Iron(II)-Catalyzed 1,2-Diamination of Styrenes Installing a Terminal NH2 Group Alongside Unprotected Amines.

1,2-Diamination of alkenes represents an attractive way to generate differentiated vicinal diamines, which are prevalent motifs in biologically active compounds and catalysts. However, existing methods are usually limited in scope and produce diamines where one or both nitrogens are protected, adding synthetic steps for deprotection and further N-functionalization to reach a desired target. Furthermore, the range of amino groups that can be introduced at the internal position is fairly limited. Here we describe a 1,2-diamination of styrenes that directly installs a free amino group at the terminal position and a wide variety of unprotected nitrogen nucleophiles (primary or secondary alkyl or aromatic amines, sulfoximines, N-heterocycles, and ammonia surrogate) at the internal position. Two complementary sets of conditions encompass electronically activated and deactivated styrenes with diverse substitution patterns and functional groups. Moreover, this strategy can be extended to the 1,2-aminothiolation of styrenes.

Difunctionalization Processes Enabled by Hexafluoroisopropanol.

In the past 5 years, hexafluoroisopropanol (HFIP) has been used as a unique solvent or additive to enable challenging transformations through substrate activation and stabilization of reactive intermediates. In this Review, we aim at describing difunctionalization processes which were unlocked when HFIP was involved. Specifically, we focus on cyclizations and additions to alkenes, alkynes, epoxides, and carbonyls that introduce a wide range of functional groups of interest.

A prebiotic Krebs cycle analog generates amino acids with H2 and NH3 over nickel.

Hydrogen (H2) has powered microbial metabolism for roughly 4 billion years. The recent discovery that it also fuels geochemical analogs of the most ancient biological carbon fixation pathway sheds light on the origin of metabolism. However, it remains unclear whether H2 can sustain more complex nonenzymatic reaction networks. Here, we show that H2 drives the nonenzymatic reductive amination of six biological ketoacids and glyoxylate to give the corresponding amino acids in good yields using ammonium concentrations ranging from 6 to 150 mM. Catalytic amounts of nickel or ground meteorites enable these reactions at 22°C and pH 8. The same conditions promote an H2-dependent ketoacid-forming reductive aldol chemistry that co-occurs with reductive amination, producing a continuous reaction network resembling amino acid synthesis in the metabolic core of ancient microbes. The results support the hypothesis that the earliest biochemical networks could have emerged without enzymes or RNA.

Rapid Access to Densely Functionalized Cyclopentenyl Sulfoximines through a Sc-Catalyzed Aza-Piancatelli Reaction.

Sulfoximines make up a class of compounds of growing interest for crop science and medicinal chemistry, but methods for directly incorporating them into complex molecular scaffolds are lacking. Here we report a scandium-catalyzed variant of the aza-Piancatelli cyclization that can directly incorporate sulfoximines as nucleophiles rather than the classical aniline substrates. Starting from 2-furylcarbinols and sulfoximines, the reaction provides direct access to 4-sulfoximinocyclopentenones, a new scaffold bearing cyclopentenone and sulfoximine motifs, both of interest for bioactive compounds.

A single phosphorylation mechanism in early metabolism - the case of phosphoenolpyruvate.

Phosphorylation is thought to be one of the fundamental reactions for the emergence of metabolism. Nearly all enzymatic phosphorylation reactions in the anabolic core of microbial metabolism act on carboxylates to give acyl phosphates, with a notable exception - the phosphorylation of pyruvate to phosphoenolpyruvate (PEP), which involves an enolate. We wondered whether an ancestral mechanism for the phosphorylation of pyruvate to PEP could also have involved carboxylate phosphorylation rather than the modern enzymatic form. The phosphorylation of pyruvate with P4O10 as a model phosphorylating agent was found to indeed occur via carboxylate phosphorylation, as verified by mechanistic studies using model substrates, time course experiments, liquid and solid-state NMR spectroscopy, and DFT calculations. The in situ generated acyl phosphate subsequently undergoes an intramolecular phosphoryl transfer to yield PEP. A single phosphorylation mechanism acting on carboxylates appears sufficient to initiate metabolic networks that include PEP, strengthening the case that metabolism emerged from self-organized chemistry.

Metal/ADP Complexes Promote Phosphorylation of Ribonucleotides.

