Efficient Total Synthesis of Bongkrekic Acid and Apoptosis Inhibitory Activity of Its Analogues

Kenji Matsumoto, Masaki Suyama, Satoshi Fujita, Takuya Moriwaki, Yukiko Sato, Yoshifumi Aso, Satoshi Muroshita, Hiroshi Matsuo, Keishi Monda, Katsuhiro Okuda, Masato Abe, Hiroyuki Fukunaga, Arihiro Kano, Mitsuru Shindo

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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. Stripped BKA: The highly efficient second-generation total synthesis of bongkrekic acid (BKA), an apoptosis inhibitor, has been developed. The synthesis features a three-component convergent strategy based on a Kocienski-Julia olefination and Suzuki-Miyaura coupling. The structure-activity relationship (SAR) is also examined for the first time (see scheme).

Original languageEnglish
Pages (from-to)11590-11602
Number of pages13
JournalChemistry - A European Journal
Volume21
Issue number32
DOIs
Publication statusPublished - Aug 1 2015

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Organic Chemistry

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    Matsumoto, K., Suyama, M., Fujita, S., Moriwaki, T., Sato, Y., Aso, Y., Muroshita, S., Matsuo, H., Monda, K., Okuda, K., Abe, M., Fukunaga, H., Kano, A., & Shindo, M. (2015). Efficient Total Synthesis of Bongkrekic Acid and Apoptosis Inhibitory Activity of Its Analogues. Chemistry - A European Journal, 21(32), 11590-11602. https://doi.org/10.1002/chem.201501304