Copper-catalyzed functionalization of enynes

The copper-catalyzed functionalization of enyne derivatives has recently emerged as a powerful approach in contemporary synthesis. Enynes are versatile and readily accessible substrates that can undergo a variety of reactions to yield densely functionalized, enantioenriched products. In this perspective, we review copper-catalyzed transformations of enynes, such as boro- and hydrofunctionalizations, copper-mediated radical difunctionalizations, and cyclizations. Particular attention is given to the regiodivergent functionalization of 1,3-enynes, and the current mechanistic understanding of such processes.

The copper-catalyzed functionalization of enynes is a powerful approach to yield densely functionalized products. This review covers various transformations, such as boro- and hydrofunctionalizations, copper-mediated radical difunctionalizations, and cyclizations.     

Cobalt and Iron Stabilized Ketyl,Ketiminyl and Aldiminyl Radical Anions

Carbonyl and iminyl based radical anions are reactive intermediates in a variety of transformations in organic synthesis. Herein, the isolation of ketyl, and more importantly unprecedented ketiminyl and aldiminyl radical anions coordinated to cobalt and iron complexes is presented. Insights into the electronic structure of these unusual metal bound radical anions is provided by X-Ray diffraction analysis, NMR, IR, UV/Vis and Mössbauer spectroscopy, solid and solution state magnetometry, as well as a by a detailed computational analysis. The metal bound radical anions are very reactive and facilitate the activation of intra- and intermolecular C−H bonds.     

Dendrimers Functionalized with Palladium Complexes of N-, N,N-, and N,N,N-Ligands

Pyridine, pyridine imine, and bipyridine imine ligands functionalized by a phenol have been synthesized and characterized, in many cases by X-ray diffraction. Several of these N-, N,N-, and N,N,N,-ligands have been grafted onto the surface of phosphorhydrazone dendrimers, from generation 1 to generation 3. The complexation ability of these monomers and dendrimers towards palladium(II) has been assayed. The corresponding complexes have been either isolated or prepared in situ. In both cases, the monomeric and dendritic complexes have been tested as catalysts in Heck couplings and in Sonogashira couplings. In some cases, a positive dendritic effect has been observed, that is, an increase of the catalytic efficiency proportional to the dendrimer generation.     

Coordinatively Unsaturated Amidotitanocene Cations with Inverted σ and π Bond Strengths: Controlled Release of Aminyl Radicals and Hydrogenation/Dehydrogenation Catalysis

Cationic amidotitanocene complexes [Cp₂Ti(NPhAr)][B(C₆F₅)₄] (Cp=η⁵-C₅H₅; Ar=phenyl ( 1 a ), p-tolyl ( 1 b ), p-anisyl ( 1 c )) were isolated. The bonding situation was studied by DFT (Density Functional Theory) using EDA-NOCV (Energy Decomposition Analysis with Natural Orbitals for Chemical Valence). The polar Ti−N bond in 1 a–c features an unusual inversion of σ and π bond strengths responsible for the balance between stability and reactivity in these coordinatively unsaturated species. In solution, 1 a–c undergo photolytic Ti−N cleavage to release Ti(III) species and aminyl radicals ⋅ NPhAr. Reaction of 1 b with H₃BNHMe₂ results in fast homolytic Ti−N cleavage to give [Cp₂Ti(H₃BNHMe₂)][B(C₆F₅)₄] ( 3 ). 1 a–c are highly active precatalysts in olefin hydrogenation and silanes/amines cross-dehydrogenative coupling, whilst 3 efficiently catalyzes amine-borane dehydrogenation. The mechanism of olefin hydrogenation was studied by DFT and the cooperative H₂ activation key step was disclosed using the Activation Strain Model (ASM).     

A data-driven,high-throughput methodology to determine tissue-specific differentially methylated regions able to discriminate body fluids

Tissue-specific differentially methylated regions (tDMRs) are regions of the genome with methylation patterns that modulate gene expression in those tissue types. The detection of tDMRs in forensic evidence can permit the identification of body fluids at trace levels. In this report, we have performed a bioinformatic analysis of an existing array dataset to determine if new tDMRs could be identified for use in body fluid identification from forensic evidence. Once these sites were identified, primers were designed and bisulfite modification was performed. The relative methylation level for each body fluid at a given locus was then determined using qPCR with high-resolution melt analysis (HRM). After screening 127 tDMR's in multiple body fluids, we were able to identify four new markers able to discriminate blood (2 markers), vaginal epithelia (1 marker) and buccal cells (1 marker). One marker for each target body fluid was also tested with pyrosequencing showing results consistent with those obtained by HRM. This work successfully demonstrates the ability of in silico analysis to develop a novel set of tDMRs capable of being differentiated by real time PCR/HRM. The method can rapidly determine the body fluids left at crime scenes, assisting the triers of fact in forensic casework.     

Programmed Multiple C-H Bond Functionalization of the Privileged 4-hydroxyquinoline Template

The introduction of substituents on bare heterocyclic scaffolds can selectively be achieved by directed C−H functionalization. However, such methods have only occasionally been used, in an iterative manner, to decorate various positions of a medicinal scaffold to build chemical libraries. We herein report the multiple, site selective, metal-catalyzed C−H functionalization of a “programmed” 4-hydroxyquinoline. This medicinally privileged template indeed possesses multiple reactive sites for diversity-oriented functionalization, of which four were targeted. The C-2 and C-8 decorations were directed by an N-oxide, before taking benefit of an O-carbamoyl protection at C-4 to perform a Fries rearrangement and install a carboxamide at C-3. This also released the carbonyl group of 4-quinolones, the ultimate directing group to functionalize position 5. Our study highlights the power of multiple C−H functionalization to generate diversity in a biologically relevant library, after showing its strong antimalarial potential.     

Geometric Inference for Probability Measures

Data often comes in the form of a point cloud sampled from an unknown compact subset of Euclidean space. The general goal of geometric inference is then to recover geometric and topological features (e.g., Betti numbers, normals) of this subset from the approximating point cloud data. It appears that the study of distance functions allows one to address many of these questions successfully. However, one of the main limitations of this framework is that it does not cope well with outliers or with background noise. In this paper, we show how to extend the framework of distance functions to overcome this problem. Replacing compact subsets by measures, we introduce a notion of distance function to a probability distribution in ℝ ^d . These functions share many properties with classical distance functions, which make them suitable for inference purposes. In particular, by considering appropriate level sets of these distance functions, we show that it is possible to reconstruct offsets of sampled shapes with topological guarantees even in the presence of outliers. Moreover, in settings where empirical measures are considered, these functions can be easily evaluated, making them of particular practical interest.     

Improving Physical Properties via C?H Oxidation: Chemical and Enzymatic Approaches

Physicochemical properties constitute a key factor for the success of a drug candidate. Whereas many strategies to improve the physicochemical properties of small heterocycle‐type leads exist, complex hydrocarbon skeletons are more challenging to derivatize because of the absence of functional groups. A variety of C H oxidation methods have been explored on the betulin skeleton to improve the solubility of this very bioactive, yet poorly water‐soluble, natural product. Capitalizing on the innate reactivity of the molecule, as well as the few molecular handles present on the core, allowed oxidations at different positions across the pentacyclic structure. Enzymatic oxidations afforded several orthogonal oxidations to chemical methods. Solubility measurements showed an enhancement for many of the synthesized compounds.