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 ca...

Inducing Axial Chirality in a Supramolecular Catalyst

“…Self‐assembly ligand systems have also been used successfully in asymmetric catalysis, and the necessary asymmetric induction has so far been achieved using building blocks with either chiral P ‐donors or an axially chiral biphenyl moiety as a stereoregulating unit . The groups of Raynal and Vidal‐Ferran achieved stereocontrol through the co‐assembly of chiral benzene‐1,3,5‐tricarboxamides (BTA) with achiral BTAs functionalized with P ‐donor moieties in a helical scaffold .…”

“…[12][13][14][15][16] Recently,control of axial chirality in a tropos ligand was demonstrated by association of small chiral molecules through hydrogen bonding. [17,18] In this manner, ab y-design nonlinear amplification of stereoselectivity was achieved.Self-assembly ligand systems have also been used successfully in asymmetric catalysis, [19] and the necessary asymmetric induction has so far been achieved using building blocks with either chiral P-donors [20][21][22][23] or an axially chiral biphenyl moiety as as tereoregulating unit. [24] Theg roups of Raynal and Vidal-Ferran achieved stereocontrol through the coassembly of chiral benzene-1,3,5-tricarboxamides (BTA) with achiral BTAs functionalized with P-donor moieties in ahelical scaffold.…”

Rhodium-catalyzed asymmetric hydrogenation of β-cyanocinnamic esters with the assistance of a single hydrogen bond in a precise position

“…Recently, substrate orientation by hydrogen bonds as a strategy in asymmetric hydrogenation has been studied and some progress has been made. 22 Therefore, we tried to utilize the ester group whose carbonyl is a very good H-bond acceptor to improve the reactivity of the electron-deficient substrate by employing ZhaoPhos-bearing H-bond donors. Although the preliminary result was moderate (entry 11, 28% conversion with 84% ee), it inspired us for further exploration.…”

Inducing Axial Chirality in a Supramolecular Catalyst

“…[1][2][3][4] However, the asymmetric synthesis of such an inflexible (atropos) backbone is often long and difficult. [17,18] In this manner, ab y-design nonlinear amplification of stereoselectivity was achieved.Self-assembly ligand systems have also been used successfully in asymmetric catalysis, [19] and the necessary asymmetric induction has so far been achieved using building blocks with either chiral P-donors [20][21][22][23] or an axially chiral biphenyl moiety as as tereoregulating unit. [5,6] In such adynamic system, the resolution into one of the diastereomers is dependent on transfer of chiral information from as tereoregulating unit.…”

“…Self-assembly ligand systems have also been used successfully in asymmetric catalysis, [19] and the necessary asymmetric induction has so far been achieved using building blocks with either chiral P-donors [20][21][22][23] or an axially chiral biphenyl moiety as as tereoregulating unit. [24] Theg roups of Raynal and Vidal-Ferran achieved stereocontrol through the coassembly of chiral benzene-1,3,5-tricarboxamides (BTA) with achiral BTAs functionalized with P-donor moieties in ahelical scaffold.…”