title: Synthetic approaches to the microtubule-stabilizing sponge alkaloid ceratamine A and desbromo analogues.
abstract: Two synthetic approaches to the microtubule-stabilizing ceratamine alkaloids are described. The first approach involved attempts to graft an aminoimidazole moiety onto an azepine ring to form partially hydrogenated versions of the unprecedented aromatic imidazo[4,5-d]azepine core of the ceratamines. This route ultimately failed because it was not possible to aromatize the partially hydrogenated ceratamine intermediates. A second approach started with tribromoimidazole that was sequentially metalated and functionalized to efficiently generate a key imidazole intermediate containing vinyl bromide and amide functionalities. An intramolecular Buchwald vinyl amidation reaction converted this key intermediate into a bicyclic imidazo[4,5-d]azepine that was at the same oxidation state as the aromatic core of the ceratamines. The 2-amino functionality present on the imidazole ring of the ceratamines was installed using a Buchwald/Hartwig amination reaction on a 2-chloroimidazole precursor. Deprotection and aromatization resulted in the first synthesis of desbromoceratamine A (55) and desmethyldesbromoceratamine A (60). An unanticipated addition of atmospheric oxygen was encountered during deprotection of the imidazole ring in the last step of the synthesis leading to C-11 oxygenated ceratamine analogues as byproducts. Evaluation of the synthetic ceratamines in a TG3 cell-based assay for mitotic arrest revealed that the C-14 and C-16 bromine substituents in ceratamine A (1) play a major role in the antimitotic potency of the natural product. The synthetic route to ceratamine analogues has provided sufficient quantities of desbromoceratamine A (55) for testing in mouse models of cancer.
authors.affiliation: Department of Chemistry, University of British Columbia, Vancouver, BC, Canada V6T 1Z1.
authors.forename: Matt
authors.initials: M
authors.lastname: Nodwell
authors.forename: Alban
authors.initials: A
authors.lastname: Pereira
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Riffell
authors.forename: Carla
authors.initials: C
authors.lastname: Zimmerman
authors.forename: Brian O
authors.initials: BO
authors.lastname: Patrick
authors.forename: Michel
authors.initials: M
authors.lastname: Roberge
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Andersen
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis*; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis*; D001969:Bromobenzenes / Q000138:chemical synthesis; D007093:Imidazoles / Q000138:chemical synthesis*; D011161:Porifera / Q000737:chemistry
chemical_list: D000470:Alkaloids; D001381:Azepines; D001969:Bromobenzenes; D007093:Imidazoles; C485389:ceratamine A