Photocatalysis in Drug Discovery - Asymmetric Preparation of Bioactive Chiral Lactones and Cyclohexanols

Project Information

PHOTO-CYCLE

Grant agreement ID: 894795

DOI

10.3030/894795

Project terminated on 27 September 2021

EC signature date 26 February 2020

Start date 1 March 2020

End date 28 February 2022

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 160 932,48

EU contribution

€ 160 932,48

Coordinated by

FUNDACIO INSTITUT CATALA D'INVESTIGACIO QUIMICA
Spain

Periodic Reporting for period 1 - PHOTO-CYCLE (Photocatalysis in Drug Discovery - Asymmetric Preparation of Bioactive Chiral Lactones and Cyclohexanols)

Reporting period: 2020-03-01 to 2022-02-28

Summary of the context and overall objectives of the project

Drug discovery must identify successful lead candidates. The growing perception is that basic, fundamental chemical research will play a greater role in pharmaceutical development. One current challenge is to develop a new kind of chemistry that yields a screening collection of optimal chiral molecules that increase the probability of success in identifying drug-candidate structures. Experience shows that successful programs for drug discovery often rely on the screening of natural-like compounds. As recent statistics indicate, more than 50% of the therapeutic agents approved between 1981 and 2011 are natural or natural-like products. The proposed research aims to develop conceptually innovative, catalytic, and cost-effective methods to rapidly generate, in one single step, architecturally complex chiral natural-like compounds based on these privileged skeletons.

We have pursued the PHOTO-CYCLE project under the guiding principle that compound development should be driven by discoveries and innovation in chemical methodology, providing real benefits to society through the discovery of new therapeutics. Additionally, the use of visible light to drive the chemical transformations involved in the project provide high environmental benefits.

The resulting synthetic platform will be used as an ideal starting point for assembling libraries featuring biologically privileged scaffolds. These scaffolds will comprise chiral polycyclic lactones and polyfunctionalized cyclohexanols, which, along with biological screening, will increase the probability of success in identifying drug-candidate structures.
Emphasis will be put on the importance of developing chemical methodology to lactones and polyfunctionalized cyclohexanols, its application towards drug synthesis, and environmental benefit of using visible light to drive chemical processes.
The goal of our research is to combine the potential of asymmetric organocatalysis and photocatalysis, two powerful fields of molecule activation, to design novel cascade reactions.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

PHOTO-CYCLE was mainly focused on the enantioselective β-functionalizations of enals through photochemical methods by unlocking the reactivities that thermal pathways couldn’t reach.

(1) A general iminium ion-based catalytic method for the enantioselective conjugate addition of carbon-centered radicals to aliphatic and aromatic enals was developed. The process uses an organic photoredox catalyst to generate radicals, in combination with ground state iminium ion, secures a consistently high level of stereoselective interception of a wide variety of radicals, including non-stabilized primary ones which are generally difficult to engage in asymmetric processes. The system also served to develop organocatalytic cascade reactions that combine an iminium-ion-based radical trap with an enamine-mediated step, affording stereochemically dense chiral products in one-step. This work has been published in Angew. Chem., Int. Ed. 2021, 60, 5357, and highlighted by Synfacts 2021, 17, 325.

(2) The system was expanded to enantioselective construction of remote δ-stereocenters utilizing cyclobutanol ring opening under visible light. The process could afford synthetic useful compounds containing δ-stereocenters as proved by the diverse derivatizations, including the chiral cyclohexanol as proposed in the target proposal triggered by an intramolecular cyclization. A series of enals, including aliphatic and aromatic, are well compatible in the reaction, affording the products in good efficiency and enantioselectivity. Mechanistic studies, including Cyclic Voltammetry, Stern-Volmer quenching, and quantum yield measurement undoubtly confirmed the proposed mechanism. Currently the manuscript is under preparation for publication.

(3) A photochemical enantioselective β-alkylation of enals using the strategy of radical umpolung was disclosed. This process was initiated by the photooxidation of supersilane and then halogen abstraction by the in situ generated silyl radical. After that, the active alkyl radical would be trapped by ground state iminium ion, followed by hydrogen atom transfer from supersilane to closed the catalytic cycle, which is a typical radical chain mechanism. On the other hand, a radical coupling of the 5π β-enaminyl radical intermediate and the active alkyl radical is also possible. Currently this reaction works well with BnBr to afford the target product in moderate yield and excellent enantioselectivity. We are still working on the optimization of such reaction to obtain improved results.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

This project aims to develop a completely new approach to organocatalytic cascade reaction by integrating the photochemical reactivity of iminium ions with polar reactivity, thus significantly expanding the synthetic applicability of asymmetric photocatalysis. The concept we propose differentiates itself radically from current organocascade reaction based on classical ground-state iminium ion/enamine reactivity, and will enable access to new complex chiral scaffolds. The strategy will pave the way for applications of these little-studied intermediates in synthetically useful transformations, making a significant addition to the organic chemists’ toolbox and stimulating further methodology development. By exploiting these innovative concepts, we will synthesize molecular targets that would be exceedingly difficult or impossible to access otherwise. These targets may display interesting biological activity and allow identification of a pharmaceutical lead compound. Considering the variety of different chiral lactones and functionalized cyclohexanols with biologically actives properties, this methodology will impact pharmaceutical R&D by providing access to novel chiral building blocks.

This project has and will create new career possibilities by providing the fellow with expertise in asymmetric photochemistry and drug discovery. He will have more opportunities in the academic and private sector due to the network of contacts and skillset that he has obtained during this project. This project has a particularly strong link to Knowledge and Technology Transfer (KTT), which is crucial for increasing the competitiveness of the European Economic Area (EEA).

The project enriched the fellow with competitive skills including knowledge on asymmetric photocatalysis, designing cascade reaction to structural dense molecules, mechanistic studies using photophysics methods, and so on, which undoubtedly expands his research area in future career. At the same time, the increasing ability of writing and communication with either researchers or funding-body will provide the fellow witth continuous scientific and financial support. The management and leadership obtained through this project will further help the fellow with his own group management. What’s more, the concept of combining fundamental synthetic research with drug discovery would be quite promising and useful. The almost two year’s experience in the frontier group would provide the fellow wiht an access to apply to national funding in China. He will start his own group in the near future and believes that all the skills and experience will help him enormously.

PHOTO-CYCLE reactions