@article{Foden2020,
abstract = {Peptides and the proteinogenic $\alpha$-amino acids are essential to all life on Earth. Peptide biosynthesis is orchestrated by a complex suite of enzymes in extant biology, but this must have been predated by a simple chemical synthesis at the origins of life. $\alpha$-Aminonitriles, the nitrile precursors of $\alpha$-amino acids, are generally readily produced by Strecker reactions, but the origin of cysteine-the thiol-bearing amino acid-is not understood. The aminothiol moiety of cysteine is chemically incompatible with nitriles at physiological pH, therefore cysteine nitrile is not stable, and it is widely believed that cysteine was a biological invention and a late addition to the genetic code. Here, we report the first high-yielding, prebiotic synthesis of cysteine peptides. Our biomimetic synthesis converts serine to cysteine, bypassing the Strecker reaction of $\beta$-mercaptoacetaldehyde, but exploits nitrile-activated dehydroalanine synthesis at near-neutral pH. We additionally demonstrate the catalytic prowess of N-acylcysteines (and related peptides and thiols) in the organocatalytic synthesis of peptides and peptidyl amidines in neutral water. Thiol catalysis directly couples kinetically stable-but energy-rich-$\alpha$-amidonitriles to proteinogenic amines, in a reaction that tolerates all twenty proteinogenic side chains. This is a rare, prebiotically plausible example of selective and efficient organocatalysis in water. Our results implicate cysteine derivatives and thiol-catalysis at the onset of evolution.},
author = {Foden, Callum and Islam, Saidul and {Fernandez Garcia}, Christian Arturo and Maugeri, Leonardo and Sheppard, Tom and Powner, Matthew},
doi = {10.1126/science.abd5680},
file = {:C$\backslash$:/Users/Benji/Downloads/865.full.pdf:pdf},
journal = {Science},
keywords = {biomimetic chemistry,cysteine side chains,organocatalysis,origins of life,peptide ligation},
number = {6518},
pages = {865--869},
title = {{Prebiotic Synthesis of Cysteine Peptides That Catalyze Peptide Ligation in Neutral Water}},
url = {https://science.sciencemag.org/content/370/6518/865},
volume = {370},
year = {2020}
}

Peptides and the proteinogenic $α$-amino acids are essential to all life on Earth. Peptide biosynthesis is orchestrated by a complex suite of enzymes in extant biology, but this must have been predated by a simple chemical synthesis at the origins of life. $α$-Aminonitriles, the nitrile precursors of $α$-amino acids, are generally readily produced by Strecker reactions, but the origin of cysteine-the thiol-bearing amino acid-is not understood. The aminothiol moiety of cysteine is chemically incompatible with nitriles at physiological pH, therefore cysteine nitrile is not stable, and it is widely believed that cysteine was a biological invention and a late addition to the genetic code. Here, we report the first high-yielding, prebiotic synthesis of cysteine peptides. Our biomimetic synthesis converts serine to cysteine, bypassing the Strecker reaction of $β$-mercaptoacetaldehyde, but exploits nitrile-activated dehydroalanine synthesis at near-neutral pH. We additionally demonstrate the catalytic prowess of N-acylcysteines (and related peptides and thiols) in the organocatalytic synthesis of peptides and peptidyl amidines in neutral water. Thiol catalysis directly couples kinetically stable-but energy-rich-$α$-amidonitriles to proteinogenic amines, in a reaction that tolerates all twenty proteinogenic side chains. This is a rare, prebiotically plausible example of selective and efficient organocatalysis in water. Our results implicate cysteine derivatives and thiol-catalysis at the onset of evolution.

@article{Aponte2019,
abstract = {Aliphatic aldehydes and ketones are essential building blocks for the synthesis of more complex organic compounds. Despite their potentially key role as precursors of astrobiologically important molecules, such as amino acids and carboxylic acids, this family of compounds has scarcely been evaluated in carbonaceous chondrites. The paucity of such analyses likely derives from the low concentration of aldehydes and ketones in the meteorites and from the currently used chromatographic methodologies that have not been optimized for meteorite analysis. In this work, we report the development of a novel analytical method to quantify the molecular distribution and compound-specific isotopic analysis of 29 aliphatic aldehydes and ketones. Using this method, we have investigated the molecular distribution and 13C-isotopic composition of aldehydes and ketones in 10 carbonaceous chondrites from the CI, CM, CR, and CV groups. The total concentration of carbonyl compounds ranged from 130 to 1000 nmol g-1 of meteorite with formaldehyde, acetaldehyde, and acetone being the most abundant species in all investigated samples. The 13C-isotopic values ranged from {\^{a}}67 to +64‰ and we did not observe clear relationships between 13C-content and molecular weight. Accurately measuring the relative abundances, determining the molecular distribution, and isotopic composition of chondritic organic compounds is central in assessing both their formation chemistry and synthetic relationships.},
author = {Aponte, Jos{\'{e}} C. and Whitaker, Daniel and Powner, Matthew W. and Elsila, Jamie E. and Dworkin, Jason P.},
doi = {10.1021/acsearthspacechem.9b00006},
issn = {24723452},
journal = {ACS Earth and Space Chemistry},
keywords = {Aldehydes,Astrobiology,Astrochemistry,Murchison,carbonaceous chondrites,ketones,meteorites},
number = {3},
pages = {463--472},
title = {{Analyses of Aliphatic Aldehydes and Ketones in Carbonaceous Chondrites}},
volume = {3},
year = {2019}
}

Aliphatic aldehydes and ketones are essential building blocks for the synthesis of more complex organic compounds. Despite their potentially key role as precursors of astrobiologically important molecules, such as amino acids and carboxylic acids, this family of compounds has scarcely been evaluated in carbonaceous chondrites. The paucity of such analyses likely derives from the low concentration of aldehydes and ketones in the meteorites and from the currently used chromatographic methodologies that have not been optimized for meteorite analysis. In this work, we report the development of a novel analytical method to quantify the molecular distribution and compound-specific isotopic analysis of 29 aliphatic aldehydes and ketones. Using this method, we have investigated the molecular distribution and 13C-isotopic composition of aldehydes and ketones in 10 carbonaceous chondrites from the CI, CM, CR, and CV groups. The total concentration of carbonyl compounds ranged from 130 to 1000 nmol g-1 of meteorite with formaldehyde, acetaldehyde, and acetone being the most abundant species in all investigated samples. The 13C-isotopic values ranged from â67 to +64‰ and we did not observe clear relationships between 13C-content and molecular weight. Accurately measuring the relative abundances, determining the molecular distribution, and isotopic composition of chondritic organic compounds is central in assessing both their formation chemistry and synthetic relationships.

@article{Ashe2019,
abstract = {The central and conserved role of peptides in extant biology suggests that they played an important role during the origins of life. Strecker amino acid synthesis appears to be prebiotic, but the high pKaH of ammonia (pKaH = 9.2) necessitates high pH reaction conditions to realise efficient synthesis, which places difficult environmental constraints on prebiotic amino acid synthesis. Here we demonstrate that diamidophosphate reacts efficiently with simple aldehydes and hydrogen cyanide in water at neutral pH to afford N-phosphoro-aminonitriles. N-Phosphoro-aminonitrile synthesis is highly selective for aldehydes; ketones give poor conversion. N-Phosphoro-aminonitriles react with hydrogen sulfide at neutral pH to furnish aminothioamides. The high yield (73{\%}–Quant.) of N-phosphoro-aminonitriles at neutral pH, and their selective transformations, may provide new insights into prebiotic amino acid synthesis and activation.},
author = {Ashe, Kathryn and Fern{\'{a}}ndez-Garc{\'{i}}a, Christian and Corpinot, Merina K. and Coggins, Adam J. and Bu{\v{c}}ar, Dejan Kre{\v{s}}imir and Powner, Matthew W.},
doi = {10.1038/s42004-019-0124-5},
issn = {23993669},
journal = {Communications Chemistry},
number = {1},
title = {{Selective prebiotic synthesis of phosphoroaminonitriles and aminothioamides in neutral water}},
volume = {2},
year = {2019}
}

The central and conserved role of peptides in extant biology suggests that they played an important role during the origins of life. Strecker amino acid synthesis appears to be prebiotic, but the high pKaH of ammonia (pKaH = 9.2) necessitates high pH reaction conditions to realise efficient synthesis, which places difficult environmental constraints on prebiotic amino acid synthesis. Here we demonstrate that diamidophosphate reacts efficiently with simple aldehydes and hydrogen cyanide in water at neutral pH to afford N-phosphoro-aminonitriles. N-Phosphoro-aminonitrile synthesis is highly selective for aldehydes; ketones give poor conversion. N-Phosphoro-aminonitriles react with hydrogen sulfide at neutral pH to furnish aminothioamides. The high yield (73%–Quant.) of N-phosphoro-aminonitriles at neutral pH, and their selective transformations, may provide new insights into prebiotic amino acid synthesis and activation.

