New Chiral Ortho-P,S-Difunctionalized Aromatic Compounds

Abstract

A new method to prepare enantioenriched sulfinates was developed to obtain optically active ortho-methylsulfinyl(phenylphosphonates). It consists of a diastereoselective oxidation of sulfenates to sulfinates. Additionally, preliminary results concerning the synthesis of ortho-phophonylated benzylic thiol derivatives via a new P═S to P═C [1,4]-rearrangement and a first synthetic application of these compounds are also described.     

Convenient Ring-Bromination of Alkylnaphthalenes using N-Bromosuccinimide in Acetonitrile

Abstract: Abstract. 1-Alkyl- and 2-alkylnaphthalenes are conveniently brominated in the 4-and 1-positions respectively using N-bromosuccinimide (NBS) in acetonitrile. The reactions are easy to perform and give higher chemical yields and better regioselectivity compared to brominations employing bromine/dichloromethane.     

Uncommon perspectives in palladium- and copper-catalysed arylation and heteroarylation of terminal alkynes following Heck or Sonogashira protocols: Interactions copper/ligand,formation of diynes,reaction and processes in ionic liquids

Conjugated alkynes are recurring building blocks in natural products and in a wide range of important compounds, such as pharmaceuticals, agrochemicals, or molecular materials. The palladium-catalysed cross-coupling reaction between the sp²-hybridized carbon atoms of aryl, heteroaryl, and vinyl halides with the sp-hybridized carbon atoms of terminal alkynes is one of the most important developments in the field of alkyne chemistry over the past 50 years. Room for improvement still exists in these important reactions of direct arylation of terminal alkynes. In this prospect, the present authors have developed several strategies aiming at improving the reactivity, the selectivity, and several aspects of processes involving the palladium-catalysed alkyne arylation and heteroarylation reactions, in relation with sustainable chemistry. Various original approaches have thus been adopted: (i) the development of catalytic systems efficient at low metal loading below 1 mol% of palladium and copper (to reduce metal contamination) from polydentate ligands chemistry, (ii) the limitation of diyne formation by undesired side-reaction, this from a better mechanistic understanding and the innovating use of copper adducts, (iii) and the development of cost-efficient catalytic reactions in ionic liquid solvents. These topics have been developed with the general outlook of a large scope in organic synthesis. In addition, the investigation of recycling opportunities and the unprecedented production of extendedly conjugated bis(aryl)diynes has been also achieved. The present account reviews all this work, as it has been presented by the corresponding author at GECOM–CONCOORD 2012 as recipient of the 2012 European journal of Inorganic Chemistry Young Investigator Award.     

Efficient Access to Peptidyl‐RNA Conjugates for Picomolar Inhibition of Non‐ribosomal FemXWv Aminoacyl Transferase

Peptidyl–RNA conjugates have various applications in studying the ribosome and enzymes participating in tRNA‐dependent pathways such as Fem transferases in peptidoglycan synthesis. Herein a convergent synthesis of peptidyl–RNAs based on Huisgen–Sharpless cycloaddition for the final ligation step is developed. Azides and alkynes are introduced into tRNA and UDP‐MurNAc‐pentapeptide, respectively. Synthesis of 2′‐azido RNA helix starts from 2′‐azido‐2′‐deoxyadenosine that is coupled to deoxycytidine by phosphoramidite chemistry. The resulting dinucleotide is deprotected and ligated to a 22‐nt RNA helix mimicking the acceptor arm of Ala‐tRNA^Ala by T4 RNA ligase. For alkyne UDP‐MurNAc‐pentapeptide, meso‐cystine is enzymatically incorporated into the peptidoglycan precursor and reduced, and L ‐Cys is converted to dehydroalanine with O‐(mesitylenesulfonyl)hydroxylamine. Reaction of but‐3‐yne‐1‐thiol with dehydroalanine affords the alkyne‐containing UDP‐MurNAc‐pentapeptide. The Cu^I‐catalyzed azide alkyne cycloaddition reaction in the presence of tris[(1‐hydroxypropyl‐1H‐1,2,3‐triazol‐4‐yl)methyl]amine provided the peptidyl‐RNA conjugate, which was tested as an inhibitor of non‐ribosomal FemX_Wv aminoacyl transferase. The bi‐substrate analogue was found to inhibit FemX_Wv with an IC₅₀ of (89±9) pM , as both moieties of the peptidyl–RNA conjugate contribute to high‐affinity binding.     

