Rapid Chemical Profiling of Filipendula ulmaria Using CPC Fractionation, 2-D Mapping of 13C NMR Data, and High-Resolution LC-MS.

Filipendula ulmaria, commonly known as meadowsweet, is a wild herbaceous flowering plant that is widely distributed in Europe. A range of salicylic acid derivatives and flavonol glycosides have been previously associated with the antirheumatic and diuretic properties of F. ulmaria. In the present work, a hydroalcoholic extract from F. ulmaria aerial parts was extensively profiled using an efficient NMR-based dereplication strategy. The approach involves the fractionation of the crude extract by centrifugal partition chromatography (CPC), 13C NMR analysis of the fractions, 2D-cluster mapping of the entire NMR dataset, and, finally, structure elucidation using a natural metabolite database, validated by 2D NMR data interpretation and liquid chromatography coupled with mass spectrometry. The chemodiversity of the aerial parts was extensive, with 28 compounds unambiguously identified, spanning various biosynthetic classes. The F. ulmaria extract and CPC fractions were screened for their potential to enhance skin epidermal barrier function and skin renewal properties using in vitro assays performed on Normal Human Epidermal Keratinocytes. Fractions containing quercetin, kaempferol glycosides, ursolic acid, pomolic acid, naringenin, ß-sitosterol, and Tellimagrandins I and II were found to upregulate genes related to skin barrier function, epidermal renewal, and stress responses. This research is significant as it could provide a natural solution for improving hydration and skin renewal properties.

Design and synthesis of calindol derivatives as potent and selective calcium sensing receptor agonists.

We report the first comprehensive structure-activity study of calindol (4, (R)-N-[(1H-indol-2-yl)methyl]-1-(1-naphthyl)ethanamine), a positive allosteric modulator, or calcimimetic, of the calcium sensing receptor (CaSR). While replacement of the naphthyl moiety of calindol by other aromatic groups (phenyl, biphenyl) was largely detrimental to calcimimetic activity, incorporation of substituents on the 4, 5 or 7 position of the indole portion of calindol was found to provide either equipotent derivatives compared to calindol (e.g., 4-phenyl, 4-hydroxy, 5-hydroxycalindol 44, 52, 53) or, in the case of 7-nitrocalindol (51), a 6-fold more active calcimimetic displaying an EC50 of 20nM. Unlike calindol, the more active CaSR calcimimetics were shown not to act as antagonists of the closely related GPRC6A receptor, suggesting a more selective profile for these new analogues.

Suzuki-Miyaura cross-coupling of potassium alkoxyethyltrifluoroborates: access to aryl/heteroarylethyloxy motifs.

The introduction of an alkoxyethyl moiety onto aromatic substructures has remained a long-standing challenge for synthetic organic chemists. The main reasons are the inherent instability of alkoxyethylmetallic species and the lack of general procedures to access them. A new method utilizing a cross-coupling strategy based on the exceptional properties of organotrifluoroborates has been developed, and the method allows an easy and efficient installation of this unit on a broad range of aryl and heteroaryl bromides.

Cross-coupling of mesylated phenol derivatives with potassium cyclopropyltrifluoroborate.

C-O activation of mesylates by a palladium catalyst and subsequent cross-coupling with potassium cyclopropyltrifluoroborate have been achieved with high yield. Both electron-enriched and electron-deficient aryl mesylates are suitable electrophilic partners for the Suzuki-Miyaura reaction. The scope was successfully extended to heteroaryl mesylates with yields up to 94%.

Cross-coupling of mesylated phenol derivatives with potassium alkoxymethyltrifluoroborates.

Cross-coupling of mesylated phenol derivatives with various potassium alkoxymethyltrifluoroborates has been achieved. The corresponding aryl and heteroaryl alkoxymethyl compounds have been obtained with equal facility with both electron-rich and electron-poor substituents on the activated alcohol.

Cross-coupling of mesylated phenol derivatives with potassium ammonio- and amidomethyltrifluoroborates.

A large array of aryl and heteroaryl mesylates have been successfully employed as electrophiles in a Csp(2)-Csp(3) Suzuki-Miyaura cross-coupling with potassium ammonio- and amidomethyltrifluoroborates to afford the corresponding products in high yields.

Nickel-catalyzed C-O activation of phenol derivatives with potassium heteroaryltrifluoroborates.

A general method based on nickel-catalyzed C-O activation of various phenol derivatives with potassium (hetero)aryltrifluoroborates has been developed. A large number of heterobiaryls can be easily obtained with yields up to 99% using methanesulfonate cross-coupling partners.

One-pot double Suzuki-Miyaura couplings: rapid access to nonsymmetrical tri(hetero)aryl derivatives.

We describe a one-pot, simultaneous Suzuki-Miyaura cross-coupling of two different aryl boronic acids with symmetrical dibromo aryl and heterocyclic substrates to give as major products the unsymmetrical disubstituted tri(hetero)aryl derivatives. Yields of unsymmetrical dicoupled products were generally in the 52-75% range. This methodology is particularly suited to the generation of chemical libraries, as well as to the synthesis of biologically active or natural product analogs.