Carboxylic Acid Directed γ-Lactonization of Unactivated Primary C-H Bonds Catalyzed by Mn Complexes: Application to Stereoselective Natural Product Diversification

Reactions that enable selective functionalization of strong aliphatic C-H bonds open new synthetic paths to rapidly increase molecular complexity and expand chemical space. Particularly valuable are reactions where site-selectivity can be directed toward a specific C-H bond by catalyst control . Herein we describe the catalytic site-and stereoselec t i v e gamma-lactonization of unactivated primary C-H bonds in carboxylic acid substrates. The system relies on a chiral Mn catalyst that activates aqueous hydrogen peroxide to promote intramolecula r lactonization under mild conditions, via carboxylate binding to the metal center. The system exhibits high site-select i v i t y and enables the oxidation of unactivated primary gamma-C-H bonds even in the presence of intrinsically weaker and a priori more reactive secondary and tertiary ones at alpha- and beta-carbons. With substrates bearing nonequivalent gamma-C-H bonds, the factors governing site-select i v i t y have been uncovered. Most remarkably, by manipulating the absolute chirality of the catalyst, gamma-lactonization at me t h y l groups in gem-dimethyl structural units of rigid cyclic and bicycli c carboxylic acids can be achieved with unprecedented levels of diastereoselectivity. Such control has been successfully exploited in the late-stage lactonization of natural products such as camphoric, camphanic, ketopinic, and isoketopinic acids. DFT analysis points toward a rebound type mechanism initiated by intramolecular 1,7-HAT from a primary gamma-C-H bond of the bound substrate to a highly reactive MnIV-oxyl intermediate, to del i v e r a carbon radical that rapidly lactonizes through carboxylate transfer. Intramolecular kinetic deuter i u m isotope effect and 18O labeling experiments provide strong support to this mechanistic picture.