What is Chirality in Chemical Synthesis?

Moll, M., Wängler, B., Wängler, C., & Röder, T. (2025). Kinetic investigation of the asymmetric hydrogenation of benzylphenylephrone in continuous flow. CHIMIA International Journal for Chemistry, 79(6), 441–448. https://doi.org/10.2533/chimia.2025.441

“This study presents the design and development of a fully automated, mL-scale continuous flow process for the asymmetric hydrogenation of benzylphenyle phrone to (R)-benzylphenylephrine (BPE). The process employs a rhodium-based homogeneous catalyst under high pressure (up to 65 bar), achieving conversions of >96%, yields of up to 95% and high enantiomeric excess (ee) of up to 91%, with residence times of less than five minutes and a molar substrate to catalyst ratio (S/C) of 750. Kinetic investigations were conducted in a continuous flow microreactor, resulting in the development of a kinetic model that closely matches experimental data… To determine the temperature dependent rate constant k(T), the activation energy Ea and thus the influence of temperature on the reaction rate were required. Experiments were carried out at 40, 60, and 80 °C. The measured concentration profiles were transferred to DynoChem® together with the previously obtained kinetics.”

Cai, I., Malig, T. C., Kurita, K. L., Derasp, J. S., Sirois, L. E., & Hein, J. E. (2024). Investigating the Origin of Epimerization Attenuation during Pd-Catalyzed Cross-Coupling Reactions. ACS Catalysis, 14(16), 12331–12341. https://doi.org/10.1021/acscatal.4c03401

“…we investigate the role of a Pd catalyst in suppressing base-mediated epimerization of a sultam stereocenter during a C–N cross-coupling reaction to access the RORγ inhibitor GDC-0022. Online high-performance liquid chromatography-mass spectrometry (HPLC-MS) was employed to acquire reaction time course profiles and to delineate epimerization behavior, identify decomposition pathways, and monitor Pd-containing species. Our ability to monitor organopalladium complexes in real time by HPLC-MS provided strong evidence that the degree of epimerization was correlated to the Pd speciation in solution…limited solubility…created logistical challenges regarding accurate sampling and HPLC analysis. To this end, we chose to employ an automated sampling platform leveraging the Mettler-Toledo EasySampler with an EasyFrit attachment. This sampling arrangement allowed the supernatant of the C–N coupling reaction to be sampled selectively. We wanted to expand on this toolkit further by using HPLC-MS to track Pd species to help delineate the role of Pd complexes on any observed epimerization attenuation.”

Hosseinalipour, M. S., Deck, L., & Mazzotti, M. (2024). On Solute Recovery and Productivity in Chiral Resolution through Solid-State Deracemization by Temperature Cycling. Crystal Growth & Design, 24(9), 3925–3932. https://doi.org/10.1021/acs.cgd.4c00233

“…we experimentally demonstrated the effect of temperature on the deracemization of N-(2-methylbenzylidene)-phenylglycine amide (NMPA). Performing temperature cycling at high temperatures was found to be beneficial in terms of process productivity…The use of high temperatures, however, comes with the drawback of lower solute recovery due to the higher level of solubility. For this reason, two process variants were experimentally investigated to increase the recovery of the solute: first, temperature cycling followed by a linear cooling ramp (TC + C), and second, the integration of temperature cycles into cooling crystallization, termed CTC…we demonstrated that faster deracemization is achieved in the former process (TC + C), which is also easier to design and implement than the latter. However, the choice of an appropriate cooling rate is essential to avoid nucleation of the undesired crystals. In contrast, in a CTC process, several factors decrease the rate of deracemization, which make the process less productive and its design much more challenging… All experiments were performed in 10 mL cylindrical glass crystallizers (2 cm diameter and 10 cm height) in an EasyMax 102 apparatus (Mettler Toledo). The device consists of two thermal blocks, each of which comprises four 10 mL crystallizers.”

Bosits, M. H., Orosz, Á., Szalay, Z., Pataki, H., Szilágyi, B., & Demeter, Á. (2023). Population Balance Modeling of diastereomeric salt Resolution. Crystal Growth & Design, 23(4), 2406–2416. https://doi.org/10.1021/acs.cgd.2c01376

“A resolution method for racemic pregabalin with L-tartaric acid was developed to obtain pure (S)-pregabalin L tartrate monohydrate crystals…A series of designed resolution experiments were executed at different cooling rates and temperature endpoints to estimate the crystallization kinetics using population balance modeling. Inline ATR-FTIR measurements of these experiments were used to calculate concentrations in the crystallization phase and to collect solid−liquid equilibrium data by the solubility trace method after product sampling…a population balance model with secondary nucleation, growth, and agglomeration mechanisms was identified, and the simulated supersaturation profiles and product size distributions well reproduced the measured data… The concentration of pregabalin tartrate was measured using Mettler Toledo ReactIR 15, a real-time analytical tool based on Fourier transform infrared (FTIR) spectroscopy using an attenuated total reflectance (ATR) probe…Inline FBRM measurement was applied to monitor the process.”

Kukor, A. J., Depner, N., Cai, I., Tucker, J. L., Culhane, J. C., & Hein, J. E. (2022). Enantioselective synthesis of (−)-tetrabenazine via continuous crystallization-induced diastereomer transformation. Chemical Science, 13(36), 10765–10772. https://doi.org/10.1039/d2sc01825j

“A multi-well continuous CIDT approach with inline racemization of the solution phase is presented. Using two in-house built PATs and a flow reactor, we were able to successfully crystallize an enantiopure salt of TBZ…inline racemization combined with careful control of crystallization conditions allowed for multigram quantities of enantiopure material to be harvested using our setup. Critically, this control was made possible by the use of PATs to observe and quantify the composition of both the solid and solution phases…While sampling from crystallizations can be challenging due to the presence of solids and supersaturation concerns, our lab has recently developed a tool that attaches to Mettler-Toledo's EasySampler probe. This modification allows for the selective sampling of the solution phase of crystallizations without clogging or probe fouling. Combined with online HPLC analysis of samples, we are able to obtain real-time solution phase component concentration data to track solution-phase equilibria, and even back-calculate the composition of the solid phase when the total system composition is known. Critically, this allows us to monitor solution-phase equilibria during a CIDT while simultaneously calculating solid phase yield and enantiomeric excess (e.e.) when chiral chromatography is used.”

Rehman, G. U., Vetter, T., & Martin, P. A. (2022). Design, development, and analysis of an automated sampling loop for online monitoring of chiral crystallization. Organic Process Research & Development, 26(4), 1063–1077. https://doi.org/10.1021/acs.oprd.1c00320

“...process analytical technology able to measure the enantiomeric composition of both the solid phase and the liquid phase would be valuable to track and eventually control such processes. This study presents the design and development of a novel automated analytical monitoring system that achieves this. The designed setup tracks the enantiomeric excess (ee) using a continuous closed-loop sampling loop that is coupled to a polarimeter and an attenuated total reflection Fourier transform infrared spectroscopy spectrometer [ReactIR]. By heating the loop and alternately sampling either the liquid or the suspension, the combination of these measurements allows tracking of the ee of both the liquid and the solid.”