@article{Morasch2019,
abstract = {Non-equilibrium conditions must have been crucial for the assembly of the first informational polymers of early life, by supporting their formation and continuous enrichment in a long-lasting environment. Here, we explore how gas bubbles in water subjected to a thermal gradient, a likely scenario within crustal mafic rocks on the early Earth, drive a complex, continuous enrichment of prebiotic molecules. RNA precursors, monomers, active ribozymes, oligonucleotides and lipids are shown to (1) cycle between dry and wet states, enabling the central step of RNA phosphorylation, (2) accumulate at the gas–water interface to drastically increase ribozymatic activity, (3) condense into hydrogels, (4) form pure crystals and (5) encapsulate into protecting vesicle aggregates that subsequently undergo fission. These effects occur within less than 30 min. The findings unite, in one location, the physical conditions that were crucial for the chemical emergence of biopolymers. They suggest that heated microbubbles could have hosted the first cycles of molecular evolution.},
author = {Morasch, Matthias and Liu, Jonathan and Dirscherl, Christina F. and Ianeselli, Alan and K{\"{u}}hnlein, Alexandra and {Le Vay}, Kristian and Schwintek, Philipp and Islam, Saidul and Corpinot, M{\'{e}}rina K. and Scheu, Bettina and Dingwell, Donald B. and Schwille, Petra and Mutschler, Hannes and Powner, Matthew W. and Mast, Christof B. and Braun, Dieter},
doi = {10.1038/s41557-019-0299-5},
issn = {17554349},
journal = {Nature Chemistry},
number = {9},
pages = {779--788},
pmid = {31358919},
title = {{Heated gas bubbles enrich, crystallize, dry, phosphorylate and encapsulate prebiotic molecules}},
volume = {11},
year = {2019}
}

Non-equilibrium conditions must have been crucial for the assembly of the first informational polymers of early life, by supporting their formation and continuous enrichment in a long-lasting environment. Here, we explore how gas bubbles in water subjected to a thermal gradient, a likely scenario within crustal mafic rocks on the early Earth, drive a complex, continuous enrichment of prebiotic molecules. RNA precursors, monomers, active ribozymes, oligonucleotides and lipids are shown to (1) cycle between dry and wet states, enabling the central step of RNA phosphorylation, (2) accumulate at the gas–water interface to drastically increase ribozymatic activity, (3) condense into hydrogels, (4) form pure crystals and (5) encapsulate into protecting vesicle aggregates that subsequently undergo fission. These effects occur within less than 30 min. The findings unite, in one location, the physical conditions that were crucial for the chemical emergence of biopolymers. They suggest that heated microbubbles could have hosted the first cycles of molecular evolution.

@article{Canavelli2019,
abstract = {Amide bond formation is one of the most important reactions in both chemistry and biology1–4, but there is currently no chemical method of achieving $\alpha$-peptide ligation in water that tolerates all of the 20 proteinogenic amino acids at the peptide ligation site. The universal genetic code establishes that the biological role of peptides predates life's last universal common ancestor and that peptides played an essential part in the origins of life5–9. The essential role of sulfur in the citric acid cycle, non-ribosomal peptide synthesis and polyketide biosynthesis point towards thioester-dependent peptide ligations preceding RNA-dependent protein synthesis during the evolution of life5,9–13. However, a robust mechanism for aminoacyl thioester formation has not been demonstrated13. Here we report a chemoselective, high-yielding $\alpha$-aminonitrile ligation that exploits only prebiotically plausible molecules—hydrogen sulfide, thioacetate12,14 and ferricyanide12,14–17 or cyanoacetylene8,14—to yield $\alpha$-peptides in water. The ligation is extremely selective for $\alpha$-aminonitrile coupling and tolerates all of the 20 proteinogenic amino acid residues. Two essential features enable peptide ligation in water: the reactivity and pKaH of $\alpha$-aminonitriles makes them compatible with ligation at neutral pH and N-acylation stabilizes the peptide product and activates the peptide precursor to (biomimetic) N-to-C peptide ligation. Our model unites prebiotic aminonitrile synthesis and biological $\alpha$-peptides, suggesting that short N-acyl peptide nitriles were plausible substrates during early evolution.},
author = {Canavelli, Pierre and Islam, Saidul and Powner, Matthew W.},
doi = {10.1038/s41586-019-1371-4},
issn = {14764687},
journal = {Nature},
number = {7766},
pages = {546--549},
pmid = {31292542},
title = {{Peptide ligation by chemoselective aminonitrile coupling in water}},
volume = {571},
year = {2019}
}

Amide bond formation is one of the most important reactions in both chemistry and biology1–4, but there is currently no chemical method of achieving $α$-peptide ligation in water that tolerates all of the 20 proteinogenic amino acids at the peptide ligation site. The universal genetic code establishes that the biological role of peptides predates life's last universal common ancestor and that peptides played an essential part in the origins of life5–9. The essential role of sulfur in the citric acid cycle, non-ribosomal peptide synthesis and polyketide biosynthesis point towards thioester-dependent peptide ligations preceding RNA-dependent protein synthesis during the evolution of life5,9–13. However, a robust mechanism for aminoacyl thioester formation has not been demonstrated13. Here we report a chemoselective, high-yielding $α$-aminonitrile ligation that exploits only prebiotically plausible molecules—hydrogen sulfide, thioacetate12,14 and ferricyanide12,14–17 or cyanoacetylene8,14—to yield $α$-peptides in water. The ligation is extremely selective for $α$-aminonitrile coupling and tolerates all of the 20 proteinogenic amino acid residues. Two essential features enable peptide ligation in water: the reactivity and pKaH of $α$-aminonitriles makes them compatible with ligation at neutral pH and N-acylation stabilizes the peptide product and activates the peptide precursor to (biomimetic) N-to-C peptide ligation. Our model unites prebiotic aminonitrile synthesis and biological $α$-peptides, suggesting that short N-acyl peptide nitriles were plausible substrates during early evolution.

@article{Janicki2018,
abstract = {Pentose aminooxazolines and oxazolidinone thiones are considered as the key precursors which could have enabled the formation of RNA nucleotides under the conditions of early Earth. UV-irradiation experiments and quantum-chemical calculations demonstrate that these compounds are remarkably photostable and could accumulate over long periods of time in UV-rich prebiotic environments to undergo stereoisomeric purification.},
author = {Janicki, Miko{\l}aj J. and Roberts, Samuel J. and {\v{S}}poner, Jiř{\'{i}} and Powner, Matthew W. and G{\'{o}}ra, Robert W. and Szabla, Rafa{\l}},
doi = {10.1039/c8cc07343k},
issn = {1364548X},
journal = {Chemical Communications},
number = {95},
pages = {13407--13410},
pmid = {30426980},
title = {{Photostability of oxazoline RNA-precursors in UV-rich prebiotic environments}},
volume = {54},
year = {2018}
}

Pentose aminooxazolines and oxazolidinone thiones are considered as the key precursors which could have enabled the formation of RNA nucleotides under the conditions of early Earth. UV-irradiation experiments and quantum-chemical calculations demonstrate that these compounds are remarkably photostable and could accumulate over long periods of time in UV-rich prebiotic environments to undergo stereoisomeric purification.

@article{Roberts2018,
abstract = {Prebiotic nucleotide synthesis is crucial to understanding the origins of life on Earth. There are numerous candidates for life's first nucleic acid, however, currently no prebiotic method to selectively and concurrently synthesise the canonical Watson–Crick base-pairing pyrimidine (C, U) and purine (A, G) nucleosides exists for any genetic polymer. Here, we demonstrate the divergent prebiotic synthesis of arabinonucleic acid (ANA) nucleosides. The complete set of canonical nucleosides is delivered from one reaction sequence, with regiospecific glycosidation and complete furanosyl selectivity. We observe photochemical 8-mercaptopurine reduction is efficient for the canonical purines (A, G), but not the non-canonical purine inosine (I). Our results demonstrate that synthesis of ANA may have been facile under conditions that comply with plausible geochemical environments on early Earth and, given that ANA is capable of encoding RNA/DNA compatible information and evolving to yield catalytic ANA-zymes, ANA may have played a critical role during the origins of life.},
author = {Roberts, Samuel J. and Szabla, Rafa{\l} and Todd, Zoe R. and Stairs, Shaun and Bu{\v{c}}ar, Dejan Kre{\v{s}}imir and {\v{S}}poner, Jiř{\'{i}} and Sasselov, Dimitar D. and Powner, Matthew W.},
doi = {10.1038/s41467-018-06374-z},
issn = {20411723},
journal = {Nature Communications},
number = {1},
pmid = {30287815},
title = {{Selective prebiotic conversion of pyrimidine and purine anhydronucleosides into Watson-Crick base-pairing arabino-furanosyl nucleosides in water}},
volume = {9},
year = {2018}
}

Prebiotic nucleotide synthesis is crucial to understanding the origins of life on Earth. There are numerous candidates for life's first nucleic acid, however, currently no prebiotic method to selectively and concurrently synthesise the canonical Watson–Crick base-pairing pyrimidine (C, U) and purine (A, G) nucleosides exists for any genetic polymer. Here, we demonstrate the divergent prebiotic synthesis of arabinonucleic acid (ANA) nucleosides. The complete set of canonical nucleosides is delivered from one reaction sequence, with regiospecific glycosidation and complete furanosyl selectivity. We observe photochemical 8-mercaptopurine reduction is efficient for the canonical purines (A, G), but not the non-canonical purine inosine (I). Our results demonstrate that synthesis of ANA may have been facile under conditions that comply with plausible geochemical environments on early Earth and, given that ANA is capable of encoding RNA/DNA compatible information and evolving to yield catalytic ANA-zymes, ANA may have played a critical role during the origins of life.

