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Desymmetrizing C–H Activation Enables Concise Total Synthesis of (–)-Maximiscin


(–)-Maximiscin (1, Figure 1A) is a unique 4-hydroxy-2-pyridone alkaloid, a class of natural products historically represented by fascinating structural components and intriguing biological activities. Recently, 1 has been shown to induce DNA damage, activate DNA damage response pathways, and induce selective cytotoxicity against triple negative breast cancer (TNBC). The Baran group has reported the first total synthesis of 1 in a longest linear sequence of 10 steps. Their strategic bond disconnections are shown in Figure 1B.



The synthesis is summarized in Scheme 1, and showcases a C–H methoxylation step that acts to desymmetrize the pseudosymmetric α-carbon of compound 10 (note that 8 is achiral and directing group 9 is enantiopure) to afford 11. Notably, this is the most complicated example of this methodology, however there is a caveat to note, and it’s generally the “Achille’s Heel” of modern C–H activation methods, and that is the subsequent removal of the directing group (i.e., aqueous HBr, 100 C, 15 h). Not many substrates will survive conditions like this; however, many substrates used in medicinal chemistry (aromatic and heteroaromatic rings) are quite stable and thus these methods can be employed in the design of druglike molecules.

Other key transformations include an Ag/Fe co-catalyzed stereoinvertive decarboxylative Giese addition, followed by 1,5 hydrogen atom transfer (HAT) and radical oxidation (i.e., 12 to 14, Scheme 1), and an “Aza-Sakurai” cascade to construct the atropisomeric pyridone ring in the penultimate step (i.e., 5 + 6 to 18, Scheme 1). Given the creativity of the synthetic design, its biological relevance, and its first total synthesis, this manuscript can be considered suitable for publication in JACS.

Reference: McClymont, K. S.; Wang, F.-Y.; Minakar, A.; Baran, P.S. J. Am. Chem. Soc. 2020 (Just accepted April 25, 2020; doi:10.1021/jacs.0c03202

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