1.2 Explanation of the work carried out
This project is intended to develop a new, highly enantioselective, state-of-the-art synthetic route to developing a powerful methodology for the synthesis of madangamine alkaloids, based on a novel organocatalytic desymmetrisation reaction as a key step, affording the pentacyclic intermediate (tertiary amide) ready for our originally developed Iridium catalized hydrosililation and photoredox catalysis to access functionalized madangamines (Scheme 1).
The synthetic route of ,'-disubstituted nitroalkene was investigated for this project. we synthezied desired ,'-disubstituted nitroalkene through highly efficient Michael addition reaction using copper-zinc organometal spiecies to mono-substitutued nitroalkene derivative.(scheme 2).
The discovery of an ideal organocatalyst to realized the desymmetric intramolecular cyclization of nitroalkene-linked cyclohexanone is really challenging. Altough a similar reaction has been successfully studied in Dixon group, the enantioselective synthesis of bicyclic piperidines from nitroalkene. A bunch of different chiral amines were studied, and finally a bihunctional thiourea-monoamine catalyst proved to be highly successful. After some optimization studies, the product could be isolated in 95% yield and >99% ee as a single diastereomer (Scheme 3). Also, it was possible to obtain the crystal structure of the product, which allowed us to determine the absolute configuration of the product. In addition, the reactiona mechanisms and stereoselectivitiy was studied by DFT calucuration.
The key pentacyclic intermediate for derivatization through photoredox catalysis was synthesized in 19 steps from bicyclic piperidine (Schem 4). Before derivatization, total synthesis of madangamine E was completed by using LiAlH4 to reduce amides in 41% yield. There is no doubt that madangamine E is one of the important natural product because of their unknown mechanism of actions. Unfortunately, the derivatization of madangamine through photoredox catalysis, and pharmaceutical studies have not been demonstrated due to a lockdown for COVID-19.
Meanwhile, the new reverse polarity reductive functionalization of secondary amides via a dual iridium catalyzed hydrosiliration and SET strategy was demonstrated (Scheme 5). Branched secandary amines were gave from secandary amide in one-pot (up to 41% yield). Although a bunch of different reaction conditions were investigated, the acceptable chemical yield (>70%) had not been afforded.
