Institut de Chimie Moléculaire et des Matériaux d'Orsay

Laboratoire de Chimie des Procédés et des Substances Naturelles- LCPSN

Natural products : amino-acid chemistry

Valérie Alezra, Cyrille Kouklovsky, Sophie Thétiot-Laurent, Baby Viswambharan, Andrii Stanovych

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The synthesis of unnatural amino acids is one of the challenges of actual synthesis. These compounds have multiple interests, both in organic synthesis in bioorganic chemistry. Two types of unnatural amino acids are being studied in the laboratory.
We have developed a general synthetic route to enantiomerically pure β,γ-diamino acids, based on a sequence reaction Blaise / diastereoselective reduction. This method leads to cyclic β,γ-diamino acids
(Org. Lett. 2007, 9, 2521 and J. Org. Chem. 2009, 74, 4177) and to fully protected β,γ-diamino acids (Org. Biomol. Chem. 2011, 9, 394). By applying this methodology, we performed a enantioselective and diastereoselective synthesis of Nemonapride (J. Org. Chem. 2008, 73,1162), which has antipsychotic activity. We currently use these β,γ-diamino acids for the synthesis and conformational study of γ-peptides (Amino Acids. 2011, 41, 687).

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We have already synthesized hybrid peptides α shown below. NMR studies together with a restrained simulated annealing (collaboration with Dr. E. Miclet, Université Paris 6) revealed that an extended backbone conformation largely dominates in solution for as short as 4-residues long oligomers. This new fold type is devoid of any hydrogen bond and characterized by a four-fold symmetry (Chem. Commun. 2012, 48, 1982).

Original αγα tripeptides containing one β,γ-diamino acid have been also extensively studied. These studies revealed the presence of a C9 hydrogen bonded turn, which can be considered as a mimic of the well-known γ-turn. (Org. Biomol. Chem. 2012, 10, 9660).

We have also explored a new synthetic route to enantiomerically enriched quaternary α-amino acids based on the memory of chirality.

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The proposed strategy therefore uses chirality of the natural α-amino acid as the sole source of chirality. The central chirality of the starting α-amino acid is transfered to the dynamic axial chirality tertiary aromatic amides. This strategy was validated on 5 amino acids. Thus, we developed a 3-step synthesis of enantioenriched or enantiopure quaternary α-amino acids (J. Am. Chem. Soc. 2008, 130, 5864 et J. Am. Chem. Soc. 2009, 131, 10711). A collaboration with Dr. P. Archirel (Laboratory of Chemical Physics, Orsay) and Pr. D. Merlet (Laboratory of NMR, ICMMO) has been initiated to understand the mechanisms involved (Tetrahedron 2008, 64, 1743). We are currently working on several extension of this methodology, included extension to glycine. This strategy has recently been applied to the total synthesis of L-methylDOPA (J. Org. Chem. 2012, 77, 8797).

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We have extended this methodology to the simplest amino acid, glycine, which do not present any asymmetric carbon. We have thus developed an absolute asymmetric synthesis based on the frozen chirality principle. The idea is the following: crystallization in a chiral conformation of an achiral oxazolidinone lead to the generation of chirality; this axial chirality is retained during the reaction at low temperature and induces a stereoselective attack by the electrophile (Angew. Chem. Int. Ed. 2012, 51, 4981) .