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Strategies for the design of ligands that combine with metal ions to form high-symmetry coordination assemblies are reviewed. Evaluation of crystal structure evidence reveals that prior design approaches, based on the concept of complementary bonding vector angles, fail to predict the majority of known examples. After explaining the reasons for this failure, it is shown how an alternative approach, de novo structure-based design, provides a practical method that predicts a much wider range of component shapes encoded to direct the formation of such assemblies.

On the basis of (1)H NMR spectroscopic analyses and single crystal X-ray crystal structural data, the ion-pair receptor 1, bearing a calix[4]pyrrole for anion binding and calix[4]arene crown-5 for cation recognition, was found to act as a receptor for both CsF and KF ion-pairs. Both substrates are bound strongly but via different binding modes and with different complexation dynamics. Specifically, exposure to KF in 10% CD(3)OD in CDCl(3) leads first to complexation of the K(+) cation by the calix[4]arene crown-5 moiety. As the relative concentration of KF increases, then the calix[4]pyrrole subunit binds the F(-) anion. Once bound, the K(+) cation and the F(-) anion give rise to a stable 1:1 ion-pair complex that generally precipitates from solution. In contrast to what is seen with KF, the CsF ion-pair interacts with receptor 1 in two different modes in 10% CD(3)OD in CDCl(3). In the first of these, the Cs(+) cation interacts with the calix[4]arene crown-5 ring weakly. In the second interaction mode, which is thermodynamically more stable, the Cs(+) cation and the counteranion, F(-), are simultaneously bound to the receptor framework. Further proof that system 1 acts as a viable ion-pair receptor came from the finding that receptor 1 could extract KF from an aqueous phase into nitrobenzene, overcoming the high hydration energies of the K(+) and F(-) ions. It was more effective in this regard than a 1:1 mixture of the constituent cation and anion receptors (4 and 5).

Ion pair receptor 3 bearing an anion binding site and multiple cation binding sites has been synthesized and shown to function in a novel binding-release cycle that does not necessarily require displacement to effect release. The receptor forms stable complexes with the test cesium salts, CsCl and CsNO(3), in solution (10% methanol-d(4) in chloroform-d) as inferred from (1)H NMR spectroscopic analyses. The addition of KClO(4) to these cesium salt complexes leads to a novel type of cation metathesis in which the "exchanged" cations occupy different binding sites. Specifically, K(+) becomes bound at the expense of the Cs(+) cation initially present in the complex. Under liquid-liquid conditions, receptor 3 is able to extract CsNO(3) and CsCl from an aqueous D(2)O layer into nitrobenzene-d(5) as inferred from (1)H NMR spectroscopic analyses and radiotracer measurements. The Cs(+) cation of the CsNO(3) extracted into the nitrobenzene phase by receptor 3 may be released into the aqueous phase by contacting the loaded nitrobenzene phase with an aqueous KClO(4) solution. Additional exposure of the nitrobenzene layer to chloroform and water gives 3 in its uncomplexed, ion-free form. This allows receptor 3 to be recovered for subsequent use. Support for the underlying complexation chemistry came from single-crystal X-ray diffraction analyses and gas-phase energy-minimization studies., (© 2011 American Chemical Society)

The aristolochene synthase catalysed cyclisation of farnesyl diphosphate (1) has been postulated to proceed through (S)-germacrene A (3). However, the active site acid that reprotonates this neutral intermediate has so far proved difficult to identify and, based on high level ab initio molecular orbital and density functional theory calculations, a proton transfer mechanism has recently been proposed, in which proton transfer from C12 of germacryl cation to the C6,C7-double bond of germacryl cation (2) proceeds either directly or via a tightly bound water molecule. In this work, the stereochemistry of the elimination and protonation reactions was investigated by the analysis of the reaction products from incubation of 1 and of [12,12,12,13,13,13-(2)H(6)]-farnesyl diphosphate (15) with aristolochene synthase from Penicillium roqueforti (PR-AS) in H(2)O and D(2)O. The results reveal proton loss from C12 during the reaction and incorporation of another proton from the solvent. Incubation of with PR-AS in D(2)O led to the production of (6R)-[6-(2)H] aristolochene, indicating that protonation occurs from the face of the 10-membered germacrene ring opposite the isopropylidene group. Hence these results firmly exclude proton transfer from C12 to C6 of germacryl cation. We propose here Lys 206 as the general acid/base during PR-AS catalysis. This residue is part of a conserved network of hydrogen bonds, along which protons could be delivered from the solvent to the active site.

An intramolecular proton-transfer mechanism has been proposed for the carbocationic cyclization of farnesyl pyrophosphate (FPP) to (+)-aristolochene catalyzed by aristolochene synthase. This novel mechanism, which is based on results obtained by high-level ab initio molecular orbital and density functional theory calculations, differs from the previous proposal in the key step of carbocation propagation prior to the formation of the bicyclic carbon skeleton. Previously, germacrene A was proposed to be generated as an intermediate by deprotonation of germacryl cation followed by reprotonation of the C6-C7 double bond to yield eudesmane cation. In the mechanism proposed here the direct intramolecular proton transfer has a computed barrier of about 22 kcal/mol, which is further lowered to 16-20 kcal/mol by aristolochene synthase. An alternative pathway is also possible through a proton shuttle via a pyrophosphate-bound water molecule. The mechanism proposed here is consistent with the observation that germacrene A is not a substrate of aristolochene synthase. Furthermore, the modeled substrate-enzyme complex suggests that Trp 334 and Phe 178 play key roles in positioning the substrate in the reactive orientation in the binding pocket. This is consistent with experimental findings that mutations of either residue lead to pronounced generation of aborted cyclization products.

Analogues of farnesyl diphosphate (FPP, ) containing phenyl substituents in place of methyl groups have been prepared in syntheses that feature use of a Suzuki-Miyaura reaction as a key step. These analogues were found not to act as substrates of the sesquiterpene cyclase aristolochene synthase from Penicillium roqueforti (AS). However, they were potent competitive inhibitors of AS with K(I)-values ranging from 0.8 to 1.2 microM. These results indicate that the diphosphate group contributes the largest part to the binding of the substrate to AS and that the active sites of terpene synthases are sufficiently flexible to accommodate even substrate analogues with large substituents suggesting a potential way for the generation of non-natural terpenoids. Molecular mechanics simulations of the enzyme bound inhibitors suggested that small changes in orientations of active site residues and subtle alterations of the conformation of the backbones of the inhibitors are sufficient to accommodate the phenyl-farnesyl-diphosphates.