PTALLENEST · Platinum-Catalysed Reaction of Bis-Allenes with Nucleophiles: Mechanistic Insights and Future Applications

Platinum-Catalysed Reaction of Bis-Allenes with Nucleophiles: Mechanistic Insights and Future Applications

There is a constant demand from the pharmaceutical industry for original, more potent drugs to target new and old diseases. Natural products remain a good source of pharmaceuticals, but their availability and efficacy are limited. Consequently, methods to synthesise new derivatives and novel chemical structures not tested so far is of crucial importance and one of the frontier challenges of chemistry in the 21st century. Novel synthetic tools will contribute to the progress of current approaches in the quest for “small-molecule probes” as potential therapeutic agents that will become drugs in the long term. Allenes are rather unique structures that contain two consecutive carbon carbon double bonds. Although the allene structure was predicted a long time ago they were considered chemical curiosities due to the difficulty of distinguishing them from the corresponding alkynes. The development of IR and Raman spectroscopy made possible the characterisation of these compounds, revealing the true potential of this functional groupas a versatile building block for the construction of more complex molecules, and enabling the development of their chemistry. The main objective of this project deals with a recently discovered in which molecules containing two allenes in their structure (bisallenes), react in the presence of a platinum catalysts and water or alcohols to give seven membered cycles with a molecule of the nucleophile incorporated in the final skeleton. Substituted 7-membered cycles are frequently found in many natural products with biological activity, especially in the terpene family. However, their synthesis, compared to the 5- or 6-membered cycles, still remains a challenge for synthetic chemists. Therefore, new synthetic for their preparation in an easy, atom economic manner, is of upmost importance. The process under study in the project has shown to be very sensitive to change in conditions, and side-products are sometimes observed in the reaction. The selectivity of the reaction is remarkable as the possibilities of mechanistic pathways involving the platinum and reaction with the water (or alcohol) are big in these systems. Understanding in depth this reaction and the mechanistic implications will help to improve the selectivity to a single compound and develop more efficient and selective protocols towards different more complex structures. This new reaction could involve novel interaction of the Pt atom with both allenes, but the mechanism remained unclear. Recent discoveries in the group highlight the importance of acquiring knowledge in the bis-allene coordination, since this information could lead to the preparation of more selective catalyst as well as the isolation of reactive intermediates that can be milestones for the construction of new interesting scaffolds. The present project has attempted to shed light into the Pt-bisallene interaction, to exploit the implications of the coordination modes in the reaction mechanisms, and to apply the gained knowledge to the synthesis of new natural- product like structures with potential biological activity. The results that we have obtained during this fellowship show that the mechanism of this reaction is more complex of what we envisioned at the beginning of the investigation, and although many questions have been answered, some others are still open and new ones have appeared. The studies on the coordination of the platinum to the allenes has been crucial to start to understand the different behaviour of our systems when compered with systems involving other metals. During the duration of this fellowship, we have further optimised the reaction conditions to obtain one or two products, when previously up to four products were obtained. We have expanded the scope of the reaction with different bisallenes and alcohols, and we now have a small library of cyclic compounds with extra functionalities in their skeleton that could be useful for further modifications or in pharmaceutical industry. Besides, we have been able to identify at least two different mechanisms operating in the formation of the 6- or 7-memebred rings, and we are now able to direct the reaction towards one cycle or the other by changing the structure of the starting material or the external nucleophile. This discovery is very important and will lead to new studies in order to obtain new and different structures from our initial bisallenes.

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