Chemical Approach to Explicate the Molecular Mechanism for Apoptosis

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Bongkrekic acid, which is a toxic antibiobic produced by the bacterium Pseudomonas cocovenenans, was found responsible for inhibition of apoptosis. Now, it is one of the significant biological tools in the research area of apoptosis. Since it is little available from fermentation, the supplementation by the chemical synthesis has strongly been required. Therefore we have examined the exploitation of an efficient and enantipselective syntheti route for bongkrekic acid. We chose a convergent strategy, in which the molecule is bisected two segments, the left-hand segment and fight-hand segment, and finally both can be coupled. The following three results were obtained from this research.1. Synthesis of the left-hand segment: Cis-2-buten-1, 4-diol was converted by Evans' diastereoselective alkylation protocol into the alkenylboronic ester, which was joined with the alkenyliodide utilizing Suzuki-Miyaura coupling. The trienol with a tertiary stereogenic center was transformed into the corre … More sponding sulfone, which is the left-hand segment of bongkrekic acid.2. Synthesis of the right-hand segment: (S)-Glyceraldehyde, derived from D-mannitol, was converted into the butenolide which was reduced with DIBAH followed by condensed with Wittig ylide to give the dienol with a stereogenic center. Introduction of C-3 unit via reaction of the epoxide with propargyl anion followed by hydrogenation of the triple bond with the modified Lindlar catalyst provided the (Z, Z, Z) tirenol, which was transformed into the trienyl bromide of the right-hand segment.3. Coupling of the both segments and approach to bongkrekic acid: Coupling of the both segments was realized employing standard alkylation of the left-hand sufonyl anion with the right-hand bromide. The product thus obtained possesses the required backbone of bongkrekic acid. Sequential reductive removal of the benzenesulfon group and oxidation of C1 and C22 produced the heptaene diester, which is the key intermediate for bongkrekic acid. Less