Modular Synthesis of Halogenated Xanthones by a Divergent Coupling Strategy

Abstract

A versatile strategy to halogenated xanthones was developed that relies on a modular coupling of vanillin derivatives with a dibromoquinone. Depending on the reaction conditions, either the 6-or the 7-bromo heterocycles may be obtained in a divergent manner. These heterocycles may be readily further elaborated by sequential Sonogashira couplings, and the sequence may be successfully applied to substructures of the antibiotic lysolipin.

Diversity Oriented Synthesis of Novel Xanthones Reveal Potent Doxorubicin‐Inspired Analogs

“…As exemplarily shown for hydroquinone 11 b in Table 3, we found that demethylation at the C1 anisole limits the scope of the sulfuric acid promoted cyclization. Since this demethylation occurred irrespective of the employed temperature (entries 1–3), we argued that the high Brønstedt acidity of commonly used sulfuric acid is the cause [13,17] . Indeed, less acidic methanesulfonic acid completely suppressed this demethylation and gave xanthone 12 b in useful yield after four hours at elevated temperatures (59 %, entry 4–5).…”

“…used sulfuric acid is the cause. [13,17] Indeed, less acidic methanesulfonic acid completely suppressed this demethylation and gave xanthone 12 b in useful yield after four hours at elevated temperatures (59 %, entry 4-5).…”

“…Thus, 7 b and 7 c were separated by HPLC and lactones 6 and 7 were converted to methyl benzoates 8 (Scheme 1, 69-87 %). [15] To expand the scope of synthesizable xanthones, a previously reported polar condensation, [13] namely the coupling of 8 and 9, as well as the ensuing acid promoted cyclization from 11 to 12 were optimized. As shown in Table 2, we found that limiting the reaction time to three hours was indispensable, because intermediate quinone 10 a decomposes under the reaction conditions over time (entry 1).…”

“…Ultimately, a fourfold increase in overall yield of 12 a and 12 b from common precursor 8 a highlights the improvement of these procedures over those previously available. [13] Finally, since chlorine atoms are known to impact bioactivity, [11] we wanted to find conditions to either selectively cross couple the bromine while leaving the chlorine unaffected, or to replace both halogens at once. To streamline our synthesis further, we decided to pursue this reaction without a protective group on the acidic phenols.…”

“…While synthetic access to methyl chlorobenzoate 8 a (Scheme 1) has previously been established, the extended reaction times of one of the key steps, a Fischer esterification, [13] seemed impractical for concise SAR studies. Also, we wanted to access chloro derivatives in a more versatile manner.…”