Rational Optimization of Supramolecular Catalysts for the Rhodium‐Catalyzed Asymmetric Hydrogenation Reaction

Abstract

Rational design of catalysts for asymmetric transformations is alongstanding challenge in the field of catalysis. In the current contribution we report ac atalyst in which ah ydrogen bond between the substrate and the catalyst plays ac rucial role in determining the selectivity and the rate of the catalytic hydrogenation reaction, as is evident from ac ombination of experiments and DFT calculations.D etailed insight allowed in silico mutation of the catalyst such that only this hydrogen bond interaction is stronger,p redicting that the new catalyst is faster.I ndeed, we experimentally confirmed that optimization of the catalyst can be realized by increasing the hydrogen bond strength of this interaction by going from aurea to phosphine oxide H-bond acceptor on the ligand.The asymmetric hydrogenation reaction is undoubtedly the most powerful asymmetric transformation for the fine chemical industry as it provides ar ather general strategy to create chiral centers in organic molecules. [1] As the synthesis of the desired products cannot always be reached using the existing catalysts,t he search for new methods and concepts has received considerable attention. [2] Combinatorial chemistry approaches and high-throughput catalyst screenings have been demonstrated to be increasingly important. [3] Fort he generation of catalyst libraries based on chiral ligands,the use of supramolecular ligand building blocks that form bidentate ligands by self-assembly is apowerful strategy as the number of catalysts grows exponentially with the number of synthesized building blocks. [4] Next to interactions between the two ligand building blocks,hydrogen bonding between functional groups of the substrate and the ligands at the metal complex can contribute to catalyst selectivity. [5] One of the major goals in the area of asymmetric hydrogenation, or more general in the field of catalysis,would be the rational design of transition metal catalysts.Although for several catalyst systems detailed knowledge on the reaction mechanism has been obtained, [6] prediction of the catalyst properties is still very challenging. [7] However,w hen the selectivity of ac atalytic reaction is controlled by supramolecular interactions,f urther rational optimization could be performed, guided by theoretical prediction. Herein we report the first example of rational design of ac atalyst for the asymmetric hydrogenation reaction by optimization of the supramolecular interactions between the substrate and the catalyst, leading to enhanced activity and superior selectivity in the hydrogenation of hydroxy-functionalized di-and trisubstituted alkenes.I n order to allow ar ational approach, the reaction mechanism of the supramolecular catalyst used was investigated by means of X-ray crystallography,N MR spectroscopy,k inetic studies,a nd DFT calculations of the reaction pathway. Subsequently,t he relevant supramolecular interactions between the substrate and the catalyst were optimized in silico,r esulting in the rational design of as econd generation of catalysts...

Recent Developments in Enantioselective Transition Metal Catalysis Featuring Attractive Noncovalent Interactions between Ligand and Substrate

“…In later work, further NMR studies and DFT calculations suggested that in fact the −OH group of the substrate inserts into the ligand–ligand hydrogen bond, resulting in the formation of two independent hydrogen bonds between the substrate and the complex, as shown above ( Figure 45 c). 171 , 172 Based on this understanding, phosphine oxide ligand L18 was developed, which is analogous to L17 but possesses a stronger hydrogen bond acceptor ( Figure 45 b). The resulting catalyst experienced better turnover and higher product enantiomeric excess (>99%) were observed.…”

Bifunctional Homogeneous Catalysts Based on Ruthenium, Rhodium and Iridium in Asymmetric Hydrogenation

“…For more than a decade, Reek and co-workers have been working on the application of supramolecular ligands to homogeneous catalysis. [191][192] In this context, special attention was payed to ligands able to give H-bondings to other ligands and, therefore, H-bonding phenomena involving ligands and substrates have been often highlighted. A first generation of supramolecular ligands had implied a hydrogen bond between the NH moiety of a phosphoramidite and the carbonyl of a urea-functionalized phosphine.…”

“…191 A second generation associated phosphoramidites and diphosphine monoxides. [192][193] While investigating these second generation catalysts in the rhodium catalysed AH of -unsaturated esters, the authors noticed especially high activities and enantioselectivities for substrates bearing a hydroxyl group (Scheme 56). According to NMR, kinetic and theoretical studies, the catalyst and the -conjugated ester interact through coordination of the C=C and C=O double bonds to rhodium and, additionally, by two hydrogen bonds connecting the hydroxyl group to both the phosphine oxide and the phosphoramidite NH functions.…”

“…AH of -conjugated ester using supramolecular rhodium catalysts, by Reek and co-workers. [191][192][193] In 2013, Zhang, Wang and co-workers introduced a novel chiral ferrocene-based bisphosphinethiourea ligand named ZhaoPhos, in order to take advantage from thiourea as an activating and directing group (Scheme 57). 194 This ligand design proved especially successful for applications in rhodiumpromoted asymmetric hydrogenations of functionalized, cyclic and acyclic olefins and iminium salts.…”

Effective Nephroprotection Against Acute Kidney Injury with a Star-Shaped Polyglutamate-Curcuminoid Conjugate

“…Furthermore, we explored whether St-PGA-CL-BDMC may also inhibit necroptosis, a main type of regulated necrosis actively involved in AKI. We have previously shown that cotreatment of renal tubular cells with the general caspase inhibitor z-VAD-fmk in combination with TTI (z/TTI) switches the mechanism of cell death from apoptosis to necroptosis 30,31 . In our experiments, z/TTI stimulation lowered the metabolic activity/viability of renal tubular cells by ~70% when compared to untreated control cells (Fig.…”