Gold-Catalyzed Synthesis of 5 and 6-Membered Rings for the Construction of Molecular Diversity (2017)

Over the last years our research group has been focused on the design of new gold(I) complexes, their application to the development of new synthetic methods and the study of the intriguing mechanisms of these transformations. Besides, much effort has been devoted on the development of new strategies for the synthesis of biologically active molecules featuring complex architectures as well as large polyarenes with potential applications in material science. Thus, the main goal of this Doctoral Thesis was the development of new synthetic strategies for the preparation of polyaromatic compounds and for the synthesis of natural product-based polycyclic architectures. 
Since the discovery and isolation of fullerene C60, the development of a general and effective route for its preparation and the preparation of other geodesic polyarenes has been an appealing challenge in organic synthesis. To date, all the rational synthetic approaches are based on ring-closure of suitably functionalized hydrocarbon skeletons. However, the use of trindane scaffold as the synthetic precursor of these higher polyarenes is much less extended. Likewise, strategies for the preparation of isomerically pure trindenes still remain unexplored. Therefore, we focused our investigations towards the development of a method for the selective preparation of readily available C3h C15 synthons that could allow accessing to a wide variety of derivatives, playing a role similar to that of truxene in the preparation of carbon-rich materials. In this context, a novel approach for the synthesis of a new trindane-based crushed fullerene C60 has been developed by a threefold palladium-catalyzed cross-coupling of four suitably functionalized C15 trindene fragments. The trindane C15 skeleton of the central motif has been constructed through a triple gold(I)-catalyzed oxidative cyclization, which has also enabled the preparation of a series of trindene-based C3h-symmetric polyarenes. 
In order to access naturally occurring compounds featuring octahydro-1H-indene motifs, the scope of the intramolecular gold(I)-catalyzed formal [2+2+2] cycloaddition reaction has been extended to O-protected homopropargylic and allylic oxo-1,5-enynes.
Although the preliminary results obtained for oxo-1,5-enynes demonstrated that the control of the diastereoselectivity would be more challenging with these substrates, under the optimized reaction conditions, the cyclization of (Z)- and (E)- isomers takes place with moderate to excellent yield (38-90%) and increased selectivity in most of the cases. Additionally, a theoretical study was performed to support the mechanism of this transformation and to explain the overall stereoselectivity of this process. DFT calculations suggest that after the formation of the cyclopropyl gold(I)-carbene, two competitive pathways arising from the preferred face for the nucleophilic attack of the carbonyl group are involved in this transformation and can explain the observed lack of complete stereoselectivity. Further evaluation of the biological properties of these new compounds is currently underway (Eli Lilly). 
As part of our investigations on the application of gold catalysis in the synthesis natural products, we turned our attention to the synthesis of two families of alkaloids: the pycnanthuquinones and the carexanes. Pycnanthuquinone C is the simplest of the pycnanthuquinones, which was isolated from the brown alga Cystophora harveyi. Despite the importance of these biologically active terpenoid and the singularity of its linear fused 6,6,5-ring core, only a biomimetic synthesis has been reported in the literature. Thus, we considered we could use an intramolecular gold(I)-catalyzed [4+2] cycloaddition reaction for the construction of the main tricyclic core of the molecule. Remarkably, it could be prepared in 74% yield and we are currently working on the late stage functionalization of the molecule, which proved to be more challenging than expected. On the other hand, the carexanes are a series of secondary metabolites present in the leaves of Carex distachya, an herbaceous plant found in the Mediterranean bush. We envisioned an enantioselective gold(I)-catalyzed alkoxycyclization of 1,6-enynes as the key step for the ready access to the common bicyclic core of carexanes via a 6-endo-dig cyclization. Further functionalization would lead to the preparation of the complete family of these natural products for the first time. By means of the High Throughput Experimentation facility at ICIQ, a wide range of chiral gold(I) complexes have been evaluated. To date, the corresponding enantioenriched dihydronaphthalene derivative could be obtained with moderate er values (ca.85:15). Although this result is still modest, it proved the feasibility of this strategy and encouraged us to continue this project.
Finally, we have performed a detailed computational examination of gold(I) catalyzed skeletal rearrangements of different model 1,6-enynes bearing OR groups at the propargylic position, which are prone to undergo intramolecular 1,5-migration in the absence of external nucleophiles for a deeper understanding of these transformations. DFT calculations suggest that after the initial cyclization, the 1,5-OR migration proceeds stepwise through a cyclic intermediate although the cleavage occurs though a very low barrier. The nature of the propargylic alkoxy group and the substitution pattern at the alkene moiety play a crucial role for the formation of 1,5-migration product vs the single-cleavage rearrangement product.
In this Doctoral Thesis several strategies have been explored in the context of the synthesis of polyarenes and natural products, highlighting the outstanding ability of gold catalysis for the construction of molecular diversity under mild conditions from readily assembled starting materials.