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Efficient Total Synthesis of Bongkrekic Acid and Apoptosis Inhibitory Activity of Its Analogues
Author(s) -
Matsumoto Kenji,
Suyama Masaki,
Fujita Satoshi,
Moriwaki Takuya,
Sato Yukiko,
Aso Yoshifumi,
Muroshita Satoshi,
Matsuo Hiroshi,
Monda Keishi,
Okuda Katsuhiro,
Abe Masato,
Fukunaga Hiroyuki,
Kano Arihiro,
Shindo Mitsuru
Publication year - 2015
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201501304
Subject(s) - apoptosis , adenine nucleotide translocator , chemistry , inhibitory postsynaptic potential , reagent , stereochemistry , yield (engineering) , biochemistry , biology , organic chemistry , materials science , metallurgy , neuroscience
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.