Studies On The Synthesis Of Side-Chain Of Tesetaxel And Its Analogs

Tesetaxel is a novel,orally absorbed taxane.In addition to its high anticancer activity,tesetaxel can avoid side-effects caused by intravenous infusions in the case of the same class of taxane drug and improved patients convenience.The preparation of tesetaxel in literature reports generally based on the semi-synthetic methods via the coupling of C-13 side chain with the baccatin III core structure.Developmeng of an effective synthetic route toward of C-13 side chain of tesetaxel is important for the synthesis of tesetaxel and its scalable preparation.One of the goals of this thesis is to develop an effective synthetic method for the side-chain of tesetaxel based on the literature precedents.The synthetic approach toward of the side-chain is presented as follows:3-fluoride pyridine-2-aldehyde and p-methoxyaniline affords the corresponding Schiff base,that is reacted with acetoxyacetyl chloride to give ?-acetoxy-?-lactam via Staudinger reaction.Subsequent removal of the p-methoxyphenyl group on the nitrogen atom of the ?-lactam,followed by chiral resolution using beef liver enzymes,enables the production of enantioenriched ?-acetoxy-?-lactam.Further protection of the free endocyclic N-H of ?-acetoxy-?-lactam with t-butoxycarbonyl group gives the desired compound that can serve as precursor of side chain of tesetaxel.In addition,the studies on the synthetic methodology for enantioenriched ?,?-disubstituted-?-silyloxy-?-amino acid derivatives was conducted.Efficient construction of this skeleton that possesses similar functionalization with side chains of taxane drugs was achieved by using Brook-rearrangement mediated three-component coupling strategy.Nucleophilic addition of silyllithium to ?-ketoamides,followed by 1,2-Brook rearrangement,generates nucleophilic enolates,which are then intercepted by chiral N-tert-butanesulfinyl imines to provide three-component coupling products.Use of ?-ketoamides is critical for achieving high yields(up to 99%)and diastereoselectivities(dr >20:1:0:0)in the resulting ?-hydroxy-?-amino acid derivatives.