Studies On Synthesis Of Lactam Analogues And Semisynthesis Of The Epothilones

The epothilones (Epos) are a family of natural macrolactone products, and they were first discoverd by Hofle and his co-works from Sorangium cellulosum strain 90. This new class of microtubule-stabilizing natural products exhibit the same mechanism of action as paclitaxel, and furthermore, these new antitumor angents exhibit selective cytotoxicity and are particularly effective against certain drug-resistant tumor cell lines, even in cases where Taxol fails. Epothilones aslo have better solubility in water than paclitaxel. All these features make them attactive complements in the search for effective cancer therapies. The relative simple structure of the epothilones made them easy for total synthesis or semisynthesis to get the new analogues. Recently, there were almost one thousand analogues, of which a large porportion were synthesized using a combinatorial approch. It is still an important mission to find more new analogues and study on their pharmacological activity.The lactam analogue of epothilone B received FDA approval for the treatment of metastatic or advanced breast cancer on October 16,2007. It is marketed in the US by BMS under the trade name Ixempra. And another lactam analogue of epothilone D aslo show impressive in vivo activity and was seen as a candidate anticancer drug. But the semisynthesis on epothilone lactam analogues is not mature at present, and the overall yields can't satisfy the huge clinical needs. So developing an efficient process which can adapt to a higher yield has a great deal of profits.Using epothilone C and D as raw material, The synthetic routes of their lactam analogues were studied. And a novel regio-and stereoselective Pd-catalyzed azidation reaction of a macrocyclic lactone was applied to this reaction. And the subsequent approches were the reduction and macrolactamization of the resulting azide acid intermediates. All these three steps were improved to get a higher yield. Furthermore, breaking the routine of the initial "one-pot" reaction, the first step was left alone, and the other reaction conditions were improved futher. Though there would be a little trouble when dealing with the intermediates, the overall yield of the lactam reaction using our new methods could reach 30%-35%. So at last, a satisfactory experiment result was obtained.Another more, The 14-hydroxy epothilone D was aslo modified in this thesis. Many different methylation reagents were used to evaluate the yield,and finally methyl iodide/silver oxide was choosed as the methylation reagent, which provide us with good yield of 47%. 14-methoxide epothilone D (14-OMe) was synthesised and meanwhile another macrolide which was methoxided at 15-hydroxy (STQ-15M) was also abtained. All these two compounds were first synthesised.All the intermediates and the final product lactam analogues of epothilone C and D and the new compounds 14-OMe, STQ-15M that synthesized in thesis were characteried by MS and NMR.