Thioesters are high-energy derivatives of carboxylic acids that are essential in the functioning of today’s living cells. Their central role argues in favor of their early introduction in the abiotic reaction network which led to the emergence of life on Earth. We propose that the first thioesters appeared during the establishment of the reverse tricarboxylic acid (rTCA) cycle, an effective metabolic cycle for the synthesis of organic molecules from CO2. Most of the acids in this cycle are 1,4-diacids. We show that the formation of a cyclic anhydride from aqueous solutions of succinic or citric acid is possible using drying conditions over silica, as it could happen in an evaporating pond. When these 1,4-diacids are dried in the presence of thiols, thioesters are obtained. Our experimental and theoretical results demonstrate that analogs of succinyl-CoA and citryl-CoA, thioesters from the rTCA cycle, can be produced. Such a process highlights the importance of 1,4-diacids, which would have been introduced in the metabolism then under construction because of their ability to form anhydrides and to be activated in the absence of triphosphates or of any other activating agent. At its beginning, the rTCA cycle should therefore be interpreted mainly as a “1,4-diacid cycle”.

At the origin of life, extremely diverse mixtures of oligomers and polymers could be obtained from relatively simple molecular bricks. Here, we present an example of the polymerization of two amidonitriles derived from cysteine, Cys-Ala-CN and Cys-Met-CN. The thiol function in a molecule adds onto the nitrile group of another one, allowing efficient condensation reactions and making available an extensive range of polymers containing amide bonds and/or five-membered heterocycles, namely thiazolines. Macrocycles were also identified, the biggest one containing sixteen residues (cyclo(Cys-Met)8). MALDI-TOF mass spectrometry was used to identify all the present species. What these examples show is that complex mixtures are likely to have formed on the primitive Earth and that, ultimately, the selection that must have followed may have been an even more crucial step towards life than the synthesis of the pre-biological species themselves.

Genipin is known to polymerize under basic conditions, and the obtained genipin oligomers might have an impact on the chemical and physical properties of the crosslinked materials. In this study, we intend to mimic the experimental condition in which genipin is used as a chemical crosslinker. We focus on the degradation of genipin at neutral and slightly acidic conditions using NMR. We report genipin polymerization at neutral and acidic conditions. Unlike dialdehyde crosslinkers, genipin requires heating to promote its crosslinking activity. We found that elevated temperatures enhance the degradation of genipin and promote its polymerization.

The multiplicity of simple molecules available on the primitive Earth probably made possible the development of extremely diverse prebiotic chemistry. The importance of thiols is widely recognized in the community studying the origin of life. De Duve’s “thioester world” has been considered a major contribution in this regard, where thioester bonds have high energies and thus can contribute to several chemical reactions. Herein, we propose specific models of thiols that exhibit unique activities toward several chemical reactions. Thanks to aminothiol and aminonitrile behaviors, we were able to obtain thiol-rich peptides with interesting catalytic activities leading to the formation of structurally diverse molecules. In a broader context, such chemistry could be introduced into systems chemistry scenarios in which it would be associated with the chemistry of nucleic acids or their precursors, as well as that of fatty acids.

Unlike its shorter analog, cysteine, and its methylated derivative, methionine, homocysteine is not today a proteinogenic amino acid. However, this thiol containing amino acid is capable of forming an activated species intramolecularly. Its thiolactone could have made it an interesting molecular building block at the origin of life on Earth. Here we study the cyclization of homocysteine in water and show theoretically and experimentally that in an acidic medium the proportion of thiolactone is significant. This thiolactone easily reacts with amino acids to form dipeptides. We envision that these reactions may help interpret why a methionine residue is introduced at the start of all protein synthesis.

AbstractTwo sulfur-containing amino acids are included in the list of the 20 classical protein amino acids. A methionine residue is introduced at the start of the synthesis of all current proteins. Cysteine, thanks to its thiol function, plays an essential role in a very large number of catalytic sites. Here we present what is known about the prebiotic synthesis of these two amino acids and homocysteine, and we discuss their introduction into primitive peptides and more elaborate proteins.1 Introduction2 Sulfur Sources3 Prebiotic Synthesis of Cysteine4 Prebiotic Synthesis of Methionine5 Homocysteine and Its Thiolactone6 Methionine and Cystine in Proteins7 Prebiotic Scenarios Using Sulfur Amino Acids8 Introduction of Cys and Met in the Genetic Code9 Conclusion

In this review, we examined the possibility that some halogenated organic derivatives were used in the primitive ocean at the beginning of life on Earth. Firstly, we described the existence of extraterrestrial halogenated molecules, then we studied their nonbiological syntheses on the present Earth, especially in volcanic environments. In order to demonstrate the diversity of today’s halogenated biomolecules, representative examples are given and the biosynthesis of some of them is summarized. Finally, we proposed two aspects of the chemistry of halogenated compounds that may have been useful en route to biomolecules, firstly the use of methyl chloride as the first methylation reagent, secondly the synthesis and use of α-chloro-carbonyl derivatives.

Theoretical and experimental work has been conducted about possible prebiotic syntheses of cysteine. Activated derivatives of this amino acid can oligomerize and polymerize to afford various poly-thiazolines and cysteine-rich chains.

