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 stereoselective ?-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 intramolecular lactonization under mild conditions, via carboxylate binding to the metal center. The system exhibits high site-selectivity and enables the oxidation of unactivated primary ?-C–H bonds even in the presence of intrinsically weaker and a priori more reactive secondary and tertiary ones at ?- and ?-carbons. With substrates bearing nonequivalent ?-C–H bonds, the factors governing site-selectivity have been uncovered. Most remarkably, by manipulating the absolute chirality of the catalyst, ?-lactonization at methyl groups in gem-dimethyl structural units of rigid cyclic and bicyclic 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 ?-C–H bond of the bound substrate to a highly reactive MnIV-oxyl intermediate, to deliver a carbon radical that rapidly lactonizes through carboxylate transfer. Intramolecular kinetic deuterium isotope effect and 18O labeling experiments provide strong support to this mechanistic picture.
This work has been performed in collaboration with Prof. Massimo Bietti (Università “Tor Vergata”, Italy), and has recently been published in Journal of the American Chemical Society:
A. Call, M. Cianfanelli, P. Besalú-Sala, G. Olivo, A. Palone, L. Vicens, X. Ribas, J. M. Luis, M. Bietti, and M. Costas
“Carboxylic Acid Directed ?-Lactonization of Unactivated Primary C–H Bonds Catalyzed by Mn Complexes: Application to Stereoselective Natural Product Diversification”
J. Am. Chem. Soc. 2022, 144, 19542–19558
DOI: 10.1021/jacs.2c08620
Girona, Nov. 10, 2022
For more info: gestor.iqcc@gmail.com