Jacques Taillades

N-Carbamoyl-α-Amino Acids Rather than Free α-Amino Acids Formation in the Primitive Hydrosphere: A Novel Proposal for the Emergence of Prebiotic Peptides

Our previous kinetic and thermodynamic studies upon the reactional system HCHO/HCN/ NH3 in aqueous solutions are completed. In the assumed prebiotic conditions of the primitive earth ([HCHO] and [HCN] near 1 g L−1, T = 25 °C, pH = 8, [NH3] very low), this system leads to 99.9% of α-hydroxyacetonitrile and 0.1% of α-aminoacetonitrile (precursor of the α-amino acid). The classical base-catalyzed hydration of nitriles, slow and not selective, can not modify significantly this proportion. On the contrary, we found two specific and efficient reactions of α-aminonitriles which shift the initial equilibrium in favor of the α-aminonitrile pathway. The first reaction catalyzed by formaldehyde generates α-aminoamides, precursors of α-aminoacids. The second reaction catalyzed by carbon dioxide affords hydantoins, precursors of N-carbamoyl-α-aminoacids. In the primitive hydrosphere, where the concentration in carbon dioxide was estimated to be higher than that of formaldehyde, the formation of hydantoins was consequently more efficient. The rates of hydrolysis of the α-aminoacetamide and of the hydantoin at pH 8 being very similar, the synthesis of the N-carbamoyl-α-amino acid seems then to be the fatal issue of the HCHO/HCN/NH3 system that nature used to perform its evolution. These N-protected α-amino acids offer new perspectives in prebiotic chemistry, in particular for the emergence of peptides on the prebiotic earth.

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.

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.

Kinetic study of the polymerization of α-amino acid N-carboxyanhydrides in aqueous solution using capillary electrophoresis

N-Carboxyanhydrides of amino acids (NCAs) are very reactive monomers able to polymerize into oligopeptides. They are assumed to be prebiotic precursors of the first polypeptides. Few reports have been published on the study of NCA polymerization in aqueous solution. In this work, a kinetic study focused on the hydrolysis of NCA and its coupling with amino acids and homopeptides (up to tripeptide) was carried out, taking L-valine derivatives as model compounds. For that purpose, capillary electrophoresis appeared to be an effective and reliable technique for the measurement of the kinetic constants. The electrophoretic separation conditions, the procedure for stopping NCA reactivity, as well as the conditions of reaction are discussed in detail. We report the variation of the kinetic constant of the coupling reaction of the NCA of valine with an oligovaline as a function of its degree of polymerization. Finally, a temperature study also allowed us to estimate the activation energies associated with the NCA of valine hydrolysis and its coupling reaction with valine.

SOLID PHASE DECARBAMOYLATION OF MONOALKYLUREAS AND N-CARBAMOYLPEPTIDES USING GASEOUS NOX : A NEW EASY DEPROTECTION REACTION WITH MINIMUM WASTE

Abstract Treating solid monoalkylureas (including N-carbamoylpeptides) when hydrated by ca. 1 eq. water, by gaseous NOx (nitrogen peroxide or a mixture of nitric oxide and oxygen) in stoichiometric excess, deprotects quantitatively the amino function at room temperature in less than 30 minutes. The reaction was exemplified for the N-carbamoyl-Leucine-Glycine dipeptide and N-benzylurea, and turns out to be a promising method for removing an N-carbamoyl group from various monosubstituted ureas, with no waste other than nitrogen and carbon dioxide. Solid N-carbamoylpeptide is quantitatively deprotected in 30 min at r.t. by gaseous N 2 O 4 (or NO+O 2 ) and a small amount of water, without side-reactions. Download full-size image

Influence of a hydroalcoholic solvent on the enantioselectivity of α-amino nitrile hydration catalysed by chiral ketones

The enantioselective hydration of α-aminonitriles 1, RCH(CN)NH2[1a: R = PhCH2; 1b: R = Pri; 1c: R = Ph] has been achieved in an alkaline hydroalcoholic medium in the presence of chiral ketonic catalysts. Of the different ketones used, (-)-(5R,3R,2R)-5-(methylethenyl)-3-cyano-2-methylcyclohexanone (8) gives rise to significant enantioselectivity [e.g. for the substrate 1c, kD/kL= 2.1; T= 10 °C; solvent, water–propan-2-ol (45 : 55,v/v)]. Although the structure of the catalyst could probably be improved, we show in this paper that the efficiency and especially the enantioselectivity of the catalyst are not only under steric control but also depend on the nature and composition of the hydroalcoholic solvent. Thus, for the three aminonitriles studied in the presence of the catalyst 8, the increase in percentage of propan-2-ol favours the hydration of the Dα-aminonitrile as shown for the hydration of 1c for which the ratio kD/KL increases threefold when the percentage of propan-2-ol increases from 10 to 95%.

N‐Carbamoyl Derivatives and Their Nitrosation by Gaseous NOx − A New, Promising Tool in Stepwise Peptide Synthesis

New uses of the N-carbamoyl group in peptide synthesis − as an Nα-protecting group in classical peptide coupling methods, and as a preactivating group for stepwise coupling by NCA formation − are presented. In the first application, the N-carbamoyldipeptide esters C-Val-Gly-OEt, C-Leu-Gly-OEt, C-Ala-Gly-OEt, and C-Ala-Phe-OEt were obtained in good yields by treatment of the corresponding N-carbamoylamino acids (CAA) with amino acid esters. Quantitative N-deprotection without racemisation was then achieved in the solid through nitrosation by gaseous NOx. The extent of racemisation occurring in the coupling step is discussed. In the second application, an easy route to amino acid N-carboxy anhydrides (NCAs) through nitrosation of CAA under the same conditions as above allowed straightforward “one-pot” peptide stepwise coupling, as demonstrated by the formation of Leu-Gly and Val-Gly in good yields and enantiomeric excess. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

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 :