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New Synthetic Reactions for Antitumor Natural Products

Final Report Summary - NSR-ANP (New Synthetic Reactions for Antitumor Natural Products)

The development of catalytic transformations of C(sp3)–H bonds in a regio- and stereoselective fashion is an extremely exciting challenge and ultimately aims to provide synthetic chemists with new ways to disconnect bonds. In recent years, transition metal catalysis employing ligands as directing groups to affect C(sp3)–H bond activation has led to the development of multiple C(sp3)–H bond functionalisation methods. We have recently discovered an amine directed Pd(II)-catalyzed carbonylation of C(sp3)–H bonds of secondary amines via a 5-membered palladacycle intermediate species that allows CO insertion and cyclisation for the synthesis of pyrrolidinone moieties. Thus, this strategy exploits the inherent directing ability of the amine functional group in the substrates allowing for C(sp3)–H activation, without the need of any external directing group. This new reaction works for a variety of substrates incorporating quaternary groups alfa to the amine showing enhanced reactivity for the terminal C(sp3)–H bond of methyl groups, good functional group tolerance and asymmetric induction. Therefore, this method highlights the emerging value of unactivated C(sp3)–H bonds as functional groups in organic synthesis.

Parallel efforts towards the installation of nitrogen atom functionalities into organic molecules triggered the recent discovery of a straightforward intermolecular carboamination methodology. A thioether substituent in readily accessible 2-alkyl-5-(methylthio)tetrazoles enables facile photoinduced denitrogenation and intramolecular nitrile imine 1,3 dipolar cycloaddition to afford a wide range of polycyclic pyrazoline products with excellent diastereoselectivity. The methylthio group obviates the requirement in all previous substrate systems for at least one aryl substituent and can subsequently be converted into a variety of other functionalities. This synthetic platform has been applied to the concise total syntheses of the alkaloid natural products (±) newbouldine and withasomnine.