A Platform of Regioselective Methodologies to Access to Polysubstituted 2-Methyl-1,4-Naphthoquinones Derivatives: Scope and Limitations

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Rodo, Elena Cesar | Feng, Liwen | Jida, Mouhamad | Ehrhardt, Katharina | Bielitza, Max | Boilevin, Jérémy | Lanzer, Michael | Williams, David Lee, L | Lanfranchi, Don Antoine | Davioud-Charvet, Elisabeth

Edité par CCSD ; Wiley-VCH Verlag -

International audience. A platform of synthetic methodologies was established to access a focused library of polysubstituted 3-benzylmenadione derivatives functionalized at the aromatic ring of the naphthoquinone core. Two main routes were explored: (i) the naphthol route, via either an α-tetralone, or a propiophenone, and (ii) the regioselective Diels-Alder reaction starting from various dienes and two 2-bromo-[5(or 6)methyl-1,4-benzoquinones. 6-Substituted 2-methylnaphthols were synthesized by using a xanthate-mediated free radical addition/cyclization sequence for the construction of the 6-substituted menadione subunit. Furthermore, an efficient and simple new pathway that allows the formation of two 6-or 7-substituted 3-(substituted-benzyl)menadione regioisomers from a common commercial scaffold has also been developed by the naphthol route, advantageous with regard to step economy. Our synthetic methodologies exemplified by 34 compounds has allowed structureactivity relationships to be deduced for use as the basis for the development of new antimalarial redox-active polysubstituted benzylmenadione derivatives.

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