Nonlinear Effect in Asymmetric Catalysis

Laboratoire de Catalyse Moleculaire, Institut de Chimie Moleculaire et des Materiaux d Orsay (CNRS UMR 8182), Universite Paris-Sud, Orsay, France 

Since the early times of stereochemistry, the phenomena related to chirality ( dis-symetrie moleculaire, as originally stated by Pasteur) have been treated or referred to as enantiomericaUy pure compounds. For a long time the measurement of specific rotations has been the only tool to evaluate the enantiomer distribution of an enantioimpure sample hence the expressions optical purity and optical antipodes. The usefulness of chiral assistance (natural products, circularly polarized light, etc.) for the preparation of optically active compounds, by either resolution or asymmetric synthesis, has been recognized by Pasteur, Le Bel, and van t Hoff. The first chiral auxiliaries selected for asymmetric synthesis were alkaloids such as quinine or some terpenes. Natural products with several asymmetric centers are usually enantiopure or close to 100% ee. With the necessity to devise new routes to enantiopure compounds, many simple or complex auxiliaries have been prepared from natural products or from resolved materials. Often the authors tried to get the highest enantiomeric excess values possible for the chiral auxiliaries before using them for asymmetric reactions. When a chiral reagent or catalyst could not be prepared enantiomericaUy pure, the enantiomeric excess (ee) of the product was assumed to be a minimum value or was corrected by the ee of the chiral auxiliary. The experimental data measured by polarimetry or spectroscopic methods are conveniently expressed by enantiomeric excess and enantiomeric 

New Frontiers in Asymmetric Catalysis, Edited by Koichi Mikami and Mark Lautens Copyright 2007 John Wiley Sons, Inc. 

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D. G. Blackmond, Kinetic Aspects of Nonlinear Effects in Asymmetric Catalysis, Acc. Chem. Res. 2000, 33, 402—411. 

H. B. Kagan, Nonlinear Effects in Asymmetric Catalysis A Personal Account, Synlett 2001, 888-899. 

Recently, the concept of kinetic resolution has been extended to the case where enantioimpure catalysts are used. Kagan discovered the first examples of nonlinear effects in asymmetric catalysis, where there was no proportionality between the ee of the auxiliary and the ee of product (Figure 5.27) and gave some mathematical models to discuss these effects. The nonlinear effect (NLE) originates from the formation of diastereomeric species when the chiral auxiliary is not enantiomerically pure, either inside or outside the catalytic cycle. The observed effects were classified as (+)-NLE and (-)-NLE where "asymmetric amplification" and "asymmetric depletion" respectively occured. 

Figure 5.27. Illustration of nonlinear effects in asymmetric catalysis...

Figure 5.29. ML2 model in asymmetric catalysis (H.B. Kagan, Nonlinear effects in asymmetric catalysis a personal account, Synlett SI (2001) 888).

The parameters K and g give information about the relative distribution of ligands between the three complexes. Eq. (5.128) provides a description of the nonlinear effect in asymmetric catalysis (Figure 5.30). 

Kagan, H.B., Girard, C., Gillaneux, D., Rainford, D., Samuel, O., Zhang, S.Y., Zhao, S.H. (1996) Nonlinear effects in asymmetric catalysis some recent aspects, Acta Chem. Scand. 50, 345-352. 

Blackmond, D.G. (1997) Mathematical models of nonlinear effects in asymmetric catalysis new insights based on the role of reaction rate, J. Amer. Chem. Soc., 119, 12934-12939. 

Asymmetric synthesis has emerged as a major preparative method, widely used in organic chemistry and in the total synthesis of natural products, and which is also of interest for industrial chemistry. The importance of enantiomerically pure compounds is connected with the applications in pharmaceutical industries, since very often the biological activity is strongly linked to the absolute configuration. In this article the historical developments of asymmetric synthesis will be briefly presented, as well as the main methods to prepare enantiomerically enriched compounds. Then recent asymmetric synthesis of two classes of compounds will be discussed i) Sulfoxides, chiral at sulfur ii) Ferrocenes with planar chirality. The last part of the article will be devoted to asymmetric catalysis with transition-metal complexes. The cases of asymmetric oxidation of sulfides to sulfoxides and nonlinear effects in asymmetric catalysis will be mainly considered. 

New catalytic systems are being continually introduced into organic chemistry. In particular, more and more catalytic applications are directed towards the use of chiral ligands, the synthesis of optically active compounds being a constant challenge for the pharmaceutical industry. In the latter area, the discovery of the nonlinear effect in asymmetric catalysis by Kagan represented a particularly important breakthrough. 

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