¹H DOSY Spectra of Ligands for Highly Enantioselective Reactions—A Fast and Simple NMR Method to Optimize Catalytic Reaction Conditions

Abstract

The demand for enantiopure chemicals, for example, natural products, pharmaceuticals, or materials, has been increasing rapidly for years, and the global market is continually expanding.[1] In the field of asymmetric catalysis, transitionmetal catalysts using chiral ligands represent one of the most effective and versatile approaches.[2] However, the development of highly efficient catalysts is often an unpredictable, challenging, and time-consuming process. Accordingly, every method that shortens this laborious procedure or allows an assessment of selectivity contributions is highly valued. In this context, rational models were developed to predict asymmetry in resulting products, for example, Crams rule and the Felkin-Anh model, [3] and quadrant models. [4,5] Furthermore, combinatorial libraries provide empirical strategies for ligand selection. [6][7][8] With regard to temperature optimization, the isoinversion principle provides a general model for reactions with two or more selectivity steps.[9] At present, the rational models have to address more complex issues because of the importance of noncovalent interligand interactions in organometallic complexes.[10] Even weak p-p interactions were found to influence complex structures, [11,12] for example, a cis coordination of the ligands was found for a bis(phosphonite) Pt complex and a bis(phosphoramidite) Pd complex; this coordination was explained by weak intermolecular interactions. [13,14] In a recent study, we reported a temperature-dependent interconversion, which was potentially caused by interligand interactions, of various phosphoramidite copper complexes. [15] This result raised the question of whether there is a fast and easy way to predict ligand-driven changes of the active catalysts, either by interconversion or by aggregation phenomena. However, to the best of our knowledge, no simple and general procedure has been presented to date that reliably predicts temperature-dependent changes of transition-metal catalyst sizes. Such a prediction would allow a fast determination of the temperature range applicable to the desired catalytic reaction.Herein, we present the first aggregation study of selected phosphoramidite ligands and their transition-metal complexes. The aggregation trends of the ligands, the complexes of which can catalyze highly enantioselective reactions, reveal that an easy and fast DOSY screening of the free ligands allows a prediction of the aggregation trends of their transition-metal complexes, even without knowledge about their structures. In addition, the applicability limits of this method are discussed and the type of interligand interactions is addressed.Chiral phosphoramidites have emerged as one of the privileged ligand structures, with increasing applications in various asymmetric catalytic reactions with excellent enantioselectivies. [16][17][18][19][20][21][22][23] Therefore, 1 and 2 (Scheme 1), which show high selectivities in catalysis, were chosen as model systems that represent the well-known binaphthol-and biphenolbas...

Noncovalent CH–π and π–π Interactions in Phosphoramidite Palladium(II) Complexes with Strong Conformational Preference

“…This interaction pattern can be relayed to catalysis, where it is usually not feasible to gain structural information directly, e.g., due to equilibria in copper-catalyzed reactions. [27] We are confident that the interligand interactions of the designed, nonsymmetric phosphoramidite ligands could be transferred and applied to the interactions of the ligand with the substrate. An encouraging result that confirms our point came via different approach from the ligand screening in a Cu-catalyzed reaction, which exploits the nonsymmetric phosphoramidite ligands having both aromatic and branched aliphatic substituents.…”

Noncovalent CH–π and π–π Interactions in Phosphoramidite Palladium(II) Complexes with Strong Conformational Preference

“…This interaction pattern can be relayed to catalysis,where it is usually not feasible to gain structural information directly, e.g.,due to equilibria in copper-catalyzed reactions. [27] We are confident that the interligand interactions of the designed, nonsymmetric phosphoramidite ligands could be transferred and applied to the interactions of the ligand with the substrate.A ne ncouraging result that confirms our point came via different approach from the ligand screening in aC u-catalyzed reaction, which exploits the nonsymmetric phosphoramidite ligands having both aromatic and branched aliphatic substituents. [30,31] These serve as extended interactions areas,similar to those identified in this study.Webelieve that our results,w hich are based on ligands and complexes highly relevant in catalysis,h ave the potential to be used as ad esign principle for modelling ligand-ligand or ligandsubstrate interactions independent of the transition metal employed, or as aligand screening tool in catalysis.W ehope the results presented here would aid researchers in designing and synthesizing molecules with desired properties,e .g., binding or folding.…”

“…Specifically,w es howed that the aggregation as ap robe for intermolecular interaction is independent of the transition metal used, the complex composition (number of ligands) and even the structure as long as phosphoramidite ligands (of the basic structure used in the study) are involved. [27] This previous study allows us to choose the best NMR model for investigations and to claim at the same time that these interactions should be transferable to catalytic systems.Moreover,wefirst proposed the importance of the extended interaction areas between phosphoramidite ligands as the source of stereoselectivity in TM catalysis. [27,28] Following this report, interactions between the ligand and the substrates or ligands and metal (cation-p)h ave been proposed to be responsible for the high stereoinduction observed in many metal-catalyzed reactions.…”

“…[27] This previous study allows us to choose the best NMR model for investigations and to claim at the same time that these interactions should be transferable to catalytic systems.Moreover,wefirst proposed the importance of the extended interaction areas between phosphoramidite ligands as the source of stereoselectivity in TM catalysis. [27,28] Following this report, interactions between the ligand and the substrates or ligands and metal (cation-p)h ave been proposed to be responsible for the high stereoinduction observed in many metal-catalyzed reactions. [29][30][31] Afew years ago we introduced asupramolecular balance based on bis(phosphoramidite) palladium(II) complexes, which provided the principal idea how to assess the noncovalent interactions between two ligands in TM complexes.…”

Chiral Aminoalcohols and Squaric Acid Amides as Ligands for Asymmetric Borane Reduction of Ketones: Insight to In Situ Formed Catalytic System by DOSY and Multinuclear NMR Experiments

“…DOSY [35] has proven to be a valuable tool for the investigation of molecular interactions and aggregation phenomena, including complex mixtures [36][37][38][39][40][41], supramolecular aggregates [42][43][44][45] and complexes [46][47][48][49], and to the best of our knowledge, has not been previously used to identify in situ generated intermediate species involved in oxazaborolidine formation in borane reduction of ketones. The technique has a well-established methodology, and during recent years, it has been successfully applied for the investigation of reaction intermediates in different reactions [50][51][52][53][54][55][56].…”