Asymmetric amplification activation

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. 

Feringa reported an enantioselective allylic oxidation of cyclohexene to optically active 2-cyclohexenyl propionate 25 by using a chiral copper complex prepared from Cu(OAc)2 and (S)-proline, as chiral catalyst (Scheme 9.14) [32], In the absence of additives, a negative NLE was observed, whereas in the presence of a catalytic amount of anthraquinone, a positive NLE (asymmetric amplification) was observed. Moreover, higher enantioselectiv-ity was attained when enantiopure (S)-proline was used. However, the role of the additive remains elusive. 

As described in the preceding sections, asymmetric amplification is generally a consequence of the formation of aggregates (i.e., dimers or oligomers that are homochiral or heterochiral) of a chiral catalyst. However, even a racemic catalyst can be used as a chiral catalyst with the aid of chiral additives (a simple model consisting of dimers is depicted in Scheme 9.17). If a chiral additive (R)-B is selectively associated with (S)-A in the racemic catalyst, the remaining (R)-A could operate as the chiral monomer catalyst (asymmetric deactivation). Conversely, the chiral additive (/ )-B can be selectively associated with (/ )-A in racemic catalyst to generate an active dimeric catalyst (asymmetric activation). 

VII. Asymmetric amplification in chiral poisoning or chiral activation of a racemic catalyst... 

The asymmetric amplification is a consequence of an in situ increase in the ee of the active catalyst, since racemic ligand is trapped in the unreactive or weakly reactive meso catalyst. In the reservoir effect a similar phenomenon occurs outside the catalytic cycle. Let us assume that part of the initial chiral ligand, characterized by eeaux, is diverted into a set of catalytically inactive complexes (Scheme 12). 

The most fully understood system in this class of reactions, however, is the DAIB-catalyzed addition of diethylzinc to aldehydes, due to the very detailed mechanistic studies performed by Noyori et al.32-37 They were able to determine the structure of several intermediates involved in the reaction and established the kinetic law. Part of the catalytic cycle is depicted in Scheme 13. The origin of the asymmetric amplification lies in the formation of dimers of DAIB-zinc alkoxides. The heterochiral dimer is quite stable in the concentration range of the experiment (2 x 10 1 to 5 x 10 1 M in toluene for DAIB), whereas the homodimers are prone to dissociation and react further with diethylzinc to give a di-zinc complex that is the active species in the catalytic cycle. They react with benzaldehyde and give rise to the asymmetric transfer of the ethyl group. The final product, as a zinc alkoxide, does not interfere with the reaction (and hence there is no autoinduction), since it... 

VII. ASYMMETRIC AMPLIFICATION IN CHIRAL POISONING OR CHIRAL ACTIVATION OF A RACEMIC CATALYST... 

The mechanism of the polyleucine-catalyzed epoxidation is still under investigation [74]. Kinetic studies indicate that the reaction proceeds via the reversible addition of chalcone to a polyleucine-bound hydroperoxide [75]. Recent discussions have included studies of asymmetric amplification polyleucine derived from non-enantiopure amino acid shows highly amplified epoxide enantiomeric excess, and the results fit a mathematical model requiring the active catalyst to have five terminal homochiral residues, as rationalized by molecular modeling studies [76]. 

Oguni has reported asymmetric amplification [12] ((-i-)-NLE) in an asymmetric carbonyl addition reaction of dialkylzinc reagents catalyzed by chiral ami-noalcohols such as l-piperidino-3,3-dimethyl-2-butanol (PDB) (Eq. (7.1)) [13]. Noyori et al. have reported a highly efficient aminoalcohol catalyst, 2S)-3-exo-(dimethylamino)isobomeol (DAIB) [14] and a beautiful investigation of asymmetric amplification in view of the stability and lower catalytic activity of the het-ero-chiral dimer of the zinc aminoalcohol catalyst than the homo-chiral dimer (Fig. 7-5). We have reported a positive non-linear effect in a carbonyl-ene reaction [15] with glyoxylate catalyzed by binaphthol (binol)-derived chiral titanium complex (Eq. (7.2)) [10]. Bolm has also reported (-i-)-NLE in the 1,4-addition reaction of dialkylzinc by the catalysis of nickel complex with pyridyl alcohols [16]. 

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). 

Related concepts asymmetric amplification chiral poisoning asymmetric activation... 

In the enantioselective addition of diethylzinc to aldehydes catalyzed by nonracemic amino alcohols, the phenomenon named asymmetric amplification has been well recognized as a consequence of an in situ increase in the enantiopurity of the active catalyst, as the racemic ligand is trapped in the more stable, unreactive meso species [3, 11]. Although the reaction will definitely give racemic product if only racemic Hgands are used alone, the addition of an easily accessible alternative... 

In all these cases, provided that the reaction is under kinetic control, the proportion of predominant isomer found in the product (whether enantiomeric or diastereoisomeric) is determined by the difference in the free energies of activation of the irreversible steps leading to the alternative diastereoisomeric transition states. In each of the cases noted above, the text gives some amplification of the factors which determine these differences in free energy of activation and, it is hoped, should provide an introduction to the philosophy of asymmetric synthesis. However, a few further general comments may be helpful. 

Spontaneous asymmetric synthesis has been envisaged by theoretical models for more than 50 years [1-7]. This process features the generation and amplification of optical activity during the course of a chemical reaction. It stands in contrast to asymmetric procedures, such as stoichiometric resolution, conglomerate crystallization, or chiral chromatography, in which the optical activity can be increased but no additional chiral product is formed [8]. It is also different from classical asymmetric synthesis, in which new chiral product is obtained but the resulting enantiomeric excess (ee) is usually less than or, at most, equal to that of the chiral initiator or catalyst1. 

It was soon recognized that in specific cases of asymmetric synthesis the relation between the ee of a chiral auxiliary and the ee of the product can deviate from linearity [17,18,72 - 74]. These so-called nonlinear effects (NLE) in asymmetric synthesis, in which the achievable eeprod becomes higher than the eeaux> represent chiral amplification while the opposite case represents chiral depletion. A variety of NLE have been found in asymmetric syntheses involving the interaction between organometallic compounds and chiral ligands to form enantioselective catalysts [74]. NLE reflect the complexity of the reaction mechanism involved and are usually caused by the association between chiral molecules during the course of the reaction. This leads to the formation of diastereoisomeric species (e.g., homochiral and heterochiral dimers) with possibly different relative quantities due to distinct kinetics of formation and thermodynamic stabilities, and also because of different catalytic activities. 

---