Catalysis asymmetric, nonlinear effects

The presence of a nonlinear effect, either negative or positive, is a useful piece of information for the mechanistic study of a reaction. It implies that diastereomeric species are formed from the chiral auxiliary. If an asymmetric amplification is observed, it can be indicative of the formation of meso dimers (or tetramers etc.) of low reactivity. When the kinetic study of an asymmetric catalysis shows a rate second order with respect to catalyst concentration, it may be useful to investigate the possibility of nonlinear effects in the system. Jacobsen et al., for example, studied the... 

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. 

Experiments conducted in the mid-1980s by Agami indicated a small nonlinear effect in the asymmetric catalysis in the Hajos-Parrish-Wiechert-Eder-Sauer reaction (Scheme 6.7). Agami proposed that two proline molecules were involved in the catalysis the first proline forms an enamine with the side chain ketone and the second proline molecule facilitates a proton transfer. Hajos and Parrish reported that the proline-catalyzed cyclization shown in Scheme 6.7 did not incorporate when run in the presence of labeled water. While both of these results have since been discredited—the catalysis is first order in catalyst and is incorporated into... 

Carbonyl-Ene Reaction. BINOL-TiX2 reagent exhibits a remarkable level of asymmetric catalysis in the carbonyl-ene reaction of prochiral glyoxylates, thereby providing practical access to a-hydroxy esters. These reactions exhibit a remarkable positive nonlinear effect (asymmetric amplification) that is of practical and mechanistic importance (eq 19). The desymmetrization of prochiral ene substrates with planar symmetry by the enantiofacial selective carbonyl-ene reaction provides an efficient solution to remote internal asymmetric induction (eq 20). The kinetic resolution of a racemic allylic ether by the glyoxylate-ene reaction also provides efficient access to remote but relative asymmetric induction (eq 21). Both the dibromide and dichloride catalysts provide the (2R,5S)-syn product with 97% diastereoselectivity and >95% ee. 

Keywords Asymmetric catalysis, Asymmetric hydrogenation. Catalytic antibodies. Chiral Lewis acids. Chiral ligands. Enzymes, Organometallic catalysts. Organic catalysts. Nonlinear effects. History... 

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. 

---