Thiophosphate photochemistry enables prebiotic access to sugars and terpenoid precursors.

Over the past few years, evidence has accrued that demonstrates that terrestrial photochemical reactions could have provided numerous (proto)biomolecules with implications for the origin of life. This chemistry simply relies on UV light, inorganic sulfur species and hydrogen cyanide. Recently, we reported that, under the same conditions, reduced phosphorus species, such as those delivered by meteorites, can be oxidized to orthophosphate, generating thiophosphate in the process. Here we describe an investigation of the properties of thiophosphate as well as additional possible means for its formation on primitive Earth. We show that several reported prebiotic reactions, including the photoreduction of thioamides, carbonyl groups and cyanohydrins, can be markedly improved, and that tetroses and pentoses can be accessed from hydrogen cyanide through a Kiliani-Fischer-type process without progressing to higher sugars. We also demonstrate that thiophosphate allows photochemical reductive aminations, and that thiophosphate chemistry allows a plausible prebiotic synthesis of the C5 moieties used in extant terpene and terpenoid biosynthesis, namely dimethylallyl alcohol and isopentenyl alcohol.

Azoles as Auxiliaries and Intermediates in Prebiotic Nucleoside Synthesis.

4,5-Dicyanoimidazole and 2-aminothiazole are azoles that have previously been implicated in prebiotic nucleotide synthesis. The former compound is a byproduct of adenine synthesis, and the latter compound has been shown to be capable of separating C2 and C3 sugars via crystallization as their aminals. We now report that the elusive intermediate cyanoacetylene can be captured by 4,5-dicyanoimidazole and accumulated as the crystalline compound N-cyanovinyl-4,5-dicyanoimidazole, thus providing a solution to the problem of concentration of atmospherically formed cyanoacetylene. Importantly, this intermediate is a competent cyanoacetylene surrogate, reacting with ribo-aminooxazoline in formamide to give ribo-anhydrocytidine ─ an intermediate in the divergent synthesis of purine and pyrimidine nucleotides. We also report a prebiotically plausible synthesis of 2-aminothiazole and examine the mechanism of its formation. The utilization of each of these azoles enhances the prebiotic synthesis of ribonucleotides, while their syntheses comport with the cyanosulfidic scenario we have previously described.

A cyanosulfidic origin of the Krebs cycle.

The centrality of the Krebs cycle in metabolism has long been interpreted as evidence of its antiquity, and consequently, questions regarding its provenance, and whether it initially functioned as a cycle or not, have received much attention. The present report shows that prebiotic oxidation of α-hydroxy carboxylates can be achieved by UV photolysis of a simple geochemical species (HS-), which leads to α-oxo carboxylates that feature in the Krebs cycle and glyoxylate shunt. Further reaction of these products leads to almost all intermediates of the Krebs cycle proper, succinate semialdehyde bypass, and glyoxylate shunt. Fumarate, the missing Krebs cycle component, and the required α-hydroxy carboxylates can be provided by a highly related hydrogen cyanide chemistry, which also provides precursors for amino acids, nucleotides, and phospholipids.

Timescales for Prebiotic Photochemistry Under Realistic Surface Ultraviolet Conditions.

Ultraviolet (UV) light has long been invoked as a source of energy for prebiotic chemical synthesis, but experimental support does not involve sources of UV light that look like the young Sun. Here we experimentally investigate whether the UV flux available on the surface of early Earth, given a favorable atmosphere, can facilitate a variety of prebiotic chemical syntheses. We construct a solar simulator for the UV light of the faint young Sun on the surface of early Earth, called StarLab. We then attempt a series of reactions testing different aspects of a prebiotic chemical scenario involving hydrogen cyanide (HCN), sulfites, and sulfides under the UV light of StarLab, including hypophosphite oxidation by UV light and hydrogen sulfide, photoreduction of HCN with bisulfite, the photoanomerization of α-thiocytidine, the production of a chemical precursor of a potentially prebiotic activating agent (nitroprusside), the photoreduction of thioanhydrouridine and thioanhydroadenosine, and the oxidation of ethanol (EtOH) by photochemically generated hydroxyl radicals. We compare the output of StarLab to the light of the faint young Sun to constrain the timescales over which these reactions would occur on the surface of early Earth. We predict that hypophosphite oxidation, HCN reduction, and photoproduction of nitroprusside would all operate on the surface of early Earth in a matter of days to weeks. The photoanomerization of α-thiocytidine would take months to complete, and the production of oxidation products from hydroxyl radicals would take years. The photoreduction of thioanhydrouridine with hydrogen sulfide did not succeed even after a long period of irradiation, providing a lower limit on the timescale of several years. The photoreduction of thioanhydroadenosine with bisulfite produced 2'-deoxyriboadenosine (dA) on the timescale of days. This suggests the plausibility of the photoproduction of purine deoxyribonucleotides, such as the photoproduction of simple sugars, proceeds more efficiently in the presence of bisulfite.

