Synthesis Study Of Verucopeptin,a Cyclic Depsipeptide Natural Product Overcoming Tumor Drug Resistance

Natural products have long been an important source of clinical drugs due to their diverse structural types and biological activities.Verucopeptin is a 19-membered depsipeptide natural product,which was first isolated from Actinomadura verrucosospora Q886-2 in 1993 and exhibits potent tumor inhibitory activity in vitro and in vivo.What’s more,Verucopeptin was found to target the vesicular ATPase(V-ATPase)and maintain its inhibitory activity against multidrug-resistant tumors by inhibiting the ATP hydrolysis activity and the downstream mTORC1 signaling pathway.However,due to the extremely low natural abundance and complex chemical structure,access to this natural product through both natural extraction and organic synthesis is a great challenge.Therefore,the development of efficient access to the active natural product Verucopeptin is of great research value.In particular,in organic synthesis,the first total synthesis of Verucopeptin was not reported until 2019,and the synthetic route reported by Kakeya et al.is long(the longest linear step is 26)and low efficiency,so more efficient synthetic methods for Verucopeptin remain to be investigated.We have innovatively designed a convergent route for the synthesis of Verucopeptin.Based on a retrosynthetic analysis,Verucopeptin was divided into three fragments:a cyclo-depsipeptide(A fragment),a six-membered ring hemiketal(B fragment)and a chiral aliphatic chain(C fragment).The separate synthesis and efficient linkage of the three fragments is expected to improve the synthetic efficiency of Verucopeptin.To this end,this thesis investigates the synthesis of Fragments A and C of Verucopeptin.Fragment A is a cyclo-depsipeptide consisting of six amino acids,among which exist three unnatural amino acids(R)-hexahydro-pyridazine-3-carboxylic acid,β-(hydroxy)leucine and 2-(hydroxyamino)acetic acid.We first achieved gram-scale preparation of the three non-natural amino acid derivatives(compounds A3,A9 and A26)by selecting suitable protecting groups for functional group blockage from commercially available raw materials.We then realized the assembly of six amino acid derivatives by acid-amine condensation reactions,esterification reactions and AgCN-catalyzed coupling reactions,respectively.Finally,ring closure by acid-amine condensation and the synthesis of the depsipeptide was achieved via an 11-step reactions synthesis.The construction of the three chiral centers and the conversion of functional groups are the key points and difficulties in the synthesis of chiral aliphatic chains of C fragments.We screened for different chiral auxiliary groups and reaction conditions to improve the stereoselectivity of the chiral centers in the C fragment.We also attempted to construct chiral centres and extend the C fragment carbon chain by the Aldol reaction,but the chiral induction effect of the α-position methyl group of the ketone carbonyl of compound C24 was weak and did not match that of the chiral aldehyde C20 according to the Felkin-Anh rule,so the stereoselectivity of this strategy for constructing chiral centers was poor.Finally,we selected(R)-4-benzyl-2-oxazolidinone(Evans chiral auxiliary group)and D-prolinol as chiral auxiliary groups to construct the chiral centers and achieve carbon chain extension through asymmetric alkylation reactions;the carboxylic acid was subsequently reduced by removing the chiral auxiliary groups,and a gram-scale preparation of the primary alcohol compound C13 was achieved through an 11-step reaction.We then verified the feasibility of the Seyferth-Gilbert reaction and the terminal alkyne methylation reaction for the functional group conversion by simplifying the reaction substrates and investigated the regioselectivity and cis-trans stereoselectivity of the hydrozirconization reaction.The results show that the functional group conversion strategy is feasible and the regioselectivity and cis-trans stereoselectivity are good.In conclusion,this thesis has carried out important synthetic exploration work on the A and C fragments of the natural product Verucopeptin,completing the gram-scale synthesis of the A fragment and the diastereoselective construction of the three chiral centers of the C fragment,which will provide an important research methodological basis and material guarantee for the efficient total synthesis of Verucopeptin.