Transaminase Catalysis for Enantiopure Saturated Heterocycles as Potential Drug Scaffolds

Abstract

As efforts in rational drug design are driving the pharmaceutical industry towards more complex molecules, the synthesis and production of these new drugs can benefit from new reaction routes. In addition to the introduction of new centers of asymmetry, complexity can be also increased by ring saturation, which also provides improved developability measures. Therefore, in this report, our aim was to develop transaminase (TA)-catalyzed asymmetric synthesis of a new group of potential chiral drug scaffolds comprising a saturated amine heterocycle backbone and an asymmetric primary amine sidechain (55a–g). We screened the Codex® Amine Transaminase Kit of 24 transaminases with the morpholine containing ketone 57a, resulting in one (R)-selective TA and three (S)-selective TAs operating at 100 mM substrate concentration and 25 v/v% isopropylamine (IPA) content. The optimized reaction conditions were than applied for asymmetric transamination of further six ketones (57b–g) containing various amine heterocycles, in which a strong effect of the substitution pattern of the γ-position relative to the substituted N-atom could be observed. Mediated by the most enantiotope selective (S)-TAs in scaled-up process, the (S)-amines [(S)-55a–g] were isolated with moderate-to-excellent yields (47–94%) in enantiopure form (>99% ee).

Solvent Switching in Continuous Multistep Chemoenzymatic Synthesis: Telescoping Enzymatic Synthesis of Chiral, Pyridine-Containing Amines with Cross-Coupling as a Case Study

“…Crucial to the process is access to the chiral amine from inexpensive and readily available starting materials. Several enzymatic routes have been reported ,− as well as more classical synthetic methods , with the latter often struggling in achieving high enantiomeric excess (ranging from 80 to 92% and exceptionally achieving 98%). Among the myriad of transaminases reported for the transformation of prochiral ketones to access enantiomerically pure amines both in their free and immobilized forms, here the use of an ( R )-selective transaminase from Thermocyces Stellatus (TsRTA) was chosen for its excellent activity against a broad range of prochiral ketones. , The immobilization, specifically, offered an interesting opportunity compared to the traditional synthetic approach since it would allow the recovery and reuse of the catalyst after a number of reaction cycles, enhancing in this way the sustainability of the whole process.…”