A Prebiotic Synthesis of Pterins

The genesis of life on Earth is a hypothesis of evolutionary science that can be, at least partially, tested experimentally. The prebiotic synthesis of cofactors or coenzymes is a poorly explored issue, likely because their formation under plausible prebiotic conditions is not clear. In this sense, it has been proposed that the cofactors are “molecular fossils” of an early phase of life. In contrast, Eschenmoser and Loewenthal suggested a prebiotic hydrocyanic origin of cofactor building blocks. In the present paper, the formation of a set of pterins from cyanide polymerizations is demonstrated, showing that the main structure of some cofactors can be prebiotically formed. Indeed, it was observed that aqueous aerosols additionally increase the relative composition for pterins in the insoluble NH₄CN polymers synthesized. The novel identification of pterins in NH₄CN polymers, together with the previous detection of other important biomonomers, indicates that cyanide polymerizations were essential in the early state of prebiotic chemistry.     

Proto‐Urea‐RNA (Wöhler RNA) Containing Unusually Stable Urea Nucleosides

The RNA world hypothesis assumes that life on Earth began with nucleotides that formed information‐carrying RNA oligomers able to self‐replicate. Prebiotic reactions leading to the contemporary nucleosides are now known, but their execution often requires specific starting materials and lengthy reaction sequences. It was therefore proposed that the RNA world was likely proceeded by a proto‐RNA world constructed from molecules that were likely present on the early Earth in greater abundance. Herein, we show that the prebiotic starting molecules bis‐urea (biuret) and tris‐urea (triuret) are able to directly react with ribose. The urea‐ribosides are remarkably stable because they are held together by a network of intramolecular, bifurcated hydrogen bonds. This even allowed the synthesis of phosphoramidite building blocks and incorporation of the units into RNA. Investigations of the nucleotides’ base‐pairing potential showed that triuret:G RNA base pairs closely resemble U:G wobble base pairs. Based on the probable abundance of urea on the early Earth, we postulate that urea‐containing RNA bases are good candidates for a proto‐RNA world.     

A Stark Contrast to Modern Earth: Phosphate Mineral Transformation and Nucleoside Phosphorylation in an Iron‐ and Cyanide‐Rich Early Earth Scenario

Organophosphates were likely an important class of prebiotic molecules. However, their presence on the early Earth is strongly debated because the low availability of phosphate, which is generally assumed to have been sequestered in insoluble calcium and iron minerals, is widely viewed as a major barrier to organophosphate generation. Herein, we demonstrate that cyanide (an essential prebiotic precursor) and urea‐based solvents could promote nucleoside phosphorylation by transforming insoluble phosphate minerals in a “warm little pond” scenario into more soluble and reactive species. Our results suggest that cyanide and its derivatives (metal cyanide complexes, urea, ammonium formate, and formamide) were key reagents for the participation of phosphorus in chemical evolution. These results allow us to propose a holistic scenario in which an evaporitic environment could concentrate abiotically formed organics and transform the underlying minerals, allowing significant organic phosphorylation under plausible prebiotic conditions.     

Peptide bond formation in gas-phase ion/molecule reactions of amino acids: a novel proposal for the synthesis of prebiotic oligopeptides

There is a general fascination with regard to the origin of life on Earth. There is an intriguing possibility that prebiotic precursors of life occurred in the interstellar space and were then transported to the early Earth by comets, asteroids and meteorites. It is probable that some part of the prebiotic molecules may have been generated by gas-phase ion/molecule reactions. Here we show experimentally that gaseous ion/molecule reactions of the amino acids, Glu and Met, may promote the synthesis of protonated dipeptides such as (Glu-Glu)H(+) and (Glu-Met)H(+) and their chemical growth to larger protonated peptides.     

Mechanochemical Activation of Iron Cyano Complexes: A Prebiotic Impact Scenario for the Synthesis of α‐Amino Acid Derivatives

Mechanochemical activation of iron cyano complexes by ball milling results in the formation of HCN, which can be trapped and incorporated into α‐aminonitriles. This prebiotic impact scenario can be extended by mechanochemically transforming the resulting α‐aminonitriles into α‐amino amides using a chemical route related to early Earth conditions.     

