Electronic tuning of site-selectivity

Abstract

Site-selective functionalizations of complex small molecules can generate targeted derivatives with exceptional step efficiency, but general strategies for maximizing selectivity in this context are rare. Here, we report that site-selectivity can be tuned by simply modifying the electronic nature of the reagents. A Hammett analysis is consistent with linking this phenomenon to the Hammond postulate: electronic tuning to a more product-like transition state amplifies site-discriminating interactions between a reagent and its substrate. This strategy transformed a minimally site-selective acylation reaction into a highly selective and thus preparatively useful one. Electronic tuning of both an acylpyridinium donor and its carboxylate counterion further promoted site-divergent functionalizations. With these advances, we achieve a range of modifications to just one of the many hydroxyl groups appended to the ion channel-forming natural product amphotericin B. Thus, electronic tuning of reagents represents an effective strategy for discovering and optimizing site-selective functionalization reactions.

Figure 1. Overview of an approach to functionalize AmB to probe a possible interaction with ergosterol

a, The Hammond postulate applied to site-selectivity. More electron-rich acylpyridinium ions are predicted to react via a more product-like transition state in which the site-discriminating interactions between the acylating reagent and the polyol substrate are magnified. These enhanced interactions increase the difference in activation energies (ΔΔG^ŧ) for the acylation of one hydroxyl group (solid line) versus another (dashed line). b, Amphotericin B (AmB) and a putative interaction between the hydroxyl group at C2' and ergosterol. c, A strategy for site-selective functionalization of just one of many distinct secondary hydroxyl groups appended to AmB.

Figure 2. Analysis of acylation reactions with para-substituted benzoyl chlorides

a, A Hammett study of site-selective acylation. As the electron-withdrawing capacity of the substituent increased, the selectivity decreased and the rate increased. b, A Hammett plot of the log of the ratio of the product monoacylated at C2' to all other products as a function of σ_para. c, A Hammett plot of the log of the initial rate as a function of σ_para. d, A plot of the ratio of site isomers as a function of the initial rate. Values for the %C2'-OH selectivity, ratio of site isomers, and initial rate all represent the average of three trials.

Figure 3. Selective functionalizations at the C2' position of AmB

Electronic tuning of the acyl donor enables selective acylation at the C2' hydroxyl of intermediate 1. The acyl group acts as a temporary protecting group that is removed after orthogonal protection of the remaining hydroxyl groups leaving only the C2' hydroxyl exposed. The C2' hydroxyl group can then undergo a variety of functionalizations such as deoxygenation, stereochemical inversion, or acylation to form AmB-small molecule conjugates.