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

Abstract

A platform of synthetic methodologies has been established to access a focused library of polysubstituted 3‐benzylmenadione derivatives functionalized on the aromatic ring of the naphthoquinone core. Two main routes were explored: 1) The naphthol route, starting from either an α‐tetralone or a propiophenone, and 2) 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 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 have allowed structure–activity relationships to be deduced for use as the basis for the development of new antimalarial redox‐active polysubstituted benzylmenadione derivatives.

A high susceptibility to redox imbalance of the transmissible stages of Plasmodium falciparum revealed with a luciferase‐based mature gametocyte assay

“…Inhibitors MB trihydrate and paracetamol were purchased from Sigma. The carboxylic acids GR inhibitors M5 (Davioud-Charvet et al, 2001;Salmon-Chemin et al, 2001;Biot et al, 2004) and benzoylmenadione 3f (M€ uller et al, 2011), plasmodione 1c (M€ uller et al, 2011), 6-fluoro-plasmodione 17e (Cesar Rodo et al, 2016) and benzoylmenadione 3c (the putative metabolite I of plasmodione) (M€ uller et al, 2011) were freshly prepared as cited. Anthony Pinkerton, Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, CA kindly provided the compound ML304 (Maloney et al, 2012).…”

The Redox Cycler Plasmodione Is a Fast-Acting Antimalarial Lead Compound with Pronounced Activity against Sexual and Early Asexual Blood-Stage Parasites

“…The generation of analogues needs to be approached by total synthesis of 1,4-naphthoquinones substituted at the phenyl ring of the menadione core, thus requiring complete regiocontrol of the chemical reactions. Efficient synthetic methodologies have been established (4,5) and will allow preparation of a large array of diverse benzylmenadiones for further structureactivity relationship investigations. Already developed chemoinformatic tools are available for predicting the redox potentials of polysubstituted menadiones (6,7).…”

“…The synthesis of plasmodione is achieved in only one step from cheap commercially available starting materials, and its low-molecular-weight structure provides a large chemical space for optimization by derivatization (3). Its structure served as a starting point for development of chemical optimization strategies aimed at generating benzylmenadione derivatives with superior pharmacokinetic or pharmacodynamic properties (4)(5)(6)(7).…”

Synthesis of plasmodione metabolites and13C-enriched plasmodione as chemical tools for drug metabolism investigation

“…The two resulting intermediates 13 C10-tetralone 3b and 13 C7-ptrifluoromethylbenzadehyde 6b were combined through an optimized "express tetralone route" to produce 13 C18-plasmodione 10b in 4 steps as described in our previous study (Scheme 5). 29 First, a condensation reaction from previously described ptrifluoromethylbenzaldehyde 6a/6b and tetralone 3a/3b under classical conditions (KOH as a base) led to the tetralone with an exo double bond 7a/7b with 90% and 75% yield, respectively. Then, the isomerization reaction with RhCl3 catalysis proceeded with similar yields (80%) to obtain the α-benzyl naphthols 8a/8b.…”

“…According to previous studies about radical methylation based on the Kochi-Anderson reaction, the methyl radical is less stable and more reactive, and might be the cause of the destruction of the desired product. 29 In order to follow the reaction kinetics and to track the reaction products by 1 H NMR spectroscopy (Figure 1), we used unlabeled 2-(4-(trifluoromethyl)benzyl)-naphthalene-1,4dione 9a and 13 C1-acetic acid as starting materials in a model reaction. As observed, after 15 min stirring, the reaction conversion reached almost 50% and the desired product 10a was quickly generated.…”