Energy profiles, enantioselectivity

The methods of organic synthesis have continued to advance rapidly and we have made an effort to reflect those advances in this Fifth Edition. Among the broad areas that have seen major developments are enantioselective reactions and transition metal catalysis. Computational chemistry is having an expanding impact on synthetic chemistry by evaluating the energy profiles of mechanisms and providing structural representation of unobservable intermediates and transition states. 

The energy profiles for an enantioselective and a diasteroselective synthesis are compared in Figure 14.2. An interesting feature of the asymmetric catalytic synthesis is the nonlinear correlation between the optical purity of the chiral catalyst or auxiliary and that of the reaction product, reported... 

Figure 14.2 Energy profiles for enantioselective and diastereoselective syntheses.

QM/MM methods are already a widely established tool for the calculation of free energy profiles for complex systems in homogeneous catalysis. They are especially suited for mononuclear systems where the explicit introduction of bulky ligands in the calculation is necessary to reproduce the experimental behavior. The need to introduce the real bulky ligand explicitly in the calculation is more frequent in problems involving regioselectivity and enantioselectivity. 

The first study compared PA-EC with PA-AF [12]. The mutation of S67A in one part of the active site leads to weaker interactions with H-bonding probes in PA-AF. Several other amino acid differences between the enzymes translate into different interaction strengths or even structural differences of the protein backbone, which are reflected in the shape of the MIFs and the interaction energy maxima. Together with docking calculations of model substrates, the authors were able to explain the experimental selectivity profile and the enantioselectivity of the enzymes. 

Consider the reaction profiles depicted in Figure 1. The diastereomeric transition states refer to the enantioselective step both in Figure la (the exothermic reaction) and Figure lb (the endothermic reaction). The energy minima labeled... 

Figure 1.12 Sections of profiles of free energy for the enantioselective stages of the four different catalytic pathways in hydrogenation of 26 catalyzed by 8. (Reprinted with permission from Gridnev, I. D. et al., ACS Catal., 4, 203-219. Copyright 2014 American Chemical Society.)...

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