Positive nonlinear effects

Jacobsen developed a method employing (pybox)YbCl3 for TMSCN addition to meso-epoxides (Scheme 7.22) [46] with enantioselectivities as high as 92%. Unfortunately, the practical utility of this method is limited because low temperatures must be maintained for very long reaction times (up to seven days). This reaction displayed a second-order dependence on catalyst concentration and a positive nonlinear effect, suggesting a cooperative bimetallic mechanism analogous to that proposed for (salen)Cr-catalyzed ARO reactions (Scheme 7.5). 

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... 

As shown in Figure 4.5, a remarkably high positive nonlinear effect was observed in the La-BINOL-Ph3PO complex-catalysed epoxidation of chalcone (either with CMHP or with TBHP as an oxidant)1121, which strongly suggests that the active catalyst leading to high enantioselection does not have a monomeric structure but may exist as a thermodynamically stable dinuclear complex. 

Catalytic amounts of this addend (4 equiv relative to Cu) increase the selectivity of the allylic oxidation when TBHP is used as the oxidant. No change was observed with terf-butyl perbenzoate. This observation suggests a dichotomy in the mechanism of this reaction when using the two oxidants. Furthermore, in the absence of anthraquinone, a small negative nonlinear effect (78) is observed while in its presence, a small positive nonlinear effect appears. The reasons for this reversal are not clear, although the authors observed that low enantiopurity catalysts lead to turbid... 

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. 

The positive nonlinear effect is of great current interest. The possibility of using an enantioimpure chiral auxiliary for the preparation of a desired product in high ee... 

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... 

Interestingly, even a 5% ee of alanine gave rise to the full ICD in 34 as induced by optically pure alanine (Fig. 17c), indicating a very strong majority rule (positive nonlinear) effect between the ee of amino acids and the observed ICD intensity [88]. This noticeable chiral amplification of 34 made it possible to detect an extremely small enantiomeric imbalance in the amino... 

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. 

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... 

The catalytic process was also applied to enantioselective additions of meth-allyltributylstannane and allenyltributylstannane to aldehydes [13,14]. The methyl group of methallytin compound does not affect the chemical yield or enantioselectivity in the reaction [13]. A positive nonlinear effect was observed for... 

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. 

The topic of chiral amplification has been reviewed, but is most well understood in the alkylation of aldehydes with dialkylzinc reagents. The origin of the remarkable positive nonlinear effect is due to dimerisation of alkylzinc intermediates. In order for reaction to occur, the aldehyde must be able to coordinate to the zinc atom of the monomer (6.19). However, the monomer (6.19) is in equilibrium with the dimer (6.18). When the dimer is comprised of the two different enantiomers of aminoalcohol (heterochiral) it is particularly stable and reaction does not proceed through it. However, the dimer comprised of aminoalcohols of the... 

The titanium/BINOL catalysed ene reaction is subject to a strong positive nonlinear effect (see Section 6.1). Thus, the use of BINOL of only 33% ee still provides product (7.86) with 91% ee. Higher enantioselectivites (91-99%) in this reaction have been obtained using as little as 0.1 mol% of catalysts prepared from 2 1 molar ratios of BINOLititanium under nearly solvent-free conditions. 

Uemura et al. found that the combination Ti(OPr%/binaphthol/water in ratio 1 2 >10 acts as a catalyst for oxidation of aryl methyl sulfides into the corresponding sulfoxides by Bu OOH (see also Section 1.4.1) [159]. A mechanistic study showed that the titanium complex was a sulfoxidation catalyst (initial ee -50%) as well as a catalyst for the overoxidation into sulfones, with an enhancement of the ee of the residual sulfoxides (because the minor sulfoxide enantiomer is preferentially oxidized). In a subsequent paper, the authors reported the kinetic resolution of racemic aryl methyl sulfoxides by the same catalyst [160]. A stereoselectivity factor s of 2.6 was calculated for the kinetic resolution of racemic methyl p-tolyl sulfoxide. For example, methyl p-tolyl sulfoxide (<99% ee) could be recovered from oxidation at about 75% conversion. Using partially resolved l,l -binaphthol, a positive nonlinear effect was established. 

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. - ... 

This process, like the proline-catalyzed nitroso aldol reaction, has been shown to exhibit the unusual characteristics of a rising reaction rate and a positive nonlinear effect [31]. An autoinductive reaction resulting in selective formation of a proline-product species in the catalytic cycle, analogous to that depicted in Scheme 2.3, has been invoked by Blackmond [32] to account for these results. 

As with most of the in situ generated catalysts the structure of the catalytically active species is not rigorously known but Maruoka and co-workers did observe a peak for the p-oxo titanium dimer 71 in ESI-MS. They also demonstrate a positive nonlinear effect in the enantioselectivity when the catalyst was generated from enriched BINOL as opposed to enantiopure BESfOL. This non linear effect reinforces the hypothesis that the active catalyst contains two molecules of BINOL. 

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). 

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