Total Synthesis of Bongkrekic Acid and Derivates

Bongkrekic acid is a highly toxic natural product, produced by the microorganism Pseudomonas cocovenenans. Its toxicity derives from the ability of inhibiting the translocation of ATP/ADP through the mitochondrial inner membrane and thereby preventing eukaryotic cells from using their essential energy transporter. Bongkrekic acid was first isolated in 1970[1] and has been implicated in deaths resulting from soybean- and coconut-based dishes in Indonesia. However, as a potent inhibitor of the mitochondrial permeability transition (MTP) pore formation Bongkrekic acid and derivatives thereof may be highly useful as antiapoptotic agents. MTP opening has been recognized as a key step in initiating cell death in response to pathologic conditions, such as stroke or myocardial infarction [2] . At present, Bongkrekic acid is commercially available from fermentation processes at prices of around 1000 /mg and is used as tool compound for biological research. Chemically, Bongkrekic acid is a highly unsaturated tri-acid, containing a 21-carbon atom chain with two remote stereocenters and seven double bonds, six of which are grouped into three dienes and one is isolated in the middle of the molecule. Although two total syntheses have previously been published [3] , none of them seems practical. Therefore, the total synthesis of Bongkrekic acid and further derivatives, such as the previously isolated but synthetically so far intractable Isobongkrekic acid remains a synthetic challenge of high significance. The goal of the proposed research project is the development of a total synthesis of Bongkrekic acid, which is price competitive with the fermentation process. This will, for the first time, allow to obtain reasonable quantities of this natural product for further characterization of its biological activity and therapeutic potential. The envisaged synthesis should be flexible enough as to yield the naturally occurring derivative Isobonkrekic acid as well as other derivatives of Bonkrekic acid via the analogous sequence of synthetic transformations. Therefore, the proposed total synthesis scheme for Bonkrekic acid relies heavily on current transition metal catalyzed cross-coupling reactions, such as Sonogashira or Heck reactions and Wittig-type reactions, such as the Takai or Wittig reaction. The two strategic key components of the proposed total synthesis are the generation of the two stereocenters - one involves the hydrolysis of prochiral butandiacetal (BDA)-protected 1,2-diols and would generate the required chemical setup from D-mannitol; the second key transformation involves a Heck-reaction of a non-bisactivated 1,2 disubstituted alkene with a vinyl halide, ultimately generating the second stereocenter. Further derivatives for SAR studies should be accessible via this route by changing the coupling partners and conditions of the attempted coupling reactions. The proposed host institution for this project is the group of Steven Ley at the department of chemistry, University of Cambridge, UK. [1.] Lijmbach G. W. M., H. C. Cox & W. Berends, Tetrahedron, 1970, 26, 5993. [2.] a) Friberg H. & T. Wieloch, Biochimie, 2002, 84, 241, b)Pei Y., A. K. Carroll, C. M. Anderson, W. H. Moos, S. S. Gosh, Synthesis, 2003, 11, 1717. [3.] a) Corey E. J. & A. Tramontano, J. Am. Chem. Soc., 1984, 106, 462; b) Shindo M., T. Sugioka, Y. Umaba & K. Shishido, Tetrahedron Lett., 2004, 45, 8863.