An induced-fit model for asymmetric organocatalytic reactions: a case study of the activation of olefins via chiral Brønsted acid catalysts

We elucidate the stereo-controlling factors of the asymmetric intramolecular hydroalkoxylation of terminal olefins catalyzed by bulky Brønsted acids [Science 2018, 359 (6383), 1501–1505] using high-level electronic structure methods. The catalyst–substrate interaction is described using a dispersion-driven induced-fit model, in which the conformational changes of the catalyst and of the substrate in the transition states are governed to a large extent by London dispersion forces. The distortion energy of the catalyst is dominated by the change in the intramolecular dispersion interactions, while intermolecular catalyst–substrate dispersion interactions are the major stabilizing contribution in the transition state. This model provides a new general framework in which to discuss the stereoselectivity of transformations catalyzed by such confined organocatalysts

Can domain-based local pair natural orbitals approaches accurately predict phosphorescence energies?

Since the discovery of the peculiar conducting and optical properties of aromatics, many efforts have been made to characterize and predict their phosphorescence. This physical process is exploited in modern Organic Emitting Light Diodes (OLEDs), and it is also one of the processes decreasing the efficiency of Dye-sensitized solar cells (DSSCs). Herein, we propose a computational strategy for the accurate calculation of singlet–triplet gaps of aromatic compounds, which provides results that are in excellent agreement with available experimental data. Our approach relies on the domain-based local pair natural orbital (DLPNO) variant of the “gold standard” CCSD(T) method. The convergence of our results with respect to the key technical parameters of the calculation, such as the basis set used, the approximations employed in the perturbative triples correction, and the dimension of the PNOs space, was thoroughly discussed

Fragment-Based Local Coupled Cluster Embedding Approach for the Quantification and Analysis of Noncovalent Interactions: Exploring the Many-Body Expansion of the Local Coupled Cluster Energy

Herein, we introduce a fragment-based local coupled cluster embedding approach for the accurate quantification and analysis of noncovalent interactions in molecular aggregates. Our scheme combines two different expansions of the domain-based local pair natural orbital coupled cluster (DLPNO-CCSD(T)) energy: the many-body expansion (MBE) and the local energy decomposition (LED). The low-order terms in the MBE are initially computed in the presence of an environment that is treated at a low level of theory. Then, LED is used to decompose the energy of each term in the embedded MBE into additive fragment and fragment-pairwise contributions. This information is used to quantify the total energy of the system while providing at the same time in-depth insights into the nature and cooperativity of noncovalent interactions. Two different approaches are introduced and tested, in which the environment is treated at different levels of theory: the local coupled cluster in the Hartree–Fock (LCC-in-HF) method, in which the environment is treated at the HF level; and the electrostatically embedded local coupled cluster method (LCC-in-EE), in which the environment is replaced by point charges. Both schemes are designed to preserve as much as possible the accuracy of the parent local coupled cluster method for total energies, while being embarrassingly parallel and less memory intensive. These schemes appear to be particularly promising for the study of large and complex molecular aggregates at the coupled cluster level, such as condensed phase systems and protein–ligand interactions

From Serendipity to Rational Design: Heteroleptic Dirhodium Amidate Complexes for Diastereodivergent Asymmetric Cyclopropanation

A heteroleptic dirhodium paddlewheel complex comprising three chiral carboxylate ligands and one achiral acetamidate ligand has recently been found to be uniquely effective in catalyzing the asymmetric cyclopropanation of olefins with α-stannylated (silylated and germylated) α-diazoacetate derivatives. A number of control experiments in combination with detailed computational studies provide compelling evidence that an interligand hydrogen bond between the −NH group of the amidate and the ester carbonyl group of the reactive rhodium carbene intermediate plays a quintessential role in the stereodetermining transition state. The penalty for distorting this array outweighs steric arguments and renders two of the four conceivable transitions states unviable. Based on this mechanistic insight, the design of the parent catalyst is revisited herein: placement of appropriate peripheral substituents allows high levels of diastereocontrol to be imposed upon cyclopropanation, which the original catalyst lacks. Because the new complexes allow either trans- or cis-configured stannylated cyclopropanes to be made selectively and in excellent optical purity, this transformation also marks a rare case of diastereodivergent asymmetric catalysis. The products are amenable to stereospecific cross coupling with aryl halides or alkenyl triflates; these transformations appear to be the first examples of the formation of stereogenic quaternary carbon centers by the Stille reaction; carbonylative coupling is also achieved. Moreover, tin/lithium exchange affords chiral lithium enolates, which can be intercepted with a variety of electrophilic partners. The virtues and inherent flexibility of this new methodology are illustrated by an efficient synthesis of two salinilactones, extremely scarce bacterial metabolites with signaling function involved in the self-regulatory growth inhibition of the producing strain

Triple Resonance Experiments for the Rapid Detection of ¹⁰³Rh NMR Shifts: A Combined Experimental and Theoretical Study into Dirhodium and Bismuth–Rhodium Paddlewheel Complexes

A H(C)Rh triple resonance NMR experiment makes the rapid detection of 103Rh chemical shifts possible, which were previously beyond reach. It served to analyze a series of dirhodium and bismuth–rhodium paddlewheel complexes of the utmost importance for metal–carbene chemistry. The excellent match between the experimental and computed 103Rh shifts in combination with a detailed analysis of the pertinent shielding tensors forms a sound basis for a qualitative and quantitative interpretation of these otherwise (basically) inaccessible data. The observed trends clearly reflect the influence exerted by the equatorial ligands (carboxylate versus carboxamidate), the axial ligands (solvents), and the internal “metalloligand” (Rh versus Bi) on the electronic estate of the reactive Rh(II) center

