著者

村上 悌一 芝上 基成

出版者

天然有機化合物討論会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

no.50, pp.617-622, 2008-09-01

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Sphingofungins (A-F) are a family of antifungal metabolites produced by microorganisms, and have been shown to be potent and specific inhibitors of serine palmitoyl transferase, an essential enzyme for the biosynthesis of sphingolipids. These compounds have a lipid tail and a polyhydroxy-amino acid head moiety with four contiguous chiral centers and a trans-olefinic function. Due to their biological activity and structural complexity, the sphingofungins have inspired a number of synthetic efforts. We report here a novel synthetic approach to sphingofungins using D-gluconolactone as a chiral source of the head moiety. Gluconolactone 1 was converted to 2-azido-mannonate derivative 3, from which C5-aldehyde derivative 4 was readily prepared. The hydrophobic portion containing (R)-hydroxy group was prepared via asymmetric transfer hydrogenation of pentadec-8-yn-7-one 13. The resulting pentadec-1-yn-9(R)-ol derivative 15 was converted to pentadec-1(E)-enyl-zinc derivative 17, which was reacted with the C5-aldehyde 4 to give separable diastereomeric adducts (7:1). The major adduct was deduced to be natural C5-(S)-alcohol 18, a key intermediate for the synthesis of sphingofungins A-D. Acidic hydrolysis of 18 gave the azide-lactone 19, and the azide was reduced with zinc in acetic acid to give the amine 20. When the reduction was carried out in the presence of acetic anhydride, the acetamide 21 was obtained. Mild basic hydrolysis of 20 and 21 afforded sphingofungins B and D, respectively.

著者

村上 悌一 芝上 基成

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.50, pp.617-622, 2008

---

Sphingofungins (A-F) are a family of antifungal metabolites produced by microorganisms, and have been shown to be potent and specific inhibitors of serine palmitoyl transferase, an essential enzyme for the biosynthesis of sphingolipids. These compounds have a lipid tail and a polyhydroxy-amino acid head moiety with four contiguous chiral centers and a trans-olefinic function. Due to their biological activity and structural complexity, the sphingofungins have inspired a number of synthetic efforts. We report here a novel synthetic approach to sphingofungins using D-gluconolactone as a chiral source of the head moiety. Gluconolactone 1 was converted to 2-azido-mannonate derivative 3, from which C5-aldehyde derivative 4 was readily prepared. The hydrophobic portion containing (R)-hydroxy group was prepared via asymmetric transfer hydrogenation of pentadec-8-yn-7-one 13. The resulting pentadec-1-yn-9(R)-ol derivative 15 was converted to pentadec-1(E)-enyl-zinc derivative 17, which was reacted with the C5-aldehyde 4 to give separable diastereomeric adducts (7:1). The major adduct was deduced to be natural C5-(S)-alcohol 18, a key intermediate for the synthesis of sphingofungins A-D. Acidic hydrolysis of 18 gave the azide-lactone 19, and the azide was reduced with zinc in acetic acid to give the amine 20. When the reduction was carried out in the presence of acetic anhydride, the acetamide 21 was obtained. Mild basic hydrolysis of 20 and 21 afforded sphingofungins B and D, respectively.