The
halogen bonded adduct between the commonly used constituents
quinuclidine and iodobenzene is based on a single weak nitrogen–iodine
contact, and the isolation of this adduct was initially unexpected.
Iodobenzene does not contain any electron-withdrawing group and therefore
represents an unconventional halogen bond donor. Based on excellent
diffraction data of high resolution, an electron density study was
successfully accomplished and confirmed one of the longest N···I
molecular halogen bonds with a distance of 2.9301(4) Å. The topological
analysis identified the XB as a directional but weak σ hole
interaction and revealed secondary contacts between peripheral regions
of opposite charge. These additional contacts and their competition
with a nitrogen-based interaction were confirmed by NOESY experiments
in solution. Integration enabled us to determine the relative NOE
ratios and provided insight regarding the existing interactions.
Natural product (NP) structures are a rich source of inspiration for the discovery of new biologically relevant chemical matter. In natural product inspired pseudo‐NPs, NP‐derived fragments are combined de novo in unprecedented arrangements. Described here is the design and synthesis of a 155‐member pyrroquinoline pseudo‐NP collection in which fragments characteristic of the tetrahydroquinoline and pyrrolidine NP classes are combined with eight different connectivities and regioisomeric arrangements. Cheminformatic analysis and biological evaluation of the compound collection by means of phenotyping in the morphological “cell painting” assay followed by principal component analysis revealed that the pseudo‐NP classes are chemically diverse and that bioactivity patterns differ markedly, and are dependent on connectivity and regioisomeric arrangement of the fragments.
Axially
chiral atropisomeric compounds are widely applied in asymmetric
catalysis and medicinal chemistry, and efficient methods for their
synthesis are in high demand. This applies in particular to atropisomers
derived from five-membered aromatic rings because their lower barrier
for rotation among the biaryl axis limits their asymmetric synthesis.
We report here an enantioselective C–H functionalization method
using our chiral RhJasCp complex for the synthesis
of the biaryl atropisomer types that can be accessed from three different
five-membered-ring heterocycles.
RhIII‐catalyzed C−H functionalization reaction yielding isoindolinones from aryl hydroxamates and ortho‐substituted styrenes is reported. The reaction proceeds smoothly under mild conditions at room temperature, and tolerates a range of functional groups. Experimental and computational investigations support that the high regioselectivity observed for these substrates results from the presence of an ortho‐substituent embedded in the styrene. The resulting isoindolinones are valuable building blocks for the synthesis of bioactive compounds. They provide easy access to the natural‐product‐like compounds, isoindolobenzazepines, in a one‐pot two‐step reaction. Selected isoindolinones inhibited Hedgehog (Hh)‐dependent differentiation of multipotent murine mesenchymal progenitor stem cells into osteoblasts.
We describe the synthesis and biological evaluation of a new natural product‐inspired compound class obtained by combining the conceptually complementary pseudo‐natural product (pseudo‐NP) design strategy and a formal adaptation of the complexity‐to‐diversity ring distortion approach. Fragment‐sized α‐methylene‐sesquiterpene lactones, whose scaffolds can formally be viewed as related to each other or are obtained by ring distortion, were combined with alkaloid‐derived pyrrolidine fragments by means of highly selective stereocomplementary 1,3‐dipolar cycloaddition reactions. The resulting pseudo‐sesquiterpenoid alkaloids were found to be both chemically and biologically diverse, and their biological performance distinctly depends on both the structure of the sesquiterpene lactone‐derived scaffolds and the stereochemistry of the pyrrolidine fragment. Biological investigation of the compound collection led to the discovery of a novel chemotype inhibiting Hedgehog‐dependent osteoblast differentiation
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