University of York Department of Chemistry

Natural Product Synthesis via Free Radical Pathways
Using Manganese(III) Acetate


Andrew F. Parsons, C. Barry Thomas and Grégory Bar

Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK

 Grégory Bar

A considerable number of medicinally important quinoline alkaloids have been isolated from the Rutaceae family of plants.1   Representative examples of this class of compound include atanine 1, the angular alkaloid araliopsine 2 and the linear alkaloid isoplatydesmine 3. These types of compounds have been shown to exhibit a variety of biological properties including antibacterial, antifungal and antiviral activities, and so their synthesis is of considerable importance.2 In nature, these alkaloids are believed to be formed from C-prenylation of 4-hydroxyquinolone 4, which is derived from anthranilic acid. This potentially straightforward and flexible approach has been investigated in the laboratory and, for example, the C-alkylation of quinolone 5 has been attempted by reaction with base and prenyl bromide. Unfortunately, this biomimetic approach proceeds in very low yields because of competitive dialkylation and O-alkylation reactions.3 The unselective nature of this ionic alkylation reaction attracted our attention and led us to investigate the formation of these types of alkaloids using a radical alkylation reaction mediated by manganese(III) acetate.4

Scheme 1
Manganese(III) acetate is a one-electron oxidant which can generate radicals in the ß-position of carbonyl compounds. The mechanism of the reaction is unclear but is thought to proceed as follows:
Scheme 2
This methodology has been shown to provide an attractive route to quinolinones and this allowed the synthesis of araliopsine 2.5, 6
Scheme 3

However, the use of manganese(III) acetate on an industrial scale is problematic because the reactions usually require at least 2 equivalents of manganese (for radical generation and oxidation) leading to the production of large amounts of metal wastes.  Moreover, the solvent of choice for the reaction is acetic acid, preventing the methodology to be applied to acid sensitive substrates.

Current work is concerned with the study of the mechanism, development of either a catalytic system or a way of recovering the metal at the end of the reaction (i.e. supported metal) and then natural product synthesis.
 

1 J. P. Michael, Nat. Prod. Rep., 2000, 17, 603-620 and earlier reviews in the same series.
2 For a recent synthetic approach see: D. R. Boyd, N. D. Sharma, S. A. Barr, J. G. Carroll, D. MacKerracher and J. F. Malone, J. Chem. Soc., Perkin Trans. 1, 2000, 3397-3405.
3 (a) N. Shobana, P. Yeshoda and P. Shanmugam, Tetrahedron 1989,45, 757-762.  (b) J. Reisch and M. Iding, Pharmazie, 1994, 49, 62-63.  (c) V. S. Rao, and M. Darbarwar, Synthesis, 1989, 139-141.  (d) K. C. Majumdar, Y. Bhattacharyya, Synth. Commun., 1998, 2907-2923.
4 (a) B. B. Snider, Chem. Rev., 1996, 96, 339-363. (b) G. G. Melikyan,  Aldrichimica Acta, 1998, 31, 50-64.
5 G. Bar, A. F. Parsons  and C. B. Thomas,  Tetrahedron Lett., 2000, 41, 7751-7755.
6 Bar G, Parsons A F,  and Thomas C B, Tetrahedron, 2001, 57, 4719-4728
 

top_of_page

Radical Chemistry Group What is Radical Chemistry? Books Research Interests
Publications Contacts Radical Chemistry Links Radical Course Notes

Back to Home Page  Back to Home Page
Back to Main Staff Page  Back to Main Staff Page


Last Updated: 6th November 2004. These pages are maintained by Tom Hunt.
Any comments or suggestions are welcome.

© Department of Chemistry, University of York.