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A survey of crystal structures containing the xanthine ring shows that caffeine-like molecules tend to stack in parallel in a variety of stacking geometries, suggesting that a stacked pair of caffeine molecules has many conformations of comparable energy. Molecular modelling suggests that the caffeine dimer, the major associated species in aqueous solution, may occur in nine distinct conformations. In agreement with the crystal survey and the modelling results, NMR spectra of caffeine solutions exhibit intermolecular nuclear Overhauser enhancements (NOEs), consistent with a dynamic equilibrium of several conformations of the dimer of comparable energies.Key words: caffeine, dimer, self-association, molecular modelling, intermolecular nuclear Overhauser enhancements (NOEs).

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A suitable process for the preparation of kilogram quantities of a TNF-r converting enzyme (TACE) inhibitor (WAY-281418) was developed using isatin 13 as starting material and an efficient coupling step for the formation of sulfonamide 8 in a 15% overall yield. Process preparation of (+)-(1S,2R)-2-aminocyclopentane-1carboxylic acid (7, (+)-cispentacin), a chiral component for WAY-281418, was successfully scaled up via an asymmetric hydrogenation reaction. Crystallization allowed the isolation of all intermediates and the final product 9.