Biocatalytic Deracemisation of Atropisomeric Drug Candidates

Drugs that are chiral due to slow bond rotation (atropisomeric) are becoming more prevalent, and atropisomerism is increasingly recognised as an asset rather than a hindrance in medicinal chemistry programmes. However, although some asymmetric routes to atropisomers are established, very few methods are applicable to ‘drug-like’ atropisomers – namely those that are heavily functionalised, hydrophilic and often heterocyclic target molecules, meaning that enantiomerically pure atropisomeric drug candidates are typically obtained by wasteful and inefficient resolution methods.This proposal will address this problem by developing the concept of enzymatic deracemisation – discovered incidentally during an ERC AdG study of controlled molecular motion – to the atropisomer classes typically found in medicinal chemistry development programmes. In contrast to classical means of obtaining enantiopure atropisomers, this proposed biocatalytic method overcomes the yield and waste limitations of classical resolution and is uniquely applicable to the polar, water-soluble drug candidates for which existing asymmetric methods fail. The method stands out as sustainable, versatile and capable of making potential chiral drugs of enormous value and will be transformative for how the chemical and pharmaceutical sectors produce atropisomeric drug molecules. The originality of the project stems directly from a newly discovered chemical process unique to our laboratory. The Research Team is composed of diverse specialists in synthesis, biocatalysis, complex reaction networks and drug development. Development of the method will involve close partnership with industrial partners to identify enzyme classes, methods and target molecules for use as case-studies to quantify the benefits of the technology.