@article{Fernandez-Garcia2018,
abstract = {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 $\alpha$-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 $\alpha$-cytidine-5′-phosphate to produce the natural $\beta$-pyrimidine ribonucleotide-5′-phosphates required for RNA synthesis.},
author = {Fern{\'{a}}ndez-Garc{\'{i}}a, Christian and Grefenstette, Natalie M. and Powner, Matthew W.},
doi = {10.1039/c8cc01929k},
issn = {1364548X},
journal = {Chemical Communications},
number = {38},
pages = {4850--4853},
pmid = {29697101},
title = {{Selective aqueous acetylation controls the photoanomerization of $\alpha$-cytidine-5′-phosphate}},
volume = {54},
year = {2018}
}

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.

@article{Whitaker2018,
abstract = {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 investigation.},
author = {Whitaker, Daniel and Powner, Matthew W.},
booktitle = {Nature Communications},
doi = {10.1038/s41467-018-07221-x},
issn = {20411723},
number = {1},
pmid = {30538228},
title = {{Prebiotic nucleic acids need space to grow}},
volume = {9},
year = {2018}
}

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 investigation.

@article{Islam2018,
abstract = {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.},
author = {Islam, Saidul and Powner, Matthew W.},
booktitle = {Nature Catalysis},
doi = {10.1038/s41929-018-0131-4},
issn = {25201158},
number = {8},
pages = {569--570},
title = {{Protocells realize their potential}},
volume = {1},
year = {2018}
}

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.

@article{Islam2017,
abstract = {A central problem for the prebiotic synthesis of biological amino acids and nucleotides is to avoid the concomitant synthesis of undesired or irrelevant by-products. Additionally, multistep pathways require mechanisms that enable the sequential addition of reactants and purification of intermediates that are consistent with reasonable geochemical scenarios. Here, we show that 2-aminothiazole reacts selectively with two- and three-carbon sugars (glycolaldehyde and glyceraldehyde, respectively), which results in their accumulation and purification as stable crystalline aminals. This permits ribonucleotide synthesis, even from complex sugar mixtures. Remarkably, aminal formation also overcomes the thermodynamically favoured isomerization of glyceraldehyde into dihydroxyacetone because only the aminal of glyceraldehyde separates from the equilibrating mixture. Finally, we show that aminal formation provides a novel pathway to amino acids that avoids the synthesis of the non-proteinogenic $\alpha$,$\alpha$-disubstituted analogues. The common physicochemical mechanism that controls the proteinogenic amino acid and ribonucleotide assembly from prebiotic mixtures suggests that these essential classes of metabolite had a unified chemical origin.},
author = {Islam, Saidul and Bu{\v{c}}ar, Dejan Kre{\v{s}}imir and Powner, Matthew W.},
doi = {10.1038/nchem.2703},
issn = {17554349},
journal = {Nature Chemistry},
number = {6},
pages = {584--589},
title = {{Prebiotic selection and assembly of proteinogenic amino acids and natural nucleotides from complex mixtures}},
volume = {9},
year = {2017}
}

A central problem for the prebiotic synthesis of biological amino acids and nucleotides is to avoid the concomitant synthesis of undesired or irrelevant by-products. Additionally, multistep pathways require mechanisms that enable the sequential addition of reactants and purification of intermediates that are consistent with reasonable geochemical scenarios. Here, we show that 2-aminothiazole reacts selectively with two- and three-carbon sugars (glycolaldehyde and glyceraldehyde, respectively), which results in their accumulation and purification as stable crystalline aminals. This permits ribonucleotide synthesis, even from complex sugar mixtures. Remarkably, aminal formation also overcomes the thermodynamically favoured isomerization of glyceraldehyde into dihydroxyacetone because only the aminal of glyceraldehyde separates from the equilibrating mixture. Finally, we show that aminal formation provides a novel pathway to amino acids that avoids the synthesis of the non-proteinogenic $α$,$α$-disubstituted analogues. The common physicochemical mechanism that controls the proteinogenic amino acid and ribonucleotide assembly from prebiotic mixtures suggests that these essential classes of metabolite had a unified chemical origin.

@article{Fernandez-Garcia2017,
abstract = {The central role that phosphates play in biological systems, suggests they also played an important role in the emergence of life on Earth. In recent years, numerous important advances have been made towards understanding the influence that phosphates may have had on prebiotic chemistry, and here, we highlight two important aspects of prebiotic phosphate chemistry. Firstly, we discuss prebiotic phosphorylation reactions; we specifically contrast aqueous electrophilic phosphorylation, and aqueous nucleophilic phosphorylation strategies, with dry-state phosphorylations that are mediated by dissociative phosphoryl-transfer. Secondly, we discuss the non-structural roles that phosphates can play in prebiotic chemistry. Here, we focus on the mechanisms by which phosphate has guided prebiotic reactivity through catalysis or buffering effects, to facilitating selective transformations in neutral water. Several prebiotic routes towards the synthesis of nucleotides, amino acids, and core metabolites, that have been facilitated or controlled by phosphate acting as a general acid–base catalyst, pH buffer, or a chemical buffer, are outlined. These facile and subtle mechanisms for incorporation and exploitation of phosphates to orchestrate selective, robust prebiotic chemistry, coupled with the central and universally conserved roles of phosphates in biochemistry, provide an increasingly clear message that understanding phosphate chemistry will be a key element in elucidating the origins of life on Earth.},
author = {Fern{\'{a}}ndez-Garc{\'{i}}a, Christian and Coggins, Adam J. and Powner, Matthew W.},
booktitle = {Life},
doi = {10.3390/life7030031},
issn = {20751729},
keywords = {Amino acids,General acid-base catalyst,Nucleotides,Phosphate,Phosphorylation,Prebiotic chemistry},
number = {3},
title = {{A chemist's perspective on the role of phosphorus at the origins of life}},
volume = {7},
year = {2017}
}

The central role that phosphates play in biological systems, suggests they also played an important role in the emergence of life on Earth. In recent years, numerous important advances have been made towards understanding the influence that phosphates may have had on prebiotic chemistry, and here, we highlight two important aspects of prebiotic phosphate chemistry. Firstly, we discuss prebiotic phosphorylation reactions; we specifically contrast aqueous electrophilic phosphorylation, and aqueous nucleophilic phosphorylation strategies, with dry-state phosphorylations that are mediated by dissociative phosphoryl-transfer. Secondly, we discuss the non-structural roles that phosphates can play in prebiotic chemistry. Here, we focus on the mechanisms by which phosphate has guided prebiotic reactivity through catalysis or buffering effects, to facilitating selective transformations in neutral water. Several prebiotic routes towards the synthesis of nucleotides, amino acids, and core metabolites, that have been facilitated or controlled by phosphate acting as a general acid–base catalyst, pH buffer, or a chemical buffer, are outlined. These facile and subtle mechanisms for incorporation and exploitation of phosphates to orchestrate selective, robust prebiotic chemistry, coupled with the central and universally conserved roles of phosphates in biochemistry, provide an increasingly clear message that understanding phosphate chemistry will be a key element in elucidating the origins of life on Earth.

