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Pure Appl. Chem., Vol. 70, No. 11, pp. 2135, 1998

Multicomponent condensations — Model studies towards an efficient synthesis of okadaic acid*

I.E. Markó^*, V. Scheirmann, F. Chellé, A.P. Dobbs, and D. J. Bayston

Université catholique de Louvain, Laboratory of Organic Chemistry, place L. Pasteur 1, B-1348 Louvain-la-Neuve, Belgium
E-mail: [email protected]

Abstract: The total synthesis of complex natural products, still the most challenging endeavour of organic chemistry, has considerably evolved over the past decades. Today, is it no longer sufficient to construct the final molecule, by any possible and usually lengthy sequence of reactions. Other stringent criteria such as efficiency and convergency have to be carefully included in the synthetic plan. These added yardsticks have in turn prompted the development of novel methodologies, especially muticomponent and cascade-type processes. The Silyl-Modified Sakurai Reaction (SMS) and its intramolecular variant (the ISMS reaction) are powerful tools for the rapid assembly of homoallylic ethers¹, polysubstituted tetrahydropyran derivatives² and spiroketals.³

In this communication, we will describe the results of our efforts directed towards the efficient synthesis of several complex natural products embodying in their structure some or all of these subunits. Typical examples involve milbemycin b 3⁴ and okadaic acid⁵. The combination of an ene-reaction and an ISMS condensation serves as the key step in our approach towards the interesting antibiotic pseudomonic acid and the antifungal agent ambuticin.⁶ Finally, this methodology, coupled with a fragmentation reaction, functions as the cornerstone of our strategy towards the complex antifungal compound amphidinol.

1. A. Mekhalfia and I.E. Markó, Tetrahedron Lett., 1991, 32, 4779.
2. I.E. Markó, A. Mekhalfia, D.J. Bayston and H. Adams, J. Org. Chem., 1992, 57, 2211.
3. I.E. Markó and A. Mekhalfia, Tetrahedron Lett., 1992, 33, 1799.
4. I.E. Markó, M. Bailey, F. Murphy, J-P. Declercq, B. Tinant, J. Fineau-Dupont, A. Krief and W. Dumont, Synlett, 1995, 123.
5. (a) I.E. Markó and F. Chellé, Tetrahedron Lett., 1997, 38, 2895; (b) I.E. Markó, A.P. Dobbs, V. Scheirmann, F. Chellé and D.J. Bayston, Tetrahedron Lett., 1997, 38, 2899
6. I.E. Markó and D.J. Bayston, Synthesis, 1996, 2, 297

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* Invited lecture presented at the International Conference on Bioversity and Bioresources: Conservation and Utilization, 23-37 November 1997, Phuket, Thailand.

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