Positive nonlinear effect, asymmetric

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. 

It has recently been found that Et2Zn promotes the 1,3-dipolar cycloaddition of nitrile oxides to allyl alcohol in the presence of catalytic amounts of diisopropyl tartrate (DIPT). By this method, 2-isoxazlines are obtained in good yields and up to 96% ee (Eq. 8.73).124a A positive nonlinear effect (amplification of ee of the product) has been observed in this reaction. There is an excellent review on positive and negative nonlinear effects in asymmetric induction.124b... 

The expression positive nonlinear effect reflects the fact that the observed ee (eCprod) is higher then the expected ee (eeiinear) calculated on the basis of Eq. (7.1). For example, let us consider an enantiopure catalyst that generates a product of 60% ee (eemax)- If the ligand is of 50% ee (eeaux), one now calculates eeprod = 30%. If instead the reaction provides a product of 58% ee, this can be considered as an excellent case of asymmetric amplification. 

Recently, examples of catalytic asymmetric synthesis have been reported in which the enantiomeric purity of the product is much higher than that of the chiral catalyst. A positive nonlinear effect, that is, asymmetric amplification, is synthetically useful because a chiral catalyst of high enantiopurity is not needed to prepare a chiral product with high enantiomeric excess (% ee) (Scheme 9.1). 

In the case of proline-catalyzed a-amination of aldehydes, the generally accepted catalytic cycle presented in Scheme 2.25 does not seem detailed enough to explain some of the results obtained for this particular transformation by Black-mond and co-workers [9]. In fact, their studies revealed product acceleration, a positive nonlinear effect, and asymmetric amplification. These properties of the... 

The formation of 64 using catalyst (S,S)-62 exhibits a positive nonlinear effect, fitting well with Kagan s two ligand model [78] whereas the more hindered catalyst (S,S)-63 led to a perfect linear asymmetric induction suggesting that the product arose from a transition structure involving only one chiral phosphoramide. The kinetic study of this aldol reaction is in accordance with these re-... 

It was established for several examples that it was possible to observe some departure from the expected proportionality between the enantiomeric excess of the catalyst and the enantiomeric excess of the product. Nonlinear effects (NLE) are categorized as a positive nonlinear effect ((-i-)-NLE) if the curve ee(product) = f(ee(catalyst)) is above the straight line characterizing the expected proportionality between ee(product) and ee(catalyst). The (-i-)-NLE has also been named asymmetric amplification [92]. A negative nonlinear effect ((-)-NLE) means that the experimental curve ee(product) =f( ee(catalyst)) lies below the straight line of the linear correlation. The departure from linearity reflects the formation of diastereomeric species (catalytically active or not) which perturb the predictions based only on mixture of enantiomeric catalysts and the... 

Mikami and coworkers conducted the Diels-Alder reaction with a catalyst prepared by mixing enantiomerically pure R)-56 and racemic 56 and observed a positive nonlinear effect however, they found no asymmetric amplification when they prepared the catalyst by mixing enantiomerically pure R)-56 and enantiomerically pure (S)-56 (i.e., linear correlation between catalyst and product ee). Introduction of molecular sieves restores the asymmetric amplification in the latter case, apparently by equilibration of R) R) and (S)(S) dimers into catalytically less active R) S) dimers. As expected, the reaction rate was faster for R)-56 than for ( )-56 derived from racemic binaphthol hgand ca. 5-fold faster). 

It was also suggested that aggregation of the catalysts influenced the selectiv-ities in the Diels-Alder reactions, and the reaction of 3-(2-butenoyl)-l,3-oxazo-lidin-2-one with cyclopentadiene using ( R)-(+)-binaphthol in lower enantiomeric excesses was examined [84]. The results are shown in Fig. 1. Very interestingly, a positive nonlinear effect was observed in the chiral Sc catalyst. In the chiral Yb catalysts, on the other hand, the effect was dependent on the additives. The extent of asymmetric induction in catalyst A did not deviate from the enantiomeric excesses of ( R)-(+)-binaphthol in the range 60-100% ee [85], while a negative nonlinear effect was observed in catalyst B. These results can be ascribed to a difference in aggregation between the Sc catalyst, Yb catalyst A, and Yb catalyst B. 

