Hélène Collet

A new simple and quantitative synthesis of α-aminoacid-N-carboxyanhydrides (oxazolidines-2,5-dione)

Abstract Nitrosation of chiral N-carbamoylaminoacids with a mixture of NO and O 2 gives, with the same configuration and in quantitative yield the corresponding α-aminoacid-N-carboxyanhydrides (NCA), well known precursors of peptides. The by products of this reaction are N 2 and H 2 O.

An Expeditious Multigram-Scale Synthesis of Lysine Dendrigraft (DGL) Polymers by Aqueous N-Carboxyanhydride Polycondensation

The synthesis and characterisation of new arborescent architectures of poly(L-lysine), called lysine dendrigraft (DGL) polymers, are described. DGL polymers were prepared through a multiple-generation scheme (up to generation 5) in a weakly acidic aqueous medium by polycondensing N(epsilon)-trifluoroacetyl-L-lysine-N-carboxyanhydride (Lys(Tfa)-NCA) onto the previous generation G(n-1) of DGL, which was used as a macroinitiator. The first generation employed spontaneous NCA polycondensation in water without a macroinitiator; this afforded low-molecular-weight, linear poly(L-lysine) G1 with a polymerisation degree of 8 and a polydispersity index of 1.2. The spontaneous precipitation of the growing N(epsilon)-Tfa-protected polymer (GnP) ensures moderate control of the molecular weight (with unimodal distribution) and easy work-up. The subsequent alkaline removal of Tfa protecting groups afforded generation Gn of DGL as a free form (with 35-60% overall yield from NCA precursor, depending on the DGL generation) that was either used directly in the synthesis of the next generation (G(n+1)) or collected for other uses. Unprotected forms of DGL G1-G5 were characterised by size-exclusion chromatography, capillary electrophoresis and (1)H NMR spectroscopy. The latter technique allowed us to assess the branching density of DGL, the degree of which (ca. 25%) turned out to be intermediate between previously described dendritic graft poly(L-lysines) and lysine dendrimers. An optimised monomer (NCA) versus macroinitiator (DGL G(n-1)) ratio allowed us to obtain unimodal molecular weight distributions with polydispersity indexes ranging from 1.3 to 1.5. Together with the possibility of reaching high molecular weights (with a polymerisation degree of ca. 1000 for G5) within a few synthetic steps, this synthetic route to DGL provides an easy, cost-efficient, multigram-scale access to dendritic polylysines with various potential applications in biology and in other domains.

DYNAMIC CO-EVOLUTION OF PEPTIDES AND CHEMICAL ENERGETICS, A GATEWAY TO THE EMERGENCE OF HOMOCHIRALITY AND THE CATALYTIC ACTIVITY OF PEPTIDES

We propose a scenario for the dynamic co-evolution of peptides and energy on the primitive Earth. From a multi component system consisting of hydrogen cyanide, several carbonyl compounds, ammonia, alkyl amine, carbonic anhydride, borate and isocyanic acid, we show that the reversibility of this system leads to several intermediate nitriles, that irreversibly evolve to α-amino acids and N-carbamoyl amino acids via selective catalytic processes. On the primitive Earth these N-carbamoyl amino acids combined with energetic molecules (NOx) may have been the core of a molecular engine producing peptides permanently and assuring their recycling and evolution. We present this molecular engine, a production example, and its various selectivities. The perspectives for such a dynamic approach to the emergence of peptides are evoked in the conclusion.

Monitoring surface functionalization of dendrigraft poly-l-lysines via click chemistry by capillary electrophoresis and Taylor dispersion analysis

Click chemistry by copper-mediated azide/alkyne cycloaddition reaction is known as a very efficient synthetic pathway for chemical coupling and for surface functionalization. The attractiveness of this reaction is due to the selectivity of the reaction of azides and alkynes. Nevertheless, the control of the kinetics of the reaction and the characterization of the reaction products requires the use of adequate analytical techniques. This is especially the case for the monitoring of the functionalization of polymeric compounds and the control of the homogeneity of the chemical composition of these products. In this work, the third generation of dendrigraft poly-L-lysines derivatized with acetylenic groups was decorated with tryptophan-PEG-azide arms via triazole ring formation. Pressure assisted capillary electrophoresis was used to monitor the progress and the kinetics of the click chemistry reaction. As expected the click product was obtained with excellent yields within 20 min reaction time at room temperature. Diffusion coefficients and hydrodynamic radii of dendrigraft poly-L-lysines and their click reaction products were determined by Taylor dispersion analysis. Finally, capillary electrophoresis was found very useful to check the purity and the homogeneity in the chemical composition of the decorated structures.

Synthesis of Nɛ-protected-L-lysine and γ-benzyl-L-glutamate N-carboxyanhydrides (NCA) by carbamoylation and nitrosation

Summary.This paper reports on an original process to synthesize N-carboxyanhydrides, which consists of nitrosating N-carbamoylamino acids with a NO/O2 gas mixture in acetonitrile. The synthesis of several N-carbamoylamino acids of L-lysine was described using potassium cyanate in water. The latter were then nitrosated to yield the corresponding NCA with more or less efficiency. Indeed, the NCA carrying an acid-sensitive protecting group led to a partial deprotection to give the L-lysine NCA salt. The NCA of Nɛ-trifluoroacetyl-L-lysine, Nɛ-benzyloxycarbonyl-L-lysine and γ-benzyl-L-glutamate were successfully synthesized with satisfactory yields. Their polymerizability was compared to that of the Nɛ-trifluoroacetyl-L-lysine NCA initiated by n-hexylamine in N,N-dimethylformamide. It also showed that this new process of NCA synthesis could be applied to the synthesis of polypeptides and more generally to the protein chemistry.

Influence of a perfluorobutyl substituent on the rearrangement of prop-2-ynyl diethylphosphites to allenic phosphonates

The Prop-2-ynyl diethylphosphites n-C4F9–CC-CR1R2OP(OEt)2 are obtained from the reaction of the corresponding prop-2-ynyl alcohols with diethyl chlorophosphite; the rearrangement of these phosphates into α-perfluorobutylallenic phosphonates is found to depend on the nature of the substituent R1 and R2, and an unexpected HF elimination is found for R1= H, R2= Me.

Prebiotic synthesis of N-carbamoylaminoacids, promising intermediates for peptide synthesis

Our work aims to propose a new hypothesis for the prebiotic formation of ot-aminoacids and peptides. In a first part, we present kinetic and thermodynamic studies upon the equilibria between the prebiotic compounds : H2CO, HCN and NH3 in aqueous solution. These studies show that the ratio between the concentrations of the two products CH2(NH2)CN and CH2(OH)CN (precursors of glycine and o~-hydroxyethanoic acid respectively) is proportional to the concentration of free ammonia 1 :