I present detailed mechanistic analysis on the chemistry of glyoxylate as it pertains to forming biologically relevant molecules on the Hadean Earth. Chemistry covered includes: 1) the dimerization of glyoxylate to form dihydroxyfumarate(DHF), a heretofore unknown reaction, important to substantiating Eschenmoser's glyoxylate scenario. 2) Formation of sugars from polymerization of glyoxylate. 3) Formation of tartrate and sugar acids from high pH reactions of DHF. 4) Formation of glycine polypeptides from glyoxylate by transamination and coupling promoted by hexamethylenetetramine. 5) Formation of glyoxylate under conditions which could be plausibly found on the early earth.

The origin of the first RNA polymers is central to most current theories regarding the origin of life. However, difficulties associated with the prebiotic formation of RNA have lead many researchers to conclude that simpler polymers, or proto-RNAs, preceded RNA. These earlier polymers would have been replaced by RNA over the course of evolution. A remaining difficulty for this theory is that the de novo synthesis of a feasible proto-RNA has not yet been demonstrated by plausible prebiotic reactions. This thesis focuses on two problems associated with prebiotic proto-RNA synthesis: The formation of nucleosides and the necessity of reversible backbone linkages for error correction in nucleic acid polymers. "The Nucleoside Problem", or the lack of success in forming pyrimidine nucleosides by plausible prebiotic reactions, represents a significant stumbling block to the RNA world hypothesis. Nearly four decades ago Orgel and coworkers demonstrated that the purine nucleosides adenosine and inosine are synthesized by heating and drying their respective bases and ribose in the presence of magnesium, but these reaction conditions do not yield the pyrimidine nucleosides uridine or cytidine from their respective bases. In this thesis a potential solution to The Nucleoside Problem is hypothesized based upon a proposed chemical mechanism for nucleoside formation. This hypothesis is supported by the successful synthesis of 2-pyrimidinone nucleosides by a plausible prebiotic reaction in good yield, demonstrating that pyrimidine nucleosides could have been available in the prebiotic chemical inventory, but that uridine and cytidine were likely not abundant. Reversible backbone linkages are necessary to provide a mechanism for error correction in non-enzymatic template-directed syntheses of proto-RNAs. In this thesis, acetals are explored as low-energy, reversible linkage groups for nucleosides in polymers. The synthesis of glyoxylate-acetal nucleic acids (gaNAs) through simple heating-drying reactions from neutral aqueous solutions is demonstrated, and these linkages are shown to be hydrolytically stable under a considerable range of solution conditions. Computational models demonstrate that the glyoxylate linkage is an excellent electronic and isosteric replacement for phosphate. Molecular dynamics simulations also indicate that a gaNA duplex would have structural properties that closely match a phosphate-linked RNA helix, suggesting the possibility for cross-pairing between gaNAs and RNAs, allowing for sequence transfer and genetic continuity through the evolution from proto-RNAs to RNA. The principles illustrated in this thesis by 2-pyrimidinone nucleoside and gaNA synthesis can be extended to other prebiotic condensation reactions. Factors affecting condensation yield, such as thermodynamics, kinetics, reactant solubility, and salt effects, are summarized herein.

La thèse aborde différentes questions de chimie prébiotique dans le contexte de l’origine de la vie par une approche de chimie systémique. La première partie est dédiée à l’étude de processus d’activation chimique important non seulement pour la formation de polymères, mais aussi pour alimenter le système en énergie de manière à le maintenir dans un état éloigné de l’équilibre, un prérequis pour l’auto-organisation. Il a été suggéré que les intermédiaires 5(4H)-oxazolones formés par l’activation de l’extrémité C-terminale des peptides pourrait être impliquée dans l’auto-organisation du vivant. Dans ce but, nous avons évalué la réactivité de réactifs pertinents dans un contexte prébiotique et décrits dans la littérature comme capables d’activer des acides α-aminés. Aucun d’entre eux n’a manifesté une activité satisfaisante pour l’activation C-terminale des peptides, montrant qu’une voie possible pour alimenter un protométabolisme des peptides en énergie n’est pas identifiée à ce jour à l’exception notable des N-carboxyanhydrides (NCA) qui peuvent être formé par des voies prébiotiquement plausibles. Nous avons par ailleurs démontré que les carbodiimides sont aussi efficaces pour l’activation des N-carbamoylamino acides que pour celle du carboxyle terminal des peptides en milieu aqueux dilué. La seconde partie du document expose de nouveaux résultats en faveur d’un processus de coévolution peptides-nucléotides. D’abord, une étude de la réactivité d’agents d’aminoacylation de l’extrémité 3’ de l’ARN est présentée. Ensuite, nous évaluons des co-polymères acides α-aminés-nucléotides liés par des enchaînements phosphoramidate et esters comme partenaires éventuels de l’évolution chimique. La pertinence cinétique de ces structures est démontrée ainsi que des voies chimiques permettant leur formation. / The thesis addresses several issues in prebiotic chemistry in the context of the origins of life through a systems chemistry approach. The first part is devoted to the study of chemical activation processes that are not only important in the formation of polymers, but also to feed the system with energy in order that a far from equilibrium state is maintained, a prerequisite for self-organization. It has been suggested that 5(4H)-oxazolones intermediates formed by C-terminus peptide activation could be involved in self-organization of life. To this aim, we have checked the reactivity of relevant prebiotic reagents previously proposed to activate α-amino acids. None of them led to a satisfactory C-terminus activation of peptides, showing that no general process for feeding a protometabolism of peptides with energy is identified yet, with the notable exception of N-carboxyanhydrides (NCAs) that can be formed through prebiotically relevant pathways. Additionally, we demonstrated that carbodiimides reagents are as efficient in the activation of N-carbamoyl amino acids as in that of the C-terminus of peptides in diluted aqueous media. The second part of the dissertation discloses new results in support of a process of coevolution of peptides and nucleotides. Firstly, a study of non-enzymatic aminoacylation reagents of the 3’-terminus of RNA is presented. Secondly, we assessed co-polymers of α-amino acids and nucleotides bound by phosphoramidate and ester linkages as potential players in chemical evolution. The kinetic relevance of these structures was demonstrated as well as potential chemical processes that allow their formation.