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project's title

 

 

by Veroniki P. Vidali

  • Development of methodology towards the synthesis of bisorbicillinoids and designed analogues

  • Novel cycloaddition and dimerization reactions

  • Chemistry of o-quinols and related aromatic systems

  • Confirmation of proposed biosynthetic pathway

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Bisorbicillinoids, a growing class of novel natural products, are isolated from several species of fungi, exhibiting a broad range of interesting biological activities. For instance, Trichodimerol, a fungal metabolite isolated from three different species of fungi (Trichoderma longibrachiatum, Penicillium chrysogenum and Trichoderma sp. USF-2690), is characterised by an important biological activity and potential in medicine. Furthermore, bisorbicillinol, bisorbibutenolide and bisorbicillinolide isolated from Trichoderma sp. USF-2690 exhibit significant antioxidant properties. The unusual combination of impressive molecular structure, unique and diverse bioactivity and intriguing biosynthetic avenues, inspired us to focus on the biomimetic total synthesis of bisorbicillinoids and designed analogues.

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Bisorbicillinoids, a growing family of novel natural products originating from sorbicillin.

photo1Bisorbicillinoids, isolated from several species of fungi, exhibit a broad range of interesting biological activities (antioxidant and antifungal properties, tumor necrosis factor a ( TNF-a ) inhibitory activities e.t.c.). Despite their molecular complexity, all bisorbicillinoids could originate from the natural product sorbicillin. Indeed, through our research it was discovered that sorbicillin outperformed any other precursor for the facile synthesis of the family of bisorbicillinoids and for the exploration of the proposed biosynthetic pathways.
Retrosynthetic pathway for bisorbicillinol, bisorbibutenolide and bisorbicillinolide.

photo2The o-quinol which can be easily derived from the natural product sorbicillin by oxidation, is a keyinterrmediate in the synthesis of all the members of the family of bisorbicillinoids. The existence of more than one active sites and the tedency to equilibrate between different forms, due to tautomerization, allows the quinol molecules to combine intermolecularly in more than one ways. Thus, when the o-quinol system acts as a pair of diene-dienophile a [4+2] dimerization, in a complete regio- and stereo- specific manner, takes place forming bisorbicillinol. The latter can then rearrange intramolecularly to bisorbibutenolide and bisorbicillinolide. This is, also, the proposed biosynthetic pathway to these three natural products.
Retrosynthetic and proposed biosynthetic pathway for Trichodimerol and Bisvertinol.

photo3Oxidation of Sorbicillin leads to o-quinol, a key intermediate in the synthesis of the family of bisorbicillinoids. Its tedency to tautomerize and the existence of more than one active sites, allows the quinol molecules to combine intermolecularly in various ways, depending on conditions. Thus, when the quinol system acts as a pair of Michael donor- Michael acceptor it can lead either to Trichodimerol or to Bisvertinol, via different cascade reactions.

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  • For the term bisorbicillinoids:

The term was introduced by Nicolaou et al to describe all dimeric sorbicillin-derived natural products: Nicolaou, K. C. ; Jautelat, R.; Vassilikogiannakis, G.; Baran, P. S.; Simonsen, K.B. Chem. Eur. J., 1999, 5, 3651-3665.

  • For the isolation, biological activities and proposed biosynthetic pathway of Trichodimerol:

(a): R. Andrade, W. A., Ayer, P. P. Mebe, Can. J. Chem., 1992, 70, 2526-2535;

(b): G. A. Warr, J. A. Veitch, A. W. Walsh, G. A. Hessler, D. M. Pirnik, J. E. Leet, P. F. M. Lin, I. A. Medina, K. D. McBrien, S. Forenza, J. M. Clark, K. S. Lam J. Antibiot., 1996, 49, 234-240.

  • For the isolation, biological properties and proposed biosynthetic pathways of bisorbicillinol, bisorbibutenolide and bisorbicillinolide:

(a): Abe, N.; Murata, T.; Hirota, A. Biosci. Biotechnol. Biochem., 1998, 62, 661-666;

(b): Abe, N.; Murata, T.; Hirota, A. Biosci. Biotechnol. Biochem., 1998, 62, 2120-2126.

  • For the isolation, proposed biosynthetic pathways and biological properties of Bisvertinol and Bisvertinolone:

(a): Kontani, M.; Sakagami, Y.; Maruno, S. Tetrahedron Lett., 1994, 35, 2577-2580;

(b): Trifonov, L. S.; Hilpert, H.; Floersheim, P.; Dreiding, A. S.; Rast, D. M.; Skrivanova, R,; Hoesch, L. Tetrahedron, 1986, 42, 3157-3179.

  • For the isolation and total synthesis of Sorbicillin:

(a): D. J. Cram, M. Tishler, J. Am. Chem. Soc., 1948, 70, 4238-4239:

(b): D. J. Cram, J. Am. Chem. Soc., 1948, 70, 4240-4243:

(c): Mc Omie, J. F. W.; Tute, M. S. J. Chem. Soc., 1958, 3226-3227;

(d): Bigi, F.; Casiraghi, G.; Marchesi, S.; Sartori, G.; Vignali, C. Tetrahedron, 1984, 40, 4081-4084.

  • For the total synthesis of Trichodimerol, Bisorbicillinol and bisorbibutenolide, exploration of novel dimerization reactions and the synthesis of designed analogues:

(a): K. C. Nicolaou, K. B. Simonsen, G. Vassilikogiannakis, P. S. Baran, V. P. Vidali, E. N. Pitsinos, E. A. Couladouros, Angew. Int. Ed., 1999, 38, 3555-3559;

(b): K. C. Nicolaou, K. B. Simonsen, G. Vassilikogiannakis, P. S. Baran, Y. Zong, V. P. Vidali, E. N. Pitsinos, E. A. Couladouros, J. Am. Soc., 2000, 122, 3071-3079.

(c): D. Barnes-Seeman, E. J. Corey, Org. Lett., 1999, 1, 1503-1504.

 

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  • V.P. VIDALI
  • E. N. PITSINOS
  • E. A. COULADOUROS
  • K. C. NICOLAOU

  • G. VASSILIKOGIANNAKIS

  • K. B. SIMONSEN

  • P. S. BARAN

  • Y. ZHONG

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Edited by Veroniki P. Vidali

 

Prof. Elias A. Couladouros
E-Mail: ecoula@chem.demokritos.gr

Last Updated: [1-6-2000]