Phosphorimidazolide

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General chemical structure of a phosphorimidazolide reagent Phosphorimidazolide.svg
General chemical structure of a phosphorimidazolide reagent

A phosphorimidazolide is a chemical compound in which a phosphoryl mono-ester is covalently bound to a nitrogen atom in an imidazole ring. They are a type of phosphoramidate. These phosphorus (V) compounds are encountered as reagents used for making new phosphoanhydride bonds with phosphate mono-esters, and as reactive intermediates in phosphoryl transfer reactions in some enzyme-catalyzed transformations. They are also being studied as critical chemical intermediates for the polymerization of nucleotides in pre-biotic settings. [1] They are sometimes referred to as phosphorimidazolidates, imidazole-activated phosphoryl groups, and P-imidazolides.

Contents

Role in Oligonucleotide formation

Phosphorimidazolides have been investigated for their mechanistic role in abiogenesis (the natural process by which life arose from non-living matter). Specifically, they have been proposed as the active electrophilic species which may have mediated the formation of inter-nucleotide phosphodiester bonds, thereby enabling template-directed oligonucleotide replication before the advent of enzymes. Phosphorimidazolides were originally proposed as mediators of this process by Leslie Orgel in 1968. [2] Early studies showed that divalent metal cations such as Mg2+, Zn2+, and Pb2+ and a complementary template were required for the formation of short oligonucleotides, although nucleotides exhibited 5'-2' connectivity instead of 5'-3' connectivity of present-day life forms. It was also shown that Montmorillonite clay could provide a surface for phosphorimidazolide-mediated oligonucleotide formation with lengths of 20-50 bases. [3]

The research group of Jack W. Szostak has continued to investigate the role of phosphorimidazolides in pre-biotic nucleotide polymerization. The group has investigated a number of imidazole derivatives in the search for chemical moieties which provide longer oligonucleotides necessary for propagating genetic information. [1] Significantly, they discovered that phosphorimidazolides promote template-directed oligonucleotide formation via imidazolium-bridged dinucleotide intermediates. [4]

John D. Sutherland and colleagues have proposed that phosphorimidazolides may have formed in the chemical environment of early Earth via the activation of ribonucleotide phosphates by methyl isocyanaide and acetaldehyde followed by substitution with imidazole. [5]

Phosphoanhydride Bond formation

While early studies of phosphorimidazolide derivatives of nucleotides found that oligonucleotides could form in the presence of a complementary template, pyrophosphate-linked dimers formed predominantly in the absence of a template. [2] This proclivity for forming new phosphoanhydride bonds has been used in the synthesis of several pyrophosphate-containing organic compounds. A variety of modified nucleotide triphosphates were synthesized using a cyanoethyl-protected phosphorimidazolide reagent. [6] Phosphoanhydride bond forming reactions were found to proceed most rapidly in amide-based organic solvents such as N,N-dimethylformamide and particularly in N,N-dimethylacetamide with Mg2+ or Zn2+ catalysts. [7]

Synthesis

Phosphorimidazolide reagents have been synthesized from phosphate mono-esters.

In one method, a phosphate mono-ester is dissolved in anhydrous pyridine [8] or N,N-dimethylformamide (DMF) and activated using triphenylphosphine (PPh3) and 2,2’-Dithiodipyridine (2,2’-DTDP) in the presence of triethylamine (TEA) base and excess imidazole. In another method using fewer reagents, a phosphate mono-ester is dissolved in DMF and carbonyldiimidazole (CDI) is used to both remove an oxygen atom from the phosphate group and supply the imidazole substituent. The product of either reaction may be collected by precipitation using acetonitrile or acetone as antisolvent with sodium or lithium perchlorate to supply the sodium or lithium salt of the phosphorimidazolide respectively. Alternatively, the phosphorimidazolide may be isolated by reverse-phase flash column chromatography with TEAB buffer and acetonitrile. [9]

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<span class="mw-page-title-main">Amide</span> Organic compounds of the form RC(=O)NR′R″

In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula R−C(=O)−NR′R″, where R, R', and R″ represent any group, typically organyl groups or hydrogen atoms. The amide group is called a peptide bond when it is part of the main chain of a protein, and an isopeptide bond when it occurs in a side chain, as in asparagine and glutamine. It can be viewed as a derivative of a carboxylic acid with the hydroxyl group replaced by an amino group ; or, equivalently, an acyl (alkanoyl) group joined to an amino group.

