A Three‐Way Regioselective Synthesis of Amino Acid Decorated Imidazole, Purine and Pyrimidine Derivatives by Multicomponent Chemistry Starting from Prebiotic Diaminomaleonitrile

Abstract

Amino acid decorated imidazole, pyrimidine and purine derivatives, resembling analogues of peptide nucleic acid's building blocks, have been synthesized by a three-way multicomponent chemistry of diaminomaleonitrile, one of the most studied chemical precursors in prebiotic chemistry. The regioselectivity of the multicomponent reaction between diaminomaleonitrile, trimethyl orthoacetate and a selected panel of α-amino acids, was controlled by the energy source used for triggering the condensation. Imidazole derivatives were obtained under thermal condition, while photochemical and combined photo-thermal conditions afforded pyrimidine and purine derivatives, respectively. The three synthetic pathways were independent of each other, the type of product being controlled by the chemical intermediates prevailing in the reaction mixture. In addition to the synthetic potential of these multicomponent reactions in the preparation of a large variety of heterocycles, the control of the synthesis of peptide nucleic acid's building blocks, simply by changing the nature of the energy source, further enlarged the chemical complexity available in prebiotic conditions for the emergence of pristine pre-genetic codes.

Cerium Phosphate-Assisted Formation of Nucleosides and Nucleotides from Formamide in a One-Pot (Photo)catalytic Reaction

“…It should be noted that there are reports on a possible role of light in the formation of pre-biotic compounds. For example, the formation of guanine, adenine, and hypoxanthine in UV-Irradiated formamide solutions (Barks et al, 2010) and the regioselective synthesis of amino acid decorated imidazole, purine and pyrimidine derivatives (Bizzarri et al, 2022). In fact, there are reported cases in which photocatalysis was used for this purpose, for example, the formation of 6 of the 11 carboxylic acid intermediates of the reductive version of the citric acid cycle was obtained by UV irradiation of formamide in the presence of titanium dioxide (Saladino et al, 2011).…”

A review on pyrimidine‐based derivatives: Synthesis and their biological application

“…There are various approaches to synthesizing pyrimidine compounds, each with its own set of benefits and applications. These strategies encompass metal-catalyzed reactions [30][31][32][33], enzymatic synthesis [34,35], chalcone cycloaddition [8,36], multicomponent reactions [37][38][39], coupling isomerization [40] etc. In addition, several conditions (microwave-assisted [41], thermal [42], green synthesis [43], ultrasound [44], and others [45]) have been utilized in the synthesis of pyrimidine.…”

Multicomponent Synthesis of Diaminopurine and Guanine PNA’s Analogues Active against Influenza A Virus from Prebiotic Compounds

“…Examples of the synthesis of PNA’s building blocks in prebiotic chemistry are reported, and the emergence of structural complexity associated with chemical modification of the nucleobase and sugar is discussed in detail. , PNAs showed important biological activities, including the inhibitory effect against a large panel of viral diseases. , The prebiotic synthesis of PNA’s building blocks includes the condensation of formamide and HCN oligomers, such as aminomalononitrile (AMN) and diaminomaleonitrile (DAMN). ,, In the latter cases, urea and guanidine have been involved in multicomponent procedures with cyanoacetaldehyde, , malic acid, acrylonitrile, propionic acid, and β-alanine,. − In addition, they favored the ring-closing annulation and aromatization in the transformation of pyrimidines and purines . Recently, we reported the multicomponent synthesis of a large panel of PNA’s building blocks, starting from α-amino acids and AMN and DAMN, highlighting the role of the energy source in the chemoselectivity of the reaction. , Amino imidazole carbonitrile derivatives were recovered as key intermediates for the successive annulation step to yield purine derivatives with selective antiviral activity against influenza A virus through inhibition of the budding step in the viral replication cycle. Here, we describe an alternative synthetic pathway for the preparation of bioactive diaminopurine and guanine PNA’s building blocks by microwave-assisted multicomponent synthesis of amino imidazole carbonitrile derivatives in the presence of sustainable reaction solvents.…”

“… 24 Recently, we reported the multicomponent synthesis of a large panel of PNA’s building blocks, starting from α-amino acids and AMN and DAMN, highlighting the role of the energy source in the chemoselectivity of the reaction. 25 , 26 Amino imidazole carbonitrile derivatives were recovered as key intermediates for the successive annulation step to yield purine derivatives with selective antiviral activity against influenza A virus through inhibition of the budding step in the viral replication cycle. Here, we describe an alternative synthetic pathway for the preparation of bioactive diaminopurine and guanine PNA’s building blocks by microwave-assisted multicomponent synthesis of amino imidazole carbonitrile derivatives in the presence of sustainable reaction solvents.…”