Towards novel analogues of Jerangolid D

by Géraldine Henroteaux

Institution: Université Catholique de Louvain
Department: Molecules, Solids and Reactivity
Year: 2015
Record ID: 1074859
Full text PDF: http://hdl.handle.net/2078.1/156663


The continuous growth of fungal infections, coupled with the increased resistance of many microorganisms towards antifungal compounds, is an alarming health problem and the discovery of new antifungal agents has become a particularly important area of research. Jerangolid D is a potential antifungal agent of major interest. Recently, the first total synthesis of this natural product has been reported by our group. Its structure can be divided into three subunits: a substituted dihydropyran, an unsaturated lactone and a skipped 1,4-diene middle fragment. Our purpose is to operate a series of chemical modifications on these three subunits in order to create a set of new compounds, similar to Jerangolid D, but possessing hopefully enhanced stability, increased activity and lower toxicity. In this thesis, we shall initially describe our efforts towards the synthesis of the substituted dihydropyran. In order to do so, two methodologies have been developed, based upon previous work in our laboratory. The second one gave the best results and enabled access to the desired dihydropyran in 6 operations using an intramolecular silyl modified Sakurai cyclisation (ISMS) as the key step. The same pathway was used to construct new dihydropyrans by modifying the C-C triple bond. With the natural DHP in hand, different modifications were applied to the double bond in order to reach the right-hand fragment of jerangolid B, E and H in which the stereochemistry at C14 was still unknown. Subsequently, we will describe our efforts towards the preparation of the left-hand lactone of jerangolid D as well as a set of new analogues. Finally, we will present some preliminary investigations on the synthesis of new analogues of the central part of these natural products. (SC - Sciences)  – UCL, 2015