Supply of phosphate to early Earth by photogeochemistry after meteoritic weathering.

During terrestrial differentiation, the relatively small amount of phosphorus that migrated to the lithosphere was incorporated into igneous rock, predominantly in the form of basic calcium orthophosphate (Ca10(PO4)6(OH,F,Cl)2, apatite). Yet, the highly insoluble nature of calcium apatite presents a significant problem to those contemplating the origin of life given the foundational role of phosphate (PO4 3-) in extant biology and the apparent requirement for PO4 3- as a catalyst, buffer and reagent in prebiotic chemistry. Reduced meteorites such as enstatite chondrites are highly enriched in phosphide minerals, and upon reaction with water these minerals can release phosphorus species of various oxidation states. Here, we demonstrate how reduced phosphorus species can be fully oxidized to PO4 3- simply by the action of ultraviolet light on H2S/HS-. We used low pressure Hg lamps to simulate UV output from the young Sun and 31P NMR spectroscopy to monitor the progress of reactions. Our experimental findings provide a cosmochemically and geochemically plausible means for supply of PO4 3- that was widely available to prebiotic chemistry and nascent life on early Earth, and potentially on other planets.

Mimicking the surface and prebiotic chemistry of early Earth using flow chemistry.

When considering life's aetiology, the first questions that must be addressed are "how?" and "where?" were ostensibly complex molecules, considered necessary for life's beginning, constructed from simpler, more abundant feedstock molecules on primitive Earth. Previously, we have used multiple clues from the prebiotic synthetic requirements of (proto)biomolecules to pinpoint a set of closely related geochemical scenarios that are suggestive of flow and semi-batch chemistries. We now wish to report a multistep, uninterrupted synthesis of a key heterocycle (2-aminooxazole) en route to activated nucleotides starting from highly plausible, prebiotic feedstock molecules under conditions which mimic this scenario. Further consideration of the scenario has uncovered additional pertinent and novel aspects of prebiotic chemistry, which greatly enhance the efficiency and plausibility of the synthesis.

Photochemical reductive homologation of hydrogen cyanide using sulfite and ferrocyanide.

Photoredox cycling during UV irradiation of ferrocyanide ([FeII(CN)6]4-) in the presence of stoichiometric sulfite (SO32-) is shown to be an extremely effective way to drive the reductive homologation of hydrogen cyanide (HCN) to simple sugars and precursors of hydroxy acids and amino acids.

Common origins of RNA, protein and lipid precursors in a cyanosulfidic protometabolism.

A minimal cell can be thought of as comprising informational, compartment-forming and metabolic subsystems. To imagine the abiotic assembly of such an overall system, however, places great demands on hypothetical prebiotic chemistry. The perceived differences and incompatibilities between these subsystems have led to the widely held assumption that one or other subsystem must have preceded the others. Here we experimentally investigate the validity of this assumption by examining the assembly of various biomolecular building blocks from prebiotically plausible intermediates and one-carbon feedstock molecules. We show that precursors of ribonucleotides, amino acids and lipids can all be derived by the reductive homologation of hydrogen cyanide and some of its derivatives, and thus that all the cellular subsystems could have arisen simultaneously through common chemistry. The key reaction steps are driven by ultraviolet light, use hydrogen sulfide as the reductant and can be accelerated by Cu(I)-Cu(II) photoredox cycling.

