Direct ß- and γ-C(sp3 )-H Alkynylation of Free Carboxylic Acids*.

In this study we report the identification of a novel class of ligands for palladium-catalyzed C(sp3 )-H activation that enables the direct alkynylation of free carboxylic acid substrates. In contrast to previous synthetic methods, no introduction/removal of an exogenous directing group is required. A broad scope of acids including both α-quaternary and challenging α-non-quaternary can be used as substrates. Additionally, the alkynylation in the distal γ-position is reported. Finally, this study encompasses preliminary findings on an enantioselective variant of the title transformation as well as synthetic applications of the products obtained.

Sterically Controlled C-H Olefination of Heteroarenes.

The regioselective functionalization of heteroarenes is a highly attractive synthetic target due to the prevalence of multiply substituted heteroarenes in nature and bioactive compounds. Some substitution patterns remain challenging: While highly efficient methods for the C2-selective olefination of 3-substituted five-membered heteroarenes have been reported, analogous methods to access the 5-olefinated products have remained limited by poor regioselectivities and/or the requirement to use an excess of the valuable heteroarene starting material. Herein we report a sterically controlled C-H olefination using heteroarenes as the limiting reagent. The method enables the highly C5-selective olefination of a wide range of heteroarenes and is shown to be useful in the context of late-stage functionalization.

Ligand-Enabled γ-C(sp3 )-H Olefination of Free Carboxylic Acids.

We report the ligand-enabled C-H activation/olefination of free carboxylic acids in the γ-position. Through an intramolecular Michael addition, δ-lactones are obtained as products. Two distinct ligand classes are identified that enable the challenging palladium-catalyzed activation of free carboxylic acids in the γ-position. The developed protocol features a wide range of acid substrates and olefin reaction partners and is shown to be applicable on a preparatively useful scale. Insights into the underlying reaction mechanism obtained through kinetic studies are reported.

The Direct Conversion of α-Hydroxyketones to Alkynes.

Alkynes are highly important functional groups in organic chemistry, both as part of target structures and as versatile synthetic intermediates. In this study, a protocol for the direct conversion of α-hydroxyketones to alkynes is reported. In combination with the variety of synthetic methods that generate the required starting materials by forming the central C-C bond, it enables a highly versatile fragment coupling approach toward alkynes. A broad scope for this novel transformation is shown alongside mechanistic insights. Furthermore, the utility of our protocol is demonstrated through its application in concert with varied α-hydroxyketone syntheses, giving access to a broad spectrum of alkynes.

Imidazo[2,1-b]benzothiazol Derivatives as Potential Allosteric Inhibitors of the Glucocorticoid Receptor.

Glucocorticoid receptor (GCR) transactivation reporter gene assays were used as an initial high-throughput screening on a diversified library of 1200 compounds for their evaluation as GCR antagonists. A class of imidazo[2,1-b]benzothiazole and imidazo[2,1-b]benzoimidazole derivatives were identified for their ability to modulate GCR transactivation and anti-inflammatory transrepression effects utilizing GCR and NF-κB specific reporter gene assays. Modeling studies on the crystallographic structure of the GCR ligand binding domain provided three new analogues bearing the tetrahydroimidazo[2,1-b]benzothiazole scaffold able to antagonize the GCR in the presence of dexamethasone (DEX) and also defined their putative binding into the GCR structure. Both mRNA level measures of GCR itself and its target gene GILZ, on cells treated with the new analogues, showed a GCR transactivation inhibition, thus suggesting a potential allosteric inhibition of the GCR.

Correction: Novel chemical probes for the investigation of nonribosomal peptide assembly.

Correction for 'Novel chemical probes for the investigation of nonribosomal peptide assembly' by Y. T. Candace Ho et al., Chem. Commun., 2017, 53, 7088-7091.

Novel chemical probes for the investigation of nonribosomal peptide assembly.

Chemical probes were devised and evaluated for the capture of biosynthetic intermediates involved in the bio-assembly of the nonribosomal peptide echinomycin. Putative intermediate peptide species were isolated and characterised, providing fresh insights into pathway substrate flexibility and paving the way for novel chemoenzymatic approaches towards unnatural peptides.