Sterically Tuned N-Heterocyclic Carbene Ligands for the Efficient Formation of Hindered Products in Ru-Catalyzed Olefin Metathesis

Abstract

Formation of tetrasubstituted C–C double bonds via olefin metathesis is considered very challenging for classical Ru-based complexes. In the hope to improve this condition, three ruthenium olefin metathesis catalysts bearing sterically reduced N -heterocyclic carbene (NHC) ligands with xylyl “arms” were synthesized, characterized using both computational and experimental techniques, and tested in a number of challenging reactions. The catalysts are predicted to initiate much faster than the analogue with mesityl N -substituents. We also foreboded the rotation of xylyl side groups at ambient temperature and the existence of all four atropoisomers in the solution, which was in agreement with experimental data. These catalysts exhibited high activity at relatively low temperatures (45–60 °C) and at reduced catalyst loadings in various reactions of sterically hindered alkenes, including complex polyfunctional substrates of pharmaceutical interest, such as yangonin precursors, chrysantemic acid derivatives, analogues of cannabinoid agonists, α-terpineol, and finally a thermally unstable peroxide.

Total Synthesis of Euonymine and Euonyminol Octaacetate

“…We postulated that Grela catalyst A with the smaller o-xylyl groups of the imidazolinyl ligand was more suitable for the facile coordination of the substrate than D with the mesityl groups. 36 Indeed, we found that A cyclized the A-ring at a lower temperature (60 °C) with lower catalyst loading (10 mol %), delivering 6 in 81% yield with 18% of recovered 33 (entry 6). In this metathesis reaction, the addition of A in four portions and argon bubbling to remove the residual ethylene were essential for maintaining the catalytic efficiency of A.…”

“…The reactivity of D was enhanced upon replacing toluene with C 6 F 5 CF 3 : 50 mol % of D enabled the generation of 6 in 58% at 120 °C (entry 4) and in 83% at 80 °C (entry 5). We postulated that Grela catalyst A with the smaller o -xylyl groups of the imidazolinyl ligand was more suitable for the facile coordination of the substrate than D with the mesityl groups . Indeed, we found that A cyclized the A-ring at a lower temperature (60 °C) with lower catalyst loading (10 mol %), delivering 6 in 81% yield with 18% of recovered 33 (entry 6).…”

Ruthenium Olefin Metathesis Catalysts Bearing a Macrocyclic N‐Heterocyclic Carbene Ligand: Improved Stability and Activity

“…Noteworthy, data reported in the literature [5] allows to compare Ru6 also with the state-of-the-art complex bearing a medium-size NHC, Ru7. [5,19] Interestingly, while this trend is preserved for the derivative of isopulgeol (2 f), the RCM reaction of a 1 g-bearing one terminal and one geminally disubstituted CÀ C double bond, based on a sesquiterpene alcohol, bisabolol-leads to almost quantitative conversion for both isomers of Ru6. Importantly, also in this case the productivity of cis-Ru6 was ahead of those exhibited in the same reaction by the SITol-bearing Ru2, an industry-standard tool designed particularly for such challenging transformations (Scheme 3, row B).…”

“…In these challenging reactions cis-Ru6 outdistanced also its closest structural analogue-the phosphine-containing catalyst Ru2 [3a] -offering 9 to 56 pp (percent points) higher conversions. Noteworthy, data reported in the literature [5] allows to compare Ru6 also with the state-of-the-art complex bearing a medium-size NHC, Ru7. [5,19] Interestingly, while this trend is preserved for the derivative of isopulgeol (2 f), the RCM reaction of a 1 g-bearing one terminal and one geminally disubstituted CÀ C double bond, based on a sesquiterpene alcohol, bisabolol-leads to almost quantitative conversion for both isomers of Ru6.…”

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

“…Therefore, we decided to investigate the performance of various Ru-catalysts in RCM, leading to the formation of a tetrasubstituted olefin 47. Unfortunately, quick reconnaissance shown that a specialized ruthenium catalyst with a small NHC ligand (Planer et al, 2020) decomposes very quickly under reaction conditions in water. Similarly, Ru9BARF with a sterically augmented SIPr-like ligand gave no conversions in the case of the formation of a tetrasubstituted C-C double bond.…”