@article{Stairs2017a,
abstract = {We report the efficient and scalable synthesis of 2,2′-anhydro-5-amino-1-$\beta$-arabinofuranosylimidazole-4-carboxamide and 2,2′-anhydro-5-amino-1-$\beta$-arabinofuranosylimidazole-4-carbonitrile from commercial arabino -adenosine. 2,2′-Anhydro-5-amino-1-$\beta$-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-$\beta$-arabinofuranosylimidazole-4-carboxamide into 2,2′-anhydro-5-amino-1-$\beta$-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.},
author = {Stairs, Shaun and Powner, Matthew W.},
doi = {10.1055/s-0036-1590968},
issn = {14372096},
journal = {Synlett},
keywords = {AICAR,arabinosides,nucleosides,prebiotic,purines},
number = {19},
pages = {2650--2654},
title = {{Scalable Synthesis of 2,2′-Anhydro-arabinofuranosyl Imidazoles}},
volume = {28},
year = {2017}
}

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.

@article{Stairs2017,
abstract = {Understanding prebiotic nucleotide synthesis is a long standing challenge thought to be essential to elucidating the origins of life on Earth. Recently, remarkable progress has been made, but to date all proposed syntheses account separately for the pyrimidine and purine ribonucleotides; no divergent synthesis from common precursors has been proposed. Moreover, the prebiotic syntheses of pyrimidine and purine nucleotides that have been demonstrated operate under mutually incompatible conditions. Here, we tackle this mutual incompatibility by recognizing that the 8-oxo-purines share an underlying generational parity with the pyrimidine nucleotides. We present a divergent synthesis of pyrimidine and 8-oxo-purine nucleotides starting from a common prebiotic precursor that yields the $\beta$-ribo-stereochemistry found in the sugar phosphate backbone of biological nucleic acids. The generational relationship between pyrimidine and 8-oxo-purine nucleotides suggests that 8-oxo-purine ribonucleotides may have played a key role in primordial nucleic acids prior to the emergence of the canonical nucleotides of biology.},
author = {Stairs, Shaun and Nikmal, Arif and Bǔar, Dejan Kre{\v{s}}imir and Zheng, Shao Liang and Szostak, Jack W. and Powner, Matthew W.},
doi = {10.1038/ncomms15270},
issn = {20411723},
journal = {Nature Communications},
pmid = {28524845},
title = {{Divergent prebiotic synthesis of pyrimidine and 8-oxo-purine ribonucleotides}},
volume = {8},
year = {2017}
}

Understanding prebiotic nucleotide synthesis is a long standing challenge thought to be essential to elucidating the origins of life on Earth. Recently, remarkable progress has been made, but to date all proposed syntheses account separately for the pyrimidine and purine ribonucleotides; no divergent synthesis from common precursors has been proposed. Moreover, the prebiotic syntheses of pyrimidine and purine nucleotides that have been demonstrated operate under mutually incompatible conditions. Here, we tackle this mutual incompatibility by recognizing that the 8-oxo-purines share an underlying generational parity with the pyrimidine nucleotides. We present a divergent synthesis of pyrimidine and 8-oxo-purine nucleotides starting from a common prebiotic precursor that yields the $β$-ribo-stereochemistry found in the sugar phosphate backbone of biological nucleic acids. The generational relationship between pyrimidine and 8-oxo-purine nucleotides suggests that 8-oxo-purine ribonucleotides may have played a key role in primordial nucleic acids prior to the emergence of the canonical nucleotides of biology.

@article{Fernandez-Garcia2017a,
abstract = {A convenient selective synthesis of 2′,3′-di-O-acetyl-nucleotide-5′-phosphates, 2′,3′-di-O-acetyl-nucleotide-5′-triphosphates and 2′,3′,5′-tri-O-acetyl-nucleosides in water has been developed. Furthermore, 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 reaction may indicate a prebiotically plausible reaction pathway for the selective acylation of key metabolites to facilitate their incorporation into protometabolism.},
author = {Fern{\'{a}}ndez-Garc{\'{i}}a, Christian and Powner, Matthew W.},
doi = {10.1055/s-0036-1588626},
issn = {14372096},
journal = {Synlett},
keywords = {acylation,lipids,nucleotides,prebiotic chemistry,water},
number = {1},
pages = {78--83},
title = {{Selective Acylation of Nucleosides, Nucleotides, and Glycerol-3-phosphocholine in Water}},
volume = {28},
year = {2017}
}

A convenient selective synthesis of 2′,3′-di-O-acetyl-nucleotide-5′-phosphates, 2′,3′-di-O-acetyl-nucleotide-5′-triphosphates and 2′,3′,5′-tri-O-acetyl-nucleosides in water has been developed. Furthermore, 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 reaction may indicate a prebiotically plausible reaction pathway for the selective acylation of key metabolites to facilitate their incorporation into protometabolism.

@article{Islam2017a,
abstract = {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.},
author = {Islam, Saidul and Powner, Matthew W.},
booktitle = {Chem},
doi = {10.1016/j.chempr.2017.03.001},
issn = {24519294},
keywords = {RNA,amino acids,crystallization,metabolism,nucleotides,origins of life,prebiotic chemistry,predisposed chemistry,sugars,systems chemistry},
number = {4},
pages = {470--501},
title = {{Prebiotic Systems Chemistry: Complexity Overcoming Clutter}},
volume = {2},
year = {2017}
}

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.

@article{Coggins2017,
abstract = {Phosphoenol pyruvate is the highest-energy phosphate found in living organisms and is one of the most versatile molecules in metabolism. Consequently, it is an essential intermediate in a wide variety of biochemical pathways, including carbon fixation, the shikimate pathway, substrate-level phosphorylation, gluconeogenesis and glycolysis. Triose glycolysis (generation of ATP from glyceraldehyde 3-phosphate via phosphoenol pyruvate) is among the most central and highly conserved pathways in metabolism. Here, we demonstrate the efficient and robust synthesis of phosphoenol pyruvate from prebiotic nucleotide precursors, glycolaldehyde and glyceraldehyde. Furthermore, phosphoenol pyruvate is derived within an $\alpha$-phosphorylation controlled reaction network that gives access to glyceric acid 2-phosphate, glyceric acid 3-phosphate, phosphoserine and pyruvate. Our results demonstrate that the key components of a core metabolic pathway central to energy transduction and amino acid, sugar, nucleotide and lipid biosyntheses can be reconstituted in high yield under mild, prebiotically plausible conditions.},
author = {Coggins, Adam J. and Powner, Matthew W.},
doi = {10.1038/nchem.2624},
issn = {17554349},
journal = {Nature Chemistry},
number = {4},
pages = {310--317},
pmid = {28338685},
title = {{Prebiotic synthesis of phosphoenol pyruvate by $\alpha$-phosphorylation-controlled triose glycolysis}},
volume = {9},
year = {2016}
}

Phosphoenol pyruvate is the highest-energy phosphate found in living organisms and is one of the most versatile molecules in metabolism. Consequently, it is an essential intermediate in a wide variety of biochemical pathways, including carbon fixation, the shikimate pathway, substrate-level phosphorylation, gluconeogenesis and glycolysis. Triose glycolysis (generation of ATP from glyceraldehyde 3-phosphate via phosphoenol pyruvate) is among the most central and highly conserved pathways in metabolism. Here, we demonstrate the efficient and robust synthesis of phosphoenol pyruvate from prebiotic nucleotide precursors, glycolaldehyde and glyceraldehyde. Furthermore, phosphoenol pyruvate is derived within an $α$-phosphorylation controlled reaction network that gives access to glyceric acid 2-phosphate, glyceric acid 3-phosphate, phosphoserine and pyruvate. Our results demonstrate that the key components of a core metabolic pathway central to energy transduction and amino acid, sugar, nucleotide and lipid biosyntheses can be reconstituted in high yield under mild, prebiotically plausible conditions.

@article{Coggins2015,
abstract = {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.},
author = {Coggins, Adam J. and Tocher, Derek A. and Powner, Matthew W.},
doi = {10.1039/c5ob00210a},
issn = {14770520},
journal = {Organic and Biomolecular Chemistry},
number = {11},
pages = {3378--3381},
pmid = {25658692},
title = {{One-step protecting-group-free synthesis of azepinomycin in water}},
volume = {13},
year = {2015}
}

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.

