title: Asymmetric synthesis of 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI).
abstract: A short, asymmetric synthesis of the 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI) analogue of the CC-1065 and duocarmycin DNA alkylation subunits is described. Treatment of iodo-epoxide 5, prepared by late-stage alkylation of 4 with (S)-glycidal-3-nosylate, with EtMgBr at room temperature directly provides the optically pure alcohol 6 in 87% yield (99% ee) derived from selective metal-halogen exchange and subsequent regioselective intramolecular 6-endo-tet cyclization. The use of MeMgBr or i-PrMgBr also provides the product in high yields (82-87%), but requires larger amounts of the Grignard reagent to effect metal-halogen exchange and cyclization. Direct transannular spirocyclization of 7 following O-debenzylation of 6 provides N-Boc-CBI. This approach represents the most efficient (9-steps, 31% overall) and effective (99% ee) route to the optically pure CBI alkylation subunit yet described.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: James P
authors.initials: JP
authors.lastname: Lajiness
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D000478:Alkylation; D018360:Crystallography, X-Ray; D003500:Cyclization; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry*; D000080890:Duocarmycins; D006219:Halogens / Q000737:chemistry*; D007202:Indicators and Reagents / Q000737:chemistry*; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure
chemical_list: C445728:1,2,9,9a-tetrahydrocyclopropa(c)benz(e)indol-4-one; D003521:Cyclopropanes; D000080890:Duocarmycins; D006219:Halogens; D007202:Indicators and Reagents; D007211:Indoles; C018782:CC 1065