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. 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. Investigations with the ion-channel-forming natural product amphotericin B have revealed that site-selectivity can be tuned by simply modifying the electronic nature of the reagents.

Cite this article

Wilcock, B., Uno, B., Bromann, G. et al. Electronic tuning of site-selectivity. Nature Chem 4, 996–1003 (2012). https://doi.org/10.1038/nchem.1495

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