Tandem cycloaddition chemistry of nitroalkenes: Total synthesis of (+)-1-epiaustraline and synthesis of the pentacyclic core of (+/-)-scandine

The tandem cycloaddition chemistry of nitroalkenes has been explored in the context of alkaloid natural product synthesis. The tandem [4+2]/[3+2] nitroalkene cycloaddition was successfully applied to the total synthesis of (+)-1-epiaustraline, a perhydroxylated pyrrolizidine. In addition, the tandem conjugate addition/[3+2] nitronate cycloaddition allowed for the first synthesis of the core skeleton of (+/-)-scandine. Both of these synthetic routes focus on the in situ generation of a nitronate moiety, which undergoes efficient [3+2] cycloaddition with a pendant dipolarophile.; Starting from 1-bromobutadiene, (+)-1-epiaustraline was prepared in 10 steps and 7.0% overall yield. This synthesis featured a tandem intermolecular [4+2]/intramolecular [3+2] cycloaddition that led to the creation of four of the five stereocenters present in the alkaloid. The remaining center was established via asymmetric dihydroxylation of a terminal olefin. Initial difficulties experienced in the hydrogenolysis of the resulting nitronate were circumvented by revealing the hydroxyl groups prior to reductive cleavage resulting in the successful cyclization of the core pyrrolizidine.; Two separate approaches were explored for the total synthesis of (+)-scandine. The first involved the tandem intermolecular [4+2]/intramolecular [3+2] nitroalkene cycloaddition to establish three of the five rings of the alkaloid, whereas the remaining two were installed by a late-stage radical cyclization. The tandem cycloaddition worked well, providing the desired tricycle in high diastereoselectivity, however attempts at the radical cyclization failed.; The successful synthesis of the (+)-scandine core began with a tandem conjugate addition/ [3+2] nitronate cycloaddition. This approach proceeded with high chemical yield and modest diastereoselectivity to provide an advanced bicyclic intermediate. Construction of two of the remaining three rings was accomplished by an intramolecular Heck cyclization of a pendant aryl iodide. This process proceeded with high diastereoselectivity to build vicinal quaternary centers. The final ring was created by reductive amination of a pyrrolidine aldehyde. This synthesis provided the core structure of (+/-)-scandine in 16 steps and 4.8% overall yield from 2,4-pentadienyl dimethyl malonate.