Dynamic Resolution of Boronic Esters: A Powerful Strategy for Asymmetric Atropisomer Synthesis

Atropisomers are an unusual class of molecules in organic chemistry as they convey a defined three-dimensional shape from flat molecular fragments. Atropisomerism arises from hindrance of bond rotation about single bonds due to steric clashes, thereby making the isolation of the individual isomers possible. There are a large number of prominent molecules derived from nature as well as pharmaceuticals that exhibit atropisomerism, however stereoselective synthetic methods towards these compounds remain very challenging. We have developed a way to access specific atropisomers with high selectivity that involves the equilibration of an easily prepared stereoisomeric mixture. This method is underpinned by the chemistry of boron, which serves to both control atropisomer stereochemistry, while acting as a handle for further chemical modifications. We are only just beginning to understand the scope of this process, but we believe that it will represent a general method for preparing these important compounds. The requested grant will allow us to demonstrate the potential of the methodology, and will show that we can use it to access a very broad range of high value chemicals.

Emerging challenges associated with maintaining a healthy drug discovery pipeline means that there is a growing need for chemistries that allow access to more diverse compounds and previously inaccessible structures. The proposed research programme would generate new compounds that may find application as new pharmaceuticals, intermediates towards new drugs or as tool compounds to further the understanding of disease conditions. Thereby this research has the potential to benefit the health of the population through the introduction of new treatments and also contribute to the economy through sales of new drugs and also by reducing the loss to the economy through ill health.
Heteroaromatic motifs are widespread in small molecule drug therapies, with 11 out of the top 20 prescription drugs containing these building blocks. Moreover, an increasing proportion of new therapeutics are chiral compounds, with the vast majority being marketed as single enantiomers. The proposed programme addresses both of these areas as it aims to access aromatic and heteroaromatic compounds that are chiral by virtue of a hindered bond rotation (aromatic atropisomers). Industries involved in the synthesis of bioactive molecules including Fine Chemicals, Pharmaceuticals and Custom Research Organisations (CRO's) will also be able to take advantage of the methods developed here in their research effort towards new medicines.
Heteroaromatic and aromatic compounds are also common structures in small molecule crop protection agents. The need for crop protection is becoming increasingly important as the demand for food crops rises due to the increase in the world population and also as the demand for non-food crops grows as the market for biofuels and industrial biotechnologies develops. Annual sales of crop protection agents are $8 billion. However, many fungal pathogens are becoming resistant to existing fungicides and therefore developing new, safe compounds with novel mechanisms of action is increasingly important. In the context of agrochemicals, the majority of compounds marketed in the past few decades have contained heterocycles, and around one-third of these are chiral compounds (Lamberth et al. Science, 2013, 341, 742). Indeed, the herbicide metolachlor exists as an atropisomeric mixture but only the (S)-enantiomer is sold. Therefore, the programme described here has the opportunity to directly impact the crop protection sector also.
Overall, new medicines and agrochemicals require us to explore new areas of chemical space and this provides a compelling impetus to challenge the state-of-the art in organic synthesis. The themes explored in this project serve to advance several fields including organoboron chemistry, asymmetric synthesis and aromatic chemistry, providing new tools and strategies that will provide positive impact to the benefit of academic and industrial sectors.