b-lactams C-H activation · Discovery of novel β-lactam analogs oriented to control multidrug-resistant bacteria enabled by Pd-catalyzed C–H activation of aliphatic amines

Discovery of novel β-lactam analogs oriented to control multidrug-resistant bacteria enabled by Pd-catalyzed C–H activation of aliphatic amines

Methods that enable practical and selective functionalization of aliphatic systems are of significant importance to the continued advance of chemical synthesis. Over the last two decades, transition-metal catalysis has emerged as an effective means of C–H activation using polar functionalities such as heteroarenes, carboxylic acids, and amide derivatives to modulate the cyclometallation process. The natural evolution of the field is the use of native functional groups to direct such C-H activation process. Recently, palladium-catalyzed C–H functionalization of aliphatic amine derivatives has emerged as a potentially powerful tactic for the synthesis of complex variants of these important molecules. While the functionalization of methyl C-H bonds have been explored, a major challenge remains the selective functionalization of methylene bonds. The activation of this class of bonds, on account of them being more sterically demanding than their primary counterparts, presents difficulties to both metal insertion and reductive elimination steps. Moreover, the functionalization of methtylene C–H bonds can generate stereogenic carbon centers, potentially causing stereoselectivity issues. The main objective of this work is the development of a C-H activation approach to transform simple aliphatic amines into b-lactams. Conclusion: During the last two years, we have developed first highly regio- and diasteroselective palladium-catalyzed carbonylation of methylene bonds in secondary aliphatic amines to furnish poly substituted trans-β-lactam scaffolds. This new methodology enables to transform simple aliphatic amines into poly substituted b-lactams in one step. Given the broad tolerance of this reaction to useful functional groups, we believe that this C–H carbonylation process will be of significant interest to practitioners of synthesis and medicinal chemistry, specifically for accessing antibiotics.

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