation; D003500:Cyclization; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry*; D000080890:Duocarmycins; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D019800:Phenol / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: C445728:1,2,9,9a-tetrahydrocyclopropa(c)benz(e)indol-4-one; D003521:Cyclopropanes; D000080890:Duocarmycins; D007211:Indoles; D011355:Prodrugs; D011760:Pyrrolidinones; D019800:Phenol; C030797:cyclopropane; C058289:duocarmycin A