Theoretical Insights into the Role of a Counterion in Copper-Catalyzed Enantioselective Cyclopropanation Reactions Josÿ M. Fraile, [a] Josÿ I. GarcÌa,* [a] MarÌa J. Gil, [b] VÌctor MartÌnez-Merino,* [b] Josÿ A. Mayoral, [a] and Luis Salvatella [a] Introduction Cyclopropane derivatives are an important family of chemi- cal compounds because of their interesting biological prop- erties [1] as well as their use as starting materials and inter- mediates in organic synthesis. [2] Great efforts have therefore been made to develop efficient diastereo- and enantioselec- tive methods for the synthesis of cyclopropanes. [3] A particu- larly versatile method is metal-catalyzed cyclopropanation of olefins with diazo compounds, for which various efficient homogeneous catalysts have been developed. The use of catalysts based on copper is particularly attrac- tive because of their high efficiency in asymmetric cyclopro- panation reactions [4] and their relatively low cost in compari- son with other metal derivatives, such as catalysts based on rhodium [5] or ruthenium. [6] Various chiral ligands have been described for the enantioselective versions of the cyclopro- panation reaction, including salicylaldimines, [7] salicylaldehy- de±amino acid derivatives, [8] and semicorrins. [9] The best re- sults have been obtained with bis(oxazolines)–described in- dependently by Evans and co-workers [10] and Masamune and co-workers [11] –which can lead to almost complete enantioselectivity (up to 99% ee) when their complexes with Cu I or Cu II are used in cyclopropanation reactions. Good performance of chiral bis(oxazolines) as ligands for asym- metric cyclopropanation, as well as for other Lewis acid cat- alyzed reactions, has resulted in the recent commercial availability of some of them. For large-scale applications, the ease of use and facile re- covery of the chiral catalysts have become important fac- tors; several studies have focused on the immobilization of chiral Cu complexes for catalytic cyclopropanation reac- tions. [12] However, in both the homogeneous [10,13] and hetero- geneous [14] phases, a dramatic dependence of the stereose- lectivity on factors such as the solvent and the counterion has been described. For instance, Evans et al. have report- [a] Dr. J. M. Fraile, Dr. J. I. GarcÌa, Dr. J. A. Mayoral, Dr. L. Salvatella Departamento de QuÌmica Orgμnica Instituto de Ciencia de Materiales de AragÛn C.S.I.C.-Universidad de Zaragoza Pedro Cerbuna 12, 50009 Zaragoza (Spain) Fax: (+ 34)976762077 E-mail: jig@unizar.es [b] Dr. M. J. Gil, Dr. V. MartÌnez-Merino Departamento de QuÌmica Aplicada Universidad PÇblica de Navarra, 31006 Pamplona (Spain) Fax: (+ 34)948169606 E-mail: merino@si.unavarra.es Supporting information for this article is available on the WWW under http://www.chemeurj.org/ or from the author. Abstract: The effect of a coordinating counteranion on the mechanism of Cu I -catalyzed cyclopropanation has been investigated extensively for a medium-sized reaction model by means of theoretical calculations at the B3LYP/6-31G(d) level. The main mechanistic features are similar to those found for the cationic (without a counteranion) mechanism, the rate-lim- iting step being nitrogen extrusion from a catalyst±diazoester complex to generate a copper±carbene intermedi- ate. The cyclopropanation step takes place through a direct carbene inser- tion of the metal±carbene species to yield a catalyst±product complex, which can finally regenerate the start- ing complex. However, the presence of the counteranion has a noticeable in- fluence on the calculated geometries of all the intermediates and transition structures. Furthermore, the existence of a preequilibrium with a dimeric form of the catalyst, together with a higher activation barrier in the inser- tion step, explains the lower yield of cyclopropane products observed exper- imentally in the presence of chloride counterion. The stereochemical predic- tions of a more realistic model (made by considering a chiral bis(oxazoline)± copper(i) catalyst) have been rational- ized in terms of the lack of significant steric repulsions, and the model shows good agreement with the low enantio- selectivities observed experimentally for these kinds of catalytic systems. Keywords: asymmetric catalysis ¥ copper ¥ cyclopropanation ¥ density functional calculations ¥ ligand effects ¥ N ligands ¹ 2004 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim DOI: 10.1002/chem.200305161 Chem. Eur. J. 2004, 10, 758 ± 765 758 FULL PAPER