Total Synthesis of (±)-Oxacyclododecindione.

Racemic total synthesis of the natural product oxacyclododecindione, isolated in 2008 as the first member of the oxacyclododecindione family, is reported. Studies toward this molecule commenced with a biomimetic late-stage C-H oxidation starting from 14-deoxyoxacyclododecindione as a known precursor. This provided insights into the reactivity of the macrolactone class but did not permit the synthesis of the target natural product. Based on these results, a synthetic strategy through intramolecular Friedel-Crafts acylation combined with Barton decarboxylation to introduce the tertiary alcohol, a major challenge in previous synthetic efforts, was envisioned. This resulted in an 11-step racemic total synthesis of (±)-oxacyclododecindione, renowned for its potent anti-inflammatory and antifibrotic activities.

Total Synthesis, Structure Reassignment, and Biological Evaluation of the Anti-Inflammatory Macrolactone 13-Hydroxy-14-deoxyoxacyclododecindione.

Herein, the first total synthesis of natural 13-hydroxy-14-deoxyoxacyclododecindione along with the revision of the proposed configuration is reported. This natural product, initially discovered in 2018, belongs to the oxacyclododecindione family, renowned for their remarkable anti-inflammatory and antifibrotic activities. The synthetic route involves an esterification/Friedel-Crafts-acylation approach and uses various triol fragments. It allows the preparation of different stereoisomers, including the (revised) natural product, two threo-derivatives, and two Z-isomers of the endocyclic C═C double bond. Furthermore, a late-stage inversion of the C-13 stereocenter could transform the originally proposed structure into the revised natural product. With this comprehensive set of compounds and the previously prepared (13R,14S,15R)-isomer, deeper insights into their structural properties and biological activities were obtained. A detailed analysis of the final macrolactones using spectroscopy (NMR, IR, UV-vis) and X-ray crystallography gave new insights such as the significance of the optical rotation for the elucidation of their configuration and the light-induced E/Z double-bond photoisomerization. The pharmacological potential of the compounds was underlined by remarkably low IC50 values in biological assays addressing the inhibition of cellular inflammatory responses.

Total Synthesis and Biological Evaluation of the Anti-Inflammatory (13R,14S,15R)-13-Hydroxy-14-deoxyoxacyclododecindione.

The first total synthesis of the natural product (13R,14S,15R)-13-hydroxy-14-deoxyoxacyclododecindione, which was isolated in 2018 as a member of the oxacyclododecindione family, is reported. A synthetic strategy through intramolecular Friedel-Crafts acylation combined with the stereoselective synthesis of a new triol key fragment allowed the preparation of the macrolactone. Due to mismatching physical data of the synthetic product, a revision of the configuration of the natural product isolated in 2018 is required. Light-induced E/Z-isomerism of the macrolactone backbone is described for the first time in the class of oxacyclododecindione-type macrolactones. The hydroxylated macrolactone prepared herein was found to show highly promising IC50 values in biological assays addressing the inhibition of inflammatory responses.

Marine Pyrrole Alkaloids.

Nitrogen heterocycles are essential parts of the chemical machinery of life and often reveal intriguing structures. They are not only widespread in terrestrial habitats but can also frequently be found as natural products in the marine environment. This review highlights the important class of marine pyrrole alkaloids, well-known for their diverse biological activities. A broad overview of the marine pyrrole alkaloids with a focus on their isolation, biological activities, chemical synthesis, and derivatization covering the decade from 2010 to 2020 is provided. With relevant structural subclasses categorized, this review shall provide a clear and timely synopsis of this area.

The role of phosphopeptides in the mineralisation of silica.

We investigated the silicification activity of hyperphosphorylated peptides in combination with long-chain polyamines (LCPA). The bioinspired in vitro silicification experiments with peptides containing different amounts of phosphorylated serines showed structure-activity dependence by altering the amount and morphology of the silica precipitate. Our study provides an explanation for the considerable metabolic role of diatoms in the synthesis of hyperphosphorylated poly-cationic peptides such as natSil-1A1. The efficient late-stage phosphorylation of peptides yielded a synthetic heptaphosphopeptide whose silicification properties resemble those of natSil-1A1. As opposed to this, unphosphorylated poly-cationic peptides or LCPA require concentrations above 1 mM for silicification. Hyperphosphorylated peptides showed a linear dependence between the amount of dissolved peptides and the amount of precipitated silica in the concentration range below 1 mM. Under mildly acidic conditions and short precipitation times, the concentration of the added LCPA determined the size of the silica spheres.