Battling metastasis through inhibition of cell motility is considered a promising approach to support cancer therapies. In this context, Ena/VASP-depending signaling pathways, in particular interactions with their EVH1 domains, are promising targets for pharmaceutical intervention. However, protein–protein interactions involving proline-rich segments are notoriously difficult to address by small molecules. Hence, structure-based design efforts in combination with the chemical synthesis of additional molecular entities are required. Building on a previously developed nonpeptidic micromolar inhibitor, we determined 22 crystal structures of ENAH EVH1 in complex with inhibitors and rationally extended our library of conformationally defined proline-derived modules (ProMs) to succeed in developing a nanomolar inhibitor (Kd=120 nM,MW=734Da). In contrast to the previous inhibitor, the optimized compounds reduced extravasation of invasive breast cancer cells in a zebrafish model. This study represents an example of successful, structure-guided development of low molecular weight inhibitors specifically and selectively addressing a proline-rich sequence-recognizing domain that is characterized by a shallow epitope lacking defined binding pockets. The evolved high-affinity inhibitor may now serve as a tool in validating the basic therapeutic concept, i.e., the suppression of cancer metastasis by inhibiting a crucial protein–protein interaction involved in actin filament processing and cell migration.

Ac onceptionally new strategy for the asymmetric (2R-selective) synthesis of a-tocopherol (vitamin E) was developed. In the stereocontrolled key step, ap rochiral spiro[chromane-2,3'-cyclobutanol] unit is effectively desymmetrized under CÀCb ond activation in an unprecedented iridium-catalyzed transformation using (S)-DTBM-SegPhos as ac hiral ligand (e.r.9 7:3). To complete the synthesis, the side chain was attached through Ru-catalyzed cross-metathesis employing an alkene derivedfrom (R,R)hexahydrofarnesol. To suppress epimerization during the final hydrogenation, PtO 2 had to be used as ac atalyst instead of Pd/C.I na na lternative approach( employing a propargyl-substituted spiro-cyclobutanol), the side chain was constructed prior to the Ir-catalyzed ring fragmentation (> 99:1 d.r.) through enynec ross-metathesis (usinga n alkene derived from (R)-dihydrocitronellal) followed by Crcatalyzed 1,4-hydrogenation and (diastereoselective) Pfaltz hydrogenationo ft he resulting triple-substituted olefin. The work demonstrates the potentialo fi ridium catalysis for enantioselective CÀCbond activation.Scheme1.Retrosynthetic analysis of a-tocopherol (1)b ya symmetricfragmentation(C ÀCb ond activation) of aspirocyclobutanol of type 3.

A general and powerful method for the stereo‐controlled Pd‐catalyzed N‐allylation of amino acid esters is reported, as a previously largely unsolved synthetic challenge. Employing a new class of tartaric acid‐derived C2‐symmetric chiral diphosphane ligands the developed asymmetric amination protocol allows the conversion of various amino acid esters to the N‐allylated products with highest levels of enantio‐ or diastereoselectivity in a fully catalyst‐controlled fashion and predictable configuration. Remarkably, the in situ generated catalysts also exhibit outstanding levels of activity (ligand acceleration). The usefulness of the method was demonstrated in the stereo‐divergent synthesis of a set of new conformationally defined dipeptide mimetics, which represent new modular building blocks for the development of peptide‐inspired bioactive compounds.

A new class of chiral C2‐symmetric diphosphines (MediPhos) was recently shown to give superior results in the Pd‐catalyzed asymmetric N‐allylation of amino acid esters. We here describe a new, improved protocol for the preparation of such ligands through bidirectional SN2‐coupling of a tartrate‐derived ditosylate with 6‐alkyl‐2‐bromophenols followed by double lithiation/phosphanylation. This method gave access to a series of nine ligands with branched alkyl substituents, which were benchmarked in the enantioselective Pd‐catalyzed N‐allylation of tert‐butyl glycinate with racemic (E)‐2,8‐dimethylnona‐5‐en‐4‐yl methyl carbonate (up to 95 % ee). In addition, the analogous transformation of tert‐butyl glycinate with methyl (E)‐nona‐5‐en‐4‐yl carbonate was optimized. The obtained allylic amines were then used in the stereoselective synthesis of the conformationally restricted proline‐derived dipeptide analogs ProM‐17 and ProM‐21.

A stereo-divergent synthesis of natural and unnatural opines in stereochemically pure form is based on the direct palladiumcatalyzed N-allylation of α-amino acid esters (up to 97 % ee or 99 : 1 d.r.) using methyl (E)-2-penten-4-yl carbonate in the presence of only 1 mol% of a catalyst, prepared in-situ from the C 2 -symmetric diphosphine iPr-MediPhos and [Pd(allyl)Cl] 2 . Selected target compounds (incl. a derivative of the drug enalapril) were efficiently obtained from the N-allylated intermediates by oxidative cleavage (ozonolysis) of the allylic C=C bond under temporary N-Boc-protection.

The investigation of the iridium‐catalyzed asymmetric N‐allylation of tert‐butyl glycinate using a “branched” racemic 1‐vinyl‐alkyl methyl carbonate revealed severe limitations of existing protocols. By screening a set of 24 BINOL‐derived chiral phosphoramidites a new superior ligand (L24*) was identified which afforded the amination product with high enantioselectivity (≥95 % ee) under optimized conditions. This ligand also allowed the N‐allylation of other amino acid tert‐butyl esters (derived from alanine, phenylalanine, or proline) with outstanding levels of diastereocontrol (d.r. ≥99 : 1) and negligible matched/mismatched differences.

An exceedingly short and enantioselective synthesis of the antiepileptic drug (S)-levetiracetam was elaborated. As the chirogenic key step a Pd-catalyzed asymmetric N-allylation of methyl 4-aminobutyrate was achieved in the presence of only 1 mol% of a catalyst prepared in situ from [Pd(allyl)Cl]2 and the tartaric acid-derived C2-symmetric diphosphane ligand (S,S)-iPr-MediPhos).