A synthesis of the important FKBP ligand Shld is reported. The synthesis avoids stoichiometric use of expensive and chiral reagents, maintains enantioselectivity and provides a high overall yield (39%). The main features in the method are enantioselective alkylation for preparation of the phenyl acetic acid moiety (building block A), catalytic enantioselective reduction for obtaining the chiral diaryl-1-propanol (building block C), and direct acylation of S-pipecolic tartrate rather than use of expensive Fmoc-pipecolic acid. The assembly of the building blocks A-C is reversed in comparison to previous synthesis, which also eliminates the need for protective groups.

A series of 35 analogues of Shld with modifications in the A-residue and the C-residues were prepared and investigated for binding to FKBP and GFP accumulation in transgenic plants. The modifications investigated explored variations that were supposedly inside or outside the receptor binding site with the latter being important by influencing the overall polarity of the compounds in order to improve the absorption in plants. The binding of the new compounds to the destabilizing domain was determined using a fluorescence polarization competition assay, and the GFP expression in engineered Arabidopsis thaliana was studied. The results showed that modifications of the C-building block phenol with acidic, basic, and neutral groups led to better ligands with some being better than Shld in the plant. Generally small, polar substituents showed the best GFP accumulation.

On the basis of computational design, a focused one-bead one-compound library has been prepared on microparticleencoded PEGA 1900 beads consisting of small tripeptides with a triazole-capped N-terminal. The library was screened towards a double point-mutated version of the human FKBP12 protein, known as the destabilizing domain (DD). Inspired by the decoded library hits, unnatural peptide structures were screened in a novel on-bead assay, which was useful for a rapid structure evaluation prior to off-bead resynthesis. Subsequently, a series of 19 compounds were prepared and tested using a competitive fluorescence polarization assay, which led to the discovery of peptide ligands with low micromolar binding affinity towards the DD. The methodology represents a rapid approach for identification of a novel structure scaffold, where the screening and initial structure refinement was accomplished using small quantities of library building blocks.

Controlled alignment and self‐assembly of molecular wires is one of the challenges in the field of molecular electronics. Here, we take an approach by which two oligo(phenyleneethynylene)s (OPEs) are linked together through one vinylogous linker. These molecules thus incorporate a central stilbene part from which the two OPE wires propagate in a so‐called “H‐cruciform”‐like motif. Each ring of the central stilbene unit also contains a redox‐active dithiafulvene (DTF) unit and this part of the molecule can thus be considered as an extended tetrathiafulvalene (TTF). Here, we present how such H‐cruciforms based on OPE3 and OPE5 molecular wires are prepared by Sonogashira coupling reactions and how the OPEs are functionalized with thioester end‐caps as potential electrode anchoring groups. The optical and redox properties of these molecules are also presented. Unsymmetrical systems are achieved by subjecting a differentially protected diethynyl‐substituted derivative of terephthalaldehyde to a phosphite‐mediated coupling reaction in the presence of a 1,3‐dithiol‐2‐thione. This reaction forms the central stilbene‐extended TTF with alkyne substituents and relies on an “umpolung” of the para substituents from electron‐withdrawing CHO groups to electron‐donating DTF groups in a conversion also promoted by the phosphite.

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