Long-lived polymer-supported dimeric Cinchona alkaloid organocatalyst in the asymmetric α-amination of 2-oxindoles

Nearly quantitative yields and high enantiomeric purity (89–95% ee) were attained in the course of 100 reaction cycles of a polystyrene resin-supported Cinchona alkaloid organocatalyst in the enantioselective α-amination of 2-oxindoles with diethyl azodicarboxylate. The catalytic material proved stable for >5300 h operation time over 8 months

SUPPORTED LIGANDS AND ORGANOCATALYSTS FOR ENANTIOSELECTIVE TRANSFORMATIONS: A PRACTICAL FEASIBILITY PERSPECTIVE

A new approach for the immobilization onto organic insoluble polymers of Cinchona alkaloid derivatives was developed and the resulting insoluble polymer-bound (IPB) systems were used as enantioselective organocatalysts in different metal-free asymmetric transformations. Landmarks of this work were the scalable preparation of the IPB derivatives, the attainment of excellent catalytic performance (up to 97% ee) in selected enantioselective processes (dimerization of ketenes and a-amination of 2-oxindoles) and extended serviceability (up to 100 reaction cycles and 5300 h reaction time) of the supported catalysts

Aminopropyl-silica-supported Cu nanoparticles: An efficient catalyst for continuous-flow Huisgen azide-alkyne cycloaddition (CuAAC)

Cu nanoparticles prepared by metal vapor synthesis (MVS) were immobilized on 3-aminopropyl-functionalized silica at room temperature. HRTEM analysis of the catalyst showed that the copper nanoparticles are present with mean diameters limited in the range 1.0-4.5 nm. TPR analysis was performed in order to study the oxidation state of the supported copper nanoparticles. The supported catalyst was used both in batch and in a packed-bed reactor for continuous-flow CuAAC reaction. The activation of the copper catalyst by reduction using phenyl hydrazine in continuous-flow conditions was demonstrated. Along with the high catalytic activity (productivity up to 1689 mol/mol), the catalyst can be used several times with negligible Cu leaching in the product (<9 ppm), less than allowed Cu contaminant in pharmaceuticals. The applicability of packed-bed flow reactor was showed by sequentially converting different substrates in their corresponding products using same column

Ultrafine palladium nanoparticles immobilized into poly(4-vinylpyridine)-based porous monolith for continuous-flow Mizoroki-Heck reaction

Ultrafine Pd nanoparticles (dm = 2.3 nm), obtained by metal vapor synthesis technique, were immobilized into a poly(4-vinylpyridine)-based porous monolith by means of a new synthetic approach. The synthesis involves stabilization of Pd nanoparticles with 4-vinylpyridine ligand and their subsequent immobilization into the monolith by radical co-polymerization of the resulting metal-embedding monomer with ethylene glycol dimethacrylate in presence of porogenic agents (i.e. DMF and PEG-400) inside stainless-steel columns (HPLC type). The hybrid monolithic reactors containing highly dispersed Pd nanoparticles were effectively used as catalyst for Mizoroki-Heck cross-coupling reactions carried out under continuous-flow conditions. The devices showed long life-time (>65 h) and very low Pd leaching (<2 ppm)

Highly enantioselective catalytic synthesis of chiral pyridines

General methods to prepare chiral pyridine derivatives are greatly sought after due to their significance in medicinal chemistry. Here, we report highly enantioselective catalytic transformations of poorly reactive β-substituted alkenyl pyridines to access a wide range of alkylated chiral pyridines. The simple methodology involves reactivity enhancement via Lewis acid (LA) activation, the use of readily available and highly reactive Grignard reagents, and a copper-chiral diphosphine ligand catalyst. Apart from allowing the introduction of different linear, branched, cyclic, and functionalised alkyl chains at the β-position of alkenyl pyridines, the catalytic system also shows high functional group tolerance

