Optimizing Mechanochemical Deracemization through Solid-State Control

Details

Supervisors

Leyssens, Tom

Faculty

Faculté des sciences

Degree label

Master [120] en sciences chimiques, à finalité approfondie

Abstract

en2-Aminobutyramide is commonly used compound as a pharmaceutical intermediate; its (S)-enantiomer serves as a key building block for antiepileptic drugs such as levetiracetam and brivaracetam. In this context, developing an efficient synthetic route to access the pure (S)-enantiomer is essential. To achieve the deracemization of 2-aminobutyramide, the precursor must first be reacted with an aldehyde to form an imine, as the direct deracemization of the primary amine is impossible. To this end, various imine derivatives of 2-aminobutyramide, crystallizing as either racemic compounds or conglomerates, were investigated. This master’s thesis aims to address two main challenges in order to overcome the current limitations of the deracemization process. The first is to achieve the deracemization of imines that crystallize as racemic compounds, which, unlike conglomerates, cannot be deracemized directly. The second is to actively control the enantiomeric outcome through the use of chiral agents. This was accomplished via mechanochemical deracemization (MCDR), a highly sustainable pathway to enantiopure compounds. MCDR is a solvent-minimized technique that utilizes milling jars, grinding balls, an inert bulk material, and liquid-assisted grinding (LAG). For racemic imines, achieving control over the deracemization process first requires their transformation into a suitable cocrystal. Subsequently, chiral additives can be used to control the direction of the enrichment. However, since no viable cocrystal has yet been fully identified for these racemic imines, further investigations remain necessary. Conversely, for conglomerate imines, which inherently undergo deracemization, absolute stereocontrol was achieved by employing a chiral additive as the LAG agent. Surprisingly, this chiral agent not only successfully dictated the direction of the enantiomeric enrichment but also provided a driving force robust enough to overcome an initial enantiomeric imbalance in the starting material. Given these highly promising results, the underlying mechanism governing this stereocontrol and the ability to override initial imbalances must be thoroughly investigated to successfully apply this methodology to other compounds.