Total Syntheses of Tubulysins |
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| Authors: | Taku Shibue Toshihiro Hirai Dr Iwao Okamoto Dr Nobuyoshi Morita Dr Hyuma Masu Prof Dr Isao Azumaya Prof Dr Osamu Tamura |
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| Institution: | 1. Exploratory Research Laboratories, Kyorin Pharmaceutical Co. Ltd, 2399‐1, Nogi, Nogi‐Machi, Shimotsuga‐Gun, Tochigi 329‐0114 (Japan);2. Showa Pharmaceutical University, Higashi‐tamagawagakuen, Machida, Tokyo 194‐8543 (Japan), Fax: (+81)?42‐721‐1579;3. Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, 1314‐1 Shido, Sanuki Kagawa 769‐2193 (Japan) |
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| Abstract: | The total syntheses of tetrapeptides tubulysins D ( 1 b ), U ( 1 c ), and V ( 1 d ), which are potent tubulin polymerization inhibitors, are described. The synthesis of Tuv ( 2 ), an unusual amino acid constituent of tubulysins, includes an 1,3‐dipolar cycloaddition reaction of chiral nitrone D ‐ 6 derived from D ‐gulose with N‐acryloyl camphor sultam (?)‐ 9 employing the double asymmetric induction, whereas the synthesis of Tup ( 20 ), another unusual amino acid, involves a stereoselective Evans aldol reaction of (Z)‐boron enolate generated from (S)‐4‐isopropyl‐3‐propionyl‐2‐oxazolidinone with N‐protected phenylalaninal and a subsequent Barton deoxygenation protocol. We accomplished the total syntheses of tubulysins U ( 1 c ) and V ( 1 d ) by using these methodologies, in which the isoxazolidine ring was used as the effective protective group for γ‐amido alcohol functionality. Furthermore, to understand the structure‐activity relationship of tubulysins, we synthesized tubulysin D ( 1 b ) and cyclo‐tubulysin D ( 1 e ) from 2 ‐Me and 20 , and ent‐tubulysin D (ent‐ 1 d ) from ent‐ 2 ‐Me and ent‐ 20 , respectively. The preliminary results regarding their biological activities are also reported. |
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| Keywords: | amino acids antitumor agents stereoselectivity total synthesis tubulysins |
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