Under enzyme catalysis, adenosine triphosphate (ATP) transfers a phosphoryl group to canonical ribonucleotide diphosphates (NDPs) to form ribonucleotide triphosphates (NTPs), the direct biosynthetic precursors to RNA. However, it remains unclear whether the phosphorylation of NDPs could have occurred in water before enzymes existed and why an adenosine derivative, rather than another canonical NTP, typically performs this function. Here, we show that adenosine diphosphate (ADP) in the presence of Fe3+ or Al3+ promotes phosphoryl transfer from acetyl phosphate to all canonical NDPs to produce their corresponding NTP in water at room temperature and in the absence of enzymes. No other NDPs were found to promote phosphorylation, giving insight into why adenosine derivatives specifically became used for this purpose in biology. The metal-ADP complexes also promote phosphoryl transfer to ribonucleoside monophosphates (NMPs) to form a mixture of the corresponding NDPs and NTPs, albeit less efficiently. This work represents a rare example in which a single nucleotide carries out a function critical to biology without enzymes. ADP-metal complexes may have played an important role in nucleotide phosphorylation in prebiotic chemistry.

Catalytic Synthesis of ß-(Hetero)arylethylamines: Modern Strategies and Advances.

ß-(Hetero)arylethylamines appear in a myriad of pharmaceuticals due to their broad spectrum of biological properties, making them prime candidates for drug discovery. Conventional methods for their preparation often require engineered substrates that limit the flexibility of the synthetic routes and the diversity of compounds that can be accessed. Consequently, methods that provide rapid and versatile access to those scaffolds remain limited. To overcome these challenges, synthetic chemists have designed innovative and modular strategies to access the ß-(hetero)arylethylamine motif, paving the way for their more extensive use in future pharmaceuticals. This review outlines recent progresses in the synthesis of (hetero)arylethylamines and emphasizes how these innovations have enabled new levels of molecular complexity, selectivity, and practicality.

Metal-Pyridoxal Cooperativity in Nonenzymatic Transamination.

Coenzymes are involved in ≥30% of enzymatic reactions and likely predate enzymes, going back to prebiotic chemistry. However, they are considered poor organocatalysts, and thus their pre-enzymatic function remains unclear. Since metal ions are known to catalyze metabolic reactions in the absence of enzymes, here we explore the influence of metal ions on coenzyme catalysis under conditions relevant to the origin of life (20-75 °C, pH 5-7.5). Specifically, Fe or Al, the two most abundant metals in the Earth's crust, were found to exhibit substantial cooperative effects in transamination reactions catalyzed by pyridoxal (PL), a coenzyme scaffold used by roughly 4% of all enzymes. At 75 °C and 7.5 mol % loading of PL/metal ion, Fe3+-PL was found to be 90-fold faster at catalyzing transamination than PL alone and 174-fold faster than Fe3+ alone, whereas Al3+-PL was 85-fold faster than PL alone and 38-fold faster than Al3+ alone. Under milder conditions, reactions catalyzed by Al3+-PL were >1000 times faster than those catalyzed by PL alone. Pyridoxal phosphate (PLP) exhibited similar behavior to PL. Experimental and theoretical mechanistic studies indicate that the rate-determining step in the PL-metal-catalyzed transamination is different from metal-free and biological PL-based catalysis. Metal coordination to PL lowers the pKa of the PL-metal complex by several units and slows the hydrolysis of imine intermediates by up to 259-fold. Coenzymes, specifically pyridoxal derivatives, could have exhibited useful catalytic function even before enzymes.

Solvent Polarity under Vibrational Strong Coupling.

Vibrational strong coupling (VSC) occurs when molecular vibrations hybridize with the modes of an optical cavity, an interaction mediated by vacuum fluctuations. VSC has been shown to influence the rates and selectivity of chemical reactions. However, a clear understanding of the mechanism at play remains elusive. Here, we show that VSC affects the polarity of solvents, which is a parameter well-known to influence reactivity. The strong solvatochromic response of Reichardt's dye (RD) was used to quantify the polarity of a series of alcohol solvents at visible wavelengths. We observed that, by simultaneously coupling the OH and CH vibrational bands of the alcohols, the absorption maximum of Reichardt's dye redshifted by up to ∼15.1 nm, corresponding to an energy change of 5.1 kJ·mol-1. With aliphatic alcohols, the magnitude of the absorption change of RD was observed to be related to the length of the alkyl chain, the molecular surface area, and the polarizability, indicating that dispersion forces are impacted by strong coupling. Therefore, we propose that dispersion interactions, which themselves originate from vacuum fluctuations, are impacted under strong coupling and are therefore critical to understanding how VSC influences chemistry.

Klebsiella, a Clever Survivor Presenting As Pyogenic Liver Abscess Years After Travel.

