Efficient Synthesis of Pharmaceutically Relevant Prochiral Heterocyclic Aminoketones

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).

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“…The substrates (57a-d,f) and 4-(2-oxopropyl)piperazin-1-ium hydrochloride were synthesized according to the previously published method [64].…”

Section: Synthesis Of the Heterocyclic Ketones (57a-g)mentioning

confidence: 99%

Transaminase Catalysis for Enantiopure Saturated Heterocycles as Potential Drug Scaffolds

et al. 2021

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Efficient Synthesis of Pharmaceutically Relevant Prochiral Heterocyclic Aminoketones

Cited by 1 publication

References 14 publications

Transaminase Catalysis for Enantiopure Saturated Heterocycles as Potential Drug Scaffolds

Transaminase Catalysis for Enantiopure Saturated Heterocycles as Potential Drug Scaffolds

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