A Concise Total Synthesis of (+/-)-Triptophenolide and Formal Synthesis of (+/-)-Triptolide via a Novel Silicon-Induced Cationic Cyclization
Rachid Baatia University of Strasbourg, Faculty of Pharmacy, Laboratory of Functional ChemoSystems, 74 route durhin, 67401 Illkirch
Abstract:
(-)-Triptolide 1 was first isolated by Kupchan et al. in 1972 from the extracts of Tripterygium Wilfordii Hook F., a plant cultivated in southern China (Figure 1).1 This diterpene triepoxide exhibits impressive biological properties such as anti-tumor, immunosupressive, anti-inflammatory, and anti-fertile activities. (+)-Triptophenolide 3, which lacks the triepoxide units and isolated from the same extract, is also a powerfull anti-inflammatory and immunosuppressive agent. The challenging and unique structure of 1 associated to its unrivalled array of biological activities have attracted the attention of several synthetic groups.2
In this communication, we wish to describe an expedient synthesis of (+/-)-triptophenolide 2, and the shortest formal synthesis of (+/-)-triptolide 1, througha novel highly diastereoselective silicon-induced cationic cyclization involving allylic dithiolane substrate as initiator, a transformation with no litterature precedent.3
Figure 2 depicts our retrosynthetic analysis of 1 and 2, deriving from 3. As the key step, we identified a diastereoselective 6-endo-trig cationic cyclization of allylic dithiolane 5 to obtain diastereoselectively trans-4.
This highly efficient trans-diastereoselective reaction is assumed to be triggered-off via electrophilic silicon involving Si-S interaction leading, temporarily, to the dithiolane opening, subsequent cyclization and finally (dithiolane) ring closure. The methodology has been expanded successfully to the synthesis of novel trans-decalines useful for triptolide and triptophenolide analogues preparation for SAR studies. The development of an asymmetric version of this new transformation is under progress, as well as further mechanistical investigations.
1. S. M. Kupchan, W. A. Court, R.G. Dailey, C. J. Gilmore, R. F. Bryan, J. Am. Chem. Soc.1972, 94, 7194-7195.
2. a) E. E. van Tamelen, T. M. Leiden, J. Am. Chem. Soc.1982, 1785-1786. b) N. A. Miller, A. C. Willis, M. S. Sherburn, Chem. Commun. 2008, 1226-1228.
3. a) S. Goncalves, P. Hellier, M. Nicolas, A. Wagner, R. Baati,* Chem. Commun. 2010, 75, 4728-4736. b) S. Goncalves, P. Maillos, M. Nicolas, A. Wagner, R. Baati*Tetrahedron2010,66, 3365-3369.
