Total Synthesis of Bulgarein

Abstract

Here we report an efficient and short total synthesis of bulgarein (1), a natural compound from Bulgaria inquinans with cytotoxic activity. Key steps in the total synthesis are a Suzuki-Miyaura coupling reaction of two substituted naphthalene derivates followed by a polyphosphoric acid (PPA) mediated condensation reaction to form the benzo[j]fluoranthene skeleton. Bulgarein (1) was achieved over 4 steps with an overall yield of 25 %.

Recent advances in the synthesis and applications of fluoranthenes

“…87 Despite earlier attempts towards the synthesis of bulgarein ( 13 ), 88 the first total synthesis was reported in 2022 by Swieca and Spiteller. 89 In this eight-step synthesis (longest linear sequence), the two naphthalene units 120 and 121 were attached via a Suzuki–Miyaura coupling to give binaphthalene product 122 in 89% yield (Scheme 31). The cyclisation reaction of 122 mediated by polyphosphoric acid (PPA) led to the formation of benzo[ j ]fluoranthene product 123 in 78% yield.…”

Benzo[j]fluoranthene-Derived Natural Products

“…16 The group of Peter Spiteller presented a total synthesis of bulgarein (8) in 2022. 17 They followed a more biosynthetic approach and at first used a Suzuki coupling for the construction of protected binaphthyl derivative 17. Electrophilic aromatic substitution, oxidation to a 5,6-ortho-quinone, and deprotection furnished 8.…”

“…The group of Davadalle synthesized viridistratin D ( 15 ) in 2013 using a Suzuki coupling for the synthesis of dialdehyde 16 and a McMurry reaction for the construction of the final ring system, which is demethylated to yield the natural product . The group of Peter Spiteller presented a total synthesis of bulgarein ( 8 ) in 2022 . They followed a more biosynthetic approach and at first used a Suzuki coupling for the construction of protected binaphthyl derivative 17 .…”