Direct formation of amide/peptide bonds from carboxylic acids: no traditional coupling reagents, 1-pot, and green.

Technology for generating especially important amide and peptide bonds from carboxylic acids and amines that avoids traditional coupling reagents is described. The 1-pot processes developed rely on thioester formation, neat, using a simple dithiocarbamate, and are safe and green, and rely on Nature-inspired thioesters that are then converted to the targeted functionality.

Introducing Savie: A Biodegradable Surfactant Enabling Chemo- and Biocatalysis and Related Reactions in Recyclable Water.

Savie is a biodegradable surfactant derived from vitamin E and polysarcosine (PSar) developed for use in organic synthesis in recyclable water. This includes homogeneous catalysis (including examples employing only ppm levels of catalyst), heterogeneous catalysis, and biocatalytic transformations, including a multistep chemoenzymatic sequence. Use of Savie frequently leads to significantly higher yields than do conventional surfactants, while obviating the need for waste-generating organic solvents.

A Plausible Prebiotic Path to Nucleosides: Ribosides and Related Aldosides Generated from Ribulose, Fructose, and Similar Abiotic Precursors.

The prebiotic origins of ribose, nucleosides, and eventually RNA are enduring questions whose answers are central to the RNA world hypothesis. The abiotic synthesis of sugars was first demonstrated over a century ago, but no known prebiotic reaction produces ribose (an aldose sugar) selectively and in good yield. In contrast, ribulose, and fructose (ketose sugars) and other monosaccharides are formed in high yield by several robust abiotic reactions. It is reported here that ketose sugars - both ketopentoses and ketohexoes - serve as precursors for the formation of ribosides and other aldosides, as demonstrated by glycoside-forming reactions involving barbituric acid, a plausibly prebiotic nucleobase. Moreover, a one-pot reaction of glyceraldehyde and barbituric acid was discovered which under mild conditions, and without special minerals or other catalysts, results in the formation of glycosides. These results reveal that an exclusive or high-yielding generation of free ribose was not required for its incorporation into processes that provided the foundations for life.

A Shared Prebiotic Formation of Neopterins and Guanine Nucleosides from Pyrimidine Bases.

Invited for the cover of this issue are the groups of César Menor-Salván, Facundo Fernández and Nicholas V. Hud at the University of Alcala and the Georgia Institute of Technology. The image depicts the authors contemplating the origin of pterins and guanosine nucleosides from a common precursor, with the art-gallery setting embodying their feeling that the common synthetic pathways of these molecules in both the prebiotic world and in biochemistry is a natural work of (chemical) art. Read the full text of the article at 10.1002/chem.202200714.

A Shared Prebiotic Formation of Neopterins and Guanine Nucleosides from Pyrimidine Bases.

The prebiotic origins of biopolymers and metabolic co-factors are key questions in Origins of Life studies. In a simple warm-little-pond model, using a drying phase to produce a urea-enriched solution, we present a prebiotic synthetic path for the simultaneous formation of neopterins and tetrahydroneopterins, along with purine nucleosides. We show that, in the presence of ribose and in a formylating environment consisting of urea, ammonium formate, and water (UAFW), the formation of neopterins from pyrimidine precursors is robust, while the simultaneous formation of guanosine requires a significantly higher ribose concentration. Furthermore, these reactions provide a tetrahydropterin-pterin redox pair. This model suggests a prebiotic link in the origin of purine nucleosides and pterin cofactors that provides a possible deep prebiotic temporal connection for the emergence of nucleic acids and metabolic cofactors.

Depsipeptide Nucleic Acids: Prebiotic Formation, Oligomerization, and Self-Assembly of a New Proto-Nucleic Acid Candidate.

The mechanism by which informational polymers first formed on the early earth is currently unknown. The RNA world hypothesis implies that RNA oligomers were produced prebiotically, before the emergence of enzymes, but the demonstration of such a process remains challenging. Alternatively, RNA may have been preceded by an earlier ancestral polymer, or proto-RNA, that had a greater propensity for self-assembly than RNA, with the eventual transition to functionally superior RNA being the result of chemical or biological evolution. We report a new class of nucleic acid analog, depsipeptide nucleic acid (DepsiPNA), which displays several properties that are attractive as a candidate for proto-RNA. The monomers of depsipeptide nucleic acids can form under plausibly prebiotic conditions. These monomers oligomerize spontaneously when dried from aqueous solutions to form nucleobase-functionalized depsipeptides. Once formed, these DepsiPNA oligomers are capable of complementary self-assembly and are resistant to hydrolysis in the assembled state. These results suggest that the initial formation of primitive, self-assembling, informational polymers on the early earth may have been relatively facile if the constraints of an RNA-first scenario are relaxed.

Copper-Catalyzed Asymmetric Reductions of Aryl/Heteroaryl Ketones under Mild Aqueous Micellar Conditions.

Enantioselective syntheses of nonracemic secondary alcohols have been achieved in an aqueous micellar medium via copper-catalyzed (Cu(OAc)2·H2O/(R)-3,4,5-MeO-MeO-BIPHEP) reduction of aryl/heteroaryl ketones. This methodology serves as a green protocol to access enantio-enriched alcohols under mild conditions (0-22 °C) using a base metal catalyst, together with an inexpensive, innocuous, and convenient stoichiometric hydride source (PMHS). The secondary alcohol products are formed in good to excellent yields with ee values greater than 90%.

Conversion of Unprotected Aldose Sugars to Polyhydroxyalkyl and C-Glycosyl Furans via Zirconium Catalysis.