However, Lewis bases of this type are less practical than the previously described phoshoramides (Figure 21.1) and ALoxides (Figures 21.2 and 21.3) as they are commonly required in more than stoichiometric amounts. Furthermore, these chiral promoters are rarely recovered due to reduction of the sulfoxide functionality or decomposition during the reaction. A positive nonlinear effect observed in the asymmetric allylation of aldehydes using chiral sulfoxide 21.30 as a promoter suggests a transition state with two molecules of the catalyst coordinated to silicon in the carbon-carbon bond-forming event. - ... 

Positive nonlinear effects (curve 3) or negative nonlinear effect (curve 2). Line 1 represents the proportionality between ee mx and ecproduct h is arbitrarily assumed here that enantiopure chiral auxiliary gives 100% ee in the asymmetric synthesis (ref. 61). 

To avoid the intrinsic instability of cyanohydrins and their silyl ether, Saa and coworkers reported catalytic asymmetric cyanophosphonylation reaction of aldehydes with commercially available diethyl cyanophosphonate [58]. In these works, Lewis acid-Lewis base bifunctional catalyst (65) prepared by mixing BI-NOLAM ligand with amino arms as Lewis base and Et2AlCl was found to work nicely (Scheme 6.46). Since a strong positive nonlinear effect was observed in this reaction, actual catalyst is in equilibrium with some oligomeric species of the aluminum complexes. Bifunctional catalyst (65) could also catalyze cyanosilylation of... 

A simpler preparation of catalytic chiral indium complex based on BINOL ligand were reported by Shibasaki et al. in their asymmetric alkynylation of aldehydes [317]. InBrs was the Lewis acid of choice and the authors proposed a dual role for this bifunctional catalyst, both in activating the alkyne triple bond and the carbonyl moiety. These characteristics, and the inclusion of the chiral BINOL ligand into the In(III) center, had allowed the asymmetric addition of terminal alkynes to aldehydes with just the addition of a mild amine base (Figure 8.150). Positive nonlinear effect was observed with BINOL of varying optical enrichment, and thus the active catalytic species was expected by the authors to be most likely bimetallic in nature. 

During their studies on the Biginelli reactions of para-nitrobenzaldehyde, thiourea, and ethyl acetoacetate with the promotion of 10mol% of the nonenantiopure 3,3 -ditriphenylsilyl binol-derived phosphoric acid 5c in toluene, a strong positive nonlinear effect was observed. The asymmetric amplification was also found to occur in several other phosphoric acid-catalyzed reactions [14]. 

K. Mikami, Y. Motoyama, and M. Terada, Asymmetric catalysis of Diels-Alder cycloadditions by an MS-free binaphthol-titanium complex dramatic effect of MS, linear vs positive nonlinear relationship and synthetic applications, J. Am. Chem. Soc., 116 (1994) 2812-2820. 

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... 

Matsuoka, T., Harano, K., Uemura, T., Hisano, T. Hetero Diels-Alder reaction of N-acyl imines. I. The reaction of N -thiobenzoyl-N,N-dimethylformamidine with electron-deficient dienophiles. Stereochemical and mechanistic aspects. Chem. Pharm. Bull. 1993, 41, 50-54. Mikami, K., Motoyama, Y., Terada, M. Asymmetric Catalysis of Diels-Alder Cycloadditions by an MS-Free Binaphthol-Titanium Complex Dramatic Effect of MS, Linear vs Positive Nonlinear Relationship, and Synthetic Applications. J. Am. Chem. Soc. 1994, 116, 2812-2820. 

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