Formal Synthesis Of Natural Product(±)-aplykurodinone-1 By Conia-ene Reaction

Aplykurodinones is an important class of sterols marine natural products that exists in the body of mollusk marine organisms(sea hare).Its main physiological activity is antineoplastic effect,and there is no mature synthesis method at this stage.(±)-aplykurodinone-1 is a marine natural product molecule with a unique cis-condensed and hydrogen indane structure and six consecutive stereochemical centers C7,C8,C3,C4,C11,and C13;however,due to its low natural content and unique molecular structure makes the synthesis of its highly difficult,At present,There are few reports on the biopharmaceutical activity of(±)-Aplykurodinone-1 and its analogues.Thus,it is of great significance to artificial synthesis(±)-Aplykurodinone-1 and its analogs to provide adequate material basis for its pharmacodynamic research.Therefore,it has attracted the attention of researchers at home and abroad.In this thesis,a simple,novel and efficient synthetic route for the natural product(±)-Aplykurodinone-1 was designed.Mainly focus on the construction of molecule’s unique cis-fused hydrogen indane tricyclic skeleton structure.In this paper,the C ring was constructed by three steps to obtain the dicarbonyl compound from the starting material of Malonic acid cyclic isopropylidene ester;4-pentyn-1-ol was used to obtain the fragment alkyne bromide in two steps.The two fragments were added by Michael 1,4 to obtain the Grignard reagent addition product,and then close the ring through the key Conia-ene reaction to obtain the bicyclic product to complete the B/C ring construction;Thus,a chiral center at positions C7/C8 was constructed in one step.On this basis,through the allyl oxidation reaction,the chiral center at the C4 position is constructed to obtain the monohydroxy structure,and an α,β unsaturated ester structure is obtained by esterification with acryloyl chloride.Sequentially,the Krapcho decarboxylation reaction was used to remove the Trimethylsilyl(TMS)ethyl group at the C8 position,finally the rigid Ring lactone ring A was constructed through the key Ring closing metathesis reaction,and we successfully achieved the backbone synthesis of natural product(±)-aplykurodinone-1.This thesis adopts the "convergent formula" synthesis strategy as a valuable experience in the total synthesis of other sterol family compounds and other natural products.At the same time,the formal synthesis of(±)-aplykurodinone-1 has alsolaid an important foundation for the development of other steroid family compounds in the development of new drugs.