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Photocatalytic Reductive Coupling of Imines: A New Platform for Chiral Amine Synthesis

Periodic Reporting for period 1 - PHOTOCAMSYN (Photocatalytic Reductive Coupling of Imines: A New Platform for Chiral Amine Synthesis)

Reporting period: 2018-06-21 to 2020-06-20

1.1 Objectives

Scientific training objectives:
- Photochemical reactions and photoredox catalysis: Dr Shiomi has started a wide range investigation on a new type of photoredox catalysis. Although reverse polarity reductive functionalization of secondary amides via a dual iridium catalyzed hydrosiliration and SET strategy had been studied, the new catalytic system has not been reached as a scientific satisfied stage.
- New asymmetric reaction optimization: Dr Shiomi carried out the research and optimization of a new organocatalized intramolecular ’-disubstituted nitroalkene-tethered cyclohexanone desymmetrisation which got access to bicyclic compounds in excellent yield (95%) and superb enantioselectivity (99.2%).
- Novel synthetic strategies development: Dr Shiomi has carried out an intensive program towards the discovery of new reactions with important applications in the synthesis of complex molecules, involves oxidative lactamization reaction of aminodiol derivatives which allow access to a highly complex tricyclic skeleton (Madangamine core). Furthermore, biologically active marine alkaloid, Madangamine E, was synthesized by newly developed synthetic pathway. Although this natural product target is different from the initial proposal, madangamines are highly important and challenging synthetic target in terms of the biological activity (anti-cancer) and requisition of high-level synthetic organic chemistry.
- Structure determination by X-ray diffraction, spectroscopy, etc: Dr Shiomi has carried out an intensive hands-on training on X-ray diffraction and has been responsible (together with a DPhil student from the group) of running all X-ray diffraction studies of the researchers in Dixon group).
- Computational caluculations: Dr Shiomi has carried out computational DFT calculations on newly developed asymmetric catalysis with Mr. Yamazaki (D.Phil student in Dixon group) and Dr. Hamlin (Vrije Universiteit Amsterdam, Amsterdam, Netherlands).
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.
1.3 Impact
After this 2-year fellowship training program in oganic chemistry, the information in the original proposal regarding the impact is still relevant. This Fellowship has allowed a great improvement in the state-of-the-art in the syntheis of active organic molecules through a powerful and impacting synthetic methodology, raising the standing of EU Chemistry within this field at a global level. The reactions studied provided some important strategies for the construction of bicyclic piperidines and madangamines with great enatioselectivity and are directly useful for the preparation of natural products as well as drug target molecules with biological activity. Therefore, this Fellowship has constituted a significant contribution to the field, and will suppose a benefit for synthetic organic chemists, pharmaceutical, agrochemical and fine-chemicals industries in EU, which have already shown interest for the projects developed in this fellowship.

The research carried out during these 2-years fellowship training program has enhanced innovation capacity, created new market opportunities and strengthened competitiveness. In fact, several industries have already shown interest by this project and are currently funding a PhD in Dixon group to further develop the result of this project. Atom economy (AE) is an important parameter to evaluate the overall efficiency of a chemical reaction, the desymmetric cyclization reaction gave the bicyclic products without generating waste products. The catalysts and reactions developed during this fellowship constitute ‘sustainable’ and ‘clean’ chemical processes which avoid the generation of toxic as well as potentially hazardous materials. So, the negative image of the chemical industry and chemists in EU is overcome. This Fellowship has also benefited society in general, through the discovery of new synthetic methodologies which are going to be very useful for pharmaceutical industries. The powerful application of this method was proven by the completion of total synthesis of madangamie E. Madangamines possess significant bioactivity and they potently anti-cancer activity, the research of this project has achieved a stonemile for the synthesis of madangamine alkaloids.
Scheme 3
Scheme 4
Scheme 2
Scheme 5
Scheme 1