Inverting Small Molecule-Protein Recognition by the Fluorine Gauche Effect: Selectivity Regulated by Multiple H→F Bioisosterism

Fluorinated motifs have a venerable history in drug discovery, but as C(sp3 )@F-rich 3D scaffolds appear with increasing frequency, the effect of multiple bioisosteric changes on molecular recognition requires elucidation. Herein we demonstrate that installation of a 1,3,5-stereotriad, in the substrate for a commonly used lipase from Pseudomonas fluorescens does not inhibit recognition, but inverts stereoselectivity. This provides facile access to optically active, stereochemically well-defined organofluorine compounds (up to 98% ee). Whilst orthogonal recognition is observed with fluorine, the trend does not hold for the corresponding chlorinated substrates or mixed halogens. This phenomenon can be placed on a structural basis by considering the stereoelectronic gauche effect inherent to F@C@C@X systems (s!s*). Docking reveals that this change in selectivity (H versus F) with a common lipase results from inversion in the orientation of the bound substrate being processed as a consequence of conformation. This contrasts with the stereochemical interpretation of the biogenetic isoprene rule, whereby product divergence from a common starting material is also a consequence of conformation, albeit enforced by two discrete enzymes

Catalytic enantioselective addition of Grignard reagents to aromatic silyl ketimines

α-Chiral amines are of significant importance in medicinal chemistry, asymmetric synthesis and material science, but methods for their efficient synthesis are scarce. In particular, the synthesis of α-chiral amines with the challenging tetrasubstituted carbon stereocentre is a long-standing problem and catalytic asymmetric additions of organometallic reagents to ketimines that would give direct access to these molecules are underdeveloped. Here we report a highly enantioselective catalytic synthesis of N-sulfonyl protected α-chiral silyl amines via the addition of inexpensive, easy to handle and readily available Grignard reagents to silyl ketimines. The key to this success was our ability to suppress any unselective background addition reactions and side reduction pathway, through the identification of an inexpensive, chiral Cu-complex as the catalytically active structure

Enhancing glycan stability via site-selective fluorination: modulating substrate orientation by molecular design

Single site OH → F substitution at the termini of maltotetraose leads to significantly improved hydrolytic stability towards α-amylase and α-glucosidase relative to the natural compound. To explore the effect of molecular editing, selectively modified oligosaccharides were prepared via a convergent α-selective strategy. Incubation experiments in purified α-amylase and α-glucosidase, and in human and murine blood serum, provide insight into the influence of fluorine on the hydrolytic stability of these clinically important scaffolds. Enhancements of ca. 1 order of magnitude result from these subtle single point mutations. Modification at the monosaccharide furthest from the probable enzymatic cleavage termini leads to the greatest improvement in stability. In the case of α-amylase, docking studies revealed that retentive C2-fluorination at the reducing end inverts the orientation in which the substrate is bound. A co-crystal structure of human α-amylase revealed maltose units bound at the active-site. In view of the evolving popularity of C(sp3)–F bioisosteres in medicinal chemistry, and the importance of maltodextrins in bacterial imaging, this discovery begins to reconcile the information-rich nature of carbohydrates with their intrinsic hydrolytic vulnerabilities

Revision of the absolute configurations of chelocardin and amidochelocardin

Even with the aid of the available methods, the configurational assignment of natural products can be a challenging task that is prone to errors, and it sometimes needs to be corrected after total synthesis or single-crystal X-ray diffraction (XRD) analysis. Herein, the absolute configuration of amidochelocardin is revised using a combination of XRD, NMR spectroscopy, experimental ECD spectra, and time-dependent density-functional theory (TDDFT)-ECD calculations. As amidochelocardin was obtained via biosynthetic engineering of chelocardin, we propose the same absolute configuration for chelocardin based on the similar biosynthetic origins of the two compounds and result of TDDFT-ECD calculations. The evaluation of spectral data of two closely related analogues, 6-desmethyl-chelocardin and its semisynthetic derivative 1, also supports this conclusion