@article{Islam2013,
abstract = {In the context of prebiotic chemistry, one of the characteristics of mixed nitrogenous-oxygenous chemistry is its propensity to give rise to highly complex reaction mixtures. There is therefore an urgent need to develop improved spectroscopic techniques if onerous chromatographic separations are to be avoided. One potential avenue is the combination of pure shift methodology, in which NMR spectra are measured with greatly improved resolution by suppressing multiplet structure, with diffusion-ordered spectroscopy, in which NMR signals from different species are distinguished through their different rates of diffusion. Such a combination has the added advantage of working with intact mixtures, allowing analyses to be carried out without perturbing mixtures in which chemical entities are part of a network of reactions in equilibrium. As part of a systems chemistry approach towards investigating the self-assembly of potentially prebiotic small molecules, we have analysed the complex mixture arising from mixing glycolaldehyde and cyanamide, in a first application of pure shift DOSY NMR to the characterisation of a partially unknown reaction composition. The work presented illustrates the potential of pure shift DOSY to be applied to chemistries that give rise to mixtures of compounds in which the NMR signal resolution is poor. The direct formation of potential RNA and TNA nucleoside precursors, amongst other adducts, was observed. These preliminary observations may have implications for the potentially prebiotic assembly chemistry of pyrimidine threonucleotides, and therefore of TNA, by using recently reported chemistries that yield the activated pyridimidine ribonucleotides. Copyright {\textcopyright} 2013 WILEY-VCH Verlag GmbH {\&} Co. KGaA, Weinheim.},
author = {Islam, Saidul and Aguilar, Juan A. and Powner, Matthew W. and Nilsson, Mathias and Morris, Gareth A. and Sutherland, John D.},
doi = {10.1002/chem.201202649},
issn = {09476539},
journal = {Chemistry - A European Journal},
keywords = {NMR spectroscopy,RNA,TNA,diffusion,prebiotic},
number = {14},
pages = {4586--4595},
pmid = {23371787},
title = {{Detection of potential TNA and RNA nucleoside precursors in a prebiotic mixture by pure shift diffusion-ordered NMR spectroscopy}},
volume = {19},
year = {2013}
}

In the context of prebiotic chemistry, one of the characteristics of mixed nitrogenous-oxygenous chemistry is its propensity to give rise to highly complex reaction mixtures. There is therefore an urgent need to develop improved spectroscopic techniques if onerous chromatographic separations are to be avoided. One potential avenue is the combination of pure shift methodology, in which NMR spectra are measured with greatly improved resolution by suppressing multiplet structure, with diffusion-ordered spectroscopy, in which NMR signals from different species are distinguished through their different rates of diffusion. Such a combination has the added advantage of working with intact mixtures, allowing analyses to be carried out without perturbing mixtures in which chemical entities are part of a network of reactions in equilibrium. As part of a systems chemistry approach towards investigating the self-assembly of potentially prebiotic small molecules, we have analysed the complex mixture arising from mixing glycolaldehyde and cyanamide, in a first application of pure shift DOSY NMR to the characterisation of a partially unknown reaction composition. The work presented illustrates the potential of pure shift DOSY to be applied to chemistries that give rise to mixtures of compounds in which the NMR signal resolution is poor. The direct formation of potential RNA and TNA nucleoside precursors, amongst other adducts, was observed. These preliminary observations may have implications for the potentially prebiotic assembly chemistry of pyrimidine threonucleotides, and therefore of TNA, by using recently reported chemistries that yield the activated pyridimidine ribonucleotides. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

@article{Bowler2013,
abstract = {The recent synthesis of pyrimidine ribonucleoside-2′,3′-cyclic phosphates under prebiotically plausible conditions has strengthened the case for the involvement of ribonucleic acid (RNA) at an early stage in the origin of life. However, a prebiotic conversion of these weakly activated monomers, and their purine counterparts, to the 3′,5′-linked RNA polymers of extant biochemistry has been lacking (previous attempts led only to short oligomers with mixed linkages). Here we show that the 2′-hydroxyl group of oligoribonucleotide-3′-phosphates can be chemoselectively acetylated in water under prebiotically credible conditions, which allows rapid and efficient template-directed ligation. The 2′-O-acetyl group at the ligation junction of the product RNA strand can be removed under conditions that leave the internucleotide bonds intact. Remarkably, acetylation of mixed oligomers that possess either 2′- or 3′-terminal phosphates is selective for the 2′-hydroxyl group of the latter. This newly discovered chemistry thus suggests a prebiotic route from ribonucleoside-2′,3′-cyclic phosphates to predominantly 3′,5′-linked RNA via partially 2′-O-acetylated RNA. {\textcopyright} 2013 Macmillan Publishers Limited.},
author = {Bowler, Frank R. and Chan, Christopher K.W. and Duffy, Colm D. and Gerland, B{\'{e}}atrice and Islam, Saidul and Powner, Matthew W. and Sutherland, John D. and Xu, Jianfeng},
doi = {10.1038/nchem.1626},
issn = {17554330},
journal = {Nature Chemistry},
number = {5},
pages = {383--389},
pmid = {23609088},
title = {{Prebiotically plausible oligoribonucleotide ligation facilitated by chemoselective acetylation}},
volume = {5},
year = {2013}
}

The recent synthesis of pyrimidine ribonucleoside-2′,3′-cyclic phosphates under prebiotically plausible conditions has strengthened the case for the involvement of ribonucleic acid (RNA) at an early stage in the origin of life. However, a prebiotic conversion of these weakly activated monomers, and their purine counterparts, to the 3′,5′-linked RNA polymers of extant biochemistry has been lacking (previous attempts led only to short oligomers with mixed linkages). Here we show that the 2′-hydroxyl group of oligoribonucleotide-3′-phosphates can be chemoselectively acetylated in water under prebiotically credible conditions, which allows rapid and efficient template-directed ligation. The 2′-O-acetyl group at the ligation junction of the product RNA strand can be removed under conditions that leave the internucleotide bonds intact. Remarkably, acetylation of mixed oligomers that possess either 2′- or 3′-terminal phosphates is selective for the 2′-hydroxyl group of the latter. This newly discovered chemistry thus suggests a prebiotic route from ribonucleoside-2′,3′-cyclic phosphates to predominantly 3′,5′-linked RNA via partially 2′-O-acetylated RNA. © 2013 Macmillan Publishers Limited.

@article{Engelhart2013,
abstract = {A plausible process for non-enzymatic RNA replication would greatly simplify models of the transition from prebiotic chemistry to simple biology. However, all known conditions for the chemical copying of an RNA template result in the synthesis of a complementary strand that contains a mixture of 2′-5′ and 3′-5′ linkages, rather than the selective synthesis of only 3′-5′ linkages as found in contemporary RNA. Here we show that such backbone heterogeneity is compatible with RNA folding into defined three-dimensional structures that retain molecular recognition and catalytic properties and, therefore, would not prevent the evolution of functional RNAs such as ribozymes. Moreover, the same backbone heterogeneity lowers the melting temperature of RNA duplexes that would otherwise be too stable for thermal strand separation. By allowing copied strands to dissociate, this heterogeneity may have been one of the essential features that allowed RNA to emerge as the first biopolymer. {\textcopyright} 2013 Macmillan Publishers Limited.},
author = {Engelhart, Aaron E. and Powner, Matthew W. and Szostak, Jack W.},
doi = {10.1038/nchem.1623},
issn = {17554330},
journal = {Nature Chemistry},
number = {5},
pages = {390--394},
pmid = {23609089},
title = {{Functional RNAs exhibit tolerance for non-heritable 2′-5′ versus 3′-5′ backbone heterogeneity}},
volume = {5},
year = {2013}
}

A plausible process for non-enzymatic RNA replication would greatly simplify models of the transition from prebiotic chemistry to simple biology. However, all known conditions for the chemical copying of an RNA template result in the synthesis of a complementary strand that contains a mixture of 2′-5′ and 3′-5′ linkages, rather than the selective synthesis of only 3′-5′ linkages as found in contemporary RNA. Here we show that such backbone heterogeneity is compatible with RNA folding into defined three-dimensional structures that retain molecular recognition and catalytic properties and, therefore, would not prevent the evolution of functional RNAs such as ribozymes. Moreover, the same backbone heterogeneity lowers the melting temperature of RNA duplexes that would otherwise be too stable for thermal strand separation. By allowing copied strands to dissociate, this heterogeneity may have been one of the essential features that allowed RNA to emerge as the first biopolymer. © 2013 Macmillan Publishers Limited.

