Synthesis of 3-substituted analogues of levulinic acid via Baylis-Hillman and Mukaiyama reactions. Potential inhibitors of Porphobilinogen Synthase.
Pavel Bobál', Reinhard Neier
Institute of Chemistry, University of Neuchâtel, Av. de Bellevaux
51, CH-2000 Neuchâtel, Switzerland
The exact mechanism of the enzyme Porphobilinogen Synthase (PBGS), catalysing formation of Porphobilinogen (PBG), the second dedicated transformation of the biosynthetic pathway leading to tetrapyrroles "pigments of life", is not clear and no x-ray structure of the enzyme or complex enzyme-substrate has been published up to date. Two mechanistic proposals have been discussed in the literature by Shemin and Nandi [1] and by Jordan [2] for PBGS.
Scheme 1
In order to get further information about the mechanism of Porphobilinogen Synthase a series of 3-substituted analogues of levulinic acid (Scheme 1) as potential inhibitors (in analogy with postulated intermediate according to Shemin) were synthesised in our laboratories. We have focused on different ways for synthesis of 3-substituted derivatives of levulinic acid, using Mukaiyama [3] reaction or Baylis-Hillman [4] followed by SN2' Mitsunobu reaction [5] (Scheme 2).
Scheme 2
[1] D. L. Nandi, D. Shemin, J. Biol. Chem. 1968, 243, 1236-1242.
[2] P. M. Jordan, J. S. Seehra, J. Chem. Soc., Chem. Commun. 1980, 240-242.
[3] A. R. Chaperon, T. M. Engeloch, R. Neier, Angew. Chem. Int. Ed. 1998, 37, 358-360.
[4] H. M. R. Hoffmann, U. Eggert, W. Poly, Angew. Chem. Int. Ed. 1987, 26, 1015-1017.
[5] A. B. Charette, B. Côté, S. Monroc, S. Prescott, J. Org. Chem. 1995, 60, 6888-6894.