Efficient Total Synthesis of Bongkrekic Acid and Apoptosis Inhibitory Activity of Its Analogues |
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| Authors: | Dr. Kenji Matsumoto Masaki Suyama Satoshi Fujita Takuya Moriwaki Yukiko Sato Yoshifumi Aso Satoshi Muroshita Hiroshi Matsuo Keishi Monda Dr. Katsuhiro Okuda Dr. Masato Abe Dr. Hiroyuki Fukunaga Prof. Arihiro Kano Prof. Mitsuru Shindo |
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| Affiliation: | 1. Institute for Materials Chemistry and Engineering, Kyushu University, 6‐1, Kasuga‐koen, Kasuga 816‐8580 (Japan);2. Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6‐1, Kasuga‐koen, Kasuga 816‐8580 (Japan) |
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| Abstract: | Bongkrekic acid (BKA), isolated from the bacterium Burkholderia cocovenenans, is an inhibitor of adenine nucleotide translocator, which inhibits apoptosis, and is thus an important tool for the mechanistic investigation of apoptosis. An efficient total synthesis of BKA has been achieved by employing a three‐component convergent strategy based on Kocienski–Julia olefination and Suzuki–Miyaura coupling. It is noteworthy that segment B has been prepared as a new doubly functionalized coupling partner, which contributes to shortening of the number of steps. Torquoselective olefination with an ynolate has also been applied for the efficient construction of an unsaturated ester. Furthermore, it is revealed that 1‐methyl‐2‐azaadamantane N‐oxyl is an excellent reagent for final oxidation to afford BKA in high yield. Based on the total synthesis, several BKA analogues were prepared for structure–activity relationship studies, which indicated that the carboxylic acid moieties were essential for the apoptosis inhibitory activity of BKA. More easily available BKA analogues with potent apoptosis inhibitory activity were also developed. |
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| Keywords: | apoptosis bongkrekic acid structure– activity relationships synthesis design total synthesis |
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