Rational design of catalysts for asymmetric synthesis of pharmaceuticals

Introduction

The introduction can be found elsewhere.



Current projects


Design of novel ATH ligands

One of the biggest advantages of ATH catalytic complexes is their structural modularity. This means that known ligands can be replaced by analogous structures in order to increase the catalytic activity and/or enantioselectivity. For the rational design of new ligands,1 we first employ the techniques of molecular modelling which allows the evaluation of steric and electronic properties of novel ligands. This way, the catalyst structure can be tailored for particular substrates.

The next step is the synthesis of catalytic complexes and testing of its catalytic performance. This project is interconnected with the one below which focuses on the investigation of the compatibility of both new and existing catalysts with various structurally different substrates.
This project is currently assigned to Jakub Januščák, MSc, Jan Přech, BSc2 and Radek Majdloch, BSc.


Influence of the presence of structural fragments on the course of reaction

The presence of certain functional groups in the molecule of substrate or catalyst can significantly affect the reaction rate or enantioselectivity. A typical situation is shown in Figure 1. Catalyst 1 works with substrate 1-Me-DHIQ, whereas with 1-Ph-DHIQ the reaction does not occur and one needs to use another, yet structurally close catalyst 2.






Figure 1: Influence of the structural fragment: methyl vs. phenyl.

The aim is to carry out a detailed screening of structurally related substrates and catalysts and explanation of the experimental data. Some conclusions can also be drawn from molecular modelling which is done in parallel with experiments. We also perform experiments studying the affinity of various substrates towards the active site, i.e. competitive hydrogenations with several substrates at once.

References

1. Václavík, J.; Kačer, P.; Červený, L. Rational Design of Chiral Ruthenium Complexes for Asymmetric Hydrogenations. In Homogeneous Catalysts: Types, Reactions and Applications; Poehler, A. C., Ed.; Nova Science Publishers: New York, 2011; pp 127-153.
2. Pažout, R.; Maixner, J.; Přech, J.; Kačer, P. X-ray powder diffraction data for (1R, 5S, 7R)-7-[(S)-4-tert-Butyl-4,5-dihydrooxazole-2-yl] -1,5,7-trimethyl-3-azabicyclo-[3.3.1]-nonane-2,4-dione, a new chiral Kemp’s acid diamide. Powder Diffr. 2011, 26 (4), 335-336.
DOI: 10.1154/1.3653563