Luca Pignataro

Supramolecular ligand–ligand and ligand–substrate interactions for highly selective transition metal catalysis

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.

Rhodium-Catalyzed Asymmetric Hydrogenation of Olefins with PhthalaPhos, a New Class of Chiral Supramolecular Ligands

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.

PhthalaPhos: Chiral Supramolecular Ligands for Enantioselective Rhodium‐Catalyzed Hydrogenation 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. 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 or coordinative bonds) which can play the following roles: 1) self-assembly of two monodentate ligands to form a so-called supramolecular bidentate ligand; 2) binding the substrate(s) in proximity to the catalytic metal center in analogy to metalloenzymes. Among the different kinds of noncovalent interactions that have been used so far for developing supramolecular ligands, hydrogen bonds are arguably the most practical and efficient 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, 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

Chemical, Pharmacological, and in vitro Metabolic Stability Studies on Enantiomerically Pure RC‐33 Compounds: Promising Neuroprotective Agents Acting as σ1 Receptor Agonists

Our recent research efforts identified racemic RC‐33 as a potent and metabolically stable σ1 receptor agonist. Herein we describe the isolation of pure RC‐33 enantiomers by chiral chromatography, assignment of their absolute configuration, and in vitro biological studies in order to address the role of chirality in the biological activity of these compounds and their metabolic processing. The binding of enantiopure RC‐33 to the σ1 receptor was also investigated in silico by molecular dynamics simulations. Both RC‐33 enantiomers showed similar affinities for the σ1 receptor and appeared to be almost equally effective as σ1 receptor agonists. However, the R‐configured enantiomer showed higher in vitro hepatic metabolic stability in the presence of NADPH than the S enantiomer. Overall, the results presented herein led us to select (R)‐RC‐33 as the optimal candidate for further in vivo studies in an animal model of amyotrophic lateral sclerosis.

Unusual mechanistic course of some NHC-mediated transesterifications.

During experiments on the transesterification of vinyl benzoate with ethanol mediated by IPr and IMes, unexpected species were observed and characterized that call into question the accepted mechanism of the NHC-mediated transesterification of vinyl esters.

A Library Approach to the Development of BenzaPhos: Highly Efficient Chiral Supramolecular Ligands for Asymmetric Hydrogenation

A library of chiral supramolecular ligands, named BenzaPhos, of straightforward preparation (two steps from commercially or readily available starting materials) and modular structure, was designed and synthesized. The ligands were screened in the search for new rhodium catalysts for the enantioselective hydrogenation of several benchmark and industrially relevant substrates. Once a series of hits were identified, structural modifications were introduced on three of the best ligands and a small second-generation library was created. Members of the latter library showed outstanding levels of activity and enantioselectivity in the hydrogenation of challenging olefins, such as enamide S4 and β-dehydroamino ester S5 (>99% ee: best value ever reported in both cases). A series of control experiments were undertaken to clarify the role of hydrogen bonding in determining the catalytic properties of the new ligands. The results of these experiments, together with those of computational studies carried out on four dihydride complexes involved in the catalytic hydrogenation of substrate S4, strongly suggest that a substrate orientation takes place in the catalytic cycle by formation of a hydrogen bond between the ligand amide oxygen atom and the substrate amide NH atom.

Toward the identification of neuroprotective agents: g-scale synthesis, pharmacokinetic evaluation and CNS distribution of (R)-RC-33, a promising SIGMA1 receptor agonist.

AIM Nowadays, there is a great interest in the therapeutic potential of sigma1 receptor ligands for treating different CNS pathologies. Our previous investigations led to identify (R)-RC-33 as a potent and selective S1R agonist. RESULTS Herein, we report the gram-scale synthesis, pharmacokinetic profile and CNS distribution of (R)-RC-33 in the mouse to determine the most suitable dosage schedule for in vivo administration. For comparative purposes, the same experiments were also performed with PRE-084, the most widely used S1R agonist commonly in pharmacological experiments. DISCUSSION (R)-RC-33 shows a similar pharmacokinetic profile and a better CNS distribution when compared with PRE-084. CONCLUSION (R)-RC-33 may be a promising candidate for in vivo studies in animal models of neurodegenerative diseases.

Cyclic isoDGR and RGD Peptidomimetics Containing Bifunctional Diketopiperazine Scaffolds are Integrin Antagonists

The cyclo[DKP-isoDGR] peptidomimetics 2-5, containing bifunctional diketopiperazine (DKP) scaffolds that differ in the configuration of the two DKP stereocenters and in the substitution at the DKP nitrogen atoms, were prepared and examined in vitro in competitive binding assays with purified αv β3 and αv β5 integrin receptors. IC50 values ranged from low nanomolar (ligand 3) to submicromolar with αv β3 integrin. The biological activities of ligands cyclo[DKP3-RGD] 1 and cyclo[DKP3-isoDGR] 3, bearing the same bifunctional DKP scaffold and showing similar αV β3 integrin binding values, were compared in terms of their cellular effects in human U373 glioblastoma cells. Compounds 1 and 3 displayed overlapping inhibitory effects on the FAK/Akt integrin activated transduction pathway and on integrin-mediated cell infiltration processes, and qualify therefore, despite the different RGD and isoDGR sequences, as integrin antagonists. Both compounds induced apoptosis in glioma cells after 72 hour treatment.

Synthesis and biological evaluation of dual action cyclo-RGD/SMAC mimetic conjugates targeting αvβ3/αvβ5 integrins and IAP proteins

The rational design, synthesis and in vitro biological evaluation of dual action conjugates 11-13, containing a tumour targeting, integrin αvβ3/αvβ5 ligand portion and a pro-apoptotic SMAC mimetic portion (cyclo-RGD/SMAC mimetic conjugates) are reported. The binding strength of the two separate units is generally maintained by these dual action conjugates. In particular, the connection between the separate units (anchor points on each unit; nature, length and stability of the linker) influences the activity of each portion against its molecular targets (integrins αvβ3/αvβ5 for cyclo-RGD, IAP proteins for SMAC mimetics). Each conjugate portion tolerates different substitutions while preserving the binding affinity for each target.

Studies on the enantiomers of RC-33 as neuroprotective agents: isolation, configurational assignment, and preliminary biological profile

In this study we addressed the role of chirality in the biological activity of RC-33, recently studied by us in its racemic form. An asymmetric synthesis procedure was the first experiment, leading to the desired enantioenriched RC-33 but with an enantiomeric excess (ee) not good enough for supporting the in vitro investigation. An enantioselective high-performance liquid chromatography (HPLC) procedure was then successfully carried out, yielding both RC-33 enantiomers in amounts and optical purity suitable for the pharmacological study. The absolute configuration of pure enantiomers was easily assigned exploiting the asymmetric synthesis previously devised. As emerged in the preliminary in vitro biological investigation, (S)- and (R)-RC-33 possess a comparable affinity towards the σ1 receptor and a very a similar behavior in the calcium influx assay, resulting in an equally effective σ1 receptor agonist. Overall, the results obtained so far suggest that the interaction with the biological target is nonstereoselective and leads us to hypothesize that there is a lack of stereoselectivity in the biological activity of RC-33.