The synthesis and subsequent discovery of fungicidally active a-hydroxyarylacetamides originated from a report that phenyltartronic acid amides exhibited insecticidal activity.1 The slow-acting nature of this activity led us to speculate that these compounds might be metabolically activated via hydrolysis and then decarboxylation of one of the amide moieties. Subsequently, a synthesis programme looking at a wide range of ahydroxy-arylacetamides was instigated. This yielded, not a new insecticide, but a novel class of fungicidally active compounds of which compound 1 (Fig. 1) was an early example.2,3 A systematic study of the optimal substitution patterns in the two phenyl rings indicated that, while various electron-withdrawing groups in the 4-or 3,4-position of the mandelic acid ring gave good activity, very little change was allowed in the phenethylamine ring. One of the best analogues was compound 3 * To whom correspondence should be addressed which showed very good activity ([95% control at 50 mg litre~1) against both vine downy mildew (Plasmopara viticola Berl. & De Toni) and potato late blight (Phytophthora infestans (Mont.) de Bary.During the next stage of our optimisation studies we systematically sought to modify the bridge connecting the two phenyl rings. This work resulted in the discovery of the biologically interesting methyl-substituted analogues 4 and 5. The phenylisopropylamide 5 showed the best overall activity seen to date, and we were keen to investigate whether or not there was any biological discrimination between the four stereoisomers. The isomers were separated using chiral HPLC and the highest activity with respect to late blight was found to be associated with the two isomers possessing the RconÐguration at the phenylisopropylamide centre (Table 1). This suggests that, for this pathogen, this chiral centre is biologically more important than that associated with the mandelamide end of the molecule. The absolute conÐguration of the phenylisopropylamine was assigned via an asymmetric synthesis.4The two aryl groups of the a-hydroxyarylacetamide structure are joined by six bonds, of which only one, the amide bond, has any conformational restriction on rotation. When such a non-rigid molecule binds at an enzyme or receptor there is an entropy penalty which must be paid in terms of lowered binding affinity due to loss of free rotation. Consequently, reducing the number of free rotations, for example by introducing a double bond into a chain, can lead to an increased binding affinity at the molecular site of action.5 The preferred conformations of our compounds were studied using 331 1997 SCI. Pestic. Sci. 0031-613X/97/$17.50. Printed in Great Britain (