Seeking to selectively functionalize natural and synthetic amphiphiles, we explored acylation of model amphiphilic diols. The use of a nucleophilic catalyst enabled a remarkable shift of the site selectivity from the polar site, preferred in background noncatalyzed or base-promoted reactions, to the apolar site. This tendency was significantly enhanced for organocatalysts comprising an imidazole active site surrounded by long/branched tails. An explanation of these orthogonal modes of selectivity is supported by competitive experiments with monoalcohol substrates.

Seeking to improve the site selectivity of acylation of amphiphilic diols, which is induced by imidazole-based nucleophilic catalysts and directs the reaction toward apolar sites, as we recently reported, we examined a new improved catalytic design and an alteration of the acylating agent. The new catalysts performed slightly better selectivity-wise in the model reaction, compared to the previous set, but notably could be prepared in a much more synthetically economic way. The change of the acylating agent from anhydride to acyl chloride, particularly in combination with the new catalysts, accelerated the reaction and increased the selectivity in favor of the apolar site. The new selectivity-inducing techniques were applied to midecamycin, a natural amphiphilic antibiotic possessing a secondary alcohol moiety in each of its two domains, polar as well as apolar. In the case of the anhydride, a basic dimethylamino group, decorating this substrate, overrides the catalyst’s selectivity preference and forces selective acylation of the alcohol in the polar domain with a more than 91:1 ratio of the monoacylated products. To counteract the internal base influence, an acid additive was used or the acylating agent was changed to acyl chloride. The latter adjustment leads, in combination with our best catalyst, to the reversal of the ratio between the products to 1:11.

Two series of competitive acylation experiments with a polar and an apolar alcohol substrates, imitating two parts of amphiphilic diols, examined the influence of bases of varying strength on the substrate selectivity. While weakly basic 2,4,6-collidine only mildly accelerates the acylation of the polar substrate without affecting that of the apolar one, the acylation of both substrates is drastically hastened by strongly basic DBU. In both cases there is a notable, though not overwhelming, shift of the substrate selectivity towards the polar substrate, compared to the base-free acylation, which strongly favors that of the apolar one. The extraordinarily strong change in the substrate selectivity in favor of the polar substrate was induced, however, by aliphatic tertiary amine bases, DIPEA and TEA, of “Goldilocks” moderate base strength, which strongly accelerate the acylation of the polar substrate, while almost not affecting that of the apolar one. These effects of the bases on the substrate selectivity are reflected in the site selectivity trends observed in the acylation of a model diol amphiphile.

Among the several variants of the highly useful and versatile Robinson annulation, a particular variation that involves ketones reacting with nonenolizable enones, while the α-carbons of the ketones act as nucleophiles at both steps of this cascade process, remains largely unexplored. Moreover, such a catalytic enantioselective reaction is exceptionally rare. While pursuing catalysis of this transformation, we developed two fluorogenic assays that, in combination with other analytic techniques, enabled rapid screening of several sets of catalysts. The first set of polymer-bound aminourea bifunctional organocatalysts was screened using a two-step fluorogenic protocol, designed for slower (e.g., heterogeneous) catalysts. Robinson annulation of acetone with 4′-nitrochalcone formed 3-(4-nitrophenyl)-5-phenyl-2-cyclohexenone, which, after a “developing” reductive treatment, was converted into the corresponding amino derivative, serving as a fluorescent reporter. On the other hand, a range of potentially faster homogeneous catalyst–cocatalyst systems were examined using a direct assay, where 4′-dimethylaminochalcone is converted into the corresponding cyclohexanone fluorescent reporter already upon annulation with acetone. In both cases, the combination of the fluorogenic protocols with high-performance liquid chromatography-based enantiomeric excess estimation enabled identification of lead catalysts, which promoted the enantioselective version of this variant of the annulation.