Activated Hoveyda‐Grubbs Olefin Metathesis Catalysts Derived from a Large Scale Produced Pharmaceutical Intermediate – Sildenafil Aldehyde. Issue 19 (11th August 2021)

• Record Type: Journal Article
• Authors: Monsigny, Louis; Piątkowski, Jakub; Trzybiński, Damian; Woźniak, Krzysztof; Nienałtowski, Tomasz; Kajetanowicz, Anna; Grela, Karol
• Is Part Of: Advanced synthesis & catalysis. Volume 363:Issue 19(2021)
• Page Start: 4590
• Page End: 4604
• Publication Date: 2021-08-11
• Subjects: Catalysis -- Olefin metathesis -- Electron withdrawing group (EWG) -- Ruthenium catalysts -- N-heterocyclic carbene ligands (NHC) -- Mechanism; Catalysis -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Chemistry -- Periodicals; Chemistry, Technical -- Periodicals; Chemistry -- Periodicals; Catalysis -- Periodicals; Technology, Pharmaceutical -- Periodicals; 547.2
• DOI: 10.1002/adsc.202100669
• Languages: English
• ISSNs: 1615-4150

Abstract

Abstract: Two EWG‐activated Hoveyda‐Grubbs‐type ruthenium complexes (Sil‐II and Sil‐II' ) were obtained, characterized, and screened in a set of olefin metathesis reactions. These catalysts were conveniently synthesized from a commercially available pharmaceutical building block – Sildenafil aldehyde – in two steps only. Stability and catalytic activity tests disclosed that the bulkier NHC‐ligand bearing catalyst Sil‐II' is visibly more stable and productive than its smaller NHC‐analogue Sil‐II . Good application profile of catalyst Sil‐II' was confirmed in a set of diverse metathesis reactions including ring‐closing metathesis (RCM) and cross‐metathesis (CM) of complex polyfunctional substrates of medicinal chemistry interest, including a challenging macrocyclization of the Pacritinib precursor. Compatibility of the new catalyst with various green solvents was checked and metathesis of Sildenafil and Tadalafil‐based substrates was successfully conducted in acetone. The mechanism of Sil‐II' initiation has been investigated through kinetic experiments unveiling that the decrease of the steric hindrance of the chelating alkoxy moiety (from i PrO to EtO) favors the interchange initiation pathway over the typical dissociation pathway for other popular 2 nd generation Hoveyda‐Grubbs catalysts. Abstract :