A regio- and stereo-selective synthesis of 2-hydroxy-3-methylochromycinone in three steps from 2-bromo-5-acetoxy-1,4-naphthoquinone and 1-acetoxy-3,3-dimethyl-5-vinylcyclohexa-1,5-diene

Abstract

2-Hydroxy-3-methylochromycinone 4 has been synthesised using a three stage strategy. The Diels–Alder reaction between 2-bromo-5-acetoxy-1,4-naphthoquinone and 1-acetoxy-3,3-dimethyl-5-vinylcyclohexa-1,5-diene gives a single racemic diastereoisomer of 1-acetoxy-12a-bromo-3,3-dimethyl-7,12-dioxo-3,4,6,6a,7,12,12a,12b-octahydrobenzo[a]anthracen-8-yl acetate 5 in 63% yield, which may be epoxidised to give the bis-epoxide 8-acetoxy-12a-bromo-3,3-dimethyl-7,8-dioxo-3,4,4a,5,6,6a,7,12,12a,12b-decahydro-1aH-benzo[6,7]oxireno[2′,3′:10,10a]phenanthro[3,4-b]oxiren-12-yl acetate 6 in 82% yield. The bis-epoxide 6 may be converted directly into 2-hydroxy-3-methylochromycinone 4 in 45% yield, or via one of two intermediates [e.g. 2,5-dihydroxy-3,3-dimethyl-1,7,12-trioxo-1,2,3,4,5,6,7,12-octahydrobenzo[a]anthracen-8-yl acetate 8] in 80–85% yield. The intermediate 8 shows moderate anticancer activity at µM concentrations against lung, breast and central nervous system cancers, while the target compound 4 is only active at 10−4 M. © 2001 The Royal Society of Chemistry.