Asymmetric Construction Of Benzannulated Spiroketal Skeletons & Studies On The Total Synthesis Of Murrayazoline

This thesis aimed at the studies on the asymmetric construction of benzannulated spiroketals and the total synthesis of murrayazoline, the detail contents could be divided into the following three parts:Chapter 1. Recent Progress on the Synthesis of Spiroketal MoietiesAs spiroketal cores are the key skeletons of a variety of natural products and pharmacophores, the method for the convenient construction of spiroketals have attracted increasing attention of chemists. This chapter briefly introduced the structure features, classification and bioactivities of spiroketal compounds, and emphasized on the synthetic methods, the characteristics of various synthetic strategies, and their synthetic applications.Chapter 2. Studies on the Asymmetric Construction of Benzannulated Spiroketal SkeletonsAfter careful review of the literatures, we found that there has been limited work on the asymmetric synthesis of benzannulated spiroketals. Especially, to date, there is no report concerning the asymmetric construction of the bisbenzannulated [5,6]-spiroketal core of the rubromycin family. Based on our previous work, we designed a hydrogen-bond-induced asymmetric Diels-Alder cycloaddition strategy to synthesize these chiral spiroketal moieties, starting from chiral propargyl alcohols. Firstly, we used salicylaldehyde, terminal alkynes and dienes as substrates to build benzannulated spiroketal skeletons via a one pot tandem reaction, but the first step(construction of chiral hydroxyl) gave low enantioselectivity. Then we tried to apply this strategy in the water phase, the results showed that ynone reagent could complete nucleophilic attack and form benzofuran ring at the same time, but the Diels-Alder reaction cascade did not occur. Finally we changed the substrates and developed a tandem reaction consisting of a copper(I)-catalyzed cycloetherification and a hydrogen-bond-induced inverse electron-demand oxa-Diels- Alder cycloaddition, starting from chiral propargyl alcohols, this new approach could successfully give the chiral benzannulated [5,6]-spiroketal with high efficiency. After substrate scope investigation, we have synthesized 31 chiral [5,6]-spiroketal compounds in excellent dr and ee value. This is the first method to provide optically pure bisbenzannulated [5,6]-spiroketal cores of natural products and will be helpful for the syntheses of rubromycin natural products and other spiroketal compounds. Meanwhile, the biological activity tests showed that the compounds we synthesized have inhibitory effect on Cdc25 A phosphatase.Chapter 3. Studies on the Total Synthesis of MurrayazolineMurrayazoline is a kind of cyclic monoterpenoid pyrano[3,2-a]carbazole alkaloid isolated from Murraya in plant Murraya koenigii. These compounds have a good inhibitory effect on platelet aggregation, which is comparable to Aspirin.By analyzing the structures of these compounds, we considered that a series of natural products with similar skeleton could be obtained through the construction of Murrayazolidine(165) and the subsequent functional groups transformation.In the concrete synthesis process, using 5-amino cresol as the starting material, we successfully obtained carbazole 215 in 8 steps.Later, we tried to synthesize the benzopyran skeleton of murrayazoline alkaloids via our previously established three-component reaction, but in the experiment process we encountered some difficulties. So we changed the route and started the synthesis with carbazole aldehyde 215, after protecting group exchange and coumarin ring construction, we obtained compound 249. Then we obtained the bridged tricyclic benzopyran compound 251 through an asymmetric Diels-alder reaction, reduction/acid catalyzed intramolecular cyclization cascade. Then we synthesized the key intermediate 257 via the ozonation reaction, hydrogenation, Grignard reaction and Ts deprotection, and built the ABCEF ring of Murrayazoline. We are now trying to remove the hydroxyl group in 257 to complete the synthesis of natural product 165. The synthesis of these alkaloids is still in progress in our lab.