Soai reaction product

The origin of the various additive effects is still unknown. However, taking into account the wide variety of chiral additives that cause effects with considerable sensitivity, it can be assumed that unspecific rather than specific interactions between the additives and species involved in the reaction mechanism of the Soai reaction take place. These may cause small but directed chiral perturbations where advantage is taken of the extraordinarily strong autocatalytic amplification capacity of the system. As already demonstrated by Singleton and Vo [36], these perturbations can be extremely small without losing its enantiomeric direction. In fact, as we describe later, the assumption of interactions between these chiral additives and the Soai reaction product itself, i.e., the autocatalytic species, could provide a tentative explanation for such effects. 

Fig. 8 Early time evolution of the R and S Soai reaction products on both sides of the stepwise transition as shown in Fig. 7. a R-trapping is dominant giving rise to enantioselectivity reversal (pro-R catalyst [X]0 = 1.55 x 10 3 M) b R-catalysis is dominant resulting in the preservation of enantioselectivity (pro-R catalyst [X]o = 1.95 x 10-3). Same initial conditions and rate parameters as in Fig. 7...

A reaction process in which the product directly increases the rate of the chemical reaction is called autocatalysis. In the present case, the reaction product plays the role of a catalyst and of a potent chiral auxiliary at the same time. Hence Soai s discovery described the first example of a chirally autocatalytic reaction in organic chemistry in which the chiral product and the chiral catalyst are identical. 

Scheme 4 Soai reaction performed under achiral initial conditions giving rise in repeated experiments to a random distribution of the product enantiomers with significant nonzero final ee-, R = t-Bu-C=C-...

Figure 1 illustrates symmetry breaking in the Soai reaction that has been clearly documented in two cases by bimodal product distributions (black and... 

As a first assumption to explain the unexpected enantioselectivity reversal, Lutz et al. proposed that the chiral and achiral additives interact to form a new dimeric species that catalyzes the formation of the opposite enantiomer of the chiral catalyst [65]. As described in a later section, the interaction between the chiral additive and the reaction product of the Soai reaction could represent a second possibility to explain the phenomenon of enantioselectivity reversal. 

Sato et al. confirmed the autocatalytic nature of the Soai reaction by showing the sigmoidal time evolution of the product formation and the acceleration of the reaction by initial addition of the pyrimidyl alkanol [19]. The authors also presented a modeling attempt by using fast pre-equilibrium... 

We have provided a possible understanding of the observed reversal of enantioselectivity [82]. Extending the minimal or alternative kinetic model, two mechanistic assumptions have been evaluated from a kinetic point of view (i) the direct interaction between the two added catalysts X (chiral) and Y (achiral) to form the dimers XX, XY, and YY, or (ii) the interaction between the added catalysts X (chiral) and Y (achiral) and the products of the Soai reaction (R and S) to form the dimers XR, XS, YR and YS (Scheme 8). 

Scheme 8 Scenarios of additive-additive or additive-product interactions that have been evaluated as the possible cause for enantioselectivity reversal in the Soai reaction in the presence of chiral and achiral additives...

The effect of enantioselectivity reversal serves as an additional experimental observation that gives a possible clue for the reaction mechanism. By the proposed additive-product interactions it was predicted that even poor stereoselectivity and discriminating capability of the catalytic additive can give rise to enantioselectivity reversal. This also gives a possible kinetic explanation for the effect of miscellaneous chiral additives in the Soai reaction and their role as potent chiral initiators. 

Abstract Theoretical models and rate equations relevant to the Soai reaction are reviewed. It is found that in production of chiral molecules from an achiral substrate autocatalytic processes can induce either enantiomeric excess (ee) amplification or chiral symmetry breaking. The former means that the final ee value is larger than the initial value but is dependent upon it, whereas the latter means the selection of a unique value of the final ee, independent of the initial value. The ee amplification takes place in an irreversible reaction such that all the substrate molecules are converted to chiral products and the reaction comes to a halt. Chiral symmetry breaking is possible when recycling processes are incorporated. Reactions become reversible and the system relaxes slowly to a unique final state. The difference between the two behaviors is apparent in the flow diagram in the phase space of chiral molecule concentrations. The ee amplification takes place when the flow terminates on a line of fixed points (or a fixed line), whereas symmetry breaking corresponds to the dissolution of the fixed line accompanied by the appearance of fixed points. The relevance of the Soai reaction to the homochirality in life is also discussed. 

We consider a production of chiral enantiomers R and S from an achiral substrate A in a closed system. Actually, in the Soai reaction, chiral molecules are produced by the reaction of two achiral reactants A and B as A + R or A + B -> S. But in a closed system a substrate of smaller amount controls... 

Fig. 3.4 The Soai reaction is shown that proceeds stepwise. The first step involves the reaction of Zinc-diisopropyl with a substituted aromatic aldehyde that yields a Zinc intermediate with low ee. The reