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Enabling Catalytic Cross Couplings with only Zinc Electrophiles, Nucleophiles and Boranes

Periodic Reporting for period 3 - ECO-ZEN (Enabling Catalytic Cross Couplings with only Zinc Electrophiles, Nucleophiles and Boranes)

Reporting period: 2020-10-01 to 2022-03-31

Catalysis is a key process enabling the formation of important value added products from simpler starting materials and is ubiquitous in chemical processes. Catalysis is estimated to contribute > 35 % of global GDP and recent estimates indicate that 90% of industrial chemicals are synthesized in processes that require at least one catalytic step. However, many catalysts are based on rare and expensive elements, collectively called the platinum group metals (PGMs), that have significant supply chain risks thus are classed as critically endangered raw materials by the EU. Furthermore, these elements also have significant toxicity concerns, which imposes considerable purification costs particularly in the production of pharmaceuticals. Therefore the replacement of catalysts containing PGMs with alternatives that are based only on highly abundant, inexpensive, low-toxicity elements is a crucial endeavour.
One vital catalytic process, called cross coupling, is essential across many industries as it forms carbon-carbon bonds. This Nobel prize winning chemistry is an essential tool for constructing the carbon backbone in organic-materials, pharmaceuticals and agrochemicals. The Suzuki-Miyaura (S-M) cross coupling reaction is the most prevalent cross-coupling method as it is reliable, modular and utilises low toxicity, easy to handle starting materials based on boron, termed organoboranes. S-M couplings are ubiquitous in both academia and industry, for example they are one of the top five most utilised reactions in pharmaceutical research laboratories. Despite its undeniable power there are drawbacks and limitations associated with the S-M reaction. For example, S-M couplings are currently dependent on toxic catalysts based on a rare PGM Pd, and to a lesser extent Ni (which is also highly toxic). Furthermore, while S-M couplings are very powerful for making flat (two dimensional) molecules it does not work effectively to form more three dimensional structures, which are essential as nature is three dimensional! This has led to an over-representation of flat molecules that are less “drug-like” in pharmaceutical research programs and thus there needs to be new modular methods to make C-C bonds in three dimensional structures. Therefore the important challenges addressed by this proposal are:

Overarching Objective 1: Generating a broad scope S-M cross coupling process for forming C-C bonds in 3D molecules that uses low toxicity earth abundant catalysts based on zinc and boron. This is important to enable facile access to new 3D-molecular space.

Overarching Objective 2: Synthesising new and useful organoboranes using only simple precursors and without using PGM catalysts. These compounds will be compatible with, and utilised in the new zinc catalysed S-M reaction facilitating the construction of 3D molecules.
This reporting period covers the first 11 months of this programme (out of a total of 60 months). During this time a team of 7 chemists with complementary expertise has been assembled to tackle the two overarching objectives outlined. Work is progressing towards both key objectives, with more rapid progress to date being made towards overarching objective 2. For example, we have developed novel zinc catalysts that enable the borylation of simple substrates to form new C-B bonds and thus give access to organoboranes that are highly useful, e.g. in cross coupling reactions. Furthermore, we have discovered two novel transformations using the simple and commercially available reagent, BBr3, these also provide facile access to new C-B and unprecedented organoboranes for use in a wide range of subsequent transformations.
In the first 11 months of this project the assembled team has already delivered several new routes to form C-B bonds that go beyond the state of the art (e.g. the first zinc catalysed hydroboration, zinc catalysed C-H borylation to form C-BPin moieties, 1,1-haloboration of alkynes), which are important for use in cross coupling reactions to form C-C bonds. As the project continues we are targetting other new C-B bond forming reactions. Beyond C-B formation, we are also focused on developing novel routes to make C-C bonds in 3D molecules using zinc catalysts, this would be transformative if the process is as modular as the Pd catalysed cross coupling reaction to form planar molecules. Finally, we are investigating new routes to form C-F bonds using R3BF borates, this is important as fluorine is ubiquitous in pharmaceuticals, thus the targetted developments would be of use to medicinal chemist as they use simple fluorine sources and organoboranes to form the new C-F bonds.