title: 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.
authors.affiliation: Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Brandon C
authors.initials: BC
authors.lastname: Wilcock
authors.forename: Brice E
authors.initials: BE
authors.lastname: Uno
authors.forename: Gretchen L
authors.initials: GL
authors.lastname: Bromann
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Clark
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Anderson
authors.forename: Martin D
authors.initials: MD
authors.lastname: Burke
mesh_terms: D000215:Acylation; D001565:Benzoates / Q000737:chemistry; D001665:Binding Sites; D004581:Electronics; D004875:Ergosterol / Q000737:chemistry; D015394:Molecular Structure; D010621:Phenazopyridine / Q000737:chemistry; D013379:Substrate Specificity
chemical_list: D001565:Benzoates; D010621:Phenazopyridine; C013409:benzoyl chloride; D004875:Ergosterol