A SUGAR APPROACH TOWARD PENTALENOLACTONE

TESTERO, S. A.; MANGIONE, M. I.; PELLEGRINET, S. C.; SPANEVELLO, R. A.

Montevideo, Uruguay

Workshop; IFS/OPCW Workshop Chemistry in Nature - Natural Resources: Chemical, Biological and Enviromental Aspects; 2008

International Foundation for Science and Organization for the Prohibition of Chemical Weapons

The pentalenolactones are natural products that were isolated from a variety of Streptomyces species. Special efforts have been devoted to study the inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by pentalenolactone in Trypanosome brucei. This inhibitory effect provokes the disappearance of the parasite from the host´s bloodstream. These metabolites present an angularly fused tricyclo pentanoid lactone with different states of oxidation in each of the three rings. (Figure 1). Surprisingly, despite the sustained interest in the chemistry of these natural products due to their biological activities, only two research groups have addressed the issue of optical purity in the synthesis of (-) pentalenolactone E methyl ester by an enzymatic resolution of an advanced synthetic intermediate. However, to the best of our knowledge, no general enantiospecific approach toward the synthesis of these intricate quaternary carbon centered polycyclic structure has yet been recorded. In light of these considerations we were prompted to devise a simple means for building the pentalenolactone quinane skeleton in an enantiospecific form. Our strategy relies on the use of D-glucose as source of chirality. In a simple and straightforward synthetic sequence (Scheme 1) we have converted the methyl-a-D-glucopyranoside (1) into the polycyclic aldehyde 2 [1]. The unsymmetrical ozonolysis of this norbornene system afford compound 3 in quantitative yield [2]. Further transformations allowed the construction of the quinane system 4 and susbsequentely the lactone moiety 6 [3]. Conclusion: con-struction of the core bicycle [3.3.0] octane framework 6 was achieved in 17 steps and 16 % overall yield [3]. Intermediate 6 bears all the functionality necessary to synthesize the different members of this family of natural products.