Stereoselective functionalizations of organic molecules are of great importance to modern synthesis. A stereoselective preparation of pharmaceutically active molecules is often required to ensure the appropriate biological activity. Thereby, diastereoselective methods represent valuable tools for an efficient set-up of multiple stereocentres. In this article, highly diastereoselective Csp(3) Negishi cross-couplings of various cycloalkylzinc reagents with aryl halides are reported. In all cases, the thermodynamically most-stable stereoisomer was obtained. Remarkably, this diastereoselective coupling was successful not only for 1,2-substituted cyclic systems, but also for 1,3- and 1,4-substituted cyclohexylzinc reagents. The origin of this remote stereocontrol was investigated by NMR experiments and density functional theory calculations. A detailed mechanism based on these experimental and theoretical data is proposed.

For some decades bidentate ligands have prevailed in the field of transition-metal catalysis. [1] The superiority of bidentate ligands over monodentates was explained by the higher conformational rigidity of the ligands and their stronger coordination to the metal. [1b] However, in the last few years monodentate ligands have experienced a revival, and moreover interest in rational ligand design has grown tremendously: [2] Monodentate ligands have been developed which are able to self-assemble in the coordination sphere of the metal center through weak ligand-ligand interactions, such as hydrogen bonding [2d-g] and metal-bridged coordinative bonding. [2h-j] However, the use of weak interligand interactions based on CH-p and p-p interactions for rational ligand design is still very challenging. [2a] Various experimental and theoretical approaches have been devised to investigate and quantify noncovalent interactions such as hydrogen bonding and p-p stacking and their dependency on solvent properties. [3] The "double-mutant cycles" developed by Fersht et al. have become a powerful thermodynamic tool for the experimental quantification of single noncovalent interactions in proteins and in host-guest model systems. [4] In addition the "molecular torsion balance" developed by Wilcox and co-workers [5] has been applied to quantify CH-p interactions and aromatic interactions in organic molecules. [3a,b] However, no method has been presented to measure the contribution of noncovalent ligandligand interactions within transition-metal complexes to date. For guest-host systems binding constants are typically used for the quantification of noncovalent interactions. However, in the case of metal complexes the binding constant reflects not only noncovalent interactions, but primarily metal-ligand binding based on electronic properties such as the s-donor/pacceptor properties of the ligands. Therefore, for the measurement of pure ligand-ligand interactions, covalent and noncovalent contributions to the binding constant must be separated. In addition, possible changes in the electronic and electrostatic properties must be considered, that is, changes in the stereoelectronic properties of the metal-ligand bond and of the electrostatic contributions of the dipoles due to reorientation within the ligands upon cis-trans isomerization. To the best of our knowledge, it was previously not possible to separate and quantify the contributions of noncovalent interactions (e.g. CH-p and p-p interactions) from stereoelectronic properties and electrostatic interactions in transition-metal complexes.In this study we present the first method for the quantification of noncovalent ligand-ligand interactions in transition-metal complexes separated from stereoelectronic and electrostatic effects. Based on the formation trends of different phosphoramidite palladium complexes the free energy difference DDG caused by the formation of additional attractive CH-p interactions was determined. Moreover, 1 H 1 H NOESY measurements and 1 H chemical shi...

During the last decade, phosphoramidites have been established as a so-called privileged class of ligands in various transition metal catalyses. However, the interactions responsible for their favorable properties have hitherto remained elusive. To address this issue, the formation trends, structural features, and interligand interaction patterns of several trans- and cis-[PdLL'Cl2] complexes have been investigated by NMR spectroscopy. The energetic contribution of their interligand interactions has been measured experimentally using the supramolecular balance for transition-metal complexes. The resulting energetics combined with an analysis of the electrostatic potential surfaces reveal that in phosphoramidites not only the aryl groups but the complete (CH)CH3 Ph moieties of the amine side chains form extended quasi-planar CH-π and π-π interaction surfaces. Application of the supramolecular balance has shown that modulations in these extended interaction surfaces cause energetic differences that are relevant to enantioselective catalysis. In addition, the energetics of these interligand interactions are quite independent of the actual structures of the complexes. This is shown by similar formation and aggregation trends of complexes with the same ligand but different structures. The extended quasi-planar electrostatic interaction surface of the (CH)CH3 Ph moiety explains the known pattern of successful ligand modulation and the substrate specificity of phosphoramidites. Thus, we propose modulations in these extended CH-π and π-π interaction areas as a refined stereoselection mode for these ligands. Based on the example of phosphoramidites, this study reveals three general features potentially applicable to various ligands in asymmetric catalysis. First, specific combinations of alkyl and aryl moieties can be used to create extended anisotropic interaction areas. Second, modulations in these interaction surfaces cause energetic differences that are relevant to catalytic applications. Third, bulky substituents with matching complementary interaction surfaces should not only be considered in terms of steric hindrance but also in terms of attractive and repulsive interactions, a feature that may often be underestimated in asymmetric catalysis.

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...

A fast and easy DOSY screening of ligands that affords high enantioselectivities in catalysis allows the aggregation trends of their transition‐metal complexes to be predicted. In their Communication on R. Gschwind and co‐workers present the first aggregation study of selected phosphoramidites and their complexes. This method is useful for catalyst optimization as no knowledge of the complex structure is necessary and the temperature range applicable to the desired catalytic reaction can be quickly determined.