<span class="mw-page-title-main">Nucleotide</span> Biological molecules constituting nucleic acids

Nucleotides are organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules within all life-forms on Earth. Nucleotides are obtained in the diet and are also synthesized from common nutrients by the liver.

The iron–sulfur world hypothesis is a set of proposals for the origin of life and the early evolution of life advanced in a series of articles between 1988 and 1992 by Günter Wächtershäuser, a Munich patent lawyer with a degree in chemistry, who had been encouraged and supported by philosopher Karl R. Popper to publish his ideas. The hypothesis proposes that early life may have formed on the surface of iron sulfide minerals, hence the name. It was developed by retrodiction from extant biochemistry in conjunction with chemical experiments.

<span class="mw-page-title-main">Guanosine diphosphate</span> Chemical compound

Guanosine diphosphate, abbreviated GDP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside guanosine. GDP consists of a pyrophosphate group, a pentose sugar ribose, and the nucleobase guanine.

<span class="mw-page-title-main">Protecting group</span> Group of atoms introduced into a compound to prevent subsequent reactions

A protecting group or protective group is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep organic synthesis.

<span class="mw-page-title-main">Leslie Orgel</span> British chemist (1927–2007)

Leslie Eleazer Orgel FRS was a British chemist and member of the National Academy of Sciences, known for his theories on the origin of life.

In organic chemistry, an acyl chloride is an organic compound with the functional group −C(=O)Cl. Their formula is usually written R−COCl, where R is a side chain. They are reactive derivatives of carboxylic acids. A specific example of an acyl chloride is acetyl chloride, CH3COCl. Acyl chlorides are the most important subset of acyl halides.

Dimethylformamide, DMF is an organic compound with the chemical formula HCON(CH3)2. Its structure is HC(=O)−N(−CH3)2. Commonly abbreviated as DMF, this colourless liquid is miscible with water and the majority of organic liquids. DMF is a common solvent for chemical reactions. Dimethylformamide is odorless, but technical-grade or degraded samples often have a fishy smell due to impurity of dimethylamine. Dimethylamine degradation impurities can be removed by sparging samples with an inert gas such as argon or by sonicating the samples under reduced pressure. As its name indicates, it is structurally related to formamide, having two methyl groups in the place of the two hydrogens. DMF is a polar (hydrophilic) aprotic solvent with a high boiling point. It facilitates reactions that follow polar mechanisms, such as SN2 reactions.

<span class="mw-page-title-main">Carbonyldiimidazole</span> Chemical compound

1,1'-Carbonyldiimidazole (CDI) is an organic compound with the molecular formula (C3H3N2)2CO. It is a white crystalline solid. It is often used for the coupling of amino acids for peptide synthesis and as a reagent in organic synthesis.

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Threose nucleic acid (TNA) is an artificial genetic polymer in which the natural five-carbon ribose sugar found in RNA has been replaced by an unnatural four-carbon threose sugar. Invented by Albert Eschenmoser as part of his quest to explore the chemical etiology of RNA, TNA has become an important synthetic genetic polymer (XNA) due to its ability to efficiently base pair with complementary sequences of DNA and RNA. The main difference between TNA and DNA/RNA is their backbones. DNA and RNA have their phosphate backbones attached to the 5' carbon of the deoxyribose or ribose sugar ring, respectively. TNA, on the other hand, has its phosphate backbone directly attached to the 3' carbon in the ring, since it does not have a 5' carbon. This modified backbone makes TNA, unlike DNA and RNA, completely refractory to nuclease digestion, making it a promising nucleic acid analog for therapeutic and diagnostic applications.

