Research On The Total Synthesis Of Natural Products Of Bensamycin Based On The Discovery Of New Drugs

Heat shock protein 90(Hsp90)is a molecular chaperone that is widely distributed in eukaryotic cells to assist in the correct folding of nascent peptides or denatured proteins.It is also an important tumor marker,which has a close relationship with occurrence and development of cancer.Benzoquinone ansamycin family natural products are 19-membered macrocyclic lactams isolated from streptomyces hygroscopicus species(Fig.1),which selectively bind to Hsp90,and showed promising antitumor activity.Figure 1 Representative natural product Geldanamycin and intended modification sitesIn view of their outstanding biological activities,benzoquinone ansamycin are of important value in drug discovery.In order to solve the problems of poor aqueous solubility and severe hepatotoxicity,a large number of semi-synthetic structural optimization works have been carried out.However,outcomes from clinical studies indicated that strong hepatotoxicity is still a substantial problem that limits further clinical development.Considering the limitations of semi-synthetic method,we believe that total synthesis should be a more powerful tool to realize deep-sealed structure modifications upon benzoquinone ansamycin.Based on the co-crystal structure of benzoansamycin and Hsp90 protein,the structural modification sites(such as aromatic fragment C4-C5,C6,C8,C11,C14)shown above were determined(Fig.1).Guided by the above structural modification plan,geldanamycin was selected as the target molecule to design a total synthetic route that would meet the following two basic requirements(Fig.2):① Disperse the modification sites in different synthetic blocks.② Fragment synthesis and assembly methods should meet the needs of structural modification work as much as possible.According to the above designithe following work was carried out:1)The synthesis of C5-C12 f-ragment was completed including Sharpless asymmetric epoxidationiregeo-selective epoxy ring opening,Noyori asymmetric reduction,regeo-selective hydrostannation and Neigishi coupling.The construction strategy of the C6,C7 chiral centers and C8 methyl group provides a simple and easy chemical method for the subsequent structural modification of the C6 and C8 positions.2)The Evans?asymmetric alkylation reaction is used to establish the C14 chiral center,and the phenylsulfonyl group is introduced to complete the synthesis of the C13-C21 fragment.This kind of synthesis method provides the feasibility of modification for the C14 positions.3)The coupling of the C5-C12 and C13-C21 fragments was achieved by nuclear philic addition between phenylsulfonyl-induced carbanion and aldehyde,followed by Dess-Martin oxidation and SmI2 reduction.4)The single-step and step-wise introduction of C1-C4 fragment were investigated separately,and the later were f-ound superior.5)The total synthesis of Geldanamycin was accomplished by further steps iIcluding the lactam ring-closure under the action of BOPC1 and the removal of the protecting group by the AlCl3/Anisole system.Starting from the intermediate aldehyde C5-C12 fragment,the linear step was 16 steps with a total yield ot 10.980%.In summary,we successfully finished the total synthesis of geldanamycin.[n addition,in order to realize the rapid construction of the derivatized compound library,this paper designed a derivatized lead skeleton structure(Fig.3),and finished its synthesis work using the total synthetic route described above,which laid a solid chemical synthetic foundation for the subsequent structural modification work.