Conversion of biosynthetic precursors of RNA to those of DNA by photoredox chemistry.

Soon after the origin of RNA-based life, depletion of prebiotically synthesised ribonucleotides would have driven the evolution of a biosynthetic pathway to these key building blocks. Ribozyme-catalysed nucleosidation-the key biosynthetic step-requires that ribose and the nucleobases are produced by abiotic chemistry and are relatively stable to the conditions of their synthesis. The most plausible prebiotic synthesis of sugars involves photoreduction of cyanohydrins by hydrogen sulphide in the presence of copper(I) cyanide, and we therefore subjected ribose to these conditions whereupon it was partially converted to 2-deoxyribose. Furthermore, a derivative of uracil is reduced under similar conditions to thymine. Thus, DNA biosynthetic precursors can be formed abiotically from those of RNA allowing for an early evolutionary transition to life based on RNA and DNA.

A synthetic approach to kingianin A based on biosynthetic speculation.

A synthetic approach towards the structurally complex dimer, kingianin A is reported. The strategy involved a cascade of complexity generating reactions, inspired through biosynthetic speculation. A concise protecting group free synthesis of the proposed monomeric precursor pre-kingianin A has been achieved using a tandem Stille cross-coupling reaction and electrocyclisation process. However, preliminary studies of the key dimerisation reaction have been conducted, which indicate that the process is not spontaneous, raising questions as to the origin of this complex natural product.

A silver-mediated one-step synthesis of oxazoles.

A silver-mediated one-step procedure to 2,4-disubstituted and 2,4,5-trisubstituted oxazoles has been developed. The method is complementary to existing technologies, yet provides advantages with regard to simplicity, efficiency, and performance. The silver product can be readily recycled, thus minimizing waste.

Tuneable DNA-based asymmetric catalysis using a G-quadruplex supramolecular assembly.

Described is the first modular construction of a G-quadruplex chiral catalyst. The key objective was to use G-quadruplex structures to act as chiral ligands that would allow access to either enantiomer of the product of a Diels-Alder reaction.

A click chemistry approach to C3 symmetric, G-quadruplex stabilising ligands.

Described is the structure-based design and synthesis of a series of tris-triazole G-quadruplex binding ligands utilising the copper catalysed azide-alkyne 'click' reaction. The results of G-quadruplex stabilisation by the ligands are reported and discussed.

An efficient entry to 1,2-benzisoxazoles via 1,3-dipolar cycloaddition of in situ generated nitrile oxides and benzyne.

An efficient protocol for the synthesis of a range of 1,2-benzisoxazoles using an improved 1,3-dipolar cycloaddition of nitrile oxides and benzyne is described. Key to the procedure is the in situ generation of the reactive nitrile oxide and benzyne reactants simultaneously.

Structure-based organic synthesis of a tricyclic N-malayamycin analogue.

The solid-state structure of crystalline malayamycin A reveals a urea substituent that bisects the plane of the chairlike tetrahydropyran subunit. On the basis of this topological feature, we synthesized a tricyclic N-nucleoside analogue in which an ethano bridge linked the urea NH group with the ring junction of the bicyclic tetrahydrofuropyran unit.

Room temperature palladium catalysed coupling of acyl chlorides with terminal alkynes.

Conditions are reported for the facile, high-yielding coupling of acyl chlorides with terminal alkynes in a reaction involving palladium and copper iodide; the reaction is tolerant of a wide variety of acyl chlorides and terminal alkynes and provides a convenient one-pot route to acetylenic ketones.

Indium mediated allylation of glyoxylate oxime ethers, esters and cyanoformates.

An indium mediated procedure has been developed for the allylation of activated O-functionalised oximes and nitriles as exemplified by a variety of glyoxylate derivatives. This method gives the corresponding free (or protected) amine in a one pot-process. The method is regiospecific and is carried out under remarkably mild conditions so that even oxime esters can be subjected to the typical reaction conditions.