Ceratamine Antitumor Natural Product Total Synthesis Of A And Its Derivatives

Ceratamine A, originally isolated from marine sponge Pseudoceratina sp. collected in Papua New Guinea, is an antimitotic heterocyclic alkaloid with a novel imidazo[4,5-d]azepine core. Structurally, ceratamine A has a novel but simple chemical structure without chiral centers. Functionally, mechanism studies have manifested that ceratamine A is a microtubule-stabilizing agent, which has a totally different tubulin-binding site from that of taxol(?). While blocking the cancer cell division cycle through promoting tubulin polymerization, ceratamine A exhibits an unprecedented mitotic arrest phenotype which is distinct from all the other tubulin-stabilizing agents described to date. The unique mechanism of action implies that ceratamine A may show a different spectrum of toxicity and anticancer activity, particularly against multidrug resistance cancers. Thus ceratamine A is a promising anticancer leading compound.This paper mainly described a procedure to the total synthesis of ceratamine A. The synthetic route was further optimized, and one structural analogue has been prepared according to this route. This is the second total synthesis of ceratamine A. This work laid a solid foundation for the synthesis of the ceratamine A analogues and the investigation of structure-activity relationships. The main contents in this paper are outlined below.1. Total synthesis of ceratamine A from1,4-cyclohexanedione monoethylene acetalThe total synthesis of ceratamine A has been accomplished starting from1,4-cyclohexanedione monoethylene acetal in19steps in an overall yield of7.2%. This synthetic approach features a highly effective Schmidt rearrangement to form the azepine ring. Other key steps include the benzylation of lactam54to introduce the C-5side chain, and a highly economical SNAr reaction to install the C-2methylamine group at an advanced stage which would facilitate the structural modification of ceratamine A to a great extent. 2. Synthesis of ceratamine A from5-methoxybenzimidazoleCeratamine A was synthesized via10steps starting from5-methoxybenzimidazole in an overall yield of12.5%using the optimized synthetic route. The optimized synthetic route is very suitable for the synthesis of derivatives. 3. Synthesis of structural analogues of ceratamine AWith the optimized synthetic route, we prepared one structural analogue of ceratamine A, starting from compound53.