Synthetic Approaches to the Microtubule-Stabilizing Sponge Alkaloid Ceratamine A and Desbromo Analogues

• Published in: Journal of organic chemistry Vol. 74; no. 3; pp. 995 - 1006
• Main Authors: Nodwell, Matt, Pereira, Alban, Riffell, Jenna L, Zimmerman, Carla, Patrick, Brian O, Roberge, Michel, Andersen, Raymond J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 06-02-2009
• Subjects: Alkaloids - chemical synthesis; Animals; Azepines - chemical synthesis; Bromobenzenes - chemical synthesis; Chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Imidazoles - chemical synthesis; Organic chemistry; Porifera - chemistry; Preparations and properties; Imidazole derivatives; Nitrogen heterocycle; Deprotection; Hydrogenation; Amidation; Marine environment; Alkaloid; Amine; Amination; Functionalization; Imidazole; Vinylic compound; Bicyclic compound; Bromine Organic compounds; Aromatic compound; Metalation; Chemical synthesis; Antimitotic; Intramolecular reaction; Rodentia; Animal origin; Organic bromine compounds; Natural compound; Malignant tumor; Buchwald Hartwig reaction; Vertebrata; Aromatization; Mammalia; Valence; Mouse; Porifera; Analog; Carboxamide; Sponge; Microtubule; Invertebrata; Cancer
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo802322s

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.