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

Abstract

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.

Goldilocks Effect of Base Strength on Site Selectivity in Acylation of Amphiphilic Diols

“…Scheme 1 Site-selective acylation of amphiphilic diols, favoring acylation at the apolar or polar sites (conditions A or B, respectively). 15 Scheme 2 Substrate selectivity studies with the mono-site apolar (9) and polar (10) substrates. 15 Parallel competitive experiments with pure substrates in each reaction vessel (a), compared to experiments with equimolar substrate mixture in the reaction vessel (b), both in the absence and in the presence of DIPEA, demonstrating strong influence of substrate mixing and DIPEA presence on acylation of 10, but not on acylation of 9 (c).…”

“…(23) The synthesis and the full characterization of the substrates 9 and 10, the full characterization of their butyrylation products 11 and 12, as well as the typical chromatograms of the reaction mixtures were reported in an earlier communication (ref. 15). (24) Typical procedure for the acylation (butyrylation) reaction of the mono-site substrates (9, 10) -separate experiments.…”

“…Scheme 1 Site-selective acylation of amphiphilic diols, favoring acylation at the apolar or polar sites (conditions A or B, respectively). 15 First, we resumed the study of substrate selectivity in the acylation of model truncated monoalcohol substrates 9 and 10 in the presence of various amounts of different bases (Scheme 3), because these were demonstrated highly relevant to the understanding of the outcome of the corre-sponding site-selectivity experiments with model diol 1. 22 Initially, three weakly nucleophilic bases, weakly basic 2,4,6-collidine, moderately basic DIPEA, and strongly basic DBU, were examined.…”

“…Scheme 2 Substrate selectivity studies with the monosite apolar ( 9) and polar ( 10) substrates. 15 Parallel competitive experiments with pure substrates in each reaction vessel (a), compared to experiments with equimolar substrate mixture in the reaction vessel (b), both in the absence and in the presence of DIPEA , demonstrating strong influence of substrate mixing and DIPEA presence on acylation of 10, but not on acylation of 9 (c). The use of a stronger base, DBU, caused much faster reactions, compared to those with collidine or DIPEA.…”

“…3d,e,4a,c,5c,6b,d,7a,c, 10,14 While exploring new ways to induce site selectivity in transformations of amphiphilic substrates, we found and recently reported the opposite modes of selectivity induced by dendron-like nucleophilic organocatalysts or by a tertiary amine in acylation of model amphiphilic diols (1 or 5, Scheme 1). 15 We attributed this divergent modes to different predominant mechanisms of the reaction, operating in each instance. While in the case of imidazole-based nucleophilic organocatalysts the reaction, favoring esterification at the apolar site (products 2 or 6), presumably proceeds via a nucleophilic mechanism involving a cationic intermediate, 16 the use of DIPEA tertiary amine base, preferentially directing the acylation to the polar-arm site (products 3 or 7), most likely induces the general-or specific-base catalytic mechanism.…”