Catalytic asymmetric P(III)-additions to salicylaldehydes enable divergent stereoselective dearomatizations of phenols

Oxidative dearomatizations are useful tools in complex molecule synthesis and the development of enantioselective variants offers substantial opportunities for the field. In this article, we describe a platform for a formal enantioselective dearomatization that employs chiral nonracemic α-hydroxyphosphonates derived from salicylaldehydes to direct diastereoselective functionalization of the phenolic core. As a requisite first step, we developed a new bis(oxazoline)Cu(ii)-catalyzed hydrophosphonylation (Pudovik reaction) of salicylaldehydes, allowing access to enantioenriched material in one step. The derived α-hydroxyphosphonates participated in complementary stereoselective dearomatization sequences. A tandem phosphono-Adler–Becker oxidation/[4 + 2]-cycloaddition furnished bicyclo[2.2.2]-octanes bearing phosphonoepoxyketone functionalities in excellent regio- and diastereoselectivity for both steps. Alternatively, oxidation with phenyliodine(iii) diacetate (PIDA) provided access to either 2,5- or 2,4-cyclohexadienones, with the latter reacting in a complementary [4 + 2]-cycloaddition. Experimental and computational studies of the two paths reveal distinct modes of stereochemical relay from the α-hydroxyphosphonate adducts to the derived dearomatized Diels–Alder products. The removable α-hydroxyphosphonate and phosphonoepoxide functionalities enable downstream synthetic modifications to the stereochemically defined cycloadducts.