Novel methodology for the synthesis of the benz[a]anthracene skeleton of the angucyclines using a Suzuki-Miyaura/isomerization/ring closing metathesis strategy

• Published in: Tetrahedron 2018-01, Vol.74 (1), p.12-18
• Main Authors: Johnson, Myron M., Ngwira, Kennedy J., Rousseau, Amanda L., Lemmerer, Andreas, de Koning, Charles B.
• Format: Article
• Language: English
• Subjects: Angucyclines; Benz[a]anthracenes; Isomerization; Metathesis; Suzuki-Miyaura reaction
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2017.11.023

The synthesis of the benz[a]anthracene skeleton of the angucyclines is described. Key steps involve the Suzuki-Miyaura reaction, isomerization of an aromatic allyl substituent to the corresponding styrene, and the use of the ring closing metathesis reaction to construct a benzene ring. For example, exposure of 3-allyl-2-bromo-1,4,5-trimethoxynaphthalene to (2-formyl-4-methoxyphenyl)boronic acid under palladium catalysis conditions resulted in the formation of 2-(3-allyl-1,4,5-trimethoxynaphthalen-2-yl)-5-methoxybenzaldehyde. This 2-naphthyl benzaldehyde then underwent a Wittig reaction to furnish 3-allyl-1,4,5-trimethoxy-2-(4-methoxy-2-vinylphenyl)naphthalene. Isomerization of the allyl group of this compound afforded the diene, (E)-1,4,5-trimethoxy-2-(4-methoxy-2-vinylphenyl)-3-(prop-1-en-1yl)naphthalene. Exposure of the formed diene to the Grubbs II catalyst resulted in the formation of the benzanthracene, 3,7,8,12-tetramethoxytetraphene, which was easily oxidized to the corresponding quinone. [Display omitted]