QM/MM Modeling of Enantioselective Pybox–Ruthenium‐ and Box–Copper‐Catalyzed Cyclopropanation Reactions: Scope, Performance, and Applications to Ligand Design

Abstract

An extensive comparison of full-QM (B3LYP) and QM/MM (B3LYP:UFF) levels of theory has been made for two enantioselective catalytic systems, namely, Pybox-Ru and Box-Cu complexes, in the cyclopropanation of alkenes (ethylene and styrene) with methyl diazoacetate. The geometries of the key reaction intermediates and transition structures calculated at the QM/MM level are generally in satisfactory agreement with full-QM calculated geometries. More importantly, the relative energies calculated at the QM/MM level are in good agreement with those calculated at the full-QM level in all cases. Furthermore, the QM/MM energies are often in better agreement with the stereoselectivity experimentally observed, and this suggests that QM/MM calculations can be superior to full-QM calculations when subtle differences in inter- and intramolecular interactions are important in determining the selectivity, as is the case in enantioselective catalysis. The predictive value of the model presented is validated by the explanation of the unusual enantioselectivity behavior exhibited by a new bis-oxazoline ligand, the stereogenic centers of which are quaternary carbon atoms.

Enantioselective catalysis with chiral complexes immobilized on nanostructured supports

“…Thus, when the cyclopropanation reactions were catalyzed by the laponite-exchanged PhBox-Cu complex, in hexane or styrene, a complete reversal of the trans/cis diastereoselectivity (31:69) was observed, and even more interestingly, the major cis-cyclopropane obtained had the 5 opposite absolute configuration, with regard to homogeneous phase results. When reusing the catalyst in dichloromethane, similar selectivities as in solution were achieved, proving that the reversal in trans/cis and enantioselectivity in ciscyclopropanes was not a permanent effect but a consequence 10 of a tight interaction with the surface.…”

“…They are characterized by the lack of long-range 10 crystalline order. Amorphous silicas consist of particles of 1-100 nm which can be discrete, aggregated (1-25 µm) or agglomerated in a 3D network (silica gel).…”

Stereoselectivity induced by support confinement effects. Aza-pyridinoxazolines: A new family of C1-symmetric ligands for copper-catalyzed enantioselective cyclopropanation reactions

“…An extensive study on the importance of the nature of the support has been recently reported, confirming the need of having a lamellar anionic support to observe such surface 55 confinement effects. 10 A simple model has been proposed to explain those results, taking into account the known cyclopropanation reaction mechanism [11][12][13][14][15][16][17][18][19][20] and the strong ionpair interaction between the key copper-carbene intermediate and the support surface, as well as the steric constraints of the 60 catalytic complex. From that model we proposed the synthesis of chiral ligands without C 2 symmetry as a method to enhance the surface-complex proximity and hence the support-complex interaction, allowing the surface to effectively shield one face of the complex.…”

“…oxazolinylquinoline-copper complexes, which are much more rigid, leading to almost planar geometries. 14,29 In order to test this hypothesis, copper complexes of both isopropylsubstituted 39 C 2 -symmetric bis(oxazoline) (11) and azabis(oxazoline) (12) chiral ligands ( Figure 2) were used in the 30 same conditions. The corresponding results are gathered in Table 1 (entries 7 and 8).…”

“…15 With the aim of rationalizing the experimental results described above, and to have a better understanding of the geometries of the key intermediates and transition structures (TS), a theoretical study of the different reaction channels of the copper-catalyzed cyclopropanation reaction with C 1 -20 symmetric aza-pyox ligands was done. Apart from the wellknown drawbacks in modeling the cyclopropanation reaction with styrene due to the flatness of the potential energy surface, [11][12][13][14][15] our main interest in this work was to evaluate the enantioselectivity of the process; therefore, all the calculations 25 were carried out using ethylene as olefin. In addition, as in previous studies, methyl diazoacetate was used in the calculations instead of ethyl diazoacetate.…”