Studies Towards The Total Synthesis Of Cylindrospermopsin And Its Analogues

Cylindrospermopsin is a potent hepatotoxic marine alkaloid which is isolated from the cyanobacteriumis and its family analogues involve 7-epicylindrospermopsin and 7-deoxycylindrospermopsin. There is a guanidine embedded in a tricyclic system and six chiral centers in its structure. This toxin continues to be a serious public health problem and does harm to the living environment seriously. Due to their special structure and strong toxicity, cylindrospermopsin and its analogues attract our interest of synthetic studies towards them. This paper describes the total synthesis of 7-deoxycylindrospermopsin and studies towards the synthesis of cylindrospermopsin and 7-epicylindrospermopsin.The first chapter briefly presents the background of cylindrospermopsin and its analogues and describes the important work reported by Snider, Weinreb, White and Williams for the total synthesis of cylindrospermopsin,7-epicylindrospermopsin and 7-deoxycylindrospermopsin.In the first section of the second chapter, we introduce the model reaction studies. Starting from 2-piperidineethanol and using the Heck reaction or Suzuki reaction to connect D-ring, the intermediate substrate was synthesized to do the model reaction, however, we only got the Michael addition product finally.The rest part of the second chapter introduces the synthetic studies towards 7-deoxycylindrospermopsin, cylindrospermopsin and 7-epicylindrospermopsin. After treating starting reactant 4-methoxy-pyridine with Troc or Cbz reagent, eventually we found that Cbz protecting group was difficult to remove, however Troc protecting group could be easily removed and then the substrate underwent subsequent reaction; Heck or Sonogashira reaction was tried as the critical reaction, finally the D-ring was successfully connected by Sonogashira reaction.Eventually after treating starting reactant 4-methoxy-pyridine with TrocCl, the intermediate underwent nucleophilic attack by the vinyl Grignard, and then methyl group was introduced at the adjacent of carbonyl group. After the Michael addition reaction of TIPS-protected propargyl bromide and L-selectride reduction of the carbonyl group, the four stereogenic centers contained in A-ring are correct. After the transformation of the double bond, the reaction was carried out to form guanidine, making A-ring and B ring connected together. The A, B, D rings have been constructed using Sonogashira reaction after removal of TIPS protecting group. The C-ring formed after the attempts to remove the protecting group followed by Michael addition using concentrated hydrochloric acid. After reduction of the double bond and then being treated with sulfur trioxide, the total synthesis of 7-deoxycylindrospermopsin and 8-epi-7-deoxycylindrospermopsin have been accomplished in 14 steps. Further attempts of total synthesis of cylindrospermnopsin and 7-epicylindrospermopsin are still in progress.