Towards the Total Synthesis of Amphidinolide H2

 

Markus Kalesse, Ulrike Jannsen, F. Liesener

 

Institut für Organische Chemie, Universität Hannover, Germany

 

The 26-membered macrolide Amphidinolide H2 (1) belongs to the family of amphidinolides, which were isolated from dinoflagellate Amphidinium sp. found off the coast of Okinawa/Japan in 1986.1 Their exhibited significant toxicity against murine lymphoma L1210 and human epidermoid carcinoma KB cells and their unique structural features make them an interesting target for synthetic chemists. Although there have been considerable efforts towards total syntheses of amphidinolides, only few have been achieved yet.2


 

Our retrosynthetical analysis towards the first total synthesis of 1 led us to three main fragments, which are planned to be coupled by stereoselective aldol reaction and esterification. To conclude the total synthesis we intend to apply alkyne-alkene-metathesis for macrocyclisation.

The synthesis of the C1-C13 fragment is starting from 3-methyl-glutaric acid including desymmetrization by reaction with pig liver esterase, alkyne formation, Sharpless-epoxidation and Julia-coupling. The aldehyde required for Aldol-reaction (C14-C18 fragment) is obtained from the same starting material by a-methylation of an ester group and subsequent construction of the terminal alkene.

The key step in the synthesis of the hydrophilic part is a boron-mediated vinylogous Mukaiyama-Aldol-reaction of a ketene acetale with l-glyceraldehyde, which provides the carbon backbone of the C19-C26 fragment with three definite stereocenters.3 Few following transformations including Sharpless´ asymmetric dihydoxylation lead to the desired C19-C26 fragment.

 

Coupling of the three fragments and selective removal of the protecting groups should provide Amphidinolide H2 (1) in due course.

 

 

  1. M. Ishibashi, J. i. Kobayashi, Heterocycles 1997, 44, 543.
  2. C. Aissa, R. Riveiros, J. Ragot, A. Fürstner, J. Am. Chem. Soc. 2003, 125, 15512; D. R. Williams, K. G. Meyer, J. Am. Chem. Soc. 2001, 123, 765; D. R. Williams, B. J. Myers, L. Mi, Org. Lett. 2000, 2, 945.

3. J. Hassfeld, M. Christmann, M. Kalesse, Org. Lett. 2001, 3, 3561.