Nucleophilicity Prediction via Multivariate Linear Regression Analysis.

The concept of nucleophilicity is at the basis of most transformations in chemistry. Understanding and predicting the relative reactivity of different nucleophiles is therefore of paramount importance. Mayr's nucleophilicity scale likely represents the most complete collection of reactivity data, which currently includes over 1200 nucleophiles. Several attempts have been made to theoretically predict Mayr's nucleophilicity parameters N based on calculation of molecular properties, but a general model accounting for different classes of nucleophiles could not be obtained so far. We herein show that multivariate linear regression analysis is a suitable tool for obtaining a simple model predicting N for virtually any class of nucleophiles in different solvents for a set of 341 data points. The key descriptors of the model were found to account for the proton affinity, solvation energies, and sterics.

Enantioselective α-Arylation of Ketones via a Novel Cu(I)-Bis(phosphine) Dioxide Catalytic System.

A novel catalytic system based on copper(I) and chiral bis(phosphine) dioxides is described. This allows the arylation of silyl enol ethers to access enolizable α-arylated ketones in good yields and enantiomeric excess up to 95%. Noncyclic ketones are amenable substrates with this method, which complements other approaches based on palladium catalysis. Optimization of the ligand structure is accomplished via rational design driven by correlation analysis. Preliminary mechanistic hypotheses are also evaluated in order to identify the role of chiral bis(phosphine) dioxides.

A Rational Approach to Organo-Photocatalysis: Novel Designs and Structure-Property Relationships.

Organic photocatalysts are emerging as viable and more sustainable tools than metal complexes. Recently, the field of organo-photocatalysis has experienced an explosion in terms of applications, redesign of well-established systems, and identification of novel scaffolds. A rational approach to the structural modification of the different photocatalysts is key to accessing unprecedented reactivity, while improving their catalytic performances. We herein discuss the concepts underpinning the scaffold modification of some of the most recently used photocatalysts and analyze how specific structural changes alter their physicochemical and redox properties.

Structure-Based Design of Potent Tumor-Associated Antigens: Modulation of Peptide Presentation by Single-Atom O/S or O/Se Substitutions at the Glycosidic Linkage.

GalNAc-glycopeptides derived from mucin MUC1 are an important class of tumor-associated antigens. α- O-glycosylation forces the peptide to adopt an extended conformation in solution, which is far from the structure observed in complexes with a model anti-MUC1 antibody. Herein, we propose a new strategy for designing potent antigen mimics based on modulating peptide/carbohydrate interactions by means of O → S/Se replacement at the glycosidic linkage. These minimal chemical modifications bring about two key structural changes to the glycopeptide. They increase the carbohydrate-peptide distance and change the orientation and dynamics of the glycosidic linkage. As a result, the peptide acquires a preorganized and optimal structure suited for antibody binding. Accordingly, these new glycopeptides display improved binding toward a representative anti-MUC1 antibody relative to the native antigens. To prove the potential of these glycopeptides as tumor-associated MUC1 antigen mimics, the derivative bearing the S-glycosidic linkage was conjugated to gold nanoparticles and tested as an immunogenic formulation in mice without any adjuvant, which resulted in a significant humoral immune response. Importantly, the mice antisera recognize cancer cells in biopsies of breast cancer patients with high selectivity. This finding demonstrates that the antibodies elicited against the mimetic antigen indeed recognize the naturally occurring antigen in its physiological context. Clinically, the exploitation of tumor-associated antigen mimics may contribute to the development of cancer vaccines and to the improvement of cancer diagnosis based on anti-MUC1 antibodies. The methodology presented here is of general interest for applications because it may be extended to modulate the affinity of biologically relevant glycopeptides toward their receptors.

Fluorinated triazole-containing sphingosine analogues. Syntheses and in vitro evaluation as SPHK inhibitors.

Sphingosine analogues with a rigid triazole moiety in the aliphatic chain and systematic modifications in the polar head and different degrees of fluorination at the terminus of the alkylic chain were synthesized from a common alkynyl aziridine key synthon. This key synthon was obtained by enantioselective organocatalyzed aziridination and it was subsequently ring opened in a regioselective manner in acidic medium. Up to 16 sphingosine analogues were prepared in a straightforward manner. The in vitro activity of the obtained products as SPHK1 and SPHK2 inhibitors was evaluated, displaying comparable activity to that of DMS.

Palladium-catalyzed allylic amination: a powerful tool for the enantioselective synthesis of acyclic nucleoside phosphonates.

Acyclic nucleoside phosphonates have been prepared in a straightforward manner and in high yields by an enantioselective palladium-catalyzed allylic substitution involving nucleic bases as nucleophiles followed by cross-metathesis reaction with diethyl allylphosphonate.

Enantiopure 1,2,3-triazolyl-ß-amino acids via click cycloaddition reaction on racemic alkynyl precursors followed by separation of stereoisomers.

In recent years, peptidomimetics have gained enormous importance in drug design aiming to achieve increased drug metabolic stability and higher selectivity. In the field of peptidomimetics, ß-peptides incorporating ß2- and ß3-amino acids (the higher homologs of natural α-amino acids) provide a powerful method for the synthesis of peptidomimetics with particular secondary structures. In this regard, 1,2,3-triazole-modified peptidomimetics can act as effective peptide surrogates, and therefore have gained considerable attention. In the present report, 1,4-disubstituted 1,2,3-triazoles attached to ß-amino acids were prepared selectively from the corresponding alkynyl-ß2-amino acids according to Huisgen's copper-catalyzed 1,3-dipolar cycloaddition (CuAAC), under mild conditions and with very high efficiency. Different azide derivatives, including some incorporating α-amino acids, were employed in this cycloaddition reaction. The enantiopure compounds were obtained via diastereomeric salt formation with chiral adjuvants, and subsequent separation.