Amplification, asymmetric

Reactions where NLE have been discovered include Sharpless asymmetric epoxi-dation of allylic alcohols, enantioselective oxidation of sulfides to sulfoxides, Diels-Alder and hetero-Diels-Alder reactions, carbonyl-ene reactions, addition of MesSiCN or organometallics on aldehydes, conjugated additions of organometal-lics on enones, enantioselective hydrogenations, copolymerization, and the Henry reaction. Because of the diversity of the reactions, it is more convenient to classify the examples according to the types of catalyst involved. 

Enantioselective organocatalysts were the first to be used as nonenzymatic catalysts in the early twentieth century. The literature on organocatalysts was reviewed in 2001.  

Only a few cases of nonlinear effects have been reported some are listed in Table 7.2. Most of the examples involve proline as the catalyst. Chiral phosphora-mides and some phase transfer catalysts were also reported to give NLEs. 

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 

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With the stcrically constrained /(-amino alcohols N-P asymmetric amplification phenomena were observed similar to the effects found with 3-e.Y0-(dimethylamino)isoborneol (vide supra). Thus, alkylation of benzaldehyde with diethylzinc, catalyzed by a partially resolved catalyst N-P, gives 1-phenyl-1-propanol with an enantiomeric excess, which impressively exceeds the optical purity of the catalyst employed12. 

A series of chiral p-hydroxysulfoximine ligands have been synthesised by Bolm et al. and further investigated for the enantioselective conjugate addition of ZnEt2 to various chalcone derivatives. The most eiScient sulfoximine, depicted in Scheme 2.33, has allowed an enantioselectivity of up to 72% ee to be obtained. These authors assumed a nonmonomeric nature of the active species in solution, as suggested by the asymmetric amplification in the catalysis with a sulfoximine of a low optical purity. 

Asymmetric amplification in autocatalytic additions of diisopropylzinc to some aldehydes 386... 

While investigating the reaction of ZnPf2 with pyrimidine-5-carboxaldehyde 190, the Soai group made the important discovery that these two compounds reacted in the presence of a catalytic amount of (enantiomeric purity (as low as 2%) to furnish the same alcohol as the addition product with ee s up to 89% (Scheme 106). This most remarkable finding was the first case of asymmetric amplification in autocatalytic reactions.275... 

It may not be necessary to employ an optically pure chiral ligand (BINOL) for the preparation of the catalyst because a high degree of asymmetric amplification can be expected. 

L-699,392, Merck s drug for the treatment of chronic asthma, is an example of asymmetric amplification on an industrial scale (see Figure 13.19). The ketone reduction can be carried out stoichiometrically with a borane-(-)-a-pinene reagent. The terpene natural products are often mixtures of isomers and enantiomers. A reagent prepared from 98% optically pure (-)-a-pinene gives a product e.e. of 97%, but a reagent prepared from less expensive 70% optically pure (-)-a-pinene yields a product e.e. of 95%, which can be pushed to >99.5% by using an excess [30]. 

Blackmond pointed out that asymmetric amplification always has, as a consequence, a decrease in reactivity when compared to the enantiopure catalyst. This can be calculated on the various models proposed for the interpretation of nonlinear effects. It is qualitatively visible in the reservoir model above as well as in the ML2 model, where the asymmetric amplification given by g < 1 (low reactivity of the meso catalyst) has as consequence the overall slowdown in reaction rate. The generalized model ML has been discussed (for n = 2,3,4) when the various species are in equilibrium. The complexity of the curve can increase sharply as soon as n > 2. 

Nowadays, this chemistry includes a wide range of applications. The organozinc compounds employed in the enantioselective addition include dialkylzincs, dialkenylzincs, dialkynylzincs, diarylzincs and the related unsymmetrical diorganozincs. Electrophiles have been expanded to aldehydes, ketones and imines. Asymmetric amplification has been observed in the enantioselective addition of organozincs. Recently, asymmetric autocatalysis, i.e. automultiplication of chiral compounds, has been created in organozinc addition to aldehydes. 

