Go for Gold: Development of a Scalable Synthesis of [1-(Ethoxycarbonyl)cyclopropyl] Triphenylphosphonium Tetrafluoroborate, a Key Reagent to Explore Covalent Monopolar Spindle 1 Inhibitors
Covalent approaches have resurged in drug discovery and chemical biology during the last decade. So-called targeted covalent inhibitors typically show a strong and persistent drug–target interaction as well as a high degree of selectivity. In our research group, RMS-07 (8), a First-in-Class covalent...
| Autores: | , , , , |
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| Tipo de documento: | artigo |
| Data de publicação: | 2025 |
| País: | España |
| Recursos: | Universitat Ramon Llull (URL) |
| Repositório: | DAU Arxiu Digital de la Universitat Ramon Llull |
| OAI Identifier: | oai:dau.url.edu:20.500.14342/5509 |
| Acesso em linha: | http://hdl.handle.net/20.500.14342/5509 https://doi.org/10.1002/open.202500106 |
| Access Level: | Acceso aberto |
| Palavra-chave: | Covalent inhibitors Ethoxycarbonylations Phosphonium salts Protein kinase inhibitors Wittig reactions Fosfoni Proteïnes quinases Reacció de Wittig 54 |
| Resumo: | Covalent approaches have resurged in drug discovery and chemical biology during the last decade. So-called targeted covalent inhibitors typically show a strong and persistent drug–target interaction as well as a high degree of selectivity. In our research group, RMS-07 (8), a First-in-Class covalent inhibitor of the protein kinase threonine tyrosine kinase (TTK)/monopolar spindle 1, which shows promising results in a variety of different solid cancer cell types and will be further optimized in terms of covalent binding kinetics, has recently been developed. However, synthetic accessibility is restricted by a high price and limited availability of [1-(ethoxycarbonyl)cyclopropyl] triphenylphosphonium tetrafluoroborate (10), a key reagent required to assemble the tricyclic core scaffold in a Wittig-type cyclization reaction. This reagent is also described as a valuable synthon for the synthesis of a range of ring systems with interesting applications in medicinal chemistry. However, reliable procedures for its large-scale synthesis are scarce. Only one prior report describes the synthesis of reagent 10, and it contains limited experimental details, making it challenging to reproduce and scale up. Herein, a concise and reproducible decigram-scale synthetic protocol for accessing key reagent 10 is described. |
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