DFT/MM Study on Copper‐Catalyzed Cyclopropanation – Enantioselectivity with No Enthalpy Barrier

Abstract

The enantioselectivity in the reaction of [Cu(adam‐box)(CHCO2Me)] {adam‐box = 2,2′‐isopropylidenebis[(4R)‐(1‐adamantyl)‐2‐oxazoline]} with Ph2C=CH2 was analyzed computationally by ONIOM(B3LYP:UFF) calculations. The lack of transition states in the potential‐energy surface precludes the use of conventional approaches and requires the definition of reaction paths in an approximate Gibbs free‐energy surface. The procedure is time consuming and intrinsically less accurate than the usual approaches based on enthalpic energy surfaces, but it produces results in reasonable agreement with experiment, which furthermore allow identification of the key interactions responsible for chiral discrimination.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

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.…”

“…5 In this paper we report the preparation of a new family of C 1 -symmetric ligands bearing the oxazoline motif, namely azapyridinoxazolines (henceforth aza-pyox), their immobilized copper complexes, and the surface effect in the benchmark enantioselective cyclopropanation reaction of styrene with 10 ethyl diazoacetate (Scheme 1), together with a molecular modeling study to explain the results obtained. The aim of this ligand design is to gather the good coordinating abilities of aza-bis(oxazoline) ligands 32 with the planarity and chemical stability of the pyridine ring, and a straightforward synthetic 15 procedure.…”

“…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.…”

“…The lack of symmetry of the ligand and, as demonstrated by preliminary calculations, the high flexibility of the Cu(I)-carbene complex 30 increased significantly the number of reaction channels to be calculated: 1) the ester group of the carbene moiety can be placed in both an anti and syn disposition with respect to the alkyl group of the oxazoline ring; 2) two main rotamers arise from the ester group, one with the carbonyl pointing to the 35 alkyl group of the oxazoline ring (I) and the other with the carbonyl group oriented in the reverse direction (II); 3) the approach of the olefin to the copper-carbene intermediate bows the chelate Cu(I) complex to two different boat conformations, either towards the alkyl group of the oxazoline 40 ring (Λ) or in the opposite direction (V); 4) finally, the nucleophilic attack of the incoming olefin can take place by the Re and Si faces of the Cu(I)-carbene plane, which determines the absolute configuration of the carbon bearing the ester group in the resulting cyclopropanes. Scheme 4 45 summarizes the different approximations of the olefin and conformers considered in the calculations, that is, four starting carbenes (15) and sixteen transition structures (ts15) overall for each aza-pyox(R 1 ,R 2 ) ligand). The theoretical ratio of cyclopropane products was calculated 50 through the energy of the different diastereomeric transition states using a Maxwell-Boltzmann distribution.…”

“…The reaction 15 was monitored by gas chromatography with SPB and Cyclodex-β columns. After total consumption of the diazoacetate the solid catalyst was filtered off.…”