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

Abstract

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.

Improving Site Selectivity in Phosphorylation of Amphiphilic Diols through Catalyst Design

“… Preparation of the catalysts of the Im family. Reagents and conditions: (i) RI, K 2 CO 3 , DMF, rt; (ii) ROH, DIAD, PPh 3 , THF, rt; (iii) LiAlH 4 , THF, rt; (iv) SOCl 2 , pyridine, CHCl 3 , rt; (v) imidazole, DMF, 90 °C [17c,19] …”

Tuning the Structure of 4‐Aminopyridine Catalysts for Improved Activity and Selectivity in Functionalization of Alcohols

“…In the case of phosphorylation a greater selectivity is observed, favoring the alcohol at the apolar arm with up to 3.9 : 1 ratio between the monofunctionalized products (at 50 % consumption) [8] . A more modest selectivity with up to 2.5 : 1 ratio of the monoester products is achieved in the case of the acylation of the model diol under standard conditions, [9] though in the acylation of an amphiphilic midecamycin natural product a ratio of above 11 : 1 was reached under optimized conditions [7] . Additional similarities and differences between the two alcohol‐transforming reactions were revealed by the comparison of the activity and selectivity of various catalysts of imidazole‐ and 4‐(methylamino)pyridine‐based families (Im and BMAP families, [10] respectively) in these processes [9] .…”

“…[4][5][6] On the other hand, acylation and phosphorylation of such diols promoted by nucleophilic organocatalysts, particularly these with the active unit wrapped in an extended outer-sphere envelope, which were developed recently in our group, form preferentially the products monofunctionalized in the apolar domain (Scheme 1b). [4,[7][8][9] In the case of phosphorylation a greater selectivity is observed, favoring the alcohol at the apolar arm with up to 3.9 : 1 ratio between the monofunctionalized products (at 50 % consumption). [8] A more modest selectivity with up to 2.5 : 1 ratio of the monoester products is achieved in the case of the acylation of the model diol under standard conditions, [9] though in the acylation of an amphiphilic midecamycin natural product a ratio of above 11 : 1 was reached under optimized conditions.…”

“…[8] A more modest selectivity with up to 2.5 : 1 ratio of the monoester products is achieved in the case of the acylation of the model diol under standard conditions, [9] though in the acylation of an amphiphilic midecamycin natural product a ratio of above 11 : 1 was reached under optimized conditions. [7] Additional similarities and differences between the two alcoholtransforming reactions were revealed by the comparison of the activity and selectivity of various catalysts of imidazole-and 4-(methylamino)pyridine-based families (Im and BMAP families, [10] respectively) in these processes. [9] While the influence of some of the structural features of the catalysts on the activity and the site selectivity of both reactions was similar, other features affected both reactions differently.…”

“…Thus, the use of tertiary aliphatic amine bases, such as N,N‐diisopropylethylamine (DIPEA) or triethylamine, leads to almost exclusive acylation of the alcohol in the polar domain of the model amphiphilic diols (Scheme 1a) [4–6] . On the other hand, acylation and phosphorylation of such diols promoted by nucleophilic organocatalysts, particularly these with the active unit wrapped in an extended outer‐sphere envelope, which were developed recently in our group, form preferentially the products monofunctionalized in the apolar domain (Scheme 1b) [4,7–9] . In the case of phosphorylation a greater selectivity is observed, favoring the alcohol at the apolar arm with up to 3.9 : 1 ratio between the monofunctionalized products (at 50 % consumption) [8] .…”