Semi–synthetic Studies Of Tesetaxel Core Ring

Tesetaxel is a novel kind of water-soluble,orally absorbed anti-cancer taxane drug that not only avoids a series of side effects caused by injection,but also has high anti-cancer activity and better efficacy to patients’absorption resulting in making use of drugs more convenient,and has a broad promising clinical application prospect.Therefore,it is of great significance to develop a highly efficient synthetic route toward the core ring of Tesetaxel.In this thesis,we first conducted a synthesis study of the Tesetaxel’s core ring starting from 10-deacetylbaccatin（10-DAB）.The strategy we adopted was converting the 7-OH into a good leaving group（OTf）after the C10-OH was selectively protected by the silyl group.Strong base DBU was used to promote aβ-elimination which provides an alkene product that could be futher reduced by hydrogen in the presence of palladium-carbon catalyst after removal of silyl groups.As a result,we obtained the 7-dehydroxylbaccatin in 5 steps with a total yield of 56%.Next,we conducted a study on the reduction of C-9 carbonyl group with BH₃-THF.We observed that addition of Lewis acid did not significantly increase the yield of reduction.Then,we found HC（OMe）₃ mediated acetalization of 9-10 dihydroxyl groups in good yield,The acetalization reaction was only applicable toα,β-unsaturated aldehydes but not toα,β-unsaturated acetals.Afterwards we performed dihydroxylation reactions with Os O₄/NMO protocol,in which the double bond can be dihydroxylated accompanying oxidation of C-13 hydroxyl group simultaneously.Finally,the synthetic method ofα,β-unsaturated N-tert-butylsulfinyl imidates via Peterson olefination reaction was developed.Nucleophilic addition ofα-silyl N-tert-butylsulfinyl imidates to aldehydes using KHMDS as base induced 1,3-silyl migration from carbon atom to oxygen atom,and subsequent syn-elimination gave rise to stereospecific preparation of a range ofα,β-unsaturated N-tert-butylsulfinyl imidates in 71-96%isolated yields.