Enantioselective Construction of α-Quaternary Cyclobutanones by Catalytic Asymmetric Allylic Alkylation

No strain, no gain! The first transition metal-catalyzed enantioselective α-alkylation of cyclobutanones is reported. This method employs palladium catalysis and an electron-deficient PHOX-type ligand to afford all-carbon α-quaternary cyclobutanones in good to excellent yields and enantioselectivities (see scheme)

Enantioselective Synthesis of α-Secondary and α-Tertiary Piperazin-2-ones and Piperazines by Catalytic Asymmetric Allylic Alkylation

The asymmetric palladium-catalyzed decarboxylative allylic alkylation of differentially N-protected piperazin-2-ones allows the synthesis of a variety of highly enantioenriched tertiary piperazine-2-ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogues. The introduction of these chiral tertiary piperazines resulted in imatinib analogues which exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts

A practical two-step procedure for the preparation of enantiopure pyridines: Multicomponent reactions of alkoxyallenes, nitriles and carboxylic acids followed by a cyclocondensation reaction

A practical approach to highly functionalized 4-hydroxypyridine derivatives with stereogenic side chains in the 2- and 6-positions is described. The presented two-step process utilizes a multicomponent reaction of alkoxyallenes, nitriles and carboxylic acids to provide β-methoxy-β-ketoenamides which are transformed into 4-hydroxypyridines in a subsequent cyclocondensation. The process shows broad substrate scope and leads to differentially substituted enantiopure pyridines in good to moderate yields. The preparation of diverse substituted lactic acid derived pyrid-4-yl nonaflates is described. Additional evidence for the postulated mechanism of the multicomponent reaction is presented

Mechanical stability of bivalent transition metal complexes analyzed by single-molecule force spectroscopy

Multivalent biomolecular interactions allow for a balanced interplay of mechanical stability and malleability, and nature makes widely use of it. For instance, systems of similar thermal stability may have very different rupture forces. Thus it is of paramount interest to study and understand the mechanical properties of multivalent systems through well-characterized model systems. We analyzed the rupture behavior of three different bivalent pyridine coordination complexes with Cu2+ in aqueous environment by single-molecule force spectroscopy. Those complexes share the same supramolecular interaction leading to similar thermal off-rates in the range of 0.09 and 0.36 s−1, compared to 1.7 s−1 for the monovalent complex. On the other hand, the backbones exhibit different flexibility, and we determined a broad range of rupture lengths between 0.3 and 1.1 nm, with higher most-probable rupture forces for the stiffer backbones. Interestingly, the medium-flexible connection has the highest rupture forces, whereas the ligands with highest and lowest rigidity seem to be prone to consecutive bond rupture. The presented approach allows separating bond and backbone effects in multivalent model systems

Mechanical Rupture of Mono- and Bivalent Transition Metal Complexes in Experiment and Theory

Biomolecular systems are commonly exposed to a manifold of forces, often acting between multivalent ligands. To understand these forces, we studied mono- and bivalent model systems of pyridine coordination complexes with Cu²⁺ and Zn²⁺ in aqueous environment by means of scanning force microscopy based single-molecule force spectroscopy in combination with <i>ab initio</i> DFT calculations. The monovalent interactions show remarkably long rupture lengths of approximately 3 Å that we attribute to a dissociation mechanism involving a hydrogen-bound intermediate state. The bivalent interaction with copper dissociates also via hydrogen-bound intermediates, leading to an even longer rupture length between 5 and 6 Å. Although the bivalent system is thermally more stable, the most probable rupture forces of both systems are similar over the range of measured loading rates. Our results prove that already in small model systems the dissociation mechanism strongly affects the mechanical stability. The presented approach offers the opportunity to study the force-reducing effects also as a function of different backbone properties