Aminomalononitrile inspired prebiotic chemistry as a novel multicomponent tool for the synthesis of imidazole and purine derivatives with anti-influenza A virus activity

Abstract

Amino imidazole carbonitrile derivatives decorated with α-amino acid side-chains have been synthesized by a multicomponent microwave assisted reaction inspired by the prebiotic chemistry of aminomalononitrile for generating high chemical diversity.

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

“…[34,35] In order to generalize the procedure, the reaction was repeated under the optimal experimental conditions (MeCN at 25 °C for 15 h) using the methyl esters of alanine 3 b, valine 3 c, serine 3 d, phenylalanine 3 e, and tyrosine 3 f. Amino-acid decorated imidazoles 4 b-4 f were isolated as the only recovered products from acceptable to high yield (Table 1, entries 6-10). In accordance with data previously reported for the multicomponent synthesis of imidazole derivatives bearing simple alkyl and aryl amine side-chains, [1,36] compounds 4 a-4 f were obtained by the concerted electrophile/nucleophile-oriented condensation of DAMN with 2 and 3 a-3 f to yield the intermediate I (not isolated), followed by ring-aromatization and internal displacement of a methanol molecule (Scheme 1 DAMN pathway, Supporting Information, section 1). As a general trend, the yield of compounds 4 a-4 f increased in the presence of aliphatic amino acids, imidazole 4 d being isolated in the highest yield (Table 1, entries 9-10 versus 3,6-8).…”

“…The formation of pyrimidine 6 a – 6 f probably occurred by the initial reaction of DAFN with compound 2 to yield the imino ether derivative 5 (that we effectively isolated from the reaction mixture), followed by addition of amino acid derivatives 3 a – 3 f , and successive internal displacement of methanol molecule, to yield the six‐ring closure of the pyrimidine ring (DAFN pathway, Supporting Information, section 1). The formation of the imino ether intermediate by reaction of AMN and compound 2 has been previously reported [1] . The effective role of imino ether 5 in the annulation process was confirmed by analyzing the reaction of isolated 5 and 3a under reported experimental conditions, in which case pyrimidine 6a was obtained in appreciable yield (Table 2, entry 2).…”

“…The formation of the imino ether intermediate by reaction of AMN and compound 2 has been previously reported. [1] The effective role of imino ether 5 in the annulation process was confirmed by analyzing the reaction of isolated 5 and 3a under reported experimental conditions, in which case pyrimidine 6a was obtained in appreciable yield (Table 2, entry 2). Again, aliphatic amino acids 3a-3d afforded pyrimidine derivatives in the highest yield (Table 2 entries 3-6).…”

“…We recently reported the multicomponent synthesis of imidazole derivatives decorated with amino acid residues, and their successive annulation to corresponding purines, by thermal condensation of aminomalononitrile (AMN) and trimethyl orthoacetate with α‐amino acids [1] . AMN is a key intermediate in the prebiotic synthesis of purine nucleobases in the framework of prebiotic chemistry, [2–7] while trimethyl orthoacetate is a well‐recognized one‐carbon donor reagent in multicomponent chemistry [8,9] .…”

Catalytic Enantioselective Diels Alder Reaction: Application in the Synthesis of Antiviral Agents

“…Recently Quadrelli et al dedicated a chapter of a book to the cycloaddition reactions used for the synthesis of antiviral compounds [7], and a recent review described the biocatalytic routes applied to antiviral agents [8]. Taking into consideration our experience in the antiviral field [9][10][11][12][13][14][15][16][17][18] and in the application of DAR to the synthesis of antiviral agents [15,18] we were interested to investigate this topic in more detail. We show some examples in which the catalytic DARs furnish useful optically active intermediates for the synthesis of selected bioactive compounds after a brief introduction of enantioselective DAR.…”