@article{Islam2013a,
abstract = {In the context of prebiotic chemistry, one of the characteristics of mixed nitrogenous-oxygenous chemistry is its propensity to give rise to highly complex reaction mixtures. There is therefore an urgent need to develop improved spectroscopic techniques if onerous chromatographic separations are to be avoided. One potential avenue is the combination of pure shift methodology, in which NMR spectra are measured with greatly improved resolution by suppressing multiplet structure, with diffusion-ordered spectroscopy, in which NMR signals from different species are distinguished through their different rates of diffusion. Such a combination has the added advantage of working with intact mixtures, allowing analyses to be carried out without perturbing mixtures in which chemical entities are part of a network of reactions in equilibrium. As part of a systems chemistry approach towards investigating the self-assembly of potentially prebiotic small molecules, we have analysed the complex mixture arising from mixing glycolaldehyde and cyanamide, in a first application of pure shift DOSY NMR to the characterisation of a partially unknown reaction composition. The work presented illustrates the potential of pure shift DOSY to be applied to chemistries that give rise to mixtures of compounds in which the NMR signal resolution is poor. The direct formation of potential RNA and TNA nucleoside precursors, amongst other adducts, was observed. These preliminary observations may have implications for the potentially prebiotic assembly chemistry of pyrimidine threonucleotides, and therefore of TNA, by using recently reported chemistries that yield the activated pyridimidine ribonucleotides. Copyright {\textcopyright} 2013 WILEY-VCH Verlag GmbH {\&} Co. KGaA, Weinheim.},
author = {Islam, Saidul and Aguilar, Juan A. and Powner, Matthew W. and Nilsson, Mathias and Morris, Gareth A. and Sutherland, John D.},
doi = {10.1002/chem.201202649},
issn = {09476539},
journal = {Chemistry - A European Journal},
keywords = {NMR spectroscopy,RNA,TNA,diffusion,prebiotic},
number = {14},
pages = {4586--4595},
pmid = {23371787},
title = {{Detection of potential TNA and RNA nucleoside precursors in a prebiotic mixture by pure shift diffusion-ordered NMR spectroscopy}},
volume = {19},
year = {2013}
}

In the context of prebiotic chemistry, one of the characteristics of mixed nitrogenous-oxygenous chemistry is its propensity to give rise to highly complex reaction mixtures. There is therefore an urgent need to develop improved spectroscopic techniques if onerous chromatographic separations are to be avoided. One potential avenue is the combination of pure shift methodology, in which NMR spectra are measured with greatly improved resolution by suppressing multiplet structure, with diffusion-ordered spectroscopy, in which NMR signals from different species are distinguished through their different rates of diffusion. Such a combination has the added advantage of working with intact mixtures, allowing analyses to be carried out without perturbing mixtures in which chemical entities are part of a network of reactions in equilibrium. As part of a systems chemistry approach towards investigating the self-assembly of potentially prebiotic small molecules, we have analysed the complex mixture arising from mixing glycolaldehyde and cyanamide, in a first application of pure shift DOSY NMR to the characterisation of a partially unknown reaction composition. The work presented illustrates the potential of pure shift DOSY to be applied to chemistries that give rise to mixtures of compounds in which the NMR signal resolution is poor. The direct formation of potential RNA and TNA nucleoside precursors, amongst other adducts, was observed. These preliminary observations may have implications for the potentially prebiotic assembly chemistry of pyrimidine threonucleotides, and therefore of TNA, by using recently reported chemistries that yield the activated pyridimidine ribonucleotides. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

@article{Powner2012,
abstract = {We propose a novel pathway for the prebiotic synthesis of 2′-deoxynucleotides. Consideration of the constitutional chemical relationships between glycolaldehyde and $\beta$-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 $\beta$-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. {\textcopyright} 2012 American Chemical Society.},
author = {Powner, Matthew W. and Zheng, Shao Liang and Szostak, Jack W.},
doi = {10.1021/ja306176n},
issn = {00027863},
journal = {Journal of the American Chemical Society},
number = {33},
pages = {13889--13895},
pmid = {22839703},
title = {{Multicomponent assembly of proposed DNA precursors in water}},
volume = {134},
year = {2012}
}

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. © 2012 American Chemical Society.

@article{Powner2011a,
abstract = {The origins of life represent one of the most fundamental chemical questions being addressed by modern science. One of the longstanding mysteries of this field is what series of chemical reactions could lead to the molecular biologists dream; a pool of homochiral nucleotides? Here we summarize those results we consider to be historically important and outline our recently published research aimed at understanding the chemoselective origins of the canonical ribonucleotides. {\textcopyright} Georg Thieme Verlag Stuttgart - New York.},
author = {Powner, Matthew W. and Sutherland, John D. and Szostak, Jack W.},
booktitle = {Synlett},
doi = {10.1055/s-0030-1261177},
issn = {09365214},
keywords = {chemoselectivity,multicomponent reactions,nucleotides,photochemistry,rearrangement},
number = {14},
pages = {1956--1964},
title = {{The origins of nucleotides}},
year = {2011}
}

The origins of life represent one of the most fundamental chemical questions being addressed by modern science. One of the longstanding mysteries of this field is what series of chemical reactions could lead to the molecular biologists dream; a pool of homochiral nucleotides? Here we summarize those results we consider to be historically important and outline our recently published research aimed at understanding the chemoselective origins of the canonical ribonucleotides. © Georg Thieme Verlag Stuttgart - New York.

@article{Powner2011,
abstract = {A variety of macromolecules and small molecules-(oligo)nucleotides, proteins, lipids and metabolites- are collectively considered essential to early life. However, previous schemes for the origin of life-e.g. the 'RNA world' hypothesis-have tended to assume the initial emergence of life based on one such molecular class followed by the sequential addition of the others, rather than the emergence of life based on a mixture of all the classes of molecules. This view is in part due to the perceived implausibility of multi-component reaction chemistry producing such a mixture. The concept of systems chemistry challenges such preconceptions by suggesting the possibility of molecular synergism in complex mixtures. If a systems chemistry method to make mixtures of all the classes of molecules considered essential for early life were to be discovered, the significant conceptual difficulties associated with pure RNA, protein, lipid or metabolism 'worlds' would be alleviated. Knowledge of the geochemical conditions conducive to the chemical origins of life is crucial, but cannot be inferred from a planetary sciences approach alone. Instead, insights from the organic reactivity of analytically accessible chemical subsystems can inform the search for the relevant geochemical conditions. If the common set of conditions under which these subsystems work productively, and compatibly, matches plausible geochemistry, an origins of life scenario can be inferred. Using chemical clues from multiple subsystems in this way is akin to triangulation, and constitutes a novel approach to discover the circumstances surrounding the transition from chemistry to biology. Here, we exemplify this strategy by finding common conditions under which chemical subsystems generate nucleotides and lipids in a compatible and potentially synergistic way. The conditions hint at a post-meteoritic impact origin of life scenario. {\textcopyright} 2011 The Royal Society.},
author = {Powner, Matthew W. and Sutherland, John D.},
doi = {10.1098/rstb.2011.0134},
issn = {14712970},
journal = {Philosophical Transactions of the Royal Society B: Biological Sciences},
keywords = {Chemoselectivity,Phosphorylation,Prebiotic chemistry,Systems chemistry},
number = {1580},
pages = {2870--2877},
title = {{Prebiotic chemistry: A new modus operandi}},
volume = {366},
year = {2011}
}

A variety of macromolecules and small molecules-(oligo)nucleotides, proteins, lipids and metabolites- are collectively considered essential to early life. However, previous schemes for the origin of life-e.g. the 'RNA world' hypothesis-have tended to assume the initial emergence of life based on one such molecular class followed by the sequential addition of the others, rather than the emergence of life based on a mixture of all the classes of molecules. This view is in part due to the perceived implausibility of multi-component reaction chemistry producing such a mixture. The concept of systems chemistry challenges such preconceptions by suggesting the possibility of molecular synergism in complex mixtures. If a systems chemistry method to make mixtures of all the classes of molecules considered essential for early life were to be discovered, the significant conceptual difficulties associated with pure RNA, protein, lipid or metabolism 'worlds' would be alleviated. Knowledge of the geochemical conditions conducive to the chemical origins of life is crucial, but cannot be inferred from a planetary sciences approach alone. Instead, insights from the organic reactivity of analytically accessible chemical subsystems can inform the search for the relevant geochemical conditions. If the common set of conditions under which these subsystems work productively, and compatibly, matches plausible geochemistry, an origins of life scenario can be inferred. Using chemical clues from multiple subsystems in this way is akin to triangulation, and constitutes a novel approach to discover the circumstances surrounding the transition from chemistry to biology. Here, we exemplify this strategy by finding common conditions under which chemical subsystems generate nucleotides and lipids in a compatible and potentially synergistic way. The conditions hint at a post-meteoritic impact origin of life scenario. © 2011 The Royal Society.

