Theoretical (DFT) Insights into the Mechanism of Copper-Catalyzed Cyclopropanation Reactions. Implications for Enantioselective Catalysis

Abstract

The mechanism of the copper(I)-catalyzed cyclopropanation reaction has been extensively investigated for a medium-size reaction model by means of B3LYP/6-31G(d) calculations. The starting ethylene complex of the N,N'-dimethylmalonaldiimine--copper (I) catalyst undergoes a ligand exchange with methyl diazoacetate to yield a reaction intermediate, which subsequently undergoes nitrogen extrusion to generate a copper--carbene complex. The cyclopropanation step takes place through a direct carbene insertion of the metal--carbene species to yield a catalyst--product complex, which can finally regenerate the starting complex. The stereochemical predictions of a more realistic model (by considering a chiral bis(oxazoline)--copper (I) catalyst) have been rationalized in terms of steric repulsions, showing good agreement with experimental data.

Enantioselective synthesis of (−)-paeonilide

“…Calculations 66 and Hammett studies 67 support the addition of a very reactive metalcarbene intermediate in the early transition state to the substrate in a concerted, yet strongly asynchronous pathway with a cationic substrate character on one alkene carbon. This is represented by transition state A, rather than in the metallacyclobutane B (Scheme 15).…”

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.…”

“…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.…”

Synthesis of DEFG ring system of cneorins

“…10 Some mechanistic studies of the intermolecular copper(I)-catalyzed cyclopropanations have also been published. [12][13][14] The intramolecular cyclopropanation of diazomalonates of type A in Scheme 2 (a 1,1-disubstituted olefin) is unprecedented in the literature, although there are earlier examples of both 1,2-disubstituted and even 1,2,2-trisubstituted olefins being cyclopropanated with copper catalysts. 8 Scheme 2.…”