Synthesis of Angucycline/Tetrangulol Derivatives Using Suzuki-Miyaura Cross-Coupling and Ring-Closing Carbonyl-Olefin Metathesis Reactions

Abstract

Key steps in the synthesis of derivatives of the angucycline, tetrangulol include the use of a palladium catalyzed Suzuki-Miyaura cross-coupling reaction for the assembly of 2-(1,4-dimethoxy-3-(2-methylprop-1-en-1-yl)naphthalen-2-yl)-3-methoxy-5-methylbenzaldehyde from 2-iodo-3-methoxy-5-methylbenzaldehyde and 2-(1,4-dimethoxy-3-(2-methylprop-1-en-1-yl)naphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The biaryl product was then subjected to an iron-catalyzed ring-closing carbonyl-olefin metathesis reaction to afford 1,7,12-trimethoxy-3-methyltetraphene, which was oxidized to the corresponding quinone. Late stage oxidation of the quinone with Ru[Cl2(p-cymene)]2 and an oxidant unexpectedly afforded the chlorinated compounds, 2,4-dichloro-11-hydroxy-1-methoxy-3-methyltetraphene-7,12-dione and 2,4-dichloro-6-hydroxy-1-methoxy-3-methyltetraphene-7,12-dione.