@article{Choudhary2010a,
abstract = {A plausible route for the spontaneous synthesis of an activated ribonucleotide that is poised for polymerization has been put forth (Powner et al. (2009) Nature, 459, 239-242). A key step in this route necessitates the regioselective phosphorylation of the secondary alcohol on C 3′ of an anhydroarabinonucleoside in the presence of the primary alcohol on C 5′. Here, we propose that this regioselectivity relies on electron delocalization between a lone pair (n) of O 5′ and an antibonding orbital ($\pi$ *) of C2=N 3. This n→$\pi$ * interaction modulates reactivity without the use of a protecting group. Thus, a stereoelectronic effect could have opened a gateway to the "RNA world", the chemical milieu from which the first forms of life are thought to have emerged on Earth some 4 billion years ago. {\textcopyright} 2010 American Chemical Society.},
author = {Choudhary, Amit and Kamer, Kimberli J. and Powner, Matthew W. and Sutherland, John D. and Raines, Ronald T.},
doi = {10.1021/cb100093g},
issn = {15548929},
journal = {ACS Chemical Biology},
number = {7},
pages = {655--657},
pmid = {20499895},
title = {{A stereoelectronic effect in prebiotic nucleotide synthesis}},
volume = {5},
year = {2010}
}

A plausible route for the spontaneous synthesis of an activated ribonucleotide that is poised for polymerization has been put forth (Powner et al. (2009) Nature, 459, 239-242). A key step in this route necessitates the regioselective phosphorylation of the secondary alcohol on C 3′ of an anhydroarabinonucleoside in the presence of the primary alcohol on C 5′. Here, we propose that this regioselectivity relies on electron delocalization between a lone pair (n) of O 5′ and an antibonding orbital ($π$ *) of C2=N 3. This n→$π$ * interaction modulates reactivity without the use of a protecting group. Thus, a stereoelectronic effect could have opened a gateway to the "RNA world", the chemical milieu from which the first forms of life are thought to have emerged on Earth some 4 billion years ago. © 2010 American Chemical Society.

@article{Powner2010,
abstract = {The recent development of a sequential, high-yielding route to activated pyrimidine nucleotides, under conditions thought to be prebiotic, is an encouraging step toward the greater goal of a plausible prebiotic pathway to RNA and the potential for an RNA world. However, this synthesis has led to a disparity in the methodology available for stepwise construction of the canonical pyrimidine and purine nucleotides. To address this problem, and further explore prebiotically accessible chemical systems, we have developed a high-yielding, aqueous, one-pot, multicomponent reaction that tethers masked-sugar moieties to prebiotically plausible purine precursors. A pH-dependent three-component reaction system has been discovered that utilizes key nucleotide synthons 2-aminooxazole and 5-aminoimidazoles, which allows the first divergent purine/pyrimidine synthesis to be proposed. Due to regiospecific aminoimidazole tethering, the pathway allows N9 purination only, thus suggesting the first prebiotically plausible mechanism for regiospecific N9 purination. {\textcopyright} 2010 American Chemical Society.},
author = {Powner, Matthew W. and Sutherland, John D. and Szostak, Jack W.},
doi = {10.1021/ja108197s},
issn = {15205126},
journal = {Journal of the American Chemical Society},
number = {46},
pages = {16677--16688},
pmid = {21043502},
title = {{Chemoselective multicomponent one-pot assembly of purine precursors in water}},
volume = {132},
year = {2010}
}

The recent development of a sequential, high-yielding route to activated pyrimidine nucleotides, under conditions thought to be prebiotic, is an encouraging step toward the greater goal of a plausible prebiotic pathway to RNA and the potential for an RNA world. However, this synthesis has led to a disparity in the methodology available for stepwise construction of the canonical pyrimidine and purine nucleotides. To address this problem, and further explore prebiotically accessible chemical systems, we have developed a high-yielding, aqueous, one-pot, multicomponent reaction that tethers masked-sugar moieties to prebiotically plausible purine precursors. A pH-dependent three-component reaction system has been discovered that utilizes key nucleotide synthons 2-aminooxazole and 5-aminoimidazoles, which allows the first divergent purine/pyrimidine synthesis to be proposed. Due to regiospecific aminoimidazole tethering, the pathway allows N9 purination only, thus suggesting the first prebiotically plausible mechanism for regiospecific N9 purination. © 2010 American Chemical Society.

@article{Powner2010a,
author = {Powner, Matthew W. and Sutherland, John D.},
doi = {10.1002/ange.201001662},
issn = {0044-8249},
journal = {Angewandte Chemie},
number = {27},
pages = {4745--4747},
title = {{Phosphate-Mediated Interconversion of Ribo- and Arabino-Configured Prebiotic Nucleotide Intermediates}},
volume = {122},
year = {2010}
}

@article{Powner2010b,
abstract = {(Represented Chemical Equation) Flipping stereochemistry: Inorganic phosphate catalyzes the interconversion of ribose and arabinose aminooxazolines, suggesting that the prebiotic synthesis of enantiopure pyrimidine ribonucleotides might have involved a single stereoinversion at Cl′ and a double stereoinversion at C2′. {\textcopyright} 2010 Wiley-VCH Verlag GmbH {\&} Co. KGaA, Weinheim.},
author = {Powner, Matthew W. and Sutherland, John D.},
doi = {10.1002/anie.201001662},
issn = {14337851},
journal = {Angewandte Chemie - International Edition},
keywords = {Chirality,Homogeneous catalysis,Nucleotides,Phosphate,Prebiotic chemistry},
number = {27},
pages = {4641--4643},
pmid = {20491113},
title = {{Phosphate-mediated interconversion of Ribo- and Arabino-configured prebiotic nucleotide intermediates}},
volume = {49},
year = {2010}
}

(Represented Chemical Equation) Flipping stereochemistry: Inorganic phosphate catalyzes the interconversion of ribose and arabinose aminooxazolines, suggesting that the prebiotic synthesis of enantiopure pyrimidine ribonucleotides might have involved a single stereoinversion at Cl′ and a double stereoinversion at C2′. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

@article{Choudhary2010,
abstract = {A plausible route for the spontaneous synthesis of an activated ribonucleotide that is poised for polymerization has been put forth (Powner et al. (2009) Nature, 459, 239-242). A key step in this route necessitates the regioselective phosphorylation of the secondary alcohol on C 3′ of an anhydroarabinonucleoside in the presence of the primary alcohol on C 5′. Here, we propose that this regioselectivity relies on electron delocalization between a lone pair (n) of O 5′ and an antibonding orbital ($\pi$ *) of C2=N 3. This n→$\pi$ * interaction modulates reactivity without the use of a protecting group. Thus, a stereoelectronic effect could have opened a gateway to the "RNA world", the chemical milieu from which the first forms of life are thought to have emerged on Earth some 4 billion years ago. {\textcopyright} 2010 American Chemical Society.},
author = {Choudhary, Amit and Kamer, Kimberli J. and Powner, Matthew W. and Sutherland, John D. and Raines, Ronald T.},
doi = {10.1021/cb100093g},
issn = {15548929},
journal = {ACS Chemical Biology},
number = {7},
pages = {655--657},
pmid = {20499895},
title = {{A stereoelectronic effect in prebiotic nucleotide synthesis}},
volume = {5},
year = {2010}
}

A plausible route for the spontaneous synthesis of an activated ribonucleotide that is poised for polymerization has been put forth (Powner et al. (2009) Nature, 459, 239-242). A key step in this route necessitates the regioselective phosphorylation of the secondary alcohol on C 3′ of an anhydroarabinonucleoside in the presence of the primary alcohol on C 5′. Here, we propose that this regioselectivity relies on electron delocalization between a lone pair (n) of O 5′ and an antibonding orbital ($π$ *) of C2=N 3. This n→$π$ * interaction modulates reactivity without the use of a protecting group. Thus, a stereoelectronic effect could have opened a gateway to the "RNA world", the chemical milieu from which the first forms of life are thought to have emerged on Earth some 4 billion years ago. © 2010 American Chemical Society.

@article{Powner2011b,
abstract = {The recent development of a sequential, high-yielding route to activated pyrimidine nucleotides, under conditions thought to be prebiotic, is an encouraging step toward the greater goal of a plausible prebiotic pathway to RNA and the potential for an RNA world. However, this synthesis has led to a disparity in the methodology available for stepwise construction of the canonical pyrimidine and purine nucleotides. To address this problem, and further explore prebiotically accessible chemical systems, we have developed a high-yielding, aqueous, one-pot, multicomponent reaction that tethers masked-sugar moieties to prebiotically plausible purine precursors. A pH-dependent three-component reaction system has been discovered that utilizes key nucleotide synthons 2-aminooxazole and 5-aminoimidazoles, which allows the first divergent purine/pyrimidine synthesis to be proposed. Due to regiospecific aminoimidazole tethering, the pathway allows N9 purination only, thus suggesting the first prebiotically plausible mechanism for regiospecific N9 purination. {\textcopyright} 2010 American Chemical Society.},
author = {Powner, Matthew W. and Sutherland, John D. and Szostak, Jack W.},
doi = {10.1021/ja108197s},
issn = {15205126},
journal = {Journal of the American Chemical Society},
number = {46},
pages = {16677--16688},
pmid = {21043502},
title = {{Chemoselective multicomponent one-pot assembly of purine precursors in water}},
volume = {132},
year = {2010}
}

The recent development of a sequential, high-yielding route to activated pyrimidine nucleotides, under conditions thought to be prebiotic, is an encouraging step toward the greater goal of a plausible prebiotic pathway to RNA and the potential for an RNA world. However, this synthesis has led to a disparity in the methodology available for stepwise construction of the canonical pyrimidine and purine nucleotides. To address this problem, and further explore prebiotically accessible chemical systems, we have developed a high-yielding, aqueous, one-pot, multicomponent reaction that tethers masked-sugar moieties to prebiotically plausible purine precursors. A pH-dependent three-component reaction system has been discovered that utilizes key nucleotide synthons 2-aminooxazole and 5-aminoimidazoles, which allows the first divergent purine/pyrimidine synthesis to be proposed. Due to regiospecific aminoimidazole tethering, the pathway allows N9 purination only, thus suggesting the first prebiotically plausible mechanism for regiospecific N9 purination. © 2010 American Chemical Society.

