Studies On The Semisynthetic Approach Towardthe Core Of Tesetaxel

Since paclitaxel was found,it has attracted much attention because of its unique anticancer mechanism.Three new taxane anti-cancer drugs have been successfully used in cancer treatment.However,the route of administration of these three drug is injection,which causes side effects such as infusion reactions,the poor absorption effect derived from its poor solubility in water.Instead,Tesetaxel is a novel taxane that is administered by mouth as a capsule and it was developed with a goal of maintaining the high antitumor activity while eliminating infusion reactions,reducing neuropathy,and increasing patient convenience.This thesis mainly focuses on the semisynthetic route toward the core of Tesetaxel starting from 10-deacetylbaccatin III（10-DAB III）.It mainly involves the dehydroxylation of the C7-OH,reduction of C9-carbonyl group and acetalization of C9-C10 double hydroxyl groups.C7-OH can be efficiently converted to triflic ester that can serve as a good leaving group when the C10-OH has been protected by silyl group.Subsequent treatment of the triflic ester with large steric hindered organic base leads to elimination reaction and provides the corresponding vinyl product that can be futher reduced to by Pd/C.As a result,the C7-OH can be effectively removed.Furthermore,C9-carbonyl group can be stereoselectively reduced by BH₃·THF and n-Bu₄NBH₄ to obtain 9β-OH product by screening a variety of hydride delivering reagents.The reductive reagents,BH3·THF and n-Bu4NBH4,only work for a limited structure defined substrates.Subsequently,various acetalization reagents were used including small to large steric hindered candidates and the acetalization reaction was found to be sensitive to the structure of substrates.Only when Acrolein diethyl acetal or Acrolein dimethyl acetal was used,can the product be get in moderate yield.Finally,synthetic methodology for the construction of vicinal diol derivatives via Brook rearrangement-mediated three-component coupling reaction of amide,acylsilane and aldehyde has been investigated.A carbamoyl anion,generated from N,N-disubstituted formamides and lithium diisopropylamide,initiated cascade reaction,in which nucleophilic addition to acylsilanes triggs 1,2-Brook rearrangment to form a reactive nucleophilic intermediate that was intercepted by aldehydes,affording vicinal diol derivatives in high yield in a one-pot operation.The improvement of the diastereoselectivity of this cascade reaction is required.