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Total Synthesis of γ‑Alkylidenebutenolides, Potent Melanogenesis Inhibitors from Thai Medicinal Plant Melodorum fruticosum

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posted on 04.07.2018, 00:00 by Genzoh Tanabe, Yoshiaki Manse, Teppei Ogawa, Naoki Sonoda, Shinsuke Marumoto, Fumihiro Ishikawa, Kiyofumi Ninomiya, Saowanee Chaipech, Yutana Pongpiriyadacha, Osamu Muraoka, Toshio Morikawa
A hitherto unreported member of γ-alkylidenebutenolides in Melodorum fruticosum (Annonaceae), (4E)-6-benzoyloxy-7-hydroxy-2,4-heptadiene-4-olide, named as isofruticosinol (4) was isolated from the methanol extract of flowers, along with the known related butenolides, namely, the (4Z)-isomer (3) of 4, melodrinol (1), and its (4E)-isomer (2). To unambiguously determine the absolute configuration at the C-6 position in these butenolides, the first total syntheses of both enantiomers of 24 were achieved over 6–7 steps from commercially available D- or L-ribose (D- and L-5). Using the same protocol, both enantiomers of 1 were also synthesized. Based on chiral HPLC analysis of all synthetic compounds (S- and R-1–4), all naturally occurring butenolides were assigned as partial racemic mixtures with respect to the chiral center at C-6 (enantiomeric ratio, 6S/6R = ∼83/17). Furthermore, the melanogenesis inhibitory activities of S- and R-14 were evaluated, with all shown to be potent inhibitors with IC50 values in the range 0.29–2.9 μM, regardless of differences in the stereochemistry at C-6. In particular, S-4 (IC50 = 0.29 μM) and R-4 (0.39 μM) showed potent inhibitory activities compared with that of reference standard arbutin (174 μM).