Activated Hoveyda‐Grubbs Olefin Metathesis Catalysts Derived from a Large Scale Produced Pharmaceutical Intermediate – Sildenafil Aldehyde

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 iPrO to EtO) favors the interchange initiation pathway over the typical dissociation pathway for other popular 2nd generation Hoveyda‐Grubbs catalysts.

Testing enabling techniques for olefin metathesis reactions of lipophilic substrates in water as a diluent

“…9, 30.4, 27.3, 22.3, 14.0. Presented analytical data are consistent with literature (Che et al, 2009;Monsigny et al, 2021aMonsigny et al, , 2021b).…”

“…diethyl 3-methylcyclopent-3-ene-1,1-dicarboxylate (12) 172.4, 137.4, 121.3, 61.4, 59.4, 44.6, 40.8, 16.0, 14.0. Presented analytical data are consistent with literature (Monsigny et al, 2021a(Monsigny et al, , 2021b. 9, 30.4, 27.3, 22.3, 14.0.…”

“…2, 136.2, 125.9, 125.8, 124.7, 124.2, 123.2, 122.3, 111.6, 54.0, 53.4; melting point: 216 C. Presented analytical data are consistent with literature (Nienałtowski et al, 2020b). pyrazolo[4,3-d]pyrimidin-7-one (24) 1, 153.6, 146.9, 146.5, 138.3, 131.3, 131.0, 130.5, 125.5, 124.5, 121.1, 113.1, 66.0, 55.0, 38.2, 27.7, 22.3, 14.6, 14.0; melting point: 187 C. Presented analytical data are consistent with literature (Monsigny et al, 2021a(Monsigny et al, , 2021b. 7, 130.4, 128.5, 128.4, 125.9, 38.9, isomer Z: 140.8, 129.0, 128.5, 128.46, 125.9, 33.5.…”

A tunable family of CAAC-ruthenium olefin metathesis catalysts modularly derived from a large-scale produced ibuprofen intermediate

“…From the point of view of catalytic olen metathesis, such a substrate exhibits a potential risk, as it contains a number of Lewis basic centres that can chelate the propagating 14-e − Ru species, thus arresting the catalyst's activity. [69][70][71][72][73] To do so, RCM of 29 was conducted at RT in DCM for 22 h, giving product 30 in 95% isolated yield with only 0.01 mol% of catalyst Ru12, which was also the best one in RCM reactions with malonate models. Previously the same N,N-diallylsulfonamide substrate 29 was tested with NHC-bearing catalysts, that however were used in 2-0.5 mol% loading.…”

Ruthenium Olefin Metathesis Catalysts Featuring N-Heterocyclic Carbene Ligands Tagged with Isonicotinic and 4-(Dimethylamino)benzoic Acid Rests: Evaluation of a Modular Synthetic Strategy

“…Based on this result, CM-reluctant Taladafil derivative P4 has been considered a substrate for the CM reaction promoted by 10. We reported recently such CM reaction of P4 with (Z)-1,4-diacetoxybutene S4 (5 equivalents) as cross partner with 1 mol% of a sulfonamide activated Hoveyda type Ru-based catalyst [54]. In such conditions, the CM reaction at room temperature afford the corresponding product in 68% with an E/Z ratio of 95/5 within 15 h. Based on this report, the RCM of S4 (1 equivalent, 0.5 M in DCM) was undertaken with 5 equivalents of the cross partner S4 and with 5 mol% of complex 10.…”