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First Total Synthesis of Pamamycin-621D

[ Vol. 15 , Issue. 1 ]

Author(s):

Hassan Norouzi-Arasi, Xavier J. Salom-Roig, Steve Lanners* and Gilles Hanquet*   Pages 105 - 109 ( 5 )

Abstract:


Aim and Objective: The objective of our work was to synthesize and fully characterize Pamamycin- 621D, one of the less abundant members of a large family of macrodiolides with antimycobacterial properties, which had never been synthesized before. Furthermore, we also wished to improve our general strategy by using a new unsaturated precursor.

Material and Method: A new unsaturated ethylketone precursor was prepared using alkene cross metathesis, and a convergent and flexible strategy based on a key diastereoselective aldol addition was implemented to afford pamamycin-621D in 12 steps from that precursor.

Results: Pamamycin-621D has been obtained and fully characterized for the first time. The structure of pamamycin-621D was confirmed by HRMS and comparison of 1H-NMR spectra with the natural pamamycin- 621D. Both optical rotation and 13C-NMR had not been published previously due to lack of material, and the latter are reported here for the first time. Given the scarce characterization available previously, our synthesis also gives additional support to the initial structural assignment of pamamycin-621D. A significant improvement of the key aldol addition via the use of a new unsaturated precursor is also reported.

Conclusion: The work described above constitutes the first total synthesis of pamamycin-621D and has enabled us to fully characterize this scarcely available natural product. More importantly, this work highlights the fact that our synthetic approach provides ready access to various members of the pamamycin family, allowing possible studies on structure-activity relationships and mode of action of even the least abundant of these natural products. The synthesis of other pamamycin congeners and biological investigations will be published in due course.

Keywords:

Pamamycin, aldol reaction, cross metathesis, natural products, macrodiolides, total synthesis.

Affiliation:

Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Institut des Biomolecules Max Mousseron (IBMM), UMR 5247, Universite de Montpellier, CNRS, ENSCM, Place Eugene Bataillon, 34095 Montpellier, Departement de Chimie, Unite de Chimie Organique, University of Namur (FUNDP), 61 rue de Bruxelles, 5000 Namur, Laboratoire de Synthese et catalyse associe au CNRS, ECPM, Universite de Strasbourg, 25 rue Becquerel, 67087 Strasbourg

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