Controlling the Site Selectivity in Acylations of Amphiphilic Diols: Directing the Reaction toward the Apolar Domain in a Model Diol and the Midecamycin A1 Macrolide Antibiotic.

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.

Base- and Catalyst-Induced Orthogonal Site Selectivities in Acylation of Amphiphilic Diols.

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.

Phosphorylation Organocatalysts Highly Active by Design.

The activity of nucleophilic organocatalysts for alcohol/phenol phosphorylation was enhanced through attaching oligoether appendages to a benzyl substituent on imidazole- or aminopyridine-based active units, presumably because of stabilizing n-cation interactions of the ethereal oxygens with the positively charged aza-heterocycle in the catalytic intermediates, and was substantially higher than that of known benchmark catalysts for a range of substrates. Density functional theory calculations and the study of analogues having a lower potential for such stabilizing interactions support our hypothesis.