Integrated Synthesis of Nucleotide and Nucleosides Directed by Amino Acids

Research on the origin of nucleic acids and proteins has been approached by either multi-step synthesis or simple one-pot reactions, but exploration of their prebiotic chemistry is normally done separately. However, if nucleotides and amino acids co-existed on early Earth, their mutual interactions and reactivity should be considered in exploring the emergence of complex chemical systems that can ultimately evolve. To explore this idea, we set out to investigate nucleotide/nucleoside formation by a simple dehydration reaction of the constituent building blocks (sugar, phosphate, and nucleobase) in the presence of amino acids (i.e. glycine, arginine, glutamic acid, threonine, methionine, phenylalanine and tryptophan). Herein, we report the first example of simultaneous formation of glycosidic bonds between ribose, purines, and pyrimidines under mild conditions without a catalyst or activated reagents, as well as nucleobase exchange. We observed not only the simultaneous formation of nucleotide and nucleoside isomers from several nucleobases, but also the selection of distribution of glycosylation products when glycine was present. This work shows how reaction networks of nucleotides and amino acids should be considered when exploring the emergence of catalytic networks in the context of molecular evolution.

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A de novo Synthesis of Oxindoles from Cyclohexanone-Derived γ-Keto-ester Acceptors Using a Desaturative Amination–Cyclization Approach

Synthesis ◽

10.1055/a-1538-8429 ◽

2021 ◽

Author(s):

Henry P. Caldora ◽

Sebastian Govaerts ◽

Shashikant U. Dighe ◽

Oliver J. Turner ◽

Daniele Leonori

Keyword(s):

Amino Acids ◽

Primary Amine ◽

De Novo ◽

Building Blocks ◽

De Novo Synthesis ◽

Keto Ester ◽

Mild Conditions ◽

Blockbuster Drug

Here we report a desaturative approach for oxindole synthesis. This method uses simple γ-ester-containing cyclohexanones and primary amine building blocks as coupling partners. A dual photoredox–cobalt manifold is used to generate a secondary aniline that, upon heating, cyclizes with the pendent ester functionality. The process operates under mild conditions and was applied to the modification of several amino acids, the blockbuster drug mexiletine, as well as the formation of dihydroquinolinones.

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One-Pot Synthesis of α-Substituted Acrylates

SynOpen ◽

10.1055/s-0037-1610357 ◽

2018 ◽

Vol 02 (02) ◽

pp. 0161-0167

Author(s):

Magdalini Matziari ◽

Yixin Xie

Keyword(s):

Amino Acids ◽

Reaction Times ◽

Synthetic Method ◽

One Pot ◽

Biologically Relevant ◽

Mild Conditions ◽

One Pot Synthesis ◽

Acrylic Esters ◽

Natural Amino Acids ◽

Work Up

A simple and efficient synthetic method towards α-substituted acrylic esters has been developed using the Horner–Wadsworth–Emmons (HWE) reaction with HCHO after alkylation of phosphonoacetates in a one-pot reaction. This method allows the smooth introduction of various side-chains, such as natural amino acids and other biologically relevant substituents. The use of mild conditions, inexpensive reagents, short reaction times and simple work-up and purification steps provides an effective and general alternative to cumbersome multistep and low-yielding procedures described to date.

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Selected Research Topics of the Dondoni Group over the Last Two Decades (2000–2020)

Synlett ◽

10.1055/s-0040-1707107 ◽

2020 ◽

Vol 31 (14) ◽

pp. 1361-1371 ◽

Cited By ~ 1

Author(s):

Alessandro Dondoni

Keyword(s):

Amino Acids ◽

Bioorganic Chemistry ◽

Multicomponent Reactions ◽

Building Blocks ◽

Synthetic Methods ◽

Research Topics ◽

Main Target ◽

Sulfur Fluoride ◽

Primary Rule ◽

Selection Of

From a selection of research topics carried out in our laboratory during the last twenty years it becomes apparent that our main target was the discovery of new or improved synthetic methods together with new properties. Our efforts were made with the aim of being of some utility to other fields of research, with particular emphasis to glycobiology and heterocyle-based bioorganic chemistry. We performed new chemistry mainly in the field of carbohydrate manipulations taking as a primary rule the simplicity and efficiency manners. Toward this end, modern synthetic tools and approaches were employed such as heterocyle-based transformations, multicomponent reactions, organocatalysis, click azide–alkyne cycloadditions, reactions in ionic liquids, click photoinduced thiol-ene coupling, and click sulfur–fluoride exchange chemistry. With these potent methodologies in hand, the syntheses of carbohydrate containing amino acids up to proteins glycosylation were performed.1 Heterocyclic Glycoconjugates and Amino Acids2 Triazole-Linked Oligonucleotides: Application of Click CuAAC3 Non-Natural Glycosyl Amino Acids4 Non-Natural Oligosaccharides5 Calixarene-Based Glycoclusters6 Carbohydrate-Based Building Blocks7 Homoazasugars and Aza-C-disaccharides8 Synthesis of Glycodendrimers9 Peptide and Protein Glycoconjugates10 Conclusions

