Chirality amplification catalytic reactions

Chirality amplification, 11,255 catalytic reactions, 289 DAIB complexes, 273 mechanism, 275 organozinc chemistry, 273 Chirality multiplication, 2... 

Amplification of Chirality. Perhaps the most striking of the nonclas-sical aspects that emerge from the enantioselective alkylation is the phenomenon illustrated in Scheme 22 (3, 14, 16, 20k, 40). A prominent nonlinear relation that allows for catalytic chiral amplification exists between the enantiomeric purity of the chiral auxiliary and the enantiomeric purity of the methylation or ethylation product (Scheme 23). Typically, when benzaldehyde and diethylzinc react in the presence of 8 mol % of (-)-DAIB of only 15% ee [(-) (+) = 57.5 42.5], the S ethylation product is obtained in 95% ee. This enantiomeric excess is close to that obtained with enantiomerically pure (—)-DAIB (98%). Evidently, chiral and achiral catalyst systems compete in the same reaction. The extent of the chiral amplification is influenced by many factors including the concentration of dialkylzincs, benzaldehyde, and chiral... 

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. 

A recent convincing case of chiral amplification opens a wide horizon in stereoselective catalysis [37 c] thus, when a 5-pyrimidyl alcohol with a small (2%) enantiomeric excess is treated with diisopropylzinc and pyrimidine-5-carboxaldehyde, it undergoes an autocatalytic reaction to generate more of the alcohol. The chiral catalyst is formed from the initial alcohol. The ee result of the (5)-isomer was successively increased in the series 2%—> 10%—>57% 81 % 89%. Amplification factors of up to ca. 1700 were recorded with the catalytic system of Scheme 2 [37 c]. This is the first case in which the enantiomeric excess of the product is greater than that of the chiral catalyst [97]. 

Non-linear effects were discovered in 1986 [5]. They are now widely recognized in many catalytic reactions, and provide a useful tool for mechanistic investigations. Moreover, they can have some practical applications. For example, in the case of asymmetric amplification it is not necessary to perform a costly complete resolution of a chiral ligand if the reaction involves a strong (-i-)-NLE. The concept of non-linearity has been extended to mixtures of diastereomeric ligands (vide supra). Finally, asymmetric amplification is very useful in reactions which display asymmetric autocatalysis, giving high levels of enantioselectivity after initiation with a catalyst of very low ee. 

Tagliavini and Umani-Ronchi found that chiral BINOL-Zr complex 9 as well as the BINOL-Ti complexes can catalyze the asymmetric allylation of aldehydes with allylic stannanes (Scheme 9) [27]. The chiral Zr catalyst 9 is prepared from (S)-BINOL and commercially available Zr(0 Pr)4 Pr0H. The reaction rate of the catalytic system is high in comparison with that of the BINOL-Ti catalyst 4, however, the Zr-catalyzed allylation reaction is sometimes accompanied by an undesired Meerwein-Ponndorf-Verley type reduction of aldehydes. The Zr complex 9 is appropriate for aromatic aldehydes to obtain high enantiomeric excess, while the Ti complex 4 is favored for aUphatic aldehydes. A chiral amplification phenomenon has, to a small extent, been observed for the chiral Zr complex-catalyzed allylation reaction of benzaldehyde. 

Chirality amplification in the proline-catalyzed a-aminoxylation of aldehydes was uncovered and analyzed by Blackmond and co-workers in 2004 [29]. These researchers found that, contrary to what happens in proline-catalyzed aldol reactions, when the reaction was carried out with non-enantiopure proline, the enantiomeric excess of the product was higher than that expected from a linear relationship, and this enantiomeric excess rose over the course of the reaction. These results were rationalized by assuming an autoinductive behavior of the a-aminoxylation product, which formed a new catalytic species via enamine formation with proline, with the additional hypothesis of a matched interaction of L-Pro with the (/ )-enantiomer of the product (Scheme 2.3). 

The high value of catalytically performed reactions as compared to non-catalytic variants is particularly evidenced in the field of enantioselective reactions. Chemists cannot complete enantioselective reactions without certain chiral information in the reacting system. This information is regularly derived from the chiral compounds present in nature, collectively named the chiral pool of the nature. Their availability is often limited, which is not an issue when they are used as catalysts, but causes significant costs of non-catalytic reactions when they are needed in equimolar quantities. The practical value of the catalytic approach to enantioselective processes cannot be overestimated. Asymmetric catalysis characterizes the amplification of chirality one chiral molecule of the catalyst generates an enormous number of chiral molecules of the product in the optically pure form. This results with high chiral economy of catalytically performed enantioselective syntheses. 

The asymmetric catalytic aldol reaction of a silyl enol ether can be performed in a double and two-directional fashion to give the 1 2 adduct in the silyl enol ether form with >99% ee and 99% de in 77% isolated yield (Scheme 8C.25) [59]. The present catalytic asymmetric aldol reaction is characterized by a kinetic amplification phenomenon of the product chirality, going from the one-directional aldol intermediate to the two-directional product (Figure 8C.8). Further transformation of the pseudo C2 symmetric product, while still being protected as the silyl enol ether, leads to a potent analog of an HIV protease inhibitor. 

Keck reported an asymmetric allylation with a catalytic amount of chiral titanium catalyst [24]. The enantioselective addition of methallylstannane to aldehydes is promoted by a chiral catalyst 13 prepared from chiral BINOL and Ti(0-i-Pr)4 (Scheme 9.10). An example of asymmetric amplification was reported by using (R)-BINOL of 50% ee, and the degree of asymmetric amplification was dependent on the reaction temperature. Tagliavini also observed an asymmetric amplification in the enantioselective allylation with a BIN0L-Zr(0-i-Pr)2 catalyst [25]. 

This book illustrates the recent aspects of amplification of chirality by asymmetric auto catalysis and by forming helical structures. The first four chapters summarize experimental asymmetric autocatalysis with amplification of enan-tiopurity, the mechanism of asymmetric autocatalysis examined by NMR and calculation, the computer simulation models of the reaction mechanism of asymmetric auto catalysis, and the theoretical models of amplification of chirality. The last chapter deals with the amplification of chirality by the formation of helical structures. However, the amplification of enantiopurity in non-auto catalytic asymmetric reaction and the amplification by enantiomer separation involving crystallization or sublimation are beyond the scope of this book. 

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]. 

The product alcohol catalyses its own formation and the reaction shows spectacular asynunetric amplification. If small amounts of product with 5% ee are added at the beginning of the reaction, new product is formed with 55% ee. If this product is used as a catalyst in consecutive reactions, nearly enantiopure product is achieved after a few runs. Even starting with completely racemic material, the reaction product is generally produced non-racemic, with stochastically either one or the other enantiomer in excess (23). Other chiral compoimds can direct the reaction towards the selective production of one particular enantiomer as well. About any form of chiral template has been shown to induce this effect, from helical hydrocarbons to chiral quartz crystals. The mechanism of this remarkable reaction was deduced with the help of kinetic studies and involves catalytically active homochiral dimers and inactive heterochiral ones (24, 25). 

When a kinetic resolution is carried out using enantioimpure catalysts, which do not interact with one another, the reaction network must be expanded. H.I. Kagan discovered the first examples of nonlinear effects (NLEs) in asymmetric catalysis, where there was no proportionality between the ee of the auxiliary and the ee of product (Fig. 5.37) and gave some mathematical models to discuss these effects. The NLE originates from the formation of diastereomeric species when the chiral auxiliary is not enantiomericaUy pure, either inside or outside the catalytic cycle. The observed effects were classified as (+)-NLE and (—)-NLE, where "asymmetric amplification" and "asymmetric depletion" respectively occurred. 

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