Molecular intelligence: The structurally novel lignan (+)‐linoxepin is synthesized in an eight‐step sequence. The enantioselective synthesis features the palladium‐catalyzed Catellani reaction as the key step. In this highly convergent multicomponent reaction, two new carbon–carbon bonds are formed, one of which results from a CH bond functionalization.

Principles of fragment-based molecular design are presented and discussed in the context of de novo drug design. The underlying idea is to dissect known drug molecules in fragments by straightforward pseudo-retro-synthesis. The resulting building blocks are then used for automated assembly of new molecules. A particular question has been whether this approach is actually able to perform scaffold-hopping. A prospective case study illustrates the usefulness of fragment-based de novo design for finding new scaffolds. We were able to identify a novel ligand disrupting the interaction between the Tat peptide and TAR RNA, which is part of the human immunodeficiency virus (HIV-1) mRNA. Using a single template structure (acetylpromazine) as reference molecule and a topological pharmacophore descriptor (CATS), new chemotypes were automatically generated by our de novo design software Flux. Flux features an evolutionary algorithm for fragment-based compound assembly and optimization. Pharmacophore superimposition and docking into the target RNA suggest perfect matching between the template molecule and the designed compound. Chemical synthesis was straightforward, and bioactivity of the designed molecule was confirmed in a FRET assay. This study demonstrates the practicability of de novo design to generating RNA ligands containing novel molecular scaffolds.

Our ongoing effort towards the development of highly selective transition‐metal‐catalysed C–H activation processes has led to the expansion of the Catellani reaction. In a Pd0/PdII/PdIV‐catalysed domino reaction, an aryl iodide, alkyl iodide and tert‐butyl acrylate were combined to synthesize the carbon framework of the novel lignan (+)‐linoxepin. The enantioselective synthesis highlights the work accomplished in our group and provides an excellent procedure for the reliable and scalable synthesis of architecturally complex scaffolds. This report outlines the synthetic approaches towards this interesting class of biologically active molecules. After the key Catellani/Heck reaction, our synthesis features a Leimeux–Johnson oxidation and a titanium tetrachloride mediated aldol condensation. Finally, a tuneable Mizoroki–Heck reaction was performed to furnish not only the natural product (+)‐linoxepin but also its isoform, which we have named isolinoxepin.

Alkene 3, a TBS‐ and Cbz‐protected derivative of vinylglycinol, safely available from methionine, undergoes efficient Heck coupling reactions in high yields. The resulting products can be converted into enantiopure α‐amino acids with aromatic and heteroaromatic side‐chains. Compound 6a, a brightly fluorescent Fmoc‐protected pyrene amino acid is of special interest. Tripeptide 8a, composed of this building block and two arginines, binds to TAR, an RNA element regulating transcriptional efficiency in HIV, with a Kd value of 50 nM. This compound also inhibits a coupled cell‐free transcription‐translation assay (IC50 = 40 μM) and shows pronounced antibacterial activity against B. subtilis. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Target TAR by NMR: Tripeptides containing arginines as terminal residues and non-natural amino acids as central residues are good leads for drug design to target the HIV trans-activation response element (TAR). The structural characterization of the RNA-ligand complex by NMR spectroscopy reveals two specific binding sites that are located at bulge residue U23 and around the pyrimidine-stretch U40-C41-U42 directly adjacent to the bulge.