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A physicochemical orthophosphate cycle via a kinetically stable thermodynamically activated intermediate enables mild prebiotic phosphorylations

Nature Communications ◽

10.1038/s41467-021-25555-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Oliver R. Maguire ◽

Iris B. A. Smokers ◽

Wilhelm T. S. Huck

Keyword(s):

Aqueous Solution ◽

Organic Compounds ◽

Prebiotic Chemistry ◽

Building Blocks ◽

General Strategy ◽

Scarce Resources ◽

Mild Conditions ◽

Phosphorylated Compounds ◽

Nucleotide Triphosphates ◽

Fundamental Challenge

AbstractThe incorporation of orthophosphate from scarce geochemical sources into the organic compounds essential for life under mild conditions is a fundamental challenge for prebiotic chemistry. Here we report a prebiotic system capable of overcoming this challenge by taking inspiration from extant life’s recycling of orthophosphate via its conversion into kinetically stable thermodynamically activated (KSTA) nucleotide triphosphates (e.g. ATP). We separate the activation of orthophosphate from its transfer to organic compounds by, crucially, first accumulating a KSTA phosphoramidate. We use cyanate to activate orthophosphate in aqueous solution under mild conditions and then react it with imidazole to accumulate the KSTA imidazole phosphate. In a paste, imidazole phosphate phosphorylates all the essential building blocks of life. Integration of this chemistry into a wet/dry cycle enables the continuous recycling of orthophosphate and the accretion of phosphorylated compounds. This system functions even at low reagent concentrations due to solutes concentrating during evaporation. Our system demonstrates a general strategy for how to maximise the usage of scarce resources based upon cycles which accumulate and then release activated intermediates.

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Fluoride Migration Catalysis Enables Simple, Stereoselective, and Iterative Glycosylation

10.26434/chemrxiv.9735785.v1 ◽

2019 ◽

Author(s):

Girish Sati ◽

Joshua Martin ◽

Yishu Xu ◽

Tanmay Malakar ◽

Paul M. Zimmerman ◽

...

Keyword(s):

Room Temperature ◽

Building Blocks ◽

Silyl Ether ◽

One Pot ◽

Glycoside Synthesis ◽

Glycosidic Bonds ◽

Stable Forms

Challenges in the assembly of glycosidic bonds pose a bottleneck in enabling the remarkable promise of advances in the glycosciences. We report a strategy that applies unique features of electrophilic boron catalysts in addressing current limitations of methods in glycoside synthesis. The strategy utilizes glycosyl fluoride donors and silyl ether acceptors while tolerating the Lewis basic environment found in carbohydrates. The method allows a simple setup at room temperature while utilizing catalyst loadings as low as 0.5 mol %, and air- and moisture stable forms of the catalyst are found to be effective. These characteristics enable a wide array of glycosylation patterns to be accessed, including all four C1-C2 stereorelationships, and the method allows one-pot, iterative glycosylations to generate oligosaccharides directly from monosaccharide building blocks.

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One-Pot Reductive Acetylation of Aldehydes using 1-Hydrosilatrane in Acetic Acid

SynOpen ◽

10.1055/s-0037-1611697 ◽

2019 ◽

Vol 03 (01) ◽

pp. 1-3 ◽

Cited By ~ 2

Author(s):

Reuben James ◽

Sharon Herlugson ◽

Sami Varjosaari ◽

Vladislav Skrypai ◽

Zainab Shakeel ◽

...

Keyword(s):

Acetic Acid ◽

Organic Synthesis ◽

Functional Group ◽

Building Blocks ◽

Flash Chromatography ◽

Primary Alcohols ◽

Facile Synthesis ◽

One Pot ◽

Aryl Aldehydes ◽

Mild Conditions

A one-pot, direct reductive acetylation of aldehydes was achieved under mild conditions using 1-hydrosilatrane as a safe and easily accessible catalyst. Described herein is a facile synthesis that produces acylated primary alcohols that can serve as valuable building blocks for organic synthesis. The method has good functional group tolerance and works for a range of aryl aldehydes, with the notable exception of electron-rich arenes. A library of esters was isolated by flash chromatography in yields as high as 92%.

