The search for new scaffolds to complement current HTS and fragment libraries is an active area of research. The development of novel strategies to synthesise compounds with 3D character in order to expand the diversity of a fragment library was explored. A range of substituted bicyclo[2,2,1]spirooxindoles were synthesised using a Diels–Alder [4+2] cycloaddition reaction. Both diastereoisomers were isolated from the reactions and these 3D fragment scaffolds were screened against the cytochrome P450 enzyme CYP121 from Mycobacterium tuberculosis. A number of hits were identified to bind to CYP121 and were shown to exhibit Type I binding interactions with the heme group.

Measurements of the endo/exo product ratios for Huisgen cycloadditions with a series of vinyl ketones, alkyl acrylates, and substituted styrenes as dipolarophiles with phthalazinium and pyridazinium dicyanomethanide 1,3-dipoles in acetonitrile and water show that as the reactions change from in-water (large hydrophobic enhancement of endo-products) to on-water, the hydrophobic enhancement of the endo-products is reduced and partially reversed (relative to acetonitrile). An expected increase of the endo-effect with increasing hydrophobic character of the dipolarophile is overcome by decreasing water solubility causing changeover to on-water conditions. On-water reactions do not show increased cycloaddition endo-effects (relative to organic solvents) as do in-water reactions.

Organic reactions that occur at the water interface for water-insoluble compounds, and reactions in water solution for water soluble compounds, has added a powerful dimension to prospects for organic synthesis under more beneficial economic and environmental conditions. Many organic molecules are partially soluble in water and reactions that appear as heterogeneous mixtures and suspensions may involve on-water and in-water reaction modes occurring simultaneously. The behavior of water molecules and organic molecules at this interface is discussed in the light of reported theoretical and experimental studies. The on-water catalytic effect, relative to neat reactions or organic solvents, ranges from factors of several hundred times to 1–2 times and it depends on the properties of reactant compounds. In some cases when on-water reactions produce quantitative yields of water-insoluble products they can reach ideal synthetic aspirations.