4‐Heterosubstituted Cyclopentenone Antiviral Compounds: Synthesis, Mechanism, and Antiviral Evaluation

Abstract

Racemic 4‐oxocyclopent‐2‐en‐1‐yl acetate was used in a short synthesis of nucleoside analogues with pyrimidine and purine heterobases. The protocol is based on a typical nucleophilic substitution process. Uracil, thymine, 6‐chloropurine, and some adenines gave the expected 4‐heterosubstituted products along with the isomeric 2‐heterosubstituted compounds as minor components. Samples of selected products were evaluated for their antiviral activity in a primary screening against a variety of viruses belonging to different classes. One of the compounds was found to be highly active against human papilloma virus (HPV).

Ene Reactions of Nitrosocarbonyl Intermediates with Trisubstituted Cycloalkenes: “Cis Effect” and Steric and Conformational Factors Drive the Selectivity

“…Moving to the synthetic point of view, unquestionably, trisubstituted 1-methylcycloalkenes provide valuable mechanistic information on nitrosocarbonyl reactivity in view of their potential synthetic applications and in particular in the preparation of nucleoside derivatives having small or large carbocyclic rings as spacer between heterobases and hydroxy functionalities (Scheme 5). 19 Since the mesylate derivatives 17 can be easily prepared from literature protocols 20 and functionalized with purine and pyrimidine heterobases to afford the cycloalkane compounds 18 , we are planning thermal or photochemical generation of suitable nitrosocarbonyl intermediates that will furnish the diastereomeric nucleoside analogues 19 through ene reaction, to be evaluated as potential antiviral compounds. More over the double bond located on the carbocyclic spacer represents a valuable functionality due to its double role: first, it is able to reduce the conformational mobility of the spacer fixing the nucleoside structure for an easier conformational analysis with suitable receptors; second, the double bond is suitable for further functionalizations, such as addition and cycloaddition reactions to introduce other functional groups for the modulation of the structure–activity relationship.…”

“…We have already reported the application of nitrosocarbonyl intermediates in the synthesis of biologically active compounds, and the results obtained in this field prompt us in pursuing these investigations on novel access to antiviral compounds. , …”

An enantiodivergent synthesis of N-Boc-protected (R)- and (S)-4-amino cyclopent-2-en-1-one

“…It should be noted again that the direct nucleophilic attack on activated forms of 3 has been infrequently reported due to competitive formation of cyclopentadienone (which subsequently undergoes cycloaddition chemistry). 21,22,27…”

“…Since some compounds of the type 1 demonstrated comparable activities to Δ 12,14 -15-deoxy-PGJ 2 in assays relevant to inflammation and ways. [16][17][18][19][20] Since the direct nucleophilic displacement of an activated form of 4-hydroxycyclopentenone is problematic and has scarce literature precedence 21,22 alternative methods for the stereocontrolled construction of 2 were considered. From 3, the ketone was initially converted into alcohol 4 via a Luche reduction.…”

Revaluation of biomass-derived furfuryl alcohol derivatives for the synthesis of carbocyclic nucleoside phosphonate analogues

“…Furfuryl alcohol is also the source of 4-hydroxy-2-cyclopentenone, which, in enantiopure form, has been used as an intermediate for the synthesis of natural products and pharmaceutical drugs [ 3 ]. Recently, racemic (+/−)-4-hydroxy-2-cyclopentenone has found application in the synthesis of nucleoside analogues [ 4 – 5 ] and some of the products have shown interesting antiviral activities. As part of our studies on carbocyclic nucleoside phosphonates [ 6 ] as potential anti-HIV agents [ 7 – 8 ], we envisioned to use bio-sourced racemic (+/−)-4- O -protected 2-cyclopentenone for the synthesis of hitherto unknown carbocyclic nucleoside methylphosphonates ( Fig.…”