An efficient, zirconium-catalyzed conversion of unprotected aldose sugars with acetylacetone to polyhydroxyalkyl furans or C-glycosylfurans is reported. The furan products are formed in up to 93% yield using 5-10 mol % ZrCl4. Pentoses are readily converted at room temperature, while hexoses and their oligosaccharides require mild heating (i.e., 50 °C). Efficient conversions of glycolaldehyde, glyceraldehyde, erythrose, a heptose, and glucosamine are also demonstrated. This approach outpaces each of the previous Lewis acid-catalyzed methods in at least one the following ways: (i) lower catalyst loadings; (ii) reduced reaction temperatures; (iii) shorter reaction times; (iv) equimolar substrate stoichiometry; (v) expanded sugar scope; (vi) higher selectivities; and (vii) the use of an Earth-abundant Zr catalyst.

Prebiotic Origin of Pre-RNA Building Blocks in a Urea "Warm Little Pond" Scenario.

Urea appears to be a key intermediate of important prebiotic synthetic pathways. Concentrated pools of urea likely existed on the surface of the early Earth, as urea is synthesized in significant quantities from hydrogen cyanide or cyanamide (widely accepted prebiotic molecules), it has extremely high water solubility, and it can concentrate to form eutectics from aqueous solutions. We propose a model for the origin of a variety of canonical and non-canonical nucleobases, including some known to form supramolecular assemblies that contain Watson-Crick-like base pairs.The dual nucleophilic-electrophilic character of urea makes it an ideal precursor for the formation of nitrogenous heterocycles. We propose a model for the origin of a variety of canonical and noncanonical nucleobases, including some known to form supramolecular assemblies that contain Watson-Crick-like base pairs. These reactions involve urea condensation with other prebiotic molecules (e. g., malonic acid) that could be driven by environmental cycles (e. g., freezing/thawing, drying/wetting). The resulting heterocycle assemblies are compatible with the formation of nucleosides and, possibly, the chemical evolution of molecular precursors to RNA. We show that urea eutectics at moderate temperature represent a robust prebiotic source of nitrogenous heterocycles. The simplicity of these pathways, and their independence from specific or rare geological events, support the idea of urea being of fundamental importance to the prebiotic chemistry that gave rise to life on Earth.

Prebiotic Syntheses of Noncanonical Nucleosides and Nucleotides.

The origin of nucleotides is a major question in origins-of-life research. Given the central importance of RNA in biology and the influential RNA World hypothesis, a great deal of this research has focused on finding possible prebiotic syntheses of the four canonical nucleotides of coding RNA. However, the use of nucleotides in other roles across the tree of life might be evidence that nucleotides have been used in noncoding roles for even longer than RNA has been used as a genetic polymer. Likewise, it is possible that early life utilized nucleotides other than the extant nucleotides as the monomers of informational polymers. Therefore, finding plausible prebiotic syntheses of potentially ancestral noncanonical nucleotides may be of great importance for understanding the origins and early evolution of life. Experimental investigations into abiotic noncanonical nucleotide synthesis reveal that many noncanonical nucleotides and related glycosides are formed much more easily than the canonical nucleotides. An analysis of the mechanisms by which nucleosides and nucleotides form in the solution phase or in drying-heating reactions from pre-existing sugars and heterocycles suggests that a wide variety of noncanonical nucleotides and related glycosides would have been present on the prebiotic Earth, if any such molecules were present.

Glycosylation of a model proto-RNA nucleobase with non-ribose sugars: implications for the prebiotic synthesis of nucleosides.

The emergence of nucleosides is an important, but poorly understood, element of the origins of life. We show that 2,4,6-triaminopyrimidine (TAP), a possible ancestral nucleobase of RNA, is glycosylated in water by non-ribose sugars in yields comparable to those previously reported for its reaction with ribose. The various sugars surveyed include ketoses and aldoses; tetroses, pentoses, and hexoses and are neutral, anionic, or cationic. Though they vary greatly in structure and properties, the data show that all sugars tested form glycosides with TAP. The structures of the eight TAP glycosides formed with glucose and two of its derivatives, glucose-6-phosphate and N-acetylglucosamine, were found to be ß-pyranosides with the glycosylation site on TAP varying with sugar identity. Our results suggest that prebiotic nucleoside formation would not have been restricted to ribose if ancestral RNA (or proto-RNA) utilized TAP and/or other proto-nucleobases with similar reactivities, and that the ability to form higher-order structures may have influenced proto-RNA monomer selection.

Spontaneous formation and base pairing of plausible prebiotic nucleotides in water.

The RNA World hypothesis presupposes that abiotic reactions originally produced nucleotides, the monomers of RNA and universal constituents of metabolism. However, compatible prebiotic reactions for the synthesis of complementary (that is, base pairing) nucleotides and mechanisms for their mutual selection within a complex chemical environment have not been reported. Here we show that two plausible prebiotic heterocycles, melamine and barbituric acid, form glycosidic linkages with ribose and ribose-5-phosphate in water to produce nucleosides and nucleotides in good yields. Even without purification, these nucleotides base pair in aqueous solution to create linear supramolecular assemblies containing thousands of ordered nucleotides. Nucleotide anomerization and supramolecular assemblies favour the biologically relevant ß-anomer form of these ribonucleotides, revealing abiotic mechanisms by which nucleotide structure and configuration could have been originally favoured. These findings indicate that nucleotide formation and selection may have been robust processes on the prebiotic Earth, if other nucleobases preceded those of extant life.