The use of non covalent supramolecular ligand-ligand and ligand-substrate interactions in transition metal-catalysed transformations is a new, rapidly emerging area of research. Non-covalent interactions between monodentate ligands such as hydrogen bonding, coordinative bonding, ion pairing, π-π interactions and the formation of inclusion compounds, have been shown to impart higher activity and chemo-, regio-, and stereoselectivity to the corresponding transition metal complexes in a number of catalytic applications. Analogously, supramolecular ligand-substrate interactions, and particularly hydrogen bonding, have been used to direct the regio- and stereochemistry of several metal-catalysed reactions. The catalytic systems relying on supramolecular interactions are generally capable of self-assembling from simpler components in the environment where catalysis is to take place, and are therefore very well-suited for combinatorial catalyst discovery strategies and high-throughput screening.

A library of 19 binol-derived chiral monophosphites that contain a phthalic acid diamide group (PhthalaPhos) has been designed and synthesized in four steps. These new ligands were screened in the rhodium-catalyzed enantioselective hydrogenation of prochiral dehydroamino esters and enamides. Several members of the library showed excellent enantioselectivity with methyl 2-acetamido acrylate (6 ligands gave >97% ee), methyl (Z)-2-acetamido cinnamate (6 ligands gave >94% ee), and N-(1-phenylvinyl)acetamide (9 ligands gave >95% ee), whilst only a few representatives afforded high enantioselectivities for challenging and industrially relevant substrates N-(3,4-dihydronaphthalen-1-yl)-acetamide (96% ee in one case) and methyl (E)-2-(acetamidomethyl)-3-phenylacrylate (99% ee in one case). In most cases, the new ligands were more active and more stereoselective than their structurally related monodentate phosphites (which are devoid of functional groups that are capable of hydrogen-bonding interactions). Control experiments and kinetic studies were carried out that allowed us to demonstrate that hydrogen-bonding interactions involving the diamide group of the PhthalaPhos ligands strongly contribute to their outstanding catalytic properties. Computational studies carried out on a rhodium precatalyst and on a conceivable intermediate in the hydrogenation catalytic cycle shed some light on the role played by hydrogen bonding, which is likely to act in a substrate-orientation effect.

Chemists have largely taken inspiration from Nature in the development of new approaches to synthetic challenges. Combinatorial chemistry stems from the concept of evolution, whereby random mutation of a chemical structure gives rise to libraries of compounds, from which an optimal lead can be found with high probability. On the other hand, Nature makes wide use of noncovalent interactions to build its complex supramolecular architectures and to achieve efficient and selective transformations. In recent years, combinatorial and supramolecular approaches to the development of new ligands for asymmetric catalysis has gained momentum. [1, 2d] The term "supramolecular ligand" encompasses all ligands possessing, besides the atom(s) coordinating to the catalytic metal atom, an additional functionality capable of noncovalent interactions (mainly hydrogen [3] or coordinative bonds [4] ) which can play the following roles: 1) self-assembly of two monodentate ligands to form a so-called supramolecular bidentate ligand; [5] 2) binding the substrate(s) in proximity to the catalytic metal center [2] in analogy to metalloenzymes.[6] Among the different kinds of noncovalent interactions that have been used so far for developing supramolecular ligands, [5] hydrogen bonds are arguably the most practical and efficient [2,3] for several reasons: 1) functional groups capable of hydrogen bonding (e.g., amides, ureas, guanidines) are stable and relatively easy to introduce; 2) hydrogen bonds are created dynamically and reversibly in the reaction medium (where catalysis is to take place), are capable of self-repair when broken, and often coexist with other interactions in a "noninvasive" manner.As a result of our continued interest in developing supramolecular ligands, [7] we report herein the design and synthesis of a novel class of chiral monodentate phosphite ligands, named PhthalaPhos, which contain a phthalic acid primary diamide moiety (Scheme 1). The phthalamidic group displays both donor and acceptor hydrogen-bonding properties that, in principle, can give rise to supramolecular interactions both between the ligands and with the reaction substrate. The modular nature of the PhthalaPhos ligands allows their properties to be tuned by simply varying structural elements such as the linker, the binol moiety, and the ancillary amide group (i.e., the amide not connected to the phosphite group), and thus parallel-combinatorial ligand optimization is possible. [1a,c] The PhthalaPhos ligands were easily prepared in four steps as outlined in Scheme 1: phthalic anhydride was treated with a primary amine to give phthalic acid mono amides 1 in 94-98 % yield.[8] Dehydration of the latter in the presence of trifluoroacetic anhydride gave phthalisoimides 2 in high yields, whose reaction with a chosen amino alcohol led to phthalic acid diamides 3.[9] Diamide mono-alcohols 3 were treated with binol-derived chlorophosphites [10] to give PhthalaPhos ligands 4.Although we synthesized and screened a relatively large library of nineteen members (4...

Heteroleptic complexes, formed selectively by using a 1 : 1 combination of a sigma-donor and a pi-acceptor ligand, are involved in Rh- and Pd-catalysed reactions.

Chemists have largely taken inspiration from Nature in the development of new approaches to synthetic challenges. Combinatorial chemistry stems from the concept of evolution, whereby random mutation of a chemical structure gives rise to libraries of compounds, from which an optimal lead can be found with high probability. On the other hand, Nature makes wide use of noncovalent interactions to build its complex supramolecular architectures and to achieve efficient and selective transformations. In recent years, combinatorial and supramolecular approaches to the development of new ligands for asymmetric catalysis has gained momentum. [1, 2d] The term "supramolecular ligand" encompasses all ligands possessing, besides the atom(s) coordinating to the catalytic metal atom, an additional functionality capable of noncovalent interactions (mainly hydrogen [3] or coordinative bonds [4] ) which can play the following roles: 1) self-assembly of two monodentate ligands to form a so-called supramolecular bidentate ligand; [5] 2) binding the substrate(s) in proximity to the catalytic metal center [2] in analogy to metalloenzymes. [6] Among the different kinds of noncovalent interactions that have been used so far for developing supramolecular ligands, [5] hydrogen bonds are arguably the most practical and efficient [2,3] for several reasons: 1) functional groups capable of hydrogen bonding (e.g., amides, ureas, guanidines) are stable and relatively easy to introduce; 2) hydrogen bonds are created dynamically and reversibly in the reaction medium (where catalysis is to take place), are capable of self-repair when broken, and often coexist with other interactions in a "noninvasive" manner.As a result of our continued interest in developing supramolecular ligands, [7] we report herein the design and synthesis of a novel class of chiral monodentate phosphite ligands, named PhthalaPhos, which contain a phthalic acid primary diamide moiety (Scheme 1). The phthalamidic group displays both donor and acceptor hydrogen-bonding properties that, in principle, can give rise to supramolecular interactions both between the ligands and with the reaction substrate. The modular nature of the PhthalaPhos ligands allows their properties to be tuned by simply varying structural elements such as the linker, the binol moiety, and the ancillary amide group (i.e., the amide not connected to the phosphite group), and thus parallel-combinatorial ligand optimization is possible. [1a,c] The PhthalaPhos ligands were easily prepared in four steps as outlined in Scheme 1: phthalic anhydride was treated with a primary amine to give phthalic acid mono amides 1 in 94-98 % yield. [8] Dehydration of the latter in the presence of trifluoroacetic anhydride gave phthalisoimides 2 in high yields, whose reaction with a chosen amino alcohol led to phthalic acid diamides 3.[9] Diamide mono-alcohols 3 were treated with binol-derived chlorophosphites [10] to give Phtha-laPhos ligands 4.Although we synthesized and screened a relatively large library of nineteen members ...