Advanced Molecular ENantiodiscrimination

Project Information

AMEN

Grant agreement ID: 101187919

DOI

10.3030/101187919

Project closed

EC signature date 23 July 2024

Start date 1 August 2024

End date 31 January 2026

Funded under

• European Research Council (ERC)

Total cost

No data

EU contribution

€ 150 000,00

Coordinated by

INSTITUT POLYTECHNIQUE DE BORDEAUX
France

Periodic Reporting for period 1 - AMEN (Advanced Molecular ENantiodiscrimination)

Reporting period: 2024-08-01 to 2026-01-31

Summary of the context and overall objectives of the project

Enantiodiscrimination is one of the major challenges in contemporary chemistry. Chiral molecules exist in two non-superimposable mirror image forms, which induce different effects in biological systems. Thus, they need to be produced in a stereoselective way, especially for pharmaceutical use.
The motivation and societal relevance of this project is based on the fact that if the wrong enantiomers are present in pharmaceuticals, their effects can be toxic or even lethal, as has been exemplified by the scandal around the use of racemic mixtures of thalidomide in the 1960ies. Subsequently, it became obvious, and strongly recommended by the FDA and European legislation, that medication should contain pure enantiomers.
Therefore, there is a strong and constantly increasing need to develop advanced technologies that allow a selective production of enantiomers by new synthesis strategies. This challenge is at the heart of the AMEN project. We plan to follow an unconventional concept, developed during the ERC Advanced grant ELECTRA, in order to obtain single enantiomers instead of racemic mixtures. This is achieved by directing the transformation of molecules towards one of the two possible enantiomers with the help of autonomously moving chiral microreactors.
The fundamental strategy has been already validated with proof-of-principle experiments during the ERC Advanced project and showed extremely high selectivity, efficiency, and controllability, however only at the laboratory scale. Therefore, we plan as a next logic step, with technology transfer character, to investigate in detail the possibility of scaling up this process and to evaluate its commercial viability and competitivity.

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

Our preliminary tests allowed us already to demonstrate that the fundamental concept is valid, as illustrated by a very high enantioselectivity (%ee > 90) and a significant increase of production rate by one order of magnitude. This confirms that the proposed solution is in principle appropriate and efficient at the laboratory scale, but needs to be tested under conditions compatible with industrial use.
Undertake research required to carry out the above activities and to address the weaknesses uncovered by them.
Despite these very encouraging results, we do not know for the moment whether the concept is scalable and can be also applied to a larger variety of different starting compounds. In the frame of AMEN, we therefore need to carry out a set of crucial experiments to check for potential weaknesses:
-test the mechanical and chemical stability of the microreactors;
-optimize the reaction vessel design to allow the accommodation of a larger quantity of microreactors, and the eventual integration of an external magnetic field, enabling a transition from milligram to gram production of enantiomers;
-study the collective behaviour of a large ensemble of microreactors (>100) to evaluate potentially inhibiting interferences in terms of cross-talk between individual microreactors;
-evaluate the performance of combinations of different reactive metal cores with other chiral oligomer or metal shells to optimize the driving force and broaden the selectivity spectrum;
-replace the currently used model target compounds with precursors that are relevant for the pharmaceutical industry (eventually in the frame of a market-pull strategy together with a pre-identified industrial partner participating in the co-development)

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)

The proposed approach is very significantly different from already existing technologies currently employed to synthesize chiral molecules from at least two points of view:
1. Chiral molecules can be obtained with high enantioselectivity by using homogeneous organo-metallic or organo-catalysts, as nicely illustrated by two Nobel prizes awarded in the last two decades. However, the main disadvantage in this case is that after the synthesis it is rather difficult to separate the soluble catalyst from the equally soluble product.
2. In order to circumvent the above-mentioned problem, heterogeneous catalysis has been suggested as an alternative approach. In this case, separating the catalyst from the product is rather straightforward by simple filtration. However, as often in heterogeneous systems, mass transport problems can considerably slow down the overall reaction kinetics. This is especially true for electrochemical systems where all educts have to reach the two-dimensional reaction space, constituted by the electrode surface, instead of reacting everywhere in the bulk of the solution. Enantioselectivity is also often less pronounced for these systems.
Carrying out enantioselective transformations by microreactors, which are autonomously moving in the solution, circumvents simultaneously both problems in an original way that has never been proposed so far. On the one hand, the microreactors can be easily removed from the reaction mixture at the end of the synthesis and, on the other hand, they combine the high selectivity of homogeneous systems with a considerably enhanced mass transport due to the self-mixing effect induced by the motion. The latter is even more efficient than artificial macroscopic stirring when introducing the above-mentioned MHD effect, because in this case the reactant flux is generated directly in the hydrodynamic boundary layer around the microreactor due to the Lorentz force acting at the molecular level. This will considerably increase the time-space yield of the process, which is a crucial parameter in industrial processes. We therefore expect that our technology should be able to outperform the classic approaches, mentioned above and currently used in the pharmaceutical industry.