Conformational constraints are the keys for the efficient synthesis of medium‐sized rings by ring‐closing olefin metathesis (RCM). While the RCM reaction has already proved itself in the synthesis of the larger macrocycles, like that found in epothilone, only recently has this reaction been increasingly used in the construction of eight‐ to ten‐membered carbo‐ and heterocycles. In the picture, a cyclopentane ring ensures the conformational constraints necessary for a successful cyclization.

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Coordination chemistry of gold catalysts bearing eight different ligands [L=PPh(3), JohnPhos (L2), Xphos (L3), DTBP, IMes, IPr, dppf, S-tolBINAP (L8)] has been studied by NMR spectroscopy in solution at room temperature. Cationic or neutral mononuclear complexes LAuX (L=L2, L3, IMes, IPr; X=charged or neutral ligand) underwent simple ligand exchange without giving any higher coordinate complexes. For L2AuX the following ligand strength series was determined: MeOH≪hex-3-yne

In this article strategies for the design and synthesis of natural product analogues are summarized and illustrated with some selected examples. Proven strategies include diverted total synthesis (DTS), function-oriented synthesis (FOS), biology-oriented synthesis (BIOS), complexity to diversity (CtD), hybrid molecules, and biosynthesis inspired synthesis. The latter includes mutasynthesis, the synthesis of natural products encoded by silent genes, and propionate scanning. Most of the examples from our group fall in the quite general concept of DTS. Thus, in case an efficient strategy to a natural product is at hand, modifications are possible at almost any stage of a synthesis. However, even for compounds of moderate complexity, organic synthesis remains a bottle neck. Unless some method for predicting the biological activity of a designed molecule becomes available, the design and synthesis of natural product analogues will remain what it is now, namely it will largely rely on trial and error.

Using gold(I)-catalyzed hydroalkoxylation of alkynes as a model reaction with a well-known mechanism, a systematic experimental study was conducted to disclose the influence of the counterion X − of a gold catalyst LAuNCMe + X − on every step of the catalytic cycle. The overall ion effect is determined as a superposition of several effects, operating on different steps of the reaction mechanism. All effects were explained from a position of hydrogen bonding, coordination chemistry at gold, and affinity for a proton.

An extensive experimental study of the mechanism of gold(I)-catalyzed hydroalkoxylation of internal alkynes has been conducted by using NMR spectroscopy. This study was focused on the organogold intermediates, observations of actual catalytic intermediates in situ, and the reaction kinetics that are involved in this reaction. Based on the experimental results, a complete mechanistic picture was established, including on- and off-cycle processes that explain the role of diaurated species. We have shown that gold-catalyzed hydroalkoxylation of internal alkynes is a reaction that requires only one gold atom for the catalytic cycle, disproving a recent hypothesis regarding the involvement of cooperative gold catalysis.

Two new bismacrocyclic Gd 3+ chelates containing a specific Ca 2+ binding site were synthesized as potential MRI contrast agents for the detection of Ca 2+ concentration changes at the millimolar level in the extracellular space. In the ligands, the Ca 2+ -sensitive BAPTA-bisamide central part is separated from the DO3A macrocycles either by an ethylene (L 1 ) or by a propylene (L 2 ) unit [H 4 BAPTA is 1,2-bis(o-aminophenoxy)ethane-N,N,N 0 ,N 0 -tetraacetic acid; H 3 DO 3 A is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid]. The sensitivity of the Gd 3+ complexes towards Ca 2+ and Mg 2+ was studied by 1 H relaxometric titrations. A maximum relaxivity increase of 15 and 10% was observed upon Ca 2+ binding to Gd 2 L 1 and Gd 2 L 2 , respectively, with a distinct selectivity of Gd 2 L 1 towards Ca 2+ compared with Mg 2+ . For Ca 2+ binding, association constants of log K = 1.9 (Gd 2 L 1 ) and log K = 2.7 (Gd 2 L 2 ) were determined by relaxometry. Luminescence lifetime measurements and UV-vis spectrophotometry on the corresponding Eu 3+ analogues proved that the complexes exist in the form of monohydrated and nonhydrated species; Ca 2+ binding in the central part of the ligand induces the formation of the monohydrated state. The increasing hydration number accounts for the relaxivity increase observed on Ca 2+ addition. A 1 H nuclear magnetic relaxation dispersion and 17 O NMR study on Gd 2 L 1 in the absence and in the presence of Ca 2+ was performed to assess the microscopic parameters influencing relaxivity. On Ca 2+ binding, the water exchange is slightly accelerated, which is likely related to the increased steric demand of the central part leading to a destabilization of the Ln-water binding interaction.

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