Sequential metalation onto the tribromoimidazole followed by functionalization led to the efficiently generate a key imidazole intermediate containing the vinyl bromide and the amide functionalities, thar are keys to the success to the total synthesis described herein.
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.
Citing Articles
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This article has been cited by 7 ACS Journal articles (5 most recent appear below).
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