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One-Pot Biocatalytic Preparation of Enantiopure Unusual α-Amino Acids from α-Hydroxy Acids via a Hydrogen-Borrowing Dual-Enzyme Cascade

Catalysts ◽

10.3390/catal10121470 ◽

2020 ◽

Vol 10 (12) ◽

pp. 1470

Author(s):

Fei Liu ◽

Junping Zhou ◽

Meijuan Xu ◽

Taowei Yang ◽

Minglong Shao ◽

...

Keyword(s):

Amino Acids ◽

Mandelic Acid ◽

Catalytic Efficiency ◽

Lactobacillus Brevis ◽

Building Blocks ◽

Hydroxy Acids ◽

One Pot ◽

Diverse Range ◽

Enzyme Cascade ◽

Keto Acids

Unusual α-amino acids (UAAs) are important fundamental building blocks and play a key role in medicinal chemistry. Here, we constructed a hydrogen-borrowing dual-enzyme cascade for efficient synthesis of UAAs from α-hydroxy acids (α-HAs). D-mandelate dehydrogenase from Lactobacillus brevis (LbMDH) was screened for the catalysis of α-HAs to α-keto acids but with low activity towards aliphatic α-HAs. Therefore, we rational engineered LbMDH to improve its activity towards aliphatic α-HAs. The substitution of residue Leu243 located in the substrate entrance channel with nonpolar amino acids like Met, Trp, and Ile significantly influenced the enzyme activity towards different α-HAs. Compared with wild type (WT), variant L243W showed 103 U/mg activity towards D-α-hydroxybutyric acid, 1.7 times of the WT’s 60.2 U/mg, while its activity towards D-mandelic acid decreased. Variant L243M showed 2.3 times activity towards D-mandelic acid compared to WT, and its half-life at 40 °C increased to 150.2 h comparing with 98.5 h of WT. By combining LbMDH with L-leucine dehydrogenase from Bacillus cereus, the synthesis of structurally diverse range of UAAs from α-HAs was constructed. We achieved 90.7% conversion for L-phenylglycine production and 66.7% conversion for L-α-aminobutyric acid production. This redox self-sufficient cascade provided high catalytic efficiency and generated pure products.

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4. The chemistry of life

Organic Chemistry: A Very Short Introduction ◽

10.1093/actrade/9780198759775.003.0004 ◽

2017 ◽

pp. 50-70

Author(s):

Graham Patrick

Keyword(s):

Amino Acids ◽

Natural Products ◽

Nucleic Acids ◽

Chemical Evolution ◽

Prebiotic Chemistry ◽

Building Blocks ◽

Complex Structures ◽

Dna And Rna ◽

Molecular Building Blocks ◽

Commercial Applications

From very simple molecular building blocks, life has created an astonishing diversity of molecules, some of which are extremely complex structures that prove very difficult to synthesize in a laboratory. ‘The chemistry of life’ describes how proteins, which serve a myriad of purposes, and nucleic acids, another form of biopolymer, are constructed from molecular building blocks called amino acids and nucleotides respectively. It goes on to explain the polymerization processes involved in the biosynthesis of many other natural products; the functions of proteins, DNA, and RNA; and the different theories proposed to explain chemical evolution, or prebiotic chemistry. Enzymes and nucleic acids are increasingly being used in commercial applications.

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A Photoredox-Catalyzed Four Component Reaction for the Atom-Efficient Synthesis of Complex Secondary Amines

10.26434/chemrxiv.11811927.v1 ◽

2020 ◽

Author(s):

Lisa Marie Kammer ◽

Matthias Krumb ◽

Benjamin Spitzbarth ◽

Benjamin Lipp ◽

Jonas Kühlborn ◽

...

Keyword(s):

Secondary Amines ◽

Efficient Synthesis ◽

One Pot ◽

Simultaneous Formation ◽

Mild Conditions ◽

Simple Protocol ◽

Reaction Proceeds ◽

Styrene Derivatives ◽

The One ◽

Single Bonds

The one-pot sulfonylation/aminoalkylation of styrene derivatives furnishing highly substituted gamma-sulfonylamines was accomplished through a photoredox-catalyzed four-component reaction. Apart from one molecule of water and the sodium counterion of the sulfinate, all atoms of the starting materials are transferred to the final product, rendering this process highly atom-efficient. The operationally simple protocol allows for the simultaneous formation of three new single bonds (C–S, C–N, and C–C) and therefore grants rapid access to structurally diverse products. The reaction proceeds under mild conditions in aqueous acetonitrile and shows a broad scope, including natural products and drug-like molecules.

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