Multicomponent Synthesis of Purines and Pyrimidines: From the Origin of Life to New Sustainable Approaches for Drug-Discovery Applications

It is widely accepted that purines and pyrimidines, the building blocks that gave origin to life on our planet, were created through multicomponent reactions (MCRs) on early abiotic Earth. These heterocyclic scaffolds gradually evolved into a wide range of biologically relevant molecules regulating many different physiological processes and thus becoming widely exploited as templates for the development of new drugs. Accordingly, over the years, the synthetic community has dedicated many efforts in the attempt to hypothesize and replicate the original abiotic synthesis of purines and pyrimidines, thus developing a number of multicomponent synthesis to access these scaffolds. The following evolution of synthetic chemistry towards green approaches for the production of new molecules and the recent interest in pharmaceutical sustainability underlines the importance of multicomponent synthesis of new heterocycles. This review article provides an overview of the most important multicomponent approaches for the synthesis of purine and pyrimidine derivatives for potential pharmacological applications.     

Prebiotic Nucleoside Synthesis: The Selectivity of Simplicity

Ever since the discovery of nucleic acids 150 years ago,^[1] major achievements have been made in understanding and decrypting the fascinating scientific questions of the genetic code.^[2] However, the most fundamental question about the origin and the evolution of the genetic code remains a mystery. How did nature manage to build up such intriguingly complex molecules able to encode structure and function from simple building blocks? What conditions were required? How could the precursors survive the unhostile environment of early Earth? Over the past decades, promising synthetic concepts were proposed providing clarity in the field of prebiotic nucleic acid research. In this Minireview, we show the current status and various approaches to answer these fascinating questions.     

Prebiotic Synthesis and Isomerization in Interstellar Analog Ice: Glycinal,Acetamide, and Their Enol Tautomers

Glycinal (HCOCH₂NH₂) and acetamide (CH₃CONH₂) are simple molecular building blocks of biomolecules in prebiotic chemistry, though their origin on early Earth and formation in interstellar media remain a mystery. These molecules are formed with their tautomers in low temperature interstellar model ices upon interaction with simulated galactic cosmic rays. Glycinal and acetamide are accessed via barrierless radical-radical reactions of vinoxy (⋅CH₂CHO) and acetyl (⋅C(O)CH₃), and then undergo keto-enol tautomerization. Exploiting tunable photoionization reflectron time-of-flight mass spectroscopy and photoionization efficiency (PIE) curves, these results demonstrate fundamental reaction pathways for the formation of complex organics through non-equilibrium ice reactions in cold molecular cloud environments. These molecules demonstrate an unconventional starting point for abiotic synthesis of organics relevant to contemporary biomolecules like polypeptides and cell membranes in deep space.     

Host–Guest Binding‐Site‐Tunable Self‐Assembly of Stimuli‐Responsive Supramolecular Polymers

Despite the remarkable progress made in controllable self‐assembly of stimuli‐responsive supramolecular polymers (SSPs), a basic issue that has not been consideration to date is the essential binding site. The noncovalent binding sites, which connect the building blocks and endow supramolecular polymers with their ability to respond to stimuli, are expected to strongly affect the self‐assembly of SSPs. Herein, the design and synthesis of a dual‐stimuli thermo‐ and photoresponsive Y‐shaped supramolecular polymer (SSP2) with two adjacent β‐cyclodextrin/azobenzene (β‐CD/Azo) binding sites, and another SSP (SSP1) with similar building blocks, but only one β‐CD/Azo binding site as a control, are described. Upon gradually increasing the polymer solution temperature or irradiating with UV light, SSP2 self‐assemblies with a higher binding‐site distribution density; exhibits a flower‐like morphology, smaller size, and more stable dynamic aggregation process; and greater controllability for drug‐release behavior than those observed with SSP1 self‐assemblies. The host–guest binding‐site‐tunable self‐assembly was attributed to the positive cooperativity generated among adjacent binding sites on the surfaces of SSP2 self‐assemblies. This work is beneficial for precisely controlling the structural parameters and controlled release function of SSP self‐assemblies.     

Caged O-phosphorothioyl amino acids as building blocks for Fmoc-based solid phase peptide synthesis

The synthesis of 1-(2-nitrophenylethyl) caged O-phosphorothioylserine, -threonine, and -tyrosine derivatives is reported. These amino acid building blocks can be directly incorporated into peptides by Fmoc-based solid phase synthesis as their pentafluorophenyl esters or as symmetric anhydrides. Upon irradiation with UV light, the thiophosphate group, representing a hydrolysis resistant phosphate analog, is revealed.     