A New Ligand Design Based on London Dispersion Empowers Chiral Bismuth–Rhodium Paddlewheel Catalysts

Heterobimetallic bismuth–rhodium paddlewheel complexes with phenylglycine ligands carrying TIPS-groups at the meta-positions of the aromatic ring exhibit outstanding levels of selectivity in reactions of donor/acceptor and donor/donor carbenes; at the same time, the reaction rates are much faster and the substrate scope is considerably wider than those of previous generations of chiral [BiRh] catalysts. As shown by a combined experimental, crystallographic, and computational study, the new catalysts draw their excellent application profile largely from the stabilization of the chiral ligand sphere by London dispersion (LD) interactions of the peripheral silyl substituents

Harnessing the ambiphilicity of silyl nitronates in a catalytic asymmetric approach to aliphatic β³-amino acids

Nitronate anions, formally generated by α-deprotonating the corresponding nitroalkanes, are highly nucleophilic and versatile intermediates in many carbon–carbon bond-forming reactions. In contrast, the corresponding silyl nitronates are ambiphilic and react, at the same carbon atom, with both electrophiles and nucleophiles. However, while their nucleophilicity has been well exploited in catalytic enantioselective reactions with imines and aldehydes, utilizing the electrophilicity of silyl nitronates in asymmetric synthesis has remained elusive. Here we report the facile, efficient and general reactivity of readily available silyl nitronates with silyl ketene acetals, catalysed by highly Lewis-acidic and confined silylium imidodiphosphorimidate catalysts. The products of this reaction, so-called nitroso acetals, are obtained in excellent enantioselectivity and can be easily converted into N-Boc-β3-amino acid esters in a single step

[Glucocorticoid induced TNFR-related protein (GITR) as marker of human regulatory T cells: expansion of the GITR(+)CD25⁻ cell subset in patients with systemic lupus erythematosus].

Objectives: Regulatory T cells (TREG) represent a T cell subset able to modulate immune response by suppressing autoreactive T-lymphocytes. The evidence of a reduced number and an impaired function of this cell population in autoimmune/ inflammatory chronic diseases led to the hypothesis of its involvement in the pathogenesis of these disorders. Glucocorticoid-induced TNFR-related protein (GITR) is a well known marker of murine TREG cells, but little is known in humans. The aim of this study was to investigate the characteristics of TREG cells in systemic lupus erythematosus (SLE) and the potential role of GITR as marker of human TREG. Methods: Nineteen SLE patients and 15 sex- and age-matched normal controls (NC) were enrolled. CD4+ T cells were magnetic sorted from peripheral blood by negative selection. Cell phenotype was analyzed through flow-cytometry using primary and secondary antibodies and real time polymerase-chain reaction (PCR) using TaqMan probes. Results: The CD25highGITRhigh subset was significantly decreased in SLE patients with respect to NC (0.37±0.21% vs 0.72±0.19%; p<0.05). On the opposite, the CD25-GITRhigh cell population was expanded in the peripheral blood of SLE patients (3.5±2.25 vs 0.70±0.32%, p<0.01). Interestingly, FoxP3 at mRNA level was expressed in both CD25- GITRhigh and CD25highGITRhigh cells, suggesting that both cell subsets have regulatory activity. Conclusions: CD4+CD25-GITRhigh cells are increased in SLE as compared to NC. The expression of high level of GITR, but not CD25, on FoxP3+ cells appears to point to a regulatory phenotype of this peculiar T cell subset

Characterization and Biological Activities of In Vitro Digested Olive Pomace Polyphenols Evaluated on Ex Vivo Human Immune Blood Cells

Olive pomace (OP) represents one of the main by-products of olive oil production, which still contains high quantities of health-promoting bioactive compounds. In the present study, three batches of sun-dried OP were characterized for their profile in phenolic compounds (by HPLC-DAD) and in vitro antioxidant properties (ABTS, FRAP and DPPH assays) before (methanolic extracts) and after (aqueous extracts) their simulated in vitro digestion and dialysis. Phenolic profiles, and, accordingly, the antioxidant activities, showed significant differences among the three OP batches, and most compounds showed good bioaccessibility after simulated digestion. Based on these preliminary screenings, the best OP aqueous extract (OP-W) was further characterized for its peptide composition and subdivided into seven fractions (OP-F). The most promising OP-F (characterized for its metabolome) and OP-W samples were then assessed for their potential anti-inflammatory properties in ex vivo human peripheral mononuclear cells (PBMCs) triggered or not with lipopolysaccharide (LPS). The levels of 16 pro-and anti-inflammatory cytokines were measured in PBMC culture media by multiplex ELISA assay, whereas the gene expressions of interleukin-6 (IL-6), IL-10 and TNF-alpha were measured by real time RT-qPCR. Interestingly, OP-W and PO-F samples had a similar effect in reducing the expressions of IL-6 and TNF-alpha, but only OP-W was able to reduce the release of these inflammatory mediators, suggesting that the anti-inflammatory activity of OP-W is different from that of OP-F