Much attention has been paid to asymmetric amplification where the enantiomeric excess ( ) of the product is higher than that of the chiral catalyst (equation 35)136. The first experiment on asymmetric amplification was reported by Kagan and coworkers in the Katsuki-Sharpless asymmetric epoxidation of allyl alcohols137. Asymmetric amplification has also been studied in the asymmetric addition of dialkylzincs to carbonyl compounds. 

In the enantioselective addition of diethylzinc to benzaldehyde, a wide variety of chiral catalysts 3, 4, 16, 23, 47, 66-73 exhibits asymmetric amplification (equation 36 and Table 1). 

Mechanistic studies of asymmetric amplification using a chiral amino alcohol catalyst have continued to dale"1 151 155. In the case of the chiral titanium complex, the observed asymmetric amplification was influenced by the method of preparation of the catalyst153. Asymmetric amplification is also observed in the catalytic addition of diphenylzinc to ketones100. 

TABLE 1. Asymmetric amplification in the enantioselective addition of diethylzinc to benzaldehyde... 

Enantioselective conjugate addition of diethylzinc proceeds in the presence of №( ) complex104. Asymmetric amplification was observed in reactions using chiral ligand l156, 66157, 47107 and 3 (equation 38)109. 

As described in the preceding section, asymmetric amplification has been reported in the non-autocatalytic enantioselective addition of dialkylzincs. In asymmetric autocatalysis, amplification of has a more significant role, because the product of the asymmetric autocatalysis itself is capable of acting as the asymmetric autocatalyst. Once the product, i.e. the asymmetric autocatalyst with an enhanced , is formed in the asymmetric autocatalytic reaction, the product catalyzes the formation of itself with higher . From the viewpoint of the molecule, an asymmetric autocatalyst with dominant absolute configuration catalyzes... 

Reetz et al. [53] prepared analogues of (R)-binol as ligands for the titanium complex in the presence of water under the same conditions as Uemura s mentioned above. In this study, (R)-octahydrobinol and its dinitro derivative were synthesized. The reaction using (R)-dinitro-octahydrobinol ligand gave (. S j-methyl p-tolyl sulfoxide (86% ee) [53], which makes a sharp contrast to the reaction using (R)-binol wherein (A1 (-methyl p-tolyl sulfoxide was formed [50]. It is probable that kinetic resolution is involved, giving some asymmetric amplification. 

A chiral catalyst is not necessarily in enantiopure form. Deviation from the Unear relationship, namely non-linear effect , is sometimes observed between the enantiomeric purity of the chiral catalysts and the optical yields of the products (Figure 8C.2). The convex deviation—which Kagan [35a] andMikami [36) independently refer to as positive non-linear effect (abbreviated as (+)-NLE) and what Oguni refers to as [35c] asymmetric amplification —is currently attracting much attention for achieving a higher level of asymmetric induction that exceeds the enantiopurity of the non-racemic (partially resolved) catalysts. In turn, (-)-NLE stands for the opposite phenomenon of concave deviation, namely negative non-linear effect. 

In an effort to develop new chiral BINOL-Ti complexes, chemical modifications of the chiral complex (f )-BINOL-Ti(OPr )2 (R-2) that can easily be prepared by simply mixing ( PrO)4Ti and (/ )-BINOL in the absence ofMS4A have been studied [37c-e]. A dimeric form has been reported for the single-crystal X-ray structure of complex R-2 [38], (I )-BINOL-Ti-p3-oxo complex, prepared via hydrolysis of complex R-2 has been shown to serve as an efficient and moisture-tolerable asymmetric catalyst [37d,e]. It is noteworthy that the (/ )-BINOL-Ti-)i3-oxo catalyst [37e] shows a remarkable level of (+)-NLE (asymmetric amplification), thereby attaining the maximum enantioselectivity for this system by using (/ )-BINOL with only 55-60% ee as the chiral source (consult Scheme 8C. 14). 

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