CORDIS - EU research results

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

Periodic Reporting for period 1 - PTALLENEST (Platinum-Catalysed Reaction of Bis-Allenes with Nucleophiles: Mechanistic Insights and Future Applications)

Reporting period: 2015-04-13 to 2016-04-12

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.
We have explored a new synthetic methodology consisting on a platinum catalysed reaction of bisallenes with nucleophiles. This process allows a divergent synthesis of six or seven membered rings, important scaffolds from a biological point of view, depending on the nucleophile used. The reaction was initially discovered in Dr Muñoz’s group, but it was not completely optimized, giving in some cases three or four products in each reaction.

During the period as a Marie Curie fellow we have managed to optimize the process further and expand the scope to different bisallenes and alcohols (manuscript in preparation).

Besides, we have started a mechanistic study on this process, since the knowledge about the mechanism can help to improve the process even further and also to extend it to more challenging substrates. Initially we studied the first step of this mechanism, which is the coordination of the platinum catalyst to the allene moiety. This knowledge is also important to other metal catalysed processes involving allenes, since they all start similarly by the interaction of the metal with the allene. This study has led us to develop a new NMR technique (publication in press in the J. Vis. Exp.) and to its application to the study of the dynamic behaviour of different platinum allene complexes (manuscript in preparation).

We carried on with our investigations of the rest of the mechanism, including isotopic labelling, Hammett analysis and kinetics, and we have found out that more than different pathways are involved in the formation of 6- versus 7-memebred rings depending on the nucleophile (water or alcohols), the structure of the bisallene starting material, or the reaction conditions used. This discovery is important to understand the chemistry of bisallenes, and will lead to new studies in order to obtain new and different structures from our initial bisallenes.
The conclusions obtained for this study will help to understand the metal-allene interactions and will be helpful to design new metal catalysed reactions of allenes. This project has provided an in-depth approach to this question making clearer the differences between platinum and other metals, and allowing a better understanding of these systems that will allow the development of new catalyst and methodologies of use in Organic Synthesis.

Furthermore, the NMR technique we have developed (SSTD NMR) will be of use, not only for our complexes, but also to obtain the thermodynamic parameters of a wide range of small organic and organometallic molecules.

These divergent methodologies are extremely useful for pharmaceutical companies, as novel chemical structures not tested so far can be obtained in an atom-economic, straight forward way, and will lead the way to future more potent drugs.

We can not forget the training dimension of the project. The Fellow has improved her skills in organic, organometallic and physical-organic chemistry, which has proven very valuable for her next career step (she has lardy been awarded a prestigious fellowship by the Spanish Government to work in a Spanish University). She has participated in many conferences, presenting the work to different audiences and in different formats, and was invited as one of the plenary speaker at the RSC South Eastern Regional Organic Chemistry Symposium in 2015.