Servizio Comunitario di Informazione in materia di Ricerca e Sviluppo - CORDIS

Periodic Report Summary 1 - DYNAMAX (Dynamic axial chirality of tertiary aromatic amides, applications in asymmetric synthesis.)

The project “DYNAMAX” is a project of fundamental research in organic chemistry, aiming to develop original strategies to synthesize non natural amino acids (quaternary alpha-amino acids mostly) and to apply these strategies to the synthesis of biologically active compounds. Non natural amino acids are important compounds because they can be used to build non natural peptides, which could show interesting biological activities (like natural peptides, being similar to them), but with increased stability in the human body (they can resist to protease activity, being non natural). In the field of organic chemistry, the project deals with asymmetric synthesis, whose goal is to synthesize a molecule with a peculiar spatial arrangement. The spatial arrangement of a molecule is related to the concept of “chirality” (a molecule is chiral if it is distinguishable from its mirror image). This concept is of crucial importance because most of the natural biologically active molecules (such as sugars, amino acids, proteins, DNA, etc…) are chiral and exist as only one mirror image (termed enantiomer). Asymmetric synthesis is thus very important because it aims to synthesize preferentially only one of the two mirror images (only one enantiomer). Using a mixture of both mirror images of one molecule can be very troublesome for biological activity, as it has been dramatically shown by Thalidomine in the sixties.
More precisely, the projects use original concepts for asymmetric synthesis such as “Memory of Chirality (MOC) and Frozen Chirality (FC)” and also dynamically chiral tertiary aromatic amides towards the stereo-selective synthesis of non proteinogenic quaternary amino acids. Thus, this project aims to synthesize a library of dynamically chiral oxazolidinones from various amino acids (glycine, alanine, leucine, valine, methionine and phenylalanine) and to develop synthetic methodologies based on MOC/FC alkylation, aldol reaction, conjugate addition etc. without using any external chiral source.
Initially, for implementing the project we started with the natural amino acid alanine and synthesized the corresponding oxazolidinone. The idea is to ‘memorize’ the initial central chirality, which is destroyed during the course of the reaction, through a ‘dynamic axial chirality’ of tertiary aromatic amides. Then proposed ‘MOC aldol’ reactions were performed with alanine-oxazolidinone and different aromatic aldehydes with excellent diastereo- and enantio-selectivity in good yields. The only source of chirality is from the starting amino acid. Detailed optimization studies were carried out by changing various reaction parameters such as temperature, time, molar concentrations etc. Hydrolysis of the MOC aldol products was achieved in single step to non-protienogenic serine derivatives in three steps with good yields. This is the first example of intermolecular aldol reaction by Memory of Chirality which leads in only 3 steps to diastereopure and enantioenriched beta-hydroxy quaternary alpha-amino acids. Extension of the current methodology to other amino acids like leucine, valine, methionine, phenylalanine etc. was not so easy and took time to optimize with each amino acid. Finally the reaction is satisfactory with leucine, methionine and valine but not for phenylalanine. This part of the project was fully studied and we made progress in the application of this strategy to the total synthesis of a biologically active compound which possesses antifungal activity. We have thus shown the synthetic potential of this MOC strategy in asymmetric synthesis and this could inspire some other groups to develop this kind of methods.
Some time has also been spent to try to get further insight in the mechanism of the reaction. For that, the fellow went for one month in the US (Brown University, Providence, Pr. Paul G. Williard laboratory) to learn techniques regarding the enolate crystallization in a specialized laboratory in this field. We did not succeed in enolate crystallization so far but the knowledge we acquired helped us to improve our reactions. This was not initially planned but brought further knowledge to the fellow. We also performed other mechanistic studies, including some in situ IR experiment and this conducted us to initiate a collaboration with another French group. Other unexpected radical reactions have been discovered and this very interesting project is now under investigation in our group. This could broad the field of MOC reactions.

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