Selective Prebiotic Synthesis of α‐Threofuranosyl Cytidine by Photochemical Anomerization

The structure of life's first genetic polymer is a question of intense ongoing debate. The “RNA world theory” suggests RNA was life's first nucleic acid. However, ribonucleotides are complex chemical structures, and simpler nucleic acids, such as threose nucleic acid (TNA), can carry genetic information. In principle, nucleic acids like TNA could have played a vital role in the origins of life. The advent of any genetic polymer in life requires synthesis of its monomers. Here we demonstrate a high‐yielding, stereo‐, regio‐ and furanosyl‐selective prebiotic synthesis of threo‐cytidine 3, an essential component of TNA. Our synthesis uses key intermediates and reactions previously exploited in the prebiotic synthesis of the canonical pyrimidine ribonucleoside cytidine 1. Furthermore, we demonstrate that erythro‐specific 2′,3′‐cyclic phosphate synthesis provides a mechanism to photochemically select TNA cytidine. These results suggest that TNA may have coexisted with RNA during the emergence of life

Selective Acylation of Nucleosides, Nucleotides, and Glycerol-3- phosphocholine in Water

A convenient selective synthesis of 2′,3′-di-O-acetyl-nucleo- tide-5′-phosphates, 2′,3′-di-O-acetyl-nucleotide-5′-triphosphates and 2′,3′,5′-tri-O-acetyl-nucleosides in water has been developed. Further- more, a long-chain selective glycerol-3-phosphocholine diacylation is elucidated. These reactions are environmentally benign, rapid, high yielding, and the products are readily purified. Importantly, this reac- tion may indicate a prebiotically plausible reaction pathway for the se- lective acylation of key metabolites to facilitate their incorporation into protometabolism

Selective aqueous acetylation controls the photoanomerization of α-cytidine-5′-phosphate

Nucleic acids are central to information transfer and replication in living systems, providing the molecular foundations of Darwinian evolution. Here we report that prebiotic acetylation of the non-natural, but prebiotically plausible, ribonucleotide α-cytidine-5′-phosphate, selectively protects the vicinal diol moiety. Vicinal diol acetylation blocks oxazolidinone formation and prevents C2′-epimerization upon irradiation with UV-light. Consequently, acetylation enhances (4-fold) the photoanomerization of α-cytidine-5′-phosphate to produce the natural β-pyrimidine ribonucleotide-5′-phosphates required for RNA synthesis

Protocells realize their potential

How the first metabolic network was organized to power a cell remains an enigma. Now, simple iron–sulfur peptides have been used to generate a pH-gradient across a protocell membrane by catalysing hydrogen peroxide reduction. This indicates that short peptides could have fulfilled the role of redox active metalloproteins in early life

Scalable Synthesis of 2,2′-Anhydro-arabinofuranosyl Imidazoles

We report the efficient and scalable synthesis of 2,2′-anhydro-5-amino-1-β-arabinofuranosylimidazole-4-carboxamide and 2,2′-anhydro-5-amino-1-β-arabinofuranosylimidazole-4-carbonitrile from commercial arabino -adenosine. 2,2′-Anhydro-5-amino-1-β-arabinofuranosylimidazole-4-carboxamide is synthesised in only five steps with a single chromatographic purification. Additionally, we report a high-yielding, three-step conversion of 2,2′-anhydro-5-amino-1-β-arabinofuranosylimidazole-4-carboxamide into 2,2′-anhydro-5-amino-1-β-arabinofuranosylimidazole-4-carbonitrile. They are proposed key intermediates of the divergent prebiotic synthesis of ribonucleotides and this facile synthesis is anticipated to be instrumental in continued investigation of the origins of nucleotides

Prebiotic nucleic acids need space to grow

What were the conditions on early Earth when nucleotides were formed, and what are the most plausible nucleoside candidates? Answering these questions will require mechanistic chemistry and planetary science to work together, enhancing not limiting each other's scope of investigatio

Prebiotic Systems Chemistry: Complexity Overcoming Clutter

Living organisms are the most complex chemical system known to exist, yet exploit only a small constellation of universally conserved metabolites to support indefinite evolution. The conserved chemical simplicity belying biological diversity strongly indicates a unified origin of life. Thus, the chemical relationship between metabolites suggests that a simple set of predisposed chemical reactions predicated the appearance of life on Earth. Conversely, if prebiotic chemistry produces highly complex mixtures, this then implies that the feasibility of elucidating life’s origins is an insurmountable task. Prebiotic systems chemistry, however, has recently been exploiting the chemical links between different metabolites to provide unprecedented scope for exploration of the origins of life, and an exciting new perspective on a 4 billion-year-old problem. At the heart of the systems approach is an understanding that individual classes of metabolites cannot be considered in isolation. This review highlights several recent advances suggesting that the canonical nucleotides and proteinogenic amino acids are predisposed chemical structures

One-step protecting-group-free synthesis of azepinomycin in water

We report an efficient, atom economical general acid-base catalyzed one-step multi-gram synthesis of azepinomycin from commercially available compounds in water. We propose that the described pH-dependent Amadori rearrangement, which couples an amino-imidazole and simple sugar, is of importance as a potential step toward predisposed purine nucleotide synthesis at the origins of life

Prebiotic synthesis of aminooxazoline-5'-phosphates in water by oxidative phosphorylation

RNA is essential to all life on Earth and is the leading candidate for the first biopolymer of life. Aminooxazolines have recently emerged as key prebiotic ribonucleotide precursors, and here we develop a novel strategy for aminooxazoline-5'-phosphate synthesis in water from prebiotic feedstocks. Oxidation of acrolein delivers glycidaldehyde (90%), which directs a regioselective phosphorylation in water and specifically affords 5'-phosphorylated nucleotide precursors in upto 36% yield. We also demonstrated a generational link between proteinogenic amino acids (Met, Glu, Gln) and nucleotide synthesis

The origin of large molecules in primordial autocatalytic reaction networks

Large molecules such as proteins and nucleic acids are crucial for life, yet their primordial origin remains a major puzzle. The production of large molecules, as we know it today, requires good catalysts, and the only good catalysts we know that can accomplish this task consist of large molecules. Thus the origin of large molecules is a chicken and egg problem in chemistry. Here we present a mechanism, based on autocatalytic sets (ACSs), that is a possible solution to this problem. We discuss a mathematical model describing the population dynamics of molecules in a stylized but prebiotically plausible chemistry. Large molecules can be produced in this chemistry by the coalescing of smaller ones, with the smallest molecules, the `food set', being buffered. Some of the reactions can be catalyzed by molecules within the chemistry with varying catalytic strengths. Normally the concentrations of large molecules in such a scenario are very small, diminishing exponentially with their size. ACSs, if present in the catalytic network, can focus the resources of the system into a sparse set of molecules. ACSs can produce a bistability in the population dynamics and, in particular, steady states wherein the ACS molecules dominate the population. However to reach these steady states from initial conditions that contain only the food set typically requires very large catalytic strengths, growing exponentially with the size of the catalyst molecule. We present a solution to this problem by studying `nested ACSs', a structure in which a small ACS is connected to a larger one and reinforces it. We show that when the network contains a cascade of nested ACSs with the catalytic strengths of molecules increasing gradually with their size (e.g., as a power law), a sparse subset of molecules including some very large molecules can come to dominate the system.Comment: 49 pages, 17 figures including supporting informatio