Towards a microchannel‐based X‐ray detector with two‐dimensional spatial and time resolution and high dynamic range

X‐ray detectors that combine two‐dimensional spatial resolution with a high time resolution are needed in numerous applications of synchrotron radiation. Most detectors with this combination of capabilities are based on semiconductor technology and are therefore limited in size. Furthermore, the time resolution is often realised through rapid time‐gating of the acquisition, followed by a slower readout. Here, a detector technology is realised based on relatively inexpensive microchannel plates that uses GHz waveform sampling for a millimeter‐scale spatial resolution and better than 100 ps time resolution. The technology is capable of continuous streaming of time‐ and location‐tagged events at rates greater than 10⁷ events per cm². Time‐gating can be used for improved dynamic range.     

Engineering Short Peptide Sequences for Uranyl Binding

Peptides are interesting tools to rationalize uranyl–protein interactions, which are relevant to uranium toxicity in vivo. Structured cyclic peptide scaffolds were chosen as promising candidates to coordinate uranyl thanks to four amino acid side chains pre‐oriented towards the dioxo cation equatorial plane. The binding of uranyl by a series of decapeptides has been investigated with complementary analytical and spectroscopic methods to determine the key parameters for the formation of stable uranyl–peptide complexes. The molar ellipticity of the uranyl complex at 195 nm is directly correlated to its stability, which demonstrates that the β‐sheet structure is optimal for high stability in the peptide series. Cyclodecapeptides with four glutamate residues exhibit the highest affinities for uranyl with log K_C=8.0–8.4 and, therefore, appear as good starting points for the design of high‐affinity uranyl‐chelating peptides.     

gem‐Difluorocarbadisaccharides: Restoring the exo‐Anomeric Effect

Molecular mimicry is an essential part of the development of drugs and molecular probes. In the chemical glycobiology field, although many glycomimetics have been developed in the past years, it has been considered that many failures in their use are related to the lack of the anomeric effects in these analogues. Additionally, the origin of the anomeric effects is still the subject of virulent scientific debates. Herein, by combining chemical synthesis, NMR methods, and theoretical calculations, we show that it is possible to restore the anomeric effect for an acetal when replacing one of the oxygen atoms by a CF₂ group. This result provides key findings in chemical sciences. On the one hand, it strongly suggests the key relevance of the stereoelectronic component of the anomeric effect. On the other hand, the CF₂ analogue adopts the natural glycoside conformation, which might provide new avenues for sugar‐based drug design.     

Gram‐Scale Enantioselective Formal Synthesis of Morphine through an ortho–para Oxidative Phenolic Coupling Strategy

A gram‐scale catalytic enantioselective formal synthesis of morphine is described. The key steps of the synthesis involve an ortho–para oxidative phenolic coupling and a highly diastereoselective “desymmetrization” of the resulting cyclohexadienone that generates three of the four morphinan ring junction stereocenters in one step. The stereochemistry is controlled from a single carbinol center installed through catalytic enantioselective hydrogenation. These transformations enabled the preparation of large quantities of key intermediates and could support a practical and scalable synthesis of morphine and related derivatives.     

Capturing the Monomeric (L)CuH in NHC‐Capped Cyclodextrin: Cavity‐Controlled Chemoselective Hydrosilylation of α,β‐Unsaturated Ketones

The encapsulation of copper inside a cyclodextrin capped with an N‐heterocyclic carbene (ICyD) allowed both to catch the elusive monomeric (L)CuH and a cavity‐controlled chemoselective copper‐catalyzed hydrosilylation of α,β‐unsaturated ketones. Remarkably, (α‐ICyD)CuCl promoted the 1,2‐addition exclusively, while (β‐ICyD)CuCl produced the fully reduced product. The chemoselectivity is controlled by the size of the cavity and weak interactions between the substrate and internal C?H bonds of the cyclodextrin.     

On the Photophysical Properties of New Luminol Derivatives and their Synthetic Phthalimide Precursors

The photophysical properties of a series of structurally related 4-aminophthalimides and the corresponding 5-aminophthalic hydrazides (luminols) are reported. Absorption, steady-state, and time-resolved fluorescence spectra of luminols exhibited substitution, solvent, and pH dependence. Singlet lifetimes have been determined by time-resolved laser flash spectroscopy. UV spectra in gas phase and DMSO solution were calculated by TD-DFT which revealed the existence of two low-energy excited singlet states with strong pH-sensitivity.