Building chemical systems that can self-assemble, process information, orchestrate reaction pathways, and ultimately self-replicate will undoubtedly have a major impact on evolving technology. However, nature has had a four-billion-year head start in implementing controlled chemical evolution, and the lessons to be learned from its prior art merely await discovery. Understanding the spontaneous emergence of life on Earth will require innovation across scientific disciplines as broad as astrophysics to phylogenetics, yet the primacy of chemistry in this task cannot be overestimated. Cellular life is a chemical system of breathtaking complexity that exploits only a small constellation of universally conserved metabolites to support indefinite evolution. The challenge for prebiotic chemistry is to elucidate the relationships between the distinct chemical substructures of life that explain how a simple set of chemicals can fit together to establish the complexities that lead to life.Living organisms are the most complex chemical system known to exist, yet they exploit only a small constellation of universally conserved metabolites to support indefinite evolution. The chemical unity that belies biodiversity strongly indicates a unified origin of life predicated by a simple set of predisposed chemical reactions. If prebiotic chemistry is prone to produce highly complex mixtures that do not reflect life's underlying unity, this then implies that the feasibility of elucidating life's origins might be an insurmountable task. However, recently, prebiotic systems chemistry has emerged to exploit the chemical links between different metabolites, providing unprecedented scope for exploration of the origins of life and an exciting new perspective on a four-billion-year-old problem. At the heart of this systems approach is an understanding that individual classes of metabolites cannot be considered in isolation, and this review highlights some recent advances that suggest that canonical metabolites are predisposed chemical structures.Download high-res image (236KB)Download full-size image

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.

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.

We propose a novel pathway for the prebiotic synthesis of 2′-deoxynucleotides. Consideration of the constitutional chemical relationships between glycolaldehyde and β-mercapto-acetaldehyde, and the corresponding proteinogenic amino acids, serine and cysteine, led us to explore the consequences of the corresponding sulfur substitution for our previously proposed pathways leading to the canonical ribonucleotides. We demonstrate that just as 2-aminooxazole–an important prebiotic ribonucleotide precursor–is readily formed from glycolaldehyde and cyanamide, so is 2-aminothiazole formed from β-mercapto-acetaldehyde and cyanamide in water at neutral pH. Indeed, both the oxazole and the thiazole can be formed together in a one-pot reaction, and can be co-purified by crystallization or sublimation. We then show that 2-aminothiazole can take part in a 3-component carbon–carbon bond-forming reaction in water that leads to the diastereoselective synthesis of masked 2′-thiosugars regiospecifically tethered to purine precursors, which would lead to 2′-deoxynucleotides upon desulfurization. The possibility of an abiotic route to the 2′-deoxynucleotides provides a new perspective on the evolutionary origins of DNA. We also show that 2-aminothiazole is able to sequester, through reversible aminal formation, the important nucleotide precursors glycolaldehyde and glyceraldehyde in a stable, crystalline form.

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.

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.