@article{Powner2009,
abstract = {At some stage in the origin of life, an informational polymer must have arisen by purely chemical means. According to one version of the RNA world hypothesis this polymer was RNA, but attempts to provide experimental support for this have failed. In particular, although there has been some success demonstrating that activated ribonucleotides can polymerize to form RNA, it is far from obvious how such ribonucleotides could have formed from their constituent parts (ribose and nucleobases). Ribose is difficult to form selectively, and the addition of nucleobases to ribose is inefficient in the case of purines and does not occur at all in the case of the canonical pyrimidines. Here we show that activated pyrimidine ribonucleotides can be formed in a short sequence that bypasses free ribose and the nucleobases, and instead proceeds through arabinose amino-oxazoline and anhydronucleoside intermediates. The starting materials for the synthesiscyanamide, cyanoacetylene, glycolaldehyde, glyceraldehyde and inorganic phosphateare plausible prebiotic feedstock molecules, and the conditions of the synthesis are consistent with potential early-Earth geochemical models. Although inorganic phosphate is only incorporated into the nucleotides at a late stage of the sequence, its presence from the start is essential as it controls three reactions in the earlier stages by acting as a general acid/base catalyst, a nucleophilic catalyst, a pH buffer and a chemical buffer. For prebiotic reaction sequences, our results highlight the importance of working with mixed chemical systems in which reactants for a particular reaction step can also control other steps. {\textcopyright} 2009 Macmillan Publishers Limited. All rights reserved.},
author = {Powner, Matthew W. and Gerland, B{\'{e}}atrice and Sutherland, John D.},
doi = {10.1038/nature08013},
issn = {00280836},
journal = {Nature},
number = {7244},
pages = {239--242},
pmid = {19444213},
title = {{Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions}},
volume = {459},
year = {2009}
}

At some stage in the origin of life, an informational polymer must have arisen by purely chemical means. According to one version of the RNA world hypothesis this polymer was RNA, but attempts to provide experimental support for this have failed. In particular, although there has been some success demonstrating that activated ribonucleotides can polymerize to form RNA, it is far from obvious how such ribonucleotides could have formed from their constituent parts (ribose and nucleobases). Ribose is difficult to form selectively, and the addition of nucleobases to ribose is inefficient in the case of purines and does not occur at all in the case of the canonical pyrimidines. Here we show that activated pyrimidine ribonucleotides can be formed in a short sequence that bypasses free ribose and the nucleobases, and instead proceeds through arabinose amino-oxazoline and anhydronucleoside intermediates. The starting materials for the synthesiscyanamide, cyanoacetylene, glycolaldehyde, glyceraldehyde and inorganic phosphateare plausible prebiotic feedstock molecules, and the conditions of the synthesis are consistent with potential early-Earth geochemical models. Although inorganic phosphate is only incorporated into the nucleotides at a late stage of the sequence, its presence from the start is essential as it controls three reactions in the earlier stages by acting as a general acid/base catalyst, a nucleophilic catalyst, a pH buffer and a chemical buffer. For prebiotic reaction sequences, our results highlight the importance of working with mixed chemical systems in which reactants for a particular reaction step can also control other steps. © 2009 Macmillan Publishers Limited. All rights reserved.

@article{Powner2008,
author = {Powner, Matthew W. and Sutherland, John D.},
doi = {10.1002/cbic.200800391},
issn = {14394227},
journal = {ChemBioChem},
keywords = {Nucleotides,Photoanomerization,Photohydrolysis,Prebiotic,RNA},
number = {15},
pages = {2386--2387},
pmid = {18798212},
title = {{Potentially prebiotic synthesis of pyrimidine $\beta$-D-ribonucleotides by photoanomerization/hydrolysis of $\alpha$-D-cytidine-2′-phosphate}},
volume = {9},
year = {2008}
}

@article{Anastasi2007,
abstract = {Spectacular advances in structural and molecular biology have added support to the 'RNA world' hypothesis, and provide a mandate for chemistry to explain how RNA might have been generated prebiotically on the early earth. Difficulties in achieving a prebiotically plausible synthesis of RNA, however, have led many to ponder the question posed in the title of this paper. Herein, we review recent experimental work on the assembly of potential RNA precursors, focusing on methods for stereoselective C-C bond construction by aldolisation and related processes. This chemistry is presented in the context of a broader picture of the potential constitutional self-assembly of RNA. Finally, the relative accessibility of RNA and alternative nucleic acids is considered. {\textcopyright} 2007 Verlag Helvetica Chimica Acta AG, Z{\"{u}}rich.},
author = {Anastasi, Carole and Buchet, Fabien F. and Crowe, Michael A. and Parkes, Alastair L. and Powner, Matthew W. and Smith, James M. and Sutherland, John D.},
booktitle = {Chemistry and Biodiversity},
doi = {10.1002/cbdv.200790060},
issn = {16121872},
number = {4},
pages = {721--739},
pmid = {17443885},
title = {{RNA: Prebiotic product, or biotic invention?}},
volume = {4},
year = {2007}
}

Spectacular advances in structural and molecular biology have added support to the 'RNA world' hypothesis, and provide a mandate for chemistry to explain how RNA might have been generated prebiotically on the early earth. Difficulties in achieving a prebiotically plausible synthesis of RNA, however, have led many to ponder the question posed in the title of this paper. Herein, we review recent experimental work on the assembly of potential RNA precursors, focusing on methods for stereoselective C-C bond construction by aldolisation and related processes. This chemistry is presented in the context of a broader picture of the potential constitutional self-assembly of RNA. Finally, the relative accessibility of RNA and alternative nucleic acids is considered. © 2007 Verlag Helvetica Chimica Acta AG, Zürich.

@article{Powner2007,
abstract = {Recent work has emphasised the importance of D-ribose amino-oxazoline 1 in the synthesis of cytidine ribonucleosides under potentially prebiotic conditions. Upon treatment with cyanoacetylene, 1 is transformed into $\alpha$-D-cytidine ($\alpha$-2), and if an efficient means of anomerising this nucleoside or a derivative thereof were to be found, then the synthesis of one of the key $\beta$-D-nucleosides required to make RNA would be realised. Photoanomerisation of $\alpha$-2 has previously been described, but the yield was extremely low. Therefore, the present study was initiated to determine whether this low yield was the result of a low conversion or competing reaction pathways. {\textcopyright} 2007 Wiley-VCH Verlag GmbH {\&} Co. KGaA.},
author = {Powner, Matthew W. and Anastasi, Carole and Crowe, Michael A. and Parkes, Alastair L. and Raftery, Jim and Sutherland, John D.},
doi = {10.1002/cbic.200700098},
issn = {14394227},
journal = {ChemBioChem},
keywords = {Nucleosides,Photoanomerisation,Photochemistry,Prebiotic,RNA},
number = {10},
pages = {1170--1179},
pmid = {17549787},
title = {{On the prebiotic synthesis of ribonucleotides: Photoanomerisation of cytosine nucleosides and nucleotides revisited}},
volume = {8},
year = {2007}
}

Recent work has emphasised the importance of D-ribose amino-oxazoline 1 in the synthesis of cytidine ribonucleosides under potentially prebiotic conditions. Upon treatment with cyanoacetylene, 1 is transformed into $α$-D-cytidine ($α$-2), and if an efficient means of anomerising this nucleoside or a derivative thereof were to be found, then the synthesis of one of the key $β$-D-nucleosides required to make RNA would be realised. Photoanomerisation of $α$-2 has previously been described, but the yield was extremely low. Therefore, the present study was initiated to determine whether this low yield was the result of a low conversion or competing reaction pathways. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA.

@article{Anastasi2006,
author = {Anastasi, Carole and Crowe, Michael A. and Powner, Matthew W. and Sutherland, John D.},
doi = {10.1002/ange.200601267},
issn = {0044-8249},
journal = {Angewandte Chemie},
number = {37},
pages = {6322--6325},
title = {{Direct Assembly of Nucleoside Precursors from Two- and Three-Carbon Units}},
volume = {118},
year = {2006}
}