Combined Catalysis: Enhancing Asymmetric Synthesis

Project Information

CombiCat

Grant agreement ID: 702385

DOI

10.3030/702385

Project closed

EC signature date 15 February 2016

Start date 1 October 2016

End date 30 September 2018

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 183 454,80

EU contribution

€ 183 454,80

Coordinated by

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom

Periodic Reporting for period 1 - CombiCat (Combined Catalysis: Enhancing Asymmetric Synthesis)

Reporting period: 2016-10-01 to 2018-09-30

Summary of the context and overall objectives of the project

This project addressed the synthesis of small organic molecules using two catalyst approaches. The particular topic examined was the cyclisation of acyclic compounds to nitrogen-containing rings, via a process called 'cycloisomerization'. Progress was made in studying asymmetric cycloisomerizations, where one enantiomer (mirror image form) of a molecule is prepared. The ability of a catalyst to control this reaction, rather than the substrate itself, is important as this allows chemists to control the reaction outcome. This project aimed to explore the use of two catalysts to improve control over such processes.

This work is important for society as the synthesis of new drug molecules requires efficient chemical processes, which generate minimal waste, and allow high control over the target molecule. Cycloisomerization fulfils these aims, and this project aimed to advance the state of the art in this area.

The objectives of the work were:

1. To establish robust methods for synthesis of substrates from cheap/commercial materials
2. To explore substrate scope and double stereodifferentiation in cyclisation reactions
3. To explore one-pot multicatalytic processes using combinations of transition metal and organocatalysis
4. Development of processes in which single enantiomer substrates are reacted using two chiral catalysts, and extension of this to diastereodivergent kinetic resolutions.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

"Work Package 1 (WP1) consisted of ""Substrate scope of cycloiosmerization and double stereodifferentiation"" which corresponds to all the results we reported in Section 1.1. Significant progress was made in exploring asymmetric rhodium-catalysed cycloisomerizations, and double stereo differentiation (cyclisation of substrates already containing stereocentres). A good understanding of the substrate scope and limitation was established.

Fewer results were obtained on (WP2) or (WP3), albeit these objectives remain under investigation by the Host Supervisor, building on the preliminary results obtained here. The main results involved the use of carbene and transition metal catalysis to construct polycyclic molecules in one step. This reactions proved more challenging to control than expected. The results obtained on double stereodifferentiation imply that a kinetic resolution process should be possible, where a racemic starting material undergoes selective reaction of just one enantiomer, the other remaining untouched. This work continues to be studied in the host group.

To maximise the benefit of the research to the fellow, a further avenue of research was undertaken, applying catalysis to the synthesis of a bioactive anticancer / antibiotic natural product stambomycin D. Here the fellow made substantial progress and established the synthesis of a 27 carbon fragment of the natural product. Key steps included an organocatalysed asymmetric aldol reaction, a zinc/titanium mediated asymmetric alkyne addition, a copper-catalysed hydroboration / oxidation, and a palladium-catalysed Suzuki cross-coupling to assemble a challenging diene part of the molecule. This work greatly enhanced the fellow's technical skillset, and was conducted in parallel with the methodology studies that formed the main focus of the grant.

"

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

There are very few examples of asymmetric cycloisomerization, and even fewer where double stereodifferentiation is explored. The project therefore advanced the state of the art in stereoselective synthesis of nitrogen-containing ring systems containing multiple stereogenic centres. The results obtained on matched and mismatched catalyst/substrate stereocontrol are highly encouraging for kinetic resolutions, where to our knowledge only three examples exist in the entire cycloisomerization field. This work is now being written up for publication. There is no socio-economic impact of this work at this time, and societal impact will be delivered only following publication.

Less success was met with on the dual catalysis element of the project. However, it may yet prove possible to carry out stepwise transformations (rather than one-pot, as we targeted) that will allow access to complex molecular frameworks in just 2-3 steps from simple acyclic starting materials.

The third element of the project goes far beyond the state of the art in the determination of bioactive polyketide structure. Our work in this area demonstrates the use of contemporary catalytic methods in the efficient and selective synthesis of around half of this natural product, and if successful will provide a new tool for the assignment of structure in new antibiotics / anticancer agents. This work has the largest potential for wider societal benefits. At present, we are preparing a manuscript to report the synthesis of this 21 carbon fragment of the natural product.

Rhodium-Catalysed asymmetric cyclizations