Novel Enantiopure Sigma Receptor Modulators: Quick (Semi-)Preparative Chiral Resolution via HPLC and Absolute Configuration Assignment

Abstract

Abstract:The identification of novel pan-sigma receptor (SR) modulators, potentially useful in cancer treatment, represents a new goal of our research. Here, we report on the preparation of novel chiral compounds characterized by a 3-C alkyl chain bridging an aromatic portion to a 4-benzyl-piperidine moiety. All of the studied compounds have been prepared both in racemic and enantiomerically-pure form, with the final aim to address the role of chirality in the SR interaction. To isolate and characterize enantiomeric compounds, high-performance liquid chromatography (HPLC) procedures were set up. A systematic analytical screening, involving several combinations of chiral stationary and mobile phases, allowed us to optimize the analytical resolution and to set up the (semi-)preparative chromatographic conditions. Applying the optimized procedure, the enantiomeric resolution of the studied compounds was successfully achieved, obtaining all of the compounds with an enantiomeric excess higher than 95%. Lastly, the absolute configuration has been empirically assigned to enantiopure compounds, combining the electronic circular dichroism (ECD) technique to the elution order study.

Chiral Separations in Preparative Scale: A Medicinal Chemistry Point of View

“…Recent examples of applications at preparative scale on polysaccharide-based CSPs include: the enantioseparation of tetrahydro-α-(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetic acid (TPA), a key intermediate for the synthesis of HIV protease inhibitors (enantiomeric purity of 99%) [54]; racemic coumarin derivatives [55]; isoborneol enantiomers [56]; high-affinity 5-HT7 receptor ligand (enantiomeric purity of 100%) [57]; synthetic E2F inhibitor HLM006474 (enantiomeric ratio higher than 99.5/0.5) [58]; novel pan-sigma receptor (SR) modulators, potentially useful in cancer treatment (enantiomeric excess higher than 95%) [59]; among others. Recently, we reported the enantioseparation of cathinone derivatives (amphetamine-like stimulant effects) at multi-milligram scale using the same type of CSPs (Figure 3) [60,61].…”

Insight into GEBR-32a: Chiral Resolution, Absolute Configuration and Enantiopreference in PDE4D Inhibition

“…Considering that both enantiomers are needed for biological testing, we synthesized racemic GEBR-32a first (according to the previously reported procedure, Scheme SI) [7] and solved the enantiomers by chiral liquid chromatography, a time-and cost-effective approach for enantiomer resolution at the discovery stage, commonly used both in Academia and the pharmaceutical industry [7,11]. To find easily scalable chiral resolution analytical methods, our standard approach to the analysis and separation of new chiral compounds consisted in the screening of polysaccharide-based chiral stationary phases (CSPs) immobilized on silica gel chiral columns characterized by wide solvent compatibility, versatility and robustness [11][12][13][14][15][16][17][18]. First, we tested a Regispack IA column containing a dimethylphenyl-derivative of amylose.…”

“…Both enantiomers have been characterized by nuclear magnetic resonance (NMR) ( 1 H-NMR and 13 C-NMR) by measuring the specific rotations ([ ] 20 ) and recording electronic circular dichroism spectra (Table 2 and Figure 3). In Table 1, the results expressed as retention (k), selectivity (α) and resolution (Rs) factors are reported.…”

Some thoughts about enantioseparations in capillary electrophoresis

“…Numerous other experimental techniques, in addition to theoretical calculations, can be applied on case‐by‐case basis with more or less success for addressing special problems related to chirality and its occurrence in the nature . HPLC in various modes, such as batch, simulated moving bed (SMB) and SFC, can be applied not only for analytical but also for preparative and product‐scale separation of enantiomers . These methods are quite complementary to each other.…”