The site-selective acylation of a steroidal natural product 19-hydroxydehydroepiandrosterone catalyzed by 1,1'-Bi(2-napthol)-derived (BINOL) chiral phosphoric acids (CPA's) is described. Systematic variation and multivariate linear regression analysis reveal that the same steric parameters typically needed for high enantioselectivity with this class of CPAs are also required for site-selectivity in this case. Density functional theory calculations identify additional weak CH-π interactions as contributors to site discrimination. We further report a rare example of site-selective acylation of phenols through the evaluation of naringenin, a flavonoid natural product, using CPA catalysis. These results suggest that BINOL-derived CPA's may have broader applications in site-selective catalysis.
Keywords: Site-selective catalysis; acylation; chiral phosphoric acids; modeling; non-covalent interactions.