Synthesis of bikaverin

Abstract

The total synthesis of bikaverin (1b) is described, from everninic acid (5) and 3,5-dihydrobenzoic acid (6). Dieckmann condensation of methyl 2-acetyl-3,5-bis(benzyloxy)phenylacetate (14), synthesised from (6), followed by treatment with protected everninic acid chloride (9) gave 1,3-bisbenzyloxy-6,8-bis(2-benzyloxy-4-methoxy-6-methylbenzoyloxy)naphthalene (16). Photoinduced Fries rearrangement of (16) afforded 1,3-bis(benzyloxy)-7-(2-benzyloxy-4-methoxy-6-methylbenzoyl)-6-(2-benzyloxy-4-methoxy-6-methylbenzoyloxy)-8-hydroxynaphthalene (23). Ring closure of (23) with tetramethylammonium hydroxide in pyridine gave the angular benzoxanthene, 1,3-bis(benzyloxy-6-hydroxy)-10-methoxy-8-methylbenzo[c]xanthen-7-one (25), which was oxidized with potassium dichromate to give the orthoquinone, 1,3-bis(benzyloxy)-10-methoxy-8-methylbenzo[c]-xanthen-5,6,7-trione (28). By a novel type of rearrangement, (28) was transformed into the linear benzoxanthen, 8,10-bis(benzyloxy)-3-methoxy-1-methylbenzo[b]xanthen-6,11,12-trione (29) by treatment with silica gel. Oxidation and debenzylation of (29) with manganese dioxide in concentrated H₂SO₄ gave norbikaverin (1a).