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).
Highlights
With the rise of rational drug design, Lipinski’s rule of five (RO5) quickly became standard practice to determine bioavailability for oral drug candidates based on physicochemical properties [1]
The transaminase-catalyzed asymmetric transamination of ketones comprising heterocyclic 3D rings (57a–g) under mild conditions proved to be an excellent alternative to “traditional” chemical methods for synthesis of chiral amines 55a–g representing a new class of potential drug scaffolds
Using morpholine-containing ketone 57a as model compound, high-performing TAs were selected from the Codex® Amine Transaminase
Summary
With the rise of rational drug design, Lipinski’s rule of five (RO5) quickly became standard practice to determine bioavailability for oral drug candidates based on physicochemical properties [1]. According to the analysis of Ritchie et al on the effect of aromatic ring count on drug developability, the increasing number of widely used aromatic rings leads to decreased druglikeness [3]. Looking at the most frequently used 2D and 3D fragments in marketed APIs, the phenyl ring (1) is in the number one position, three saturated heterocycles (morpholine (2), piperidine (3) and piperazine (4)) take the following top positions (Figure 1). These 3D fragments—by escaping from Flatland—allow the preparation of more complex and less rigid molecules by introducing asymmetric centers without significantly increasing molecular weight [6]. Increasing ring saturation count has proven to be beneficial regarding developability measures such as solubility, lipophilicity, protein binding, P450 inhibition and hERG (the human ether-à-go-go-related gene) binding [7]
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