Total Synthesis of Puupehenone,Haterumadienone and Mycoleptodiscine Marine Natural Products

Author:Wang Hong Shuang

Supervisor:wu yan chao


Degree Year:2018





As lead compound in new drug discovery,bioactive natural products have traditionally been an important source.However,new drug discovery becomes more and more difficult due to the emergence of drug resistance.Human beings urgently need to discover new natural products with novel structures,biological activity and unique mechanism of action as lead compounds for new drug development.The marine natural products possess unique biological activities because of their novel chemical structures,so more and more scientists choose to discover high-activity lead compound for their research.Puupehenone,haterumadienone and mycoleptodiscin-type marine natural products contain many amazing biological activities such as anti-tumor,anti-virus and immune regulation.Total synthesis study on the of natural products can facilitate their pharmacological research,which is of great significance.The synthesis of haterumadienone and puupehenone-type marine natural products was based on the two synthons coupling strategy.An efficient and highly stereoselective synthesis of C8-Meαsclareolide-aldehyde was developed,which increased the yield from the previous 10-25%to 66%in 4 steps.The D-ring in the structure was constructed by 1,3-cyclopentanedione or 1,3-cyclohexanedione,which discarded the previous synthetic strategy using aromatic hydrocarbon as starting material.Furthermore,the aldol condensation reaction was used as the key coupling reaction to construct the basic skeleton.The build of tetrahydropyran ring employed the hemiacetalization reaction between the D ring carbonyl group and hydroxyl groups of the terpeneyl moiety.A newly hemiacetalization/dehydroxylation/hydroxylation/retro-hemiacetalization tandem reation was developed,which could be utilized for the rapidly construction of C-D bicyclic structure.Finally,4haterumadienone-type marine natural products were synthesized in 3%-32%yield within 6-9 steps for the first time.The atom and step economical synthesis of 3puupehenone-type marine natural products were also completed in 14%-22%yield within 8-10 steps.With the key intermediate C8-Meαsclareolide-aldehyde and the synthesis method of puupehenones in hand,the collective syntheses of 7 puupehenone-type and related derived marine natural products were completed,which be based on palladium catalyzed tandem carbene migratory insertion reaction.The synthesis was also started with the structure analysis and established the palladium catalyzed coupling strategy with two synthons.The palladium-catalyzed coupling of an aryl iodine and a drimanal hydrazone was first induced to establish the skeleton of this type of bicyclic sesquiterpene marine natural products.Then the Stork-Danheiser transposition was further developed into the intramolecular one-step reaction instead of the intermolecular two-step reaction.The newly developed intramolecular oxa-Stork-Danheiser transposition tandem reaction was employed for the synthesis of puupehedione-type marine natural products for the rapidly construct of the C-D bicyclic-ring.Finally,the step economical synthesis of puupehedione was afforded in only 7 steps within 25%overall yield.In addition,one-step reduction/isomerization of allyl alcohol by Et3SiH/TFA,base-promoted enol tautomerism/electrophilic cyclization,Friedel-Crafts alkylation reaction catalyzed by Lewis acid,chemoselective synthesis by controlling the reaction sequence of hydrogenation and cyclization were developed.And these key reactions were utilized for the divergent synthesis of exceed 10 marine natural products,such as puupehenone,puupehenol,chromazonarol,yahazunone,yahazunol and pelorol from 6 to 13 steps in 6%to 25%yield.The synthesis study of relatively complex structures of bicyclic sesquiterpene-indole natural product mycoleptodiscin A and B were conducted based on the synthesis of the above bicyclic sesquiterpene compounds.The synthesis of mycoleptodiscin A started with sclareolide.The key skeleton was built by bicyclic sesquiterpene ketene and 7-methoxyindole.The phenylsulfonyl passivated site-selective cyclization was also investigated.Eventually,the synthesis of mycoleptodiscin A was completed in 12 steps within 25%yield.As for the synthesis of mycoleptodiscin B,4 bicyclic sesquiterpene fragments and 2 indole fragements were selected for the establishment of the key skeleton.The epoxidation and hydroxylation of carbonyl ortho-position strategy was used for the introduce of C-4hydroxy group,which established the cyclization precursor compound.The Friedel-Crafts alkylation and Heck reaction was employed for the cyclization.The synthesis attempt laid a solid foundation for the synthesis of mycoleptodiscin B.