Project relevance
Click chemistry, being introduces by Sharpless in the beginning of 21 century, is a powerful tool to probe for the cellular localization of small molecules and for construction of drug-like molecules (Angew. Chem. Int. Ed. 2001, 40, 2004-2021). In general, click chemistry describes reactions that are fast, simple to use, atom-economic, easy to purify, versatile, regiospecific, stereospecific, and give high product yields. Several types of click reactions are introduced in recent years including epoxide and aziridine ring opening with nucleophiles, non-aldol type carbonyl reactions, cycloaddition reactions, Staudinger ligation, Michael additions to carbon-carbon multiple bonds and others (Acc. Chem. Res. 2018, 51, 1073-1081). Among these click reactions, thiol-ene and thiol-yne click reactions, also known as hydrothiolation reactions, are the simplest and most atom-economical approaches for the synthesis of organosulfur compounds with widespread applications in natural compounds, pharmaceuticals, polymers, functional materials, and as synthetic intermediates (Angew. Chem. Int. Ed. 2010, 49, 1540-1573). The application of these hydrothiolation click reactions for bioorthogonal bioconjugations is always a big challenge for chemists. While the traditional versions of these click reactions need a catalyst or an initiator to perform, performing these reactions with strained molecules as synthetic targets without using a promoter attracts the attention of organic chemist, especially for biological applications (Angew. Chem. Int. Ed. 2018, 57, 6459-6463).
Among strained molecules, cycloalkynes received widespread applications in organic and bioorganic chemistry (Top Curr Chem, 2016, 374,16), especially in recent 15 years, after Bertozzi’s group discovered the possibility of using cyclooctyne reagents in strain-promoted azide-alkyne cycloaddition reactions (J. Am. Chem. Soc. 2004, 126, 15046-15047). In fact, the strained promoted reactions are kinetically favorable and do not need a catalyst, which is completely suitable for bioorthogonal bioconjugations. In this context, hydrothiolation of cyclic alkyne/allenes under catalyst-free conditions will be an interesting area of research.
Project methods
A diversities of simple and fused cycloalkynes will be prepared. Simple cycloalkynes will be prepared in two steps from cycloalkenes according to the known procedures (Synthesis 1978, 4, 290). Heterocyclic-fused cycloalkynes can be prepared in six steps by the method developed by Russian team (J. Am. Chem. Soc. 2021, 143, 16519−16537). It should be emphasized that the Russian team has a ready-to-use benzothiophene-fused cycloalkyne and several intermediates for the synthesis of isocoumarin-cycloalkynes, which will allow both teams to begin the study of key reactions immediately.
Cycloallenes will be prepared in two steps using Doering synthesis from cycloalkenes via cyclopropanation reaction, followed by treatment with BuLi.
Cyclic allenes conjugated with a carbonyl group will be prepared from 1-acyl-2-halocycloalkenes. These allenes are unstable and would be prepared in situ during the nucleophilic reaction.
After successful synthesis of cyclic alkynes and allenes, their reactions with in situ prepared dithiocarbamic acids from amines, xanthate salts and other thio-nucleophiles such as thiols, sulfenic acid, sulfinate salts, and hydrogen sulfite will be investigated to prepare the corresponding vinyl dithiocarbamates, vinyl xanthates, vinyl thioethers, vinyl sulfoxide, vinyl sulfone and vinyl sulfonic acid derivatives, respectively.
The novel click reaction, which proceeds under mild conditions, will be applied to amino acids, peptides, and proteins to tag them with amine and thiol residues for bioconjugation applications.
Groundwork
Recently, Azim Ziyaei Halimehjani group (Iranian team) investigated the reaction of in situ prepared dithiocarbamic acids with unactivated alkynes (Chem. Comm. 2019, 55, 1253-1255) to prepare vinyl dithiocarbamates in high yields. In addition, they investigated the Markovnikov addition reaction of dithiocarbamic acids with unactivated alkenes under neat conditions without using any catalyst (Scheme 1B) (J. Org. Chem. 2024, 89, 5353-5362). The main disadvantages of these works are performing the reaction under harsh reaction conditions (120 oC in sealed tubes), which prevent the application of these click reactions in biological systems.
In 2021, the Balova group (Russian team) developed a novel category of readily synthetically accessible hetero-cycloalkynes fused to a heterocyclic ring for bioorthogonal bioconjugation. It has been shown that by varying the natures of the heterocycle and heteroatom, it is possible to reach the optimal stability-reactivity balance for these strained systems (J. Am. Chem. Soc. 2021, 143, 16519−16537). In addition, recently, the Russian team has developed fluorescent isocoumarin-fused cycloalkynes and applied them in the reaction with non-fluorescent azides to provide fluorescent triazoles (Chem. Eur. J. 2023, 29, e202300540).
In this project, we will bring together the sulfur chemistry of the Iranian team and the cycloalkyne chemistry of the Russian team with the objective of investigating the reactions of different S-nucleophiles with cyclic alkynes and allenes. This will facilitate the search for new click-reactions with a view to furthering the range of chemical and biological applications.
Expected results
1) Development of novel click reactions in synthetic organic chemistry;
2) Application of novel click reactions in bioconjugation chemistry;
3) Publication of the project results in Q1 journals on organic or bioorganic chemistry (1-2 papers)
4) Presenting the results in international scientific conferences
5) Beginning and developing cooperation for further major projects (RSF – INSF, 2025)
Activities on attracting additional funding for further implementation of the project
It is assumed that this project will serve as a foundation for the continued collaboration between Iranian and Russian teams. The findings of this project will be published in WOS journals in 2025 (1-2 papers), which will serve as a significant foundation for the submission of a joint funding application for further major projects. A joint Russian Science Foundation (RSF) and Iranian National Science Foundation (INSF) project is planned to be applied for in 2025.
