Author: Wilcock, B.C.; Uno, B.E.; Bromann, G.L.; Clark, M.J.; Anderson, T.M.; Burke, M.D.
Description: 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.
Subject headings: Acylation; Benzoates/chemistry; Binding Sites; Electronics; Ergosterol/chemistry; Molecular Structure; Phenazopyridine/chemistry; Substrate Specificity
Publication year: 2012
Journal or book title: Nature Chemistry
Volume: 4
Issue: 12
Pages: 996-1003
Find the full text :Â https://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.789.748&rep=rep1&type=pdf
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Type: Journal Article
Serial number: 1606