Klebsiella pneumoniae is a known cause of pyogenic liver abscess and has an increased prevalence in Southeast Asia. We present two cases of individuals with remote travel history to southeast Asia presenting with fevers, chills, and abdominal pain secondary to pyogenic liver abscess. Neither individual had a comorbid medical condition or history of prior hepato-biliary pathology that would predispose them to bacterial translocation and abscess formation. These patients were both successfully treated with percutaneous drainage and antibiotics. We present these cases to add to the growing body of literature surrounding hyper-mucoid strains of Klebsiella pneumonia causing a pyogenic liver abscess.

Synthesis of functionalised isochromans: epoxides as aldehyde surrogates in hexafluoroisopropanol.

The oxa-Pictet-Spengler reaction is arguably the most straightforward and modular way to construct the privileged isochroman motif, but its scope is largely limited to benzaldehyde derivatives and to electron-rich ß-phenylethanols that lack substitution along the aliphatic chain. Here we describe a variant of this reaction starting from an epoxide, rather than an aldehyde, that greatly expands the scope and rate of the reaction (<1 h, 20 °C). Besides facilitating the initial Meinwald rearrangement, the use of hexafluoroisopropanol (HFIP) as a solvent expands the electrophile scope to include partners equivalent to ketones, aliphatic aldehydes, and phenylacetyl aldehydes, and the nucleophile scope to include modestly electronically deactivated and highly substituted ß-phenylethanols. The products could be easily further derivatised in the same pot by subsequent ring-opening, reductions, and intra- and intermolecular Friedel-Crafts reactions, also in HFIP. Finally, owing to the high pharmacological relevance of the isochroman motif, the synthesis of drug analogues was demonstrated.

Ambient temperature CO2 fixation to pyruvate and subsequently to citramalate over iron and nickel nanoparticles.

The chemical reactions that formed the building blocks of life at origins required catalysts, whereby the nature of those catalysts influenced the type of products that accumulated. Recent investigations have shown that at 100 °C awaruite, a Ni3Fe alloy that naturally occurs in serpentinizing systems, is an efficient catalyst for CO2 conversion to formate, acetate, and pyruvate. These products are identical with the intermediates and products of the acetyl-CoA pathway, the most ancient CO2 fixation pathway and the backbone of carbon metabolism in H2-dependent autotrophic microbes. Here, we show that Ni3Fe nanoparticles prepared via the hard-templating method catalyze the conversion of H2 and CO2 to formate, acetate and pyruvate at 25 °C under 25 bar. Furthermore, the 13C-labeled pyruvate can be further converted to acetate, parapyruvate, and citramalate over Ni, Fe, and Ni3Fe nanoparticles at room temperature within one hour. These findings strongly suggest that awaruite can catalyze both the formation of citramalate, the C5 product of pyruvate condensation with acetyl-CoA in microbial carbon metabolism, from pyruvate and the formation of pyruvate from CO2 at very moderate reaction conditions without organic catalysts. These results align well with theories for an autotrophic origin of microbial metabolism under hydrothermal vent conditions.

Synthesis of Unprotected ß-Arylethylamines by Iron(II)-Catalyzed 1,2-Aminoarylation of Alkenes in Hexafluoroisopropanol.

ß-Arylethylamines are prevalent structural motifs in molecules exhibiting biological activity. Here we report a sequential one-pot protocol for the 1,2-aminoarylation of alkenes with hydroxylammonium triflate salts and (hetero)arenes. Unlike existing methods, this reaction provides a direct entry to unprotected ß-arylethylamines with remarkable functional group tolerance, allowing key drug-oriented functional groups to be installed in a two-step process. The use of hexafluoroisopropanol as a solvent in combination with an iron(II) catalyst proved essential to reaching high-value nitrogen-containing molecules.

Quantification of the hydride donor abilities of NADH, NADPH, and BH3CN- in water.

The nucleophilic reactivities of the hydride donors NADH, NADPH, and BH3CN- in water were quantified using kinetic measurements with benzhydrylium ions as reference electrophiles. All three hydride donors were found to possess almost identical nucleophilic reactivities, providing a potential explanation for why they are involved in similar transformations in biochemistry and organic synthesis, respectively.

Hydrogen Drives Part of the Reverse Krebs Cycle under Metal or Meteorite Catalysis.

