A cavitand functionalized with a Kemp's triacid derivative was used to catalyze the epoxide ring-opening cyclizations of 1,5-epoxyalcohols. A deep, cylindrical cavity containing electron-rich aromatic walls and an inwardly directed carboxylic acid displayed the necessary characteristics to bind different 1,5-epoxyalcohols and initiate their cyclization reactions. The reactions inside this synthetic receptor occurred in a catalytic and regioselective manner. These results highlight that the arrangement of functionality and unique solvation provided by the structured interiors of natural enzymes can be incorporated into synthetic systems having useful physical and chemical properties.

The limitations of stereoelectronic models in assessing the stereoselective nucleophilic substitution reactions of cyclic oxocarbenium ions at high reaction rates are discussed. Evidence is provided suggesting that the diastereoselectivity of nucleophilic substitution reactions is attenuated at the limits of diffusion control. The low diastereoselectivities observed in the reactions of trimethylsilyl cyanide with five- and six-membered ring oxocarbenium ions are attributed to the high reactivity of the nucleophile and its reactions with these electrophiles at diffusion control rates.

The cyclization reaction of an epoxyalcohol is catalyzed by a synthetic cavitand receptor with an inwardly-directed carboxylic acid function. The receptor features a hydrophobic pocket in which the substrate is bound and positioned to react in a regioselective manner. The nature of this substratecatalyst complex and its dynamic properties were investigated by NMR methods and with the aid of a model compound lacking the epoxide function. The kinetic parameters of the cyclization reaction were also studied. A catalytic cycle is proposed and diverse inhibition mechanisms are identified that parallel those encounterd in enzymology.

A deep, self-folding cavitand responds to minor electronic differences between suitably sized adamantane guests. Binding constants range from <0.5 to 4000 M -1 for guests as similar as 1-bromoadamantane and 1-cyanoadamantane. The barriers to guest exchange also vary up to 3 kcal mol -1 .Enzymes can detect very small changes in substrate structures, 1 and the discrimination may be through steric or electronic effects. The replacement of hydrogen atoms with fluorine atoms, for example, has large effects on the binding constants of thrombin inhibitors, and these are attributed to variations in electronic rather than steric effects. 2 Functional groups presented to substrates by the folded enzymes are responsible for this selectivity, and some synthetic receptors can reproduce this discrimination. Fully enclosed host capsules can detect subtle differences in guest structure, generally due to changes in "fit" -capsules are responsive to the size and shape complementarity of the substrate. 3 Open-ended receptors such as cyclodextrins or cavitands are often poor at distinguishing between small changes in guest structure; any functionality that is incompatible with the cavity can be directed outwards, into the solvent. Here we report that small changes in a series of adamantane-derived guests have large effects on the properties of the complex with the cavitand. These effects appear electronic in nature rather than steric interactions with the cavitand or its substituents at the cavitand's rim. 4 Deep cavitands are held in a bowl-shaped conformation by a seam of hydrogen bonds at the open end. 5 They fold around their guests and act as enzyme mimics in a number of senses, jrebek@scripps.edu Supporting Information Available. Experimental details, 1D NMR spectra, 2D NMR kinetics data. This material is available free of charge via the internet at http://pubs.acs.org. The adamantane provides a binding "anchor" that fills the space of the cavitand, and presents C-H bonds to its aromatic surfaces. Typically, substituents emerge through the opening to the bulk solvent outside. 6a Figure 1 shows energy-minimized structures (DFT minimization; B3LYP/6-31G* basis set) of the complexes of adamantane 3a and 1-hydroxyadamantane 3e in cavitand 1. At first glance, the contacts between host and guest appear identical. Figure 1c shows that the substituent is remote from the amide seam -the calculated distance between an amide NH and the OH of 3e is 5.9Å, far longer than any hydrogen bond. This distance would preclude steric clashes between any small adamantane substituent and the cavitand's rim. NIH Public AccessA series of substituted adamantane guests were titrated with the cavitands (see Table 1). The guests are similar in size, but vary electronically. The parameters listed in Table 1 are binding constants and the energy barriers to self-exchange; values that can be easily determined by NMR techniques ( 1 H NMR integration and 2D EXSY, 7 respectively). As seen in Table 1, binding constants vary widely. Adamantane (3a) itself...

[reaction: see text] The O-to-C rearrangement of vinyl acetals is used to demonstrate that tight ion pairing is not involved in the stereoselective nucleophilic addition reactions of alkoxy-substituted cyclic oxocarbenium ions.