Non‐enzymatic Ribonucleotide Reduction in the Prebiotic Context

Model studies of prebiotic chemistry have revealed compelling routes for the formation of the building blocks of proteins and RNA, but not DNA. Today, deoxynucleotides required for the construction of DNA are produced by reduction of nucleotides catalysed by ribonucleotide reductases, which are radical enzymes. This study considers potential non‐enzymatic routes via intermediate radicals for the ancient formation of deoxynucleotides. In this context, several mechanisms for ribonucleotide reduction, in a putative H₂S/HS^. environment, are characterized using computational chemistry. A bio‐inspired mechanistic cycle involving a keto intermediate and HSSH production is found to be potentially viable. An alternative pathway, proceeding through an enol intermediate is found to exhibit similar energetic requirements. Non‐cyclical pathways, in which HSS^. is generated in the final step instead of HS^., show a markedly increased thermodynamic driving force (ca. 70 kJ mol^?1) and thus warrant serious consideration in the context of the prebiotic ribonucleotide reduction.     

Darwin's Warm Little Pond: A One‐Pot Reaction for Prebiotic Phosphorylation and the Mobilization of Phosphate from Minerals in a Urea‐Based Solvent

The poor reactivity of insoluble phosphates, such as apatite‐group minerals, has been a long‐appreciated obstacle for proposed models of prebiotic organophosphate formation. This obstacle presents a significant challenge to the nascent development of an RNA world and other models for the origins of life on Earth. Herein, we demonstrate that a scenario based on the formation of a urea/ammonium formate/water (UAFW) eutectic solution leads to an increase in phosphorylation when compared to urea alone for phosphate sources of varying solubility. In addition, under evaporative conditions and in the presence of MgSO₄, the UAFW eutectic mobilizes the phosphate sequestered in water‐insoluble hydroxyapatite, giving rise to a marked increase in phosphorylation. These results suggest that the prebiotic concentrations of urea in a geologically plausible evaporitic environment could solve the problem of organic phosphorylation on a prebiotic Earth.     

Noncanonical RNA Nucleosides as Molecular Fossils of an Early Earth—Generation by Prebiotic Methylations and Carbamoylations

The RNA‐world hypothesis assumes that life on Earth started with small RNA molecules that catalyzed their own formation. Vital to this hypothesis is the need for prebiotic routes towards RNA. Contemporary RNA, however, is not only constructed from the four canonical nucleobases (A, C, G, and U), it also contains many chemically modified (noncanonical) bases. A still open question is whether these noncanonical bases were formed in parallel to the canonical bases (chemical origin) or later, when life demanded higher functional diversity (biological origin). Here we show that isocyanates in combination with sodium nitrite establish methylating and carbamoylating reactivity compatible with early Earth conditions. These reactions lead to the formation of methylated and amino acid modified nucleosides that are still extant. Our data provide a plausible scenario for the chemical origin of certain noncanonical bases, which suggests that they are fossils of an early Earth.     

Photocontrol Over Self‐Assembled Nanostructures of π–π Stacked Dyes Supported by the Parallel Conformer of Diarylethene

Diarylethenes (DAEs) have rarely been used in the design of photoresponsive supramolecular assemblies with a well‐defined morphology transition owing to rather small structural changes upon photoisomerization. A supramolecular design based on the parallel conformation of DAEs enables the construction of photoresponsive dye assemblies that undergo remarkable nanomorphology transitions. The cooperative stacking of perylene bisimide (PBI) dyes was used to stabilize the parallel conformer of DAE through complementary hydrogen bonds. Atomic force microscopy, UV/Vis spectroscopy, and molecular modeling revealed that our DAE and PBI building blocks coassembled in nonpolar solvent to form well‐defined helical nanofibers featuring J‐type dimers of PBI dyes. Upon irradiating the coassembly solution with UV and visible light in turn, a reversible morphology change between nanofibers and nanoparticles was observed. This system involves the generation of a new self‐assembly pathway by means of photocontrol.     

Eutectic phase polymerization of activated ribonucleotide mixtures yields quasi-equimolar incorporation of purine and pyrimidine nucleobases

The RNA world hypothesis requires a plausible mechanism by which RNA itself (or precursor RNA-like polymers) can be synthesized nonenzymatically from the corresponding building blocks. Simulation experiments have exploited chemically reactive mononucleotides as monomers. Solutions of such monomers in the prebiotic environment were likely to be very dilute, but in experimental simulations of polymerization reactions dilute solutions of activated mononucleotides in the millimolar range hydrolyze extensively, and only trace amounts of dimers and trimers are formed. We report here that random medium-size RNA analogues with mixed sequences (5- to 17-mers with traces of longer products) can be synthesized in ice eutectic phases that are produced when dilute solutions of activated monomers and catalysts (Mg(II) and Pb(II)) are frozen and maintained at -18 degrees C for periods up to 38 days. Under these conditions, the monomers are concentrated as eutectics in an ice matrix. Hydrolysis of the activated mononucleotides was suppressed at low-temperature ranges, and polymerization was enhanced with yields up to 90%. Analysis of the mixed oligomers established that incorporation of both purine and pyrimidine bases proceeded at comparable rates and yields. These results suggest that ice deposits on the early Earth could have facilitated the synthesis of short- and medium-size random sequence RNA analogues and thereby provided a microenvironment suitable for the formation of biopolymers or their precursors.     

