The reactions of dihydroxyfumarate with glyoxylate and formaldehyde exhibit a unique pH-controlled mechanistic divergence leading to different product suites by two distinct pathways. The divergent reactions proceed via a central intermediate (2,3-dihydroxy-oxalosuccinate, 3, in the reaction with glyoxylate and 2-hydroxy-2-hydroxymethyl-3-oxosuccinate, 14, in the reaction with formaldehyde). At pH 7–8, products (7, 8, and 15) exclusively from a decarboxylation of the intermediate are observed, while at pH 13–14, products (9, 10, and 16) solely derived from a hydroxide-promoted fragmentation of the intermediate are formed. The decarboxylative and fragmentation pathways are mutually exclusive and do not appear to coexist under the range of pH (7–14) conditions investigated. Herein, we employ a combination of quantitative ¹³C NMR measurements and density functional theory calculations to provide a rationale for this pH-driven reaction divergence. These rationalizations also hold true for the reactions of dihydroxyfumarate produced in situ by the catalytic cyanide-mediated dimerization of glyoxylate. In addition, the non-enzymatic decarboxylation and fragmentation transformations of these central intermediates (3 and 14) appear to have intriguing parallels to the enzymatic reactions of oxalosuccinate and formation of glyceric acid derivatives in extant metabolism – the high and low pH mimicking the precise control exerted by the enzymes over reaction pathways. Copyright © 2016 John Wiley & Sons, Ltd.

Whether there was an RNA world or not, it is indisputable that there was RNA; when, where, and how is yet to be settled. The question of whether “pristine” RNA assembled directly from its components (“prebiotic clutter”), or whether it was a descendant of “simpler” ancestral system(s), is central to the ongoing debate about RNA’s origins. In this review, we look at the facts that suggest RNA is an emergent system and that each component of RNA may have been decided at the level of the oligomer/polymer, and not at the level of the prebiotic clutter, nor at the level of monomer nucleotides. The critical interdependence of RNA’s components – ribofuranose, phosphodiester backbone, and purine-pyrimidine base-pairing – for the functioning of RNA seems to be evident, and manifests itself only at the level of the polymer. Based on the power of such nuanced selections at the polymer level, and coupling it with the reality of the prebiotic mixtures at the monomer level, a scenario is presented wherein the combinatorial interactions of diverse prebiotic (systems) chemistry leads first to chimeric-heterogeneous (aka “pre-RNA”) systems, which can usher in a homogeneous system (RNA), capable of further evolution.

Although it is generally accepted that amino acids were present on the prebiotic Earth, the mechanism by which α-amino acids were condensed into polypeptides before the emergence of enzymes remains unsolved. Here, we demonstrate a prebiotically plausible mechanism for peptide (amide) bond formation that is enabled by α-hydroxy acids, which were likely present along with amino acids on the early Earth. Together, α-hydroxy acids and α-amino acids form depsipeptides—oligomers with a combination of ester and amide linkages—in model prebiotic reactions that are driven by wet–cool/dry–hot cycles. Through a combination of ester–amide bond exchange and ester bond hydrolysis, depsipeptides are enriched with amino acids over time. These results support a long-standing hypothesis that peptides might have arisen from ester-based precursors.

Although it is generally accepted that amino acids were present on the prebiotic Earth, the mechanism by which α-amino acids were condensed into polypeptides before the emergence of enzymes remains unsolved. Here, we demonstrate a prebiotically plausible mechanism for peptide (amide) bond formation that is enabled by α-hydroxy acids, which were likely present along with amino acids on the early Earth. Together, α-hydroxy acids and α-amino acids form depsipeptides—oligomers with a combination of ester and amide linkages—in model prebiotic reactions that are driven by wet–cool/dry–hot cycles. Through a combination of ester–amide bond exchange and ester bond hydrolysis, depsipeptides are enriched with amino acids over time. These results support a long-standing hypothesis that peptides might have arisen from ester-based precursors.

Under potentially prebiotic scenarios, ribose (pentose), the component of RNA is formed in meager amounts, as opposed to ribulose and xylulose (pentuloses). Consequently, replacement of ribose in RNA, with pentulose sugars, gives rise to prospective oligonucleotide candidates that are potentially prebiotic structural variants of RNA that could be formed by the same type of chemical pathways that gave rise to RNA from ribose. The potentially natural alternative (1′3′)-ribulo oligonucleotides and (4′3′)- and (1′3′)-xylulo oligonucleotides consisting of adenine and thymine were synthesized and found to exhibit no self-pairing or cross-pairing with RNA. This signifies that even though pentulose sugars may have been abundant in a prebiotic scenario, the pentulose nucleic acids (NAs), if and when formed, would not have been competitors of RNA, or interfered with the emergence of RNA as a functional informational system. The reason for the lack of base pairing in pentulose NA highlights the contrasting and central role played by the furanosyl ring in RNA and pentulose NA, enabling and optimizing the base pairing in RNA, while impeding it in pentulose NA.

The (3′2′)-phosphodiester glyceric acid backbone containing an acyclic oligomer tagged with 2,4-disubstituted pyrimidines as alternative recognition elements have been synthesized. Strong cross-pairing of a 2,4-dioxo-5-aminopyrimidine hexamer, rivaling locked nucleic acid (LNA) and peptide nucleic acid (PNA), with complementary adenine-containing DNA and RNA sequences was observed. The corresponding 2,4-diamino- and 2-amino-4-oxo-5-aminopyrimidine-tagged oligomers were synthesized, but difficulties in deprotection, purification, and isolation thwarted further investigations. The acyclic phosphate backbone structure of the protected oligomer seems to be prone to an eliminative degradation owing to the acidic hydrogen at the 2′-position—an arrangement that renders the oligomer vulnerable to the conditions used for the removal of the protecting groups on the heterocyclic recognition element. However, the free oligomers seem to be stable under the conditions investigated.