Study of total synthesis of 9α,10β-Bisangeloyloxy-7-epi-3E-agerafastin and 3-O- Feruloylcassine by copper-mediated nucleophilic substitution and gold-catalyzed cycloisomerization

Abstract

In this dissertation, the main work is the synthesis of 6-membered heterocyclic natural products by using the synthetic methods developed in our group, i.e. the copper-mediated nucleophilic substitution for synthesizing functionalized allenes, as well as, the gold-catalyzed cycloisomerization of functionalized allenes for synthesizing heterocycles. Chapter 2 demonstrates the journey of the first total synthesis of 9α,10β-Bisangeloyloxy-7 - epi- 3E- agerafastin including the racemic synthesis route and enantioselective synthesis route. In the racemic synthesis route, starting from the commercially available but-2-yn-1-ol, through the key steps of the copper-mediated SN2'-substitution of propargyl acetates and the gold-catalyzed cycloisomerization of β-hydroxyallenes, the core ring system of agerafastin was obtained. Subsequently, a sequence of epoxidation/esterification/oxidation/olefination was performed to afford the final racemic natural product. Based on the racemic synthesis, changing the starting material to the allyl alcohol, the three chiral centers of agerafastin were obtained by the Sharpless dihydroxylation, asymmetric epoxidation and selective opening of epoxide to provide enantiomerically pure core ring system. Finally, the last step of modified Julia olefination affords the natural product with high stereoselectivity as well as good E/Z ratio. Chapter 3 studies the total synthesis of (+)-3-O-Feruloylcassine based on our previous work. Starting from the propargyl alcohol, through a sequence of HWE reaction/ reduction/Mitsunobu reaction/Sharpless dihydroxylation, the important intermediate propargyl dicarbonate was obtained. Then, the NHC-ligand for the key step of CuH-catalyzed SN2'-reduction was synthesized. After that, the CuH-catalyzed SN2'-reduction of propargyl dicarbonates was optimized to give desired β-aminoallene. The other key step, gold-catalyzed cycloisomerization of β-aminoallenes, will be further optimized by using more active gold catalysts until the desired core ring system of natural product (+)-3-O-Feruloylcassine is formed with good results and the total synthesis will be continued.