Biomimetic Total Synthesis Of(-)-Equisetin And(+)-Fusarisetin A

(-)-Equisetin and (+)-fusarisetin A belong to3-acyl tetramic acid type natural products and they exhibit important biological activities.(+)-Fusarisetin A selectively inhibits cancer cell migration and invasion, which has the potential to be a good lead compound in medicinal chemistry. This dissertation will focus on the biomimetic total synthesis of these two natural products.We first analyzed the biogenetic relationship of (-)-equisetin and (+)-fusarisetin A, and proposed that (-)-equisetin is the biomimetic precursor of (+)-fusarisetin A. Based on this hypothesis, our synthetic research focuses on the biomimetic transformation of (-)-equisetin to (+)-fusarisetin A.In the first generation total synthesis, we proposed the biomimetic synthetic pathway of (+)-fusarisetin A should derive from (-)-equisetin through a single-electron oxidative process. The intramolecular Diels-Alder reaction of polyenoyl-a,β-unsaturated aldehyde, followed by Roskamp reaction lead the formation of the β-keto ester compound, which is the key intermediate for the synthesis of (-)-equisetin.(-)-Equisetin was accomplished through11steps in7.6%total yield, starting from commercially available chiral material (R)-citronellal. Mn(OAc)3, a single-electron metal oxidant, was used for the oxidative cyclization of (-)-equisetin. The oxidation of (-)-equisetin under unaerobic conditions gave the eliminated product terminal alkene; and the oxidation of (-)-equisetin under aerobic conditions gave peroxyfusarisetin.In the second generation total synthesis, we proposed the polyenoyl-amino acid is the common biomimetic precursor of both (-)-equisetin and (+)-fusarisetin A. Inspired by photosynthesis, we envisioned to use visible light、photocatalyst and oxygen to realize the biotransformation of (-)-equisetin to (+)-fusarisetin A. The polyenoyl-amino acid ester was transformed into (-)-equisetin by successive cyclization:intramolecular Diels-Alder reaction and Lacey-Dieckmann condensation. Initiated by the reactive oxygen species (ROS), which was produced by photocatalyst Ru(bpy)3Cl2·6H2O or methylene blue,(-)-equisetin was oxidized and cyclized to give peroxyfusarisetin. Trimethyl phosphite can effectively reduce peroxyfusarisetin to (+)-fusarisetin A. Thus (-)-equisetin was transformed into (+)-fusarisetin A in a one-pot operation through biomimetic approach. The biomimetic total synthesis of (+)-fusarisetin A was achieved through9steps in5.2%total yield, starting from commercially available chiral material (R)-citronellal.