Molecular complexity via domino reactions

Abstract

During my Ph.D., I focused my attention in palladium catalysis and in photo/redox catalysis. Carbolines are an important class of molecules due to their presence in many bioactive alkaloids and pharmaceuticals. We report an easy approach to THC derivatives from propargylic triptamines. The methodology uses two distinct catalysts, namely a palladium (0) complex and benzoic acid. Both experiments and DFT modelling were performed to shed light on the mechanism of this sequence. This is the first sequential isomerization/C-H activation applied to tetra-1H--hydrocarbolines synthesis starting from readily available reagents. Due to their applications in organic synthesis, conjugated 1,3-dienes represent an important building block for the access to complex structures. A variety of amines substituted with but-2-yn fragments affords the corresponding 1,3-dienes with perfect E,E – stereoselectivity. We present the first simple one-step synthetic method to conjugated 1,3-dienes starting from readily available reagents by exploiting benzoic acid and palladium (0) joint catalysis. Stable all metal aromatic tripalladium clusters ware recently described by the group. These complexes showed a surprising catalytic activity, We have studied the reactivity of palladium cluster in cycloisomerization of 1,6 enynes and internal dienynes. Both families of reagents deliver tricyclic compounds with a cyclohexene core. Cyclization of 1,6- enynes with 1 mol% of [Pd3]+ complex leads to tricyclic molecules featuring a spiro carbon in the central ring. This occurs through sequential cyclization to monocyclic 1,3-exo dienes followed by an intermolecular [4+2] reaction that proceeds with complete chemoselectivity. Using internal dienynes we describe their formal [2+2+2] cycloaddition, during which four contiguous stereocenters were formed with high diastereoselectivity (dr up to 98:2). We demonstrated the first application of a trinuclear palladium complex in C-C forming sequences. Durign my second year I went to Geraldine Masson group at CNRS – ICSN in Paris and I moved my attention to photocatalysis with metal complex in organic synthesis. We have triggered the in-situ formation of benzylic carbocations by SET on thioether C-S bonds. The use of photoredox catalysis and oxygen as oxidant permit us to access di- and tri-aryl methane derivatives under mild conditions. This formal nucleophilic substitution allows to obtain either a new C-C or even a new C-N bond when a nitrogen nucleophile is employed. A wide variety of functional groups, from phenols to unprotected amines, are tolerated thanks to the use of neutral conditions. This is the first approach to highly decorated triaryl methanes via photoredox catalysis. Tetraciclization represents a fascination approach to high complex molecules. Starting from our precedent in cyclization of poliunsatured substrates we investigate a photocatalytic approach to tetracyclization of dienynes. We reported the original behaviour of dienynes in the presence of visible light and an iridium photocatalyst. Reagents can be converted to highly complex tetracyclic frameworks by the ordered rearrangement of their four -bonds into four new -ones. By likely combining a spin-sensitizer and a redox role, the catalyst can trigger formation of a carbenoid reactive intermediate, which can be then efficiently engaged in cyclopropanation reactions. Further extension of this reactivity is currently underway.