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Efficient Synthesis using Alkynes as Masked Ylides

Final Report Summary - ESAMY (Efficient synthesis using alkynes as masked ylides)

In this project, we have investigated the use of alkynes as direct precursor for sulphur ylides under gold catalysis to develop more efficient synthetic processes. Organic synthesis underpins many societal advances, whether in the fields of medicine, agrochemicals, materials development, or biological studies and as increased ability to prepare desired organic molecules with decreased time, effort and waste production can lay the foundation for significant societal benefits as a result. New reactions delivered were to be developed into synthetic processes and the scope and limitations of the reactions explored. Following these initial discoveries, the potential of the reactions were to be evaluated in an asymmetric sense and in other processes that are known to involve the type of intermediates accessed through this chemistry. The novel reactivity was then to be explored in applications to access molecular structures of established importance. Building upon previous work in this area we have shown that we can now effectively realise truly intermolecular approaches to this field in comparison to the intramolecular processes that were previously the state of the art.

This project has involved several stages: reaction discovery; optimisation processes; reaction scope studies; exploration of the chemistry in an asymmetric context, with some stages being revisited in new lights throughout the project. Over the course of the project the research fellow has received training in, and hence developed and applied technical skills in, reaction discovery and study using transition-metal-based catalysis. These include: transition-metal-catalysed processes, parallel synthesis, reaction optimisation, Schlenk techniques, organometallic preparations and applications, reaction screening, asymmetric synthesis, multistep synthesis. A spread of modern analytical methods has been used to support the project, in particular the use of one-dimensional (1D) and 2D nuclear magnetic resonance (NMR) for structural confirmation and elucidation, further supported by X-ray single crystal analysis. As the project spans the broad and fast-moving field of gold-catalysis and also the areas of diazochemistry, sulphur-ylide chemistry and oxidations the fellow has developed a detailed understanding across these areas.

Diazo compounds are extremely useful species for accessing metal-carbenes which have widespread utility in organic synthesis, including accessing sulphur ylides which are potent reactive intermediates. Problems associated with these diazo species include structural limitations, lengthy and / or synthetically inefficient and wasteful preparations, and potential toxicity and explosive hazards. In this study we have developed an alternative approach to access sulphur ylides that provides a complementary and more efficient process to the use of diazo compounds. Optimal reaction conditions were discovered through detailed studies to afford a highly effective multicomponent transformation proceeding through an in situ formed sulphur ylide directly from a triple bond. This transformation has been studied to discover its synthetic potential and as a comparison to the diazo-approach.

As a result of the new route, an alternative approach to achieving asymmetric control in sulphur ylide processes was enabled. Asymmetric synthesis is an important area of chemistry, but has limitations in sulphur ylide Doyle-Kirmse type processes based on diazo use. The approach that we have taken potentially allowed for different control factors to be accessed than from the analogous diazochemistry and we investigated these possibilities in detail. A working system that transfers asymmetric information from an easily introduced, and subsequently easily removed, group to the newly forming asymmetric centre was discovered and variations were studied. With an effective system in-hand, the scope of the asymmetric process was studied in depth and shown to provide significant levels of diastereoselectivity in several reactions. The applicability of this approach was then studied to explore its scope and limitations.

Following the initial reaction developed in this process, two new transformations based around the same underlying reactivity principles have been discovered and studied and which provide access to new structures and structures on known biological relevance.

From this study we have been able to conclude that ynamides are a particularly suitable class of alkynes for use in gold-catalysed oxidation chemistry to access sulphur ylides. The extensive regiocontrol and reactivity profile allows for more general application of this approach. In contrast to previous work in the field, the results from this project shown that ynamides can be used as a direct replacement for diazocompounds in sulphur ylide chemistry and that analogous reactivity profiles with respect to the ylide chemistry are observed. This allows the use of sacrificial diazofunctionality, and the need to introduce it over several synthetic steps to be avoided. This potentially significantly streamlines synthetic processes and in doing so reduces the overall waste production and resource consumption required to prepare molecules.