Enzyme-catalyzed aqueous transamination provides access to chiral amines with the benefit of high selectivity, mild reaction conditions, and reduced consumption of organic solvents. Yet, process development towards an efficient and robust aqueous transamination faces numerous practical challenges, including reaction stalling, by-product formation, and often arduous workup procedure to isolate water-soluble product from complex aqueous media. This presentation will describe the development of a process using aqueous transaminase for the reductive amination of CyreneTM, a bio-based feedstock chemical derived from cellulose. The product of this transformation, which we term cyrene amine, is a key chiral amine fragment required for the synthesis of an experimental Bruton’s tyrosine kinase inhibitor for the treatment of B-cell cancers. To achieve a synthesis of cyrene amine, team identified a promising transaminase for the amination of cyrene with isopropylamine as amine donor, and subsequently engineered the enzyme by directed evolution for improved activity, diastereoselectivity, and thermostability. Further reaction optimization provided higher yields and cleaner impurity profile with improved scalability. Lastly, ‘salting out’ technique was identified to deliver robust extraction of cyrene amine, and subsequent salt formation furnished final cyrene amine tosylate salt with improved diastereomeric ratio(dr). The final process combines two renewable, bio-based solvents, CyreneTM and 2-MeTHF in an enzyme-catalyzed aqueous transamination reaction to efficiently produce a valuable chiral intermediate for the synthesis of pharmaceuticals.

Development of an aqueous transamination reaction from CyreneTM, a renewable feedstock chemical

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