Catalysis

Access to Unsaturated Bicyclic Lactones by Overriding Conventional C(sp3)-H Site Selectivity

Authors

Abstract

Selective transformation of unactivated CH bonds is one of the notable advances in synthetic chemistry in last 20 years to streamline the synthesis of complex organic molecules. Transition metal catalysis has become a powerful tool to convert unreactive aliphatic CH bonds into an array of useful functionalities.1-3 Nonetheless, selective transformation of distal aliphatic CH bonds still presents a significant challenge, more so in absence of an exogenous directing group.4-5 In this context, aliphatic acids have been identified as the choice of substrates that could be functionalized without utilizing any extra directing group. However, the weak coordination of carboxylate group has been shown to activate mostly the methyl group at  or  position, limiting the scope and applicability of aliphatic acids.6-8 Herein, we have developed a ligand enabled palladium catalyzed protocol that activates the challenging methylene CH bond of aliphatic acids in presence of methyl CH bonds to form bicyclic lactones in an intramolecular manner (mid to large size). The reported protocol allows the reversal of the general selectivity in aliphatic CH bond activation. Computational mechanistic studies suggest that the CH activation in the cycloalkane ring of the starting material is followed by -hydride elimination to give Pd-coordinated cycloalkene, C-O cyclization, and another -hydride elimination to provide bicyclic unsaturated lactones. The scope of this previously unfamiliar reaction mode has been highlighted via dehydrogenative lactonization of mid to macro ring containing acids along with CH olefination reaction with olefin and allyl alcohol. Furthermore, synthesis of a variety of complex molecules via formal synthesis of natural products underscore the generality and significance of this reaction and suggestive of a new mode of CH activation reactions in aliphatic acids that could simplify the synthesis of bicyclic lactones, that are important features of numerous natural products as well as pharmacoactive molecules.

Content

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Supplementary material

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Access to Unsaturated Bicyclic Lactones by Overriding Conventional C(sp3)-H Site Selectivity
Supporting Information