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

Citations Over TimeTop 10% of 2022 papers

Abstract

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 γ-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 γ-C-H bonds even in the presence of intrinsically weaker and a priori more reactive secondary and tertiary ones at α- and β-carbons. With substrates bearing nonequivalent γ-C-H bonds, the factors governing site-selectivity have been uncovered. Most remarkably, by manipulating the absolute chirality of the catalyst, γ-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 γ-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.

Related Papers

• → Short and stereoselective synthesis of manzacidins A and C, and their enantiomers(2008)16 cited
• → Pentafulvene-derived η3-allyltitanocenes as intermediates for the stereoselective functionalization of 5-membered carbocycles(2013)9 cited
• → UO‐Catalyzed Oligothioadenylate Synthesis with High Regio‐ and Stereoselectivity(1993)25 cited
• → Stereoselective synthesis of (±)-ancistrofuran: stereoselective reduction of a γ-hydroxyketone(1984)14 cited
• → Catalyst-Controlled Stereoselective Construction of Indole-Fused Heterocycles through Cycloadditions of Indolyl-Allenes: A Theoretical Investigation(2021)