<span class="mw-page-title-main">Formylation</span>

Formylation refers to any chemical processes in which a compound is functionalized with a formyl group (-CH=O). In organic chemistry, the term is most commonly used with regards to aromatic compounds. In biochemistry the reaction is catalysed by enzymes such as formyltransferases.

<span class="mw-page-title-main">Nucleoside phosphoramidite</span>

Nucleoside phosphoramidites are derivatives of natural or synthetic nucleosides. They are used to synthesize oligonucleotides, relatively short fragments of nucleic acid and their analogs. Nucleoside phosphoramidites were first introduced in 1981 by Beaucage and Caruthers. To avoid undesired side reactions, reactive hydroxy and exocyclic amino groups present in natural or synthetic nucleosides are appropriately protected. As long as a nucleoside analog contains at least one hydroxy group, the use of the appropriate protecting strategy allows one to convert that to the respective phosphoramidite and to incorporate the latter into synthetic nucleic acids. To be incorporated in the middle of an oligonucleotide chain using phosphoramidite strategy, the nucleoside analog must possess two hydroxy groups or, less often, a hydroxy group and another nucleophilic group (amino or mercapto). Examples include, but are not limited to, alternative nucleotides, LNA, morpholino, nucleosides modified at the 2'-position (OMe, protected NH2, F), nucleosides containing non-canonical bases (hypoxanthine and xanthine contained in natural nucleosides inosine and xanthosine, respectively, tricyclic bases such as G-clamp, etc.) or bases derivatized with a fluorescent group or a linker arm.

Oligonucleotide synthesis is the chemical synthesis of relatively short fragments of nucleic acids with defined chemical structure (sequence). The technique is extremely useful in current laboratory practice because it provides a rapid and inexpensive access to custom-made oligonucleotides of the desired sequence. Whereas enzymes synthesize DNA and RNA only in a 5' to 3' direction, chemical oligonucleotide synthesis does not have this limitation, although it is most often carried out in the opposite, 3' to 5' direction. Currently, the process is implemented as solid-phase synthesis using phosphoramidite method and phosphoramidite building blocks derived from protected 2'-deoxynucleosides, ribonucleosides, or chemically modified nucleosides, e.g. LNA or BNA.

<span class="mw-page-title-main">Jack W. Szostak</span> American biologist

Jack William Szostak is a Canadian American biologist of Polish British descent, Nobel Prize laureate, university professor at the University of Chicago, former professor of genetics at Harvard Medical School, and Alexander Rich Distinguished Investigator at Massachusetts General Hospital, Boston. Szostak has made significant contributions to the field of genetics. His achievement helped scientists to map the location of genes in mammals and to develop techniques for manipulating genes. His research findings in this area are also instrumental to the Human Genome Project. He was awarded the 2009 Nobel Prize for Physiology or Medicine, along with Elizabeth Blackburn and Carol W. Greider, for the discovery of how chromosomes are protected by telomeres.

<span class="mw-page-title-main">5-Aminoimidazole ribotide</span> Chemical compound

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James "Jim" P. Ferris was an American chemist. He is known for his contributions to the understanding of the origins of life on Earth, specifically by demonstrating a successful mechanism of clay-catalyzed polymerization of RNA, providing further evidence for the RNA World Hypothesis. Additionally, his work in atmospheric photochemistry has illuminated many of the chemical processes which occur in the atmospheres of Jupiter and Saturn's moon, Titan.

John P. Richard is a chemist and academic. He is a SUNY Distinguished Professor at the University at Buffalo.

<span class="mw-page-title-main">TCFH</span> Chemical compound

TCFH is an electrophilic amidine reagent used to activate a number of functional groups for reaction with nucleophilies. TCFH is most commonly used to activate carboxylic acids for reaction with amines in the context of amide bond formation and peptide synthesis.

References

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