The centrality of pyruvate oxidative decarboxylation into acetyl-CoA in current biochemistry is a strong argument for proposing that a similar reaction have been necessary for the development of an effective protometabolism on the primitive Earth. However, such a decarboxylation requires the use of an oxidant and a catalyst, today enzymatic. Based on the mechanisms of the pyruvate dehydrogenase complex and pyruvate-ferredoxin oxidoreductase, we propose that the initial mechanism involved disulfides and occurred via radicals. A first disulfide is obtained by reacting glyoxylate with hydrogen sulfide. It is then possible to produce a wide variety of other disulfides by exchange reactions. When reacted with pyruvate under UV light they give thioesters. This process requires no oxidant and is therefore compatible with what is known of the redox conditions of the early Earth. Neither does it require any catalyst. It could be the first way to acetyl thioesters, a way that was later improved by the introduction of catalysts, first minerals, then enzymes.

of the vinylboronic esters of pinacol (alkenyl-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolanes) with dimethylzinc, allows the nucleophilic addition of the vinyl group onto nitrones, producing allylic N -hydroxy-amines in excellent yields.

How could life emerge on an originally inorganic Earth? This is the main question faced in the field of prebiotic chemistry. In order to solve this issue, two main, and not incompatible, hypotheses have been made. An endogenous synthesis one, based on the theory that building blocks of life were synthesized in the atmosphere of the early Earth and/or in primitive oceans, and an exogenous delivery one, according to which those building blocks were synthesized in space and then brought to Earth by comets and asteroids. In this contribution, based on state-of-the-art quantum chemistry computations, both hypotheses will be considered. First, possible gas-phase formation routes in the interstellar medium for two molecules of prebiotic interest will be investigated: glycolaldehyde (HOCH2CHO), the simplest sugar-related molecule, able to ease the formation of more complex sugars and formamide (H2NCHO), a possible precursor that might be able to link the appearances of metabolism and genetics. And then, thanks to a synergy between experimental and theoretical chemistry, a potential way of forming mercaptoacetaldehyde (HSCH2CHO), a possible prebiotic precursor of cysteine, will be explored in the peculiar conditions of the early Earths ocean.

Homocysteine is a non-proteinogenic sulfur-containing amino acid. Like cysteine, it can form disulfide bridges and complex metallic cations. It is also closely related to methionine, the first amino acid in the synthesis of all contemporary proteins. Furthermore, its cyclized form, a five-membered ring thiolactone, is stable in acidic and neutral water. Here, we demonstrate that this thiolactone may have been formed in the primitive ocean directly from the Strecker precursor of homocysteine, an aminonitrile. Even though it is poorly reactive, this thiolactone may be open by some amines, yielding amides which, in turn, could be the precursors of longer peptides.

The Strecker reaction of aldehydes with ammonia and hydrogen cyanide first leads to α-aminonitriles, which are then hydrolyzed to α-amino acids. However, before reacting with water, these aminonitriles can be trapped by aminothiols, such as cysteine or homocysteine, to give 5- or 6-membered ring heterocycles, which in turn are hydrolyzed to dipeptides. We propose that this two-step process enabled the formation of thiol-containing dipeptides in the primitive ocean. These small peptides are able to promote the formation of other peptide bonds and of heterocyclic molecules. Theoretical calculations support our experimental results. They predict that α-aminonitriles should be more reactive than other nitriles, and that imidazoles should be formed from transiently formed amidinonitriles. Overall, this set of reactions delineates a possible early stage of the development of organic chemistry, hence of life, on Earth dominated by nitriles and thiol-rich peptides (TRP).

Life developed on Earth probably about 3.8 billion years ago, on a planet that was already largely covered by oceans and where the atmosphere was very humid. The reactions, which may have led to the formation of the first polymers, particularly to the first peptides and nucleic acids, must have been compatible with these conditions. This is the case of the reaction of nitriles with aminothiols, such as cysteine and homocysteine. Since aminonitriles are the probable precursors of amino acids, this condensation reaction has been able to rapidly yield dipeptides, tripeptides, oligomers and even true polymers, each containing thiol functions. These thiol-rich peptides (TRP's) would then have assumed the various catalytic roles that the peptides containing cysteine residues play today. They allowed a rapid bloom of life in the primitive ocean. In this scenario, RNA's are not the first polymers, but have been synthesized, like DNA's, thanks to the catalytic properties of thiols in a mostly TRP world. In this world, due to its ability to form a thiolactone, homocysteine may have played the leading role in enabling the previously formed oligomers to be stappled together, thus accelerating the formation of long peptide chains.

Reactive acyl trifluoromethanesulfonates are formed from the reaction of acyl fluorides with trimethylsilyl trifluoromethanesulfonate (TMSOTf). These electrophiles undergo Friedel–Crafts reactions with electron-rich aromatics at room temperature. When a sulfur atom is present at their γ position, their cyclization to acylsulfonium cations is observed and is followed by a rearrangement leading to benzothiepinones (or dibenzo[b,e]thiepinones) in 40–85% yield.

Since methionine is capable of self-activation, the dipeptides formed by the reaction of its activated form with another amino acid were over-represented in the primitive ocean. This hypothesis gives a key role to methionine in the development of life on the Earth. It could explain why a methionine residue begins the synthesis of all proteins, while it is usually not necessary for its catalytic activity, and why the start codon is relatively variable in prokaryotes.

The feasibility of the cyclization of γ-alkylthiobutyric acid derivatives to form previously unknown five-membered-ring acyl sulfonium cations was studied. Experimental results were in good agreement with our DFT calculations that predicted such cyclizations to be easy if starting with acyl iodides and mixed anhydrides of triflic acid. Particularly efficient were the reactions of γ-alkylthiobutyryl fluorides with trimethylsilyl triflate in CDCl3 solution, which led to cyclic acyl sulfonium triflates. In some cases, the observed acyl sulfonium salts were stable enough to be characterized by NMR spectroscopy. They were found to be both alkyl-transfer reagents and acylating agents. They react with amines to form amides. These findings lend some weight to our hypothesis that the acyl sulfonium derived from methionine may have played a major role in the prebiotic synthesis of the first peptides on the primitive Earth.