Photoresponsive self-assembly and self-organization of hydrogen-bonded supramolecular tapes

Self-assembling building blocks that are readily functionalizable and capable of achieving programmed hierarchical organization have enabled us to create various functional nanomaterials. We have previously demonstrated that N,N'-disubstituted 4,6-diaminopyrimidin-2(1 H)-one (DAP), a guanine-cytosine hybridized molecule, is a versatile building block for the creation of tapelike supramolecular polymer species in solution. In the current study, DAP was functionalized with azobenzene side chains. 1H NMR, UV/Vis, and dynamic light scattering studies confirmed the presence of nanometer-scale tapelike supramolecular polymers in alkane solvents at micromolar regimes. At higher concentrations (millimolar regimes), the supramolecular polymers hierarchically organized into lamellar superstructures to form organogels, as shown by X-ray diffraction and polarized optical microscopy. Remarkably, the azobenzene side chains are photoisomerizable even in the supramolecular polymers, owing to their loosely packed state supported by the rigid hydrogen-bonded scaffold, enabling us to establish photocontrollable supramolecular polymerization and higher order organization of the tapelike supramolecular polymers into lamellar superstructures.     

Synthesis of photolabile 2-(2-nitrophenyl)propyloxycarbonyl protected amino acids

The 2-(2-nitrophenyl)propyloxycarbonyl (NPPOC) group has been introduced as a photolabile amino protecting group for amino acids to be used as building blocks in photolithographic solid-phase peptide synthesis. NPPOC-protected amino acids were found to be cleaved in the presence of UV light about twice as fast as the corresponding o-nitroveratryloxycarbonyl (NVOC)-protected amino acids.     

Catalytic Chemo- and Regioselective Radical Carbocyanation of 2-Azadienes for the Synthesis of α-Amino Nitriles

α-Amino nitriles are versatile structural motifs in a variety of biologically active compounds and pharmaceuticals and they serve as valuable building blocks in synthesis. The preparation of α- and β-functionalized α-amino nitriles from readily available scaffolds, however, remains challenging. Herein is reported a novel dual catalytic photoredox/copper-catalyzed chemo- and regioselective radical carbocyanation of 2-azadienes to access functionalized α-amino nitriles by using redox-active esters (RAEs) and trimethylsilyl cyanide. This cascade process employs a broad scope of RAEs and provides the corresponding α-amino nitrile building blocks in 50–95 % yields (51 examples, regioselectivity >95 : 5). The products were transformed into prized α-amino nitriles and α-amino acids. Mechanistic studies suggest a radical cascade coupling process.     

Microfluidic Production of Pyrophosphate Catalyzed by Mineral Membranes with Steep pH Gradients

Pyrophosphate might have functioned as an energy storage/currency molecule on early Earth, essential for the emergence of life. Here we synthesized mineral membranes involving iron(II), iron(III), and other divalent metal cations (calcium, manganese, cobalt, copper, zinc, and nickel) and tested their ability to catalyze the formation of pyrophosphate from phosphate and acetyl phosphate across steep pH gradients in microfluidic devices. We studied the chemical compositions of the precipitate membranes (which included vivianite, goethite, and green rust) using in situ and ex situ micro-Raman spectroscopy. The yields of pyrophosphate were determined by aqueous ³¹P NMR spectroscopy. We found that Fe²⁺ and Ca²⁺ were the best catalysts for pyrophosphate synthesis among investigated ions; Fe³⁺ and mixed-valence iron membranes were also able to promote pyrophosphate formation. In addition, the pH gradients across the membranes affected the pyrophosphate yields and the smallest pH gradient resulted in the highest yield. These results suggest a possible route of substrate phosphorylation in prebiotic hydrothermal systems.     

Wie entstand das Leben auf der Erde?: Ammoniak aus Stickstoff unter präbiotischen Bedingungen

This article discusses natural and technical nitrogen fixation. Additionally, a possible scenario of prebiotic nitrogen fixation is presented. The way how ammonia is generated in this scenario could have been the basis for the formation of early amino acids, which are the fundamental building blocks of all nitrogen‐containing bio‐molecules.