We demonstrated recently that organocatalysts, based on a nucleophilic core (N-alkylimidazole or 4-aminopyridine) and decorated with an extensive secondary-sphere envelope (connected to the core through a benzyl substituent), strongly affect the site selectivity in acylation and phosphorylation of amphiphilic diols, sometimes entirely overriding the innate predisposition of the substrate. Preliminary studies pointed out that, despite some similarities, there are differences between the two transformations, regarding the influence of various catalyst features on the selectivity. To fully elucidate this, extended families of organocatalysts of the said design were examined, activity- and selectivity-wise, in the abovementioned transformations of model alcohol and amphiphilic diol substrates. A comparison of the influence of the catalyst design on the two reactions revealed that while the inductive electron donation of the o,o-dialkoxybenzyl substituent of the core, combined with the catalytic intermediate-stabilizing influence of some of the secondary-sphere components, causes an increase in the catalyst activity in both reactions and in the site selectivity in phosphorylation, its effect on the site selectivity in acylation is opposite. On the other hand, the lipophilicity of the secondary-sphere appendages improves the apolar site-favoring selectivity in both reactions. Thus, both factors work in concert in phosphorylation, but in opposite directions in acylation.
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.
Organocatalysts based on a nucleophilic core, decorated with long hydrocarbon or oligoether outer‐sphere tails were successfully applied for attenuating the site selectivity in phosphorylation of a model amphiphilic diol. Under the influence of the catalysts, the preference for the first functionalization of the hydroxyl at the apolar domain increased dramatically to render the ratio up to 3.9 : 1 between the monophosphorylated products, at 50 % substrate consumption (vs. 1.8 : 1 in the alike reaction without the catalyst). A considerable influence of the catalyst design, particularly the core nature and the tails structure, on the rate and the selectivity of the reaction was observed.
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