Hydrogen (H2 ) is a geological source of reducing electrons that is thought to have powered the metabolism of the last universal common ancestor to all extant life, and that is still metabolized by various modern organisms. It has been suggested that H2 drove a geochemical analogue of some or all of the reverse Krebs cycle at the emergence of the metabolic network, catalyzed by metals, but this has yet to be demonstrated experimentally. Herein, we show that three consecutive steps of the reverse Krebs cycle, converting oxaloacetate into succinate, can be driven without enzymes and in one-pot by H2 as the reducing agent under mild conditions compatible with biological chemistry. Low catalytic amounts of nickel (10-20 mol %) or platinum group metals (0.1-1 mol %) or even small amounts of ground meteorites were found to promote the reductive chemistry at temperatures between 5 and 60 °C and over a wide pH range, including pH 7. These results lend additional support to the hypothesis that geologically produced hydrogen and metal catalysts could have initiated early metabolic networks.

Quantifying Reductive Amination in Nonenzymatic Amino Acid Synthesis.

Amino acid biosynthesis initiates with the reductive amination of α-ketoglutarate with ammonia to produce glutamate. However, the other α-keto acids derived from the glyoxylate and Krebs cycles are converted into amino acids by transamination, rather than by reductive amination. Why is only one amino acid synthesized by reductive amination and not the others? To explore this question, we quantified the inherent reactivities of keto acids in nonenzymatic reduction and reductive amination by using BH3 CN- as a model nucleophile. Biological α-keto acids were found to show pronounced nonenzymatic reactivity differences for the formation of amino acids (α-ketoglutarate

Hydroarylation of enamides enabled by HFIP via a hexafluoroisopropyl ether as iminium reservoir.

Here we describe that HFIP greatly expands the scope with respect to both reaction partners of the Brønsted acid-catalyzed hydroarylation of enamides. The reaction is fast and practical and can be performed on the gram scale. A hexafluoroisopropyl ether intermediate was isolated from the reaction mixture and was shown to convert to the product when resubmitted to the reaction conditions. Extensive kinetic studies and computations reveal that the hexafluoroisopropyl ether is formed rapidly and serves as a slow-release reservoir for the key cationic intermediate, preventing the oligomerization of the substrate under the reaction conditions. Given the relatively low electrophilicity of the cationic intermediates in the present study, it seems likely that HFIP also actively participates in other reactions involving more electrophilic carbocations.

Bringing inanimate matter to lifeTransformer: The Deep Chemistry of Life and Death Nick Lane Norton, 2022. 400 pp.

A biochemist probes the origins and vital nature of the Krebs cycle.

A Nonenzymatic Analog of Pyrimidine Nucleobase Biosynthesis.

Metabolic theories for the origin of life posit that inorganic catalysts enabled self-organized chemical precursors to the pathways of metabolism, including those that make genetic molecules. Recently, experiments showing nonenzymatic versions of a number of core metabolic pathways have started to support this idea. However, experimental demonstrations of nonenzymatic reaction sequences along the de novo ribonucleotide biosynthesis pathways are limited. Here we show that all three reactions of pyrimidine nucleobase biosynthesis that convert aspartate to orotate proceed at 60 °C without photochemistry under aqueous conditions in the presence of metals such as Cu2+ and Mn4+ . Combining reactions into one-pot variants is also possible. Life may not have invented pyrimidine nucleobase biosynthesis from scratch, but simply refined existing nonenzymatic reaction channels. This work is a first step towards uniting metabolic theories of life's origin with those centered around genetic molecules.

Mechanistic Insight into Metal Ion-Catalyzed Transamination.

Several classes of biological reactions that are mediated by an enzyme and a co-factor can occur, to a slower extent, not only without the enzyme but even without the co-factor, under catalysis by metal ions. This observation has led to the proposal that metabolic pathways progressively evolved from using inorganic catalysts to using organocatalysts of increasing complexity. Transamination, the biological process by which ammonia is transferred between amino acids and α-keto acids, has a mechanism that has been well studied under enzyme/co-factor catalysis and under co-factor catalysis, but the metal ion-catalyzed variant was generally studied mostly at high temperatures (70-100 °C), and the details of its mechanism remained unclear. Here, we investigate which metal ions catalyze transamination under conditions relevant to biology (pH 7, 20-50 °C) and study the mechanism in detail. Cu2+, Ni2+, Co2+, and V5+ were identified as the most active metal ions under these constraints. Kinetic, stereochemical, and computational studies illuminate the mechanism of the reaction. Cu2+ and Co2+ are found to predominantly speed up the reaction by stabilizing a key imine intermediate. V5+ is found to accelerate the reaction by increasing the acidity of the bound imine. Ni2+ is found to do both to a limited extent. These results show that direct metal ion-catalyzed amino group transfer is highly favored even in the absence of co-factors or protein catalysts under biologically compatible reaction conditions.