Studies Toward The Total Synthesis Of Natural Product Virgatolides A-C And The Synthesis Of Benzannulated [6,6]-Spiroketals

This thesis focuses on the synthesis of benzannulated [6,6]-spiroketal.The main research contents are the total synthesis of natural products virgatolides A-C and the new synthetic methods of benzannulated [6,6]-spiroketal skeleton.The specific work is divided into the following three parts: Chapter 1.Overview of Research on Natural Products of Benzannulated SpiroketalThe benzannulated spiroketal skeleton is widely distributed in nature.As the core structure and active site of many natural products and drugs,it has attracted the attention and in-depth research of organic chemists and pharmacologists for decades.This chapter first introduces the definition,classification and properties of benzannulated spiroketal.Then,representative spiroketal natural products were introduced from the aspects of separation,structural characteristics,biological activity and biosynthesis synthesis.The chiral spiroketal ligands were also introduced as supplements.Finally,this chapter focuses on the synthesis strategies and methods of benzannulated spiroketal skeletons,and prospects for research in this field.Chapter 2.Studies toward Synthesis of Natural Product Virgatolides A-CFirst,this chapter introduced the isolation,identification,structural characteristics,biological activity,biosynthetic synthesis and total synthesis of the natural products virgatolide A-C.Based on the comprehensive research of literatures,three synthetic routes have been designed to carry out the total synthesis of the virgatolide A-C.1.The retrosynthesis analysis was carried out using the gold-catalyzed double intramolecular alkyne hydroalkoxylation developed by Dr.Yuan Zhang of our group and double Micheal addition.We accordingly used a linear route to synthesize four key precursors 2-63,2-65,2-67,and 2-69 for the construction of the spiroketal skeletons,but none of them could successfully achieved the spiroketalization process.Experiments have shown that these intermediates are unstable and various side reactions such as elimination of hydroxyl groups and reverse aldol condensation could happen.2.The synthetic route was designed via the [4+2] cycloaddition strategy,and the precursors 2-83 and 2-85 of o-methylene quinone were successfully obtained.In the synthesis of the dienophile 2-72,we meet difficulties in trying the olefination of the lactone,intramolecular alkyne hydroalkoxylation and the Michael addition.We also tried a one-step double-annulation of alkyne 2-105 with the o-methylene quinone precursor 2-121,however,the transformation was not successful.3.After summarizing the two previous routes,we then designed a convergent synthetic route using the carbonylative Sonogashira coupling reaction as the key step and completed the simulated reaction.We also obtained the o-iodophenol fragment 2-133 and the alkyne fragment 2-103.This research work is still in progress.Chapter 3.Synthesis of Benzannulated [6,6]-Spiroketals by a One-Pot Carbonylative Sonogashira Coupling/Double Annulation ReactionIn this chapter,we first introduced the discovery and reaction mechanism of the Sonogashira coupling reaction,and reviewed the research history and current status of the carbonylative Sonogashira coupling reaction.On this basis,we have envisaged that a one-pot Pd-catalyzed carbonylative Sonogashira coupling/double annulation process would result in the straightforward formation of monobenzannulated [6,6]-spiroketal 3-5 or bisbenzannulated [6,6]-spiroketal 3-6 via the chromone intermediate 3-4 or 3-7.The optimal reaction conditions for the synthesis of monobenzannulated spiroketal and bis benzannulated spiroketal were determined by screening the reaction conditions such as solvent,base and catalyst.By expanding the substrate scope,35 spiroketal products were obtained with moderate to excellent yields,good functional group tolerance and excellent diastereoselectivities.We determined the relative configuration and absolute configuration of the product by X-ray crystallography analysis,two-dimensional nuclear magnetic resonance,circular dichroism spectrum and other analytical methods.To further explore the possible reasons for the excellent ste-reoselectivities in our reactions,the relative Gibbs free energies of possible stereomers and conformers of 3-5h,3-5s and 3-6j were computed using Gaussian 09 suite of program.As a novel and highly efficient convergent synthesis method,the substrate is easy to obtain.Notably,this process was conducted under very mild conditions(under balloon pressure of CO at room temperature).This methodology will contribute to the total synthesis study of the natural products of the virgatolide family.With the advantages of environmental benignity and atom-and step-economy,this protocol would serve as an efficient and convergent way to synthesize benzannulated [6,6]-spiroketals in natural products,drugs,ligands and materials.