Microwave-assisted synthesis of dinucleoside analogues containing a thiazolidin-4-one linkage via one-pot tandem Staudinger/aza-Wittig/cyclization

Abstract

Dinucleosides containing a thiazolidin-4-one linkage were prepared by one-pot tandem Staudinger/aza-Wittig/intermolecular cyclization under microwave irradiation and their structures were confirmed. Preliminary examination of HIV-RT inhibition showed that the dinucleosides containing (R)-thiazolidin-4-one linkage are significantly more active than those containing (S)-thiazolidin-4-one linkage.

The First Solvent‐Free, Microwave‐Accelerated, Three‐Component Synthesis of Thiazolidin‐4‐ones via One‐Pot Tandem Staudinger/aza‐Wittig Reaction

“…This clearly indicates that the conversion of the azide to the phosphazene is accelerated as envisaged. This is also supported by a recent report [21] that discloses that phosphazene formation in THF occurs just in 5 min under microwave irradiation. On a similar ground, in the present study, it is understood that phosphazene formation is accelerated by microwave irradiation under solvent-free condition.…”

“…Alternatively, Staudinger/aza-Wittig reactions are a powerful tool in organic synthetic strategies towards constructing nitrogen containing heterocycles [19], that is, azides are employed as an alternative to amines. With regard to thiazolidin-4-one synthesis, to the best of our knowledge, there is only a couple of recent reports [20,21] that utilizes Staudinger/aza-Wittig reactions to afford imine intermediate that with mercaptoacetic acid affords the product (Scheme 1, route B). However, these are also solution phase protocols.…”

“…The advantage of these protocols using azides in the place of amines is that they involve elimination of nitrogen instead of water in step 1 (Scheme 1, route B). However, water elimination in step 3 and its azeotrope formation is unavoidable that affects the reaction rate and/or yield of thiazolidin-4-ones [20,21]. Thus, from the discussion vide supra, it is understood that solution phase methodologies for thiazolidin-4-one synthesis is unhealthy as they are associated with many limitations such as toxicity of the solvents, usage of condensation agents, and desiccants, the vital being accumulation of water that would restrict their broad scope and question their eco-friendliness.…”

The Sulfo‐Click Reaction and Dual Labeling of Nucleosides

“…In another example, dinucleoside analogues were synthetized through a one‐pot tandem Staudinger/aza‐Wittig/cyclization under microwave irradiation. The dinucleosides obtained containing ( R )‐ or ( S )‐thiazolidin‐4‐one linkages are active in inhibiting HIV reverse transcriptase (Shen et al., 2011). Moreover, in the literature, various dinucleoside analogues bearing non‐natural linkages have been demonstrated as possible therapeutic agents (Arenas‐Jal, Sune‐Negre, & Garcia‐Montoya, 2020; Chen et al., 2008).…”

Microwave-assisted synthesis of small molecules targeting the infectious diseases tuberculosis, HIV/AIDS, malaria and hepatitis C

“…The same group has also reported the synthesis of dinucleoside substituted thiazolidin-4-ones via a microwave-assisted one-pot Staudinger/ aza-Wittig/cyclisation sequence. 84,85 Inhibition of the HIV protease enzyme has been a successful strategy in the fight against HIV/AIDS and today there are 10 HIV-1 protease inhibitors on the market. The enzyme is responsible for cleavage of the viral polyprotein into functional enzymes and structural proteins in the final stages of viral replication and is essential for the production of new mature virions.…”