Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - ICRED (Iridium Catalyzed Reductive Cyclization Cascades)

Teaser

Amides are ubiquitous in the fine chemical, agrochemical and pharmaceutical industries, but are rarely exploited as substrates for homologous amine synthesis. By virtue of their high chemical stability, they are essentially inert to all but the harshest of chemical reagents...

Summary

Amides are ubiquitous in the fine chemical, agrochemical and pharmaceutical industries, but are rarely exploited as substrates for homologous amine synthesis. By virtue of their high chemical stability, they are essentially inert to all but the harshest of chemical reagents and to the majority of chemical transformations routinely used in organic synthesis. Accordingly, the development of chemoselective carbon-carbon bond forming methodologies arising from the functionalization of the amide functionality should find widespread use across academia and industry. During the course of this project, we have developed a new and technically simple one pot-protocol for synthesising tertiary amine using tertiary amide as starting materials and Grignard reagent as the reactive coupling partner for carbon-carbon bond formation.

The project has achieved most of its objectives and milestones for the period, with relatively minor deviations.

- New reactivity from amide and lactam feedstock chemicals: Dr Xie has developed new methodologies towards the synthesis of amine derivative through the iridium-catalyzed reductive carbon-carbon bond formation of amide and lactam, managed to apply inter molecular carbon nucleophiles instead of the proposed intra molecular ones. Thus allowed the more general utility of the amide and lactam chemicals.
- The development of new complexity generating cascade reactions: Dr Xie carried out the discovery and optimization of a new reductive coupling of amide and Grignard reagent to synthesize tertiary amine derivative and a reductive Ugi-type reactions of tertiary amide by the reductive coupling of amide and isocyanide in the presence of either acid or trimethylsilyl azide. And the later one offered an new access to the synthesis of high value Ugi amino amide and tetrazole compounds.
- New enantioselectivity in iridium catalyzed reductive cascades: The researcher has started a program towards the enantioselective synthesis of Ugi-type alpha amino amide, which has come out with some promising results.
- New approaches to complex product synthesis: The researcher has successfully applied the new transformations to the synthesis of drugs and bioactive molecules, as well as the derivativation and late stage functionalization of complex bioactive molecules.

Work performed

The first published paper Dr Xie’s have done during the fellowship is to develop a new and technically simple one pot-protocol for synthesising tertiary amines using tertiary amides as starting materials and Grignard reagents as the reactive coupling partners for carbon-carbon bond formation. The protocol pivots on the highly chemoselective catalytic reductive activation of tertiary amide substrates using Vaska’s complex and tetramethyldisiloxane, followed by efficient carbon-carbon bond formation on addition of the Grignard reagent.
In this work Dr Xie demonstrated the truly broad scope of the protocol with respect to the amide, and the Grignard reagent and showed that numerous functional groups useful for known downstream coupling reactions are well-tolerated. He showed that the organomagnesium reagents could be standard Grignard reagents from commercial sources or made via the Knochel halogen-magnesium exchange protocols (allowing incorporation of more complex/elaborate carbon-centred nucleophiles). Dr Xie has illustrated direct synthetic utility by applying the chemistry to the synthesis of a number of drug compounds and by the late stage functionalization of several drug compounds and natural product derivatives. This work has been published on Chemical Science.

After the discovery of the reductive coupling of amide and Grignard reagent, Dr Xie further investigated on the reductive coupling of amide and isocyanide, which led to the findings of a series of Ugi-type reactions of tertiary amides enabled by the chemoselective iridium-catalyzed partial reduction, followed by reaction with isocyanide and (thio)acetic acid or trimethylsilyl azide, thus providing a new multicomponent synthesis of α-amino (thio)amide or α-amino tetrazole derivatives.

Dr Xie has demonstrated the broad scope of the protocol with respect to the amide and the isocyanide, and he showed that the protocol can be used to prepare α-amino amides (Scheme 4) and thioamides, as well as α-amino tetrazole products. And given the prevalence of tertiary amides and their precursors in bioactive molecules, and the surprisingly broad scope tolerated in these amide reductive Ugi-type (thio)amide and tetrazole syntheses, further synthetic potential of this chemistry has been demonstrated by the late stage functionalization of various bioactive molecules and derivatives (Scheme 6). This work has been accept for publishing on Nature Communications, and now is in press.



The research has been published in two high-ranking journals although at least another two papers will be publish soon.

Lan-Gui Xie; Darren J. Dixon. Iridium-catalyzed reductive Ugi-type reactions of tertiary amides. Nature Communications, 2018, DOI: 10.1038/s41467-018-05192-7.

Lan-Gui Xie; Darren J. Dixon. Tertiary amine synthesis via reductive coupling of amides with Grignard reagents. Chemcal Science, 2017, 8, 7492-7497.

Final results

After this 2-year fellowship, the information in the original proposal regarding the impact is still relevant. This fellowship has allowed a great improvement in the state-of-the-art in the reductive amide functionalization, through powerful and impacting synthetic methodologies, raising the standing of EU Chemistry within this field at a global level. The reactions studied are directly useful for the preparation of drug target molecules with biological activity. Therefore, this Fellowship has constituted a significant contribution to the field, and will suppose a benefit for synthetic organic chemists, pharmaceutical, agrochemical and fine-chemicals industries in EU, which have already shown interest for the projects developed in this fellowship.

This fellowship eventually facilitated Dr Xie to get an independent academic research position at Nanjing Normal University, one of the state key universities in China. As during these 2 years he has been able to develop and widen his competences, particularly in terms of multi/interdisciplinary and inter-sectoral experience and transferable skills, as well as gain the necessary mobility and skills to achieve this final objective of begin working as an independent scientist.

The research carried out during these 2-years fellowship has enhanced innovation capacity, created new market opportunities, strengthen competitiveness and growth of companies, in fact, several industries have already shown interest by this project and are currently funding a PhD in Dixon group to further develop the first results of this project. So, the negative image of the chemical industry and chemists in EU is overcome. This Fellowship has also benefited society in general, through the discovery of new synthetic methodologies which are going to be very useful for pharmaceutical industries.

The research has been published in two high-ranking journals although at least another two papers will be publish soon. Also, it has been presented in several national and international conferences, in which a high interest has been shown from other researchers.

Website & more info

More info: http://dixon.chem.ox.ac.uk/langui.html.