Understanding the Platinum-Catalysed Reaction of Allenes with Nucleophiles: Towards New Reactivities and Novel Structures

The development of new catalytic reactions and the study of unusual reaction mechanisms is a fundamental part of science, crucial to drive the development of new chemical reactions. This essential field aims to enhance and refine our understanding of how chemical reactions work, not only to satisfy our curiosity about the world surrounding us, but also to help the synthetic and industrial chemists to rationalise results, predict outcomes and design better and more practical ways of creating new compounds by avoiding troublesome side reactions, identifying new transformations and devising safer reaction conditions.

Activation of unsaturated bonds by transition metal complexes is a very useful tool to create new C-C and C-X (X = heteroatom) bonds in a very selective and efficient way. Although transition-metal catalysed reactions of alkenes and alkynes have been widely studied, the coordination chemistry of allenes (molecules with two consecutive carbon-carbon double bonds) has only started to be explored, being the reaction with nucleophiles one of the most important examples.

Catalytic cycles involving allenes give the possibility of selective reactions towards one double bond or the other. The selection of the metal (Pd, Rh, Ir, Au, Pt) employed in the reaction is critical to control the outcome of the reaction, and different coordination modes have been proposed to explain the new reactivities encountered.

In this project we propose a mechanistic approach to the study of a recently reported Pt-catalysed reaction of allenes and nucleophiles, and the use of the knowledge gained to discover new reactivities and unravel the synthetic potential behind the proposed key reaction intermediates to give complex structures that could be exploited as new drugs.

Recent discoveries in our laboratory indicate that, under platinum-catalysed conditions, and in contrast to more conventional gold catalysis, the reaction of allenes and nucleophiles proceeds by a divergent mechanistic pathway involving a rare Pt-allene coordination, which allow the formation of new reaction products: double addition of the nucleophiles on to the terminal carbon of the allene and complete saturation of the second double bond of the allenic system occurs in the presence of platinum complexes, in contrast to the mono addition and formation of E-allylated products with other metals, like gold. We have already shown the applicability of this reaction for the synthesis of acetals and bisindolylalkanes, important products with varied biological activity.

Understanding the main reaction pathway, the parameters of the individual steps, and identification of the possible intermediates involved in this catalytic cycle, are crucial for the control of the reaction, the discovery of new catalytic cycles and new one-pot multistep transformations derived from key intermediates of the reaction towards complex molecules that incorporate important structural motifs observed in natural products. We proposed an interactive approach were the knowledge gain form the mechanistic study will be use to exploit new reactivities and divergent catalytic cycles, and improved catalytsts will be design according to the needs of the new reactivities and the mechanistic information gathered.

The work described in this proposal has the potential to influence science research in a broad sense, as it falls in a very multidisciplinary environment, and collaborations between all the chemistry disciplines and with industry will be exploited.

This project is very multidisciplinary and we envisage impact in several areas:

1. People training - social and economic impact
2. Understanding fundamental aspects of science - social and cultural impact
3. Development of new methodologies using catalysis towards biologically active compounds - social and economic impact

The project involves the mechanistic study of a recently discovered platinum-catalysed reaction of allenes and nucleophiles to obtain interesting structures from various points of view. This project is perfect for people training in fundamentals aspects of chemistry as an academic discipline but also for giving them the necessary skills to apply the knowledge acquire to more applied challenges in Academia and Industry. The direct impact in society will be the high level training of postdocs and also undergraduate students in practical new techniques, as well as in problem solving and high transferrable skills in a multidisciplinary environment.

The specific objectives of this project fit in the category of fundamental science, and will give information about how the reaction works so we can exploit it in the future. The basic concepts that we envision to discover in this project will have an important impact in society in the long run. The new reactivities and discoveries studied today will be the standard science for the chemists of tomorrow. The new reactions and their mechanisms will appear in textbooks and will be studied at universities helping to enhance cultural enrichment and form a new society based in science and scientific discoveries.

Understanding how reaction works, and in particular in catalytic systems like the reaction of study in this project, will have also economic impact in the sense that the discoveries make will serve to improve the reaction to obtain products in a more efficient and safer way. The compounds efficiently obtained can be exploited from a medicinal point of view in collaboration with industry and new and more potent drugs can be discovered, having a direct impact in the quality of life, health and well-being of our society.