Racemic catalysts, 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. 

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). 

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

Asymmetric amplification is the direct consequence of species of racemic composition being stable and of low reactivity. It should be found in all reactions dealing with chiral auxiliaries. One can expect such a phenomenon in diastereo-selective reactions performed on chiral substrates (e.g., reduction of a keto steroid by a chiral catalyst) or kinetic resolution, a hypothesis that has just recently been confirmed.82-83... 

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 strange thing is that catalysts of low enantiomeric excess, even as low as 0.1% ee, induce asymmetry of a much higher order (here 95%). This asymmetric amplification is particularly intriguing since ees of about 0.1% can be produced by irradiating racemic leucine with circularly polarised light. The true catalyst in these reactions is the zinc alkoxide 220 of the product. The initiators as they are better known, such as leucine, merely create a small amount of this true catalyst.50... 

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). 

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 principle, three approaches may be adopted for obtaining an enantio-merically pure compound. These are resolution of a racemic mixture, stereoselective synthesis starting from a chiral building block, and conversion of a prochiral substrate into a chiral product by asymmetric catalysis. The last approach, since it is catalytic, means an amplification of chirality that is, one molecule of a chiral catalyst produces several hundred or a thousand molecules of the chiral product from a starting material that is optically inactive In the past two decades this strategy has proved to be extremely useful for the commercial manufacture of a number of intermediates for biologically active compounds. A few recent examples are given in Table 9.1. 

The aldol reaction of a silyl enol ether proceeds in a double and two-directional fashion, upon addition of an excess amount of an aldehyde, to give the silyl enol ether in 77 % isolated yield and more than 99 % ee and 99 % de (Sch. 33) [92]. This asymmetric catalytic aldol reaction is characterized by kinetic amplification of product chirality on going from the one-directional aldol intermediate to the two-directional product. Further transformation of the pseudo C2 symmetric product still protected as the silyl enol ether leads to a potent analog of an HIV protease inhibitor. Kinetic resolution of racemic silyl enol ethers by the BINOL-Ti catalyst (1) has been reported by French chemists [93]. 

This result supports the view that diverse ways exist to obtain chiral biomolecules via CPL or chiral inorganic or organic crystals combined with asymmetric autoctalysis. Kenso Soai and his team studied the effect of the structure of the substituents at position 2 of the pyrimidyl alkanol (Shibata et al. 1996). They found that using 2-alkynyl-pyrimidyl alkanol after three rounds of asymmetric autocatalysis, an astonishing amplification factor of 630,0000 was reached. In the reaction, either (+) or (—) crystals of Cytosine serve as initiators that were formed spontaneously by stirring. In the Soai reaction of chiral amplification, it is crucial that dimers of the O-Zinc diisopropyl intermediate are the active catalysts Racemic pyrimidine alcohols subjected to photolysis with either right- or left-handed CPL produced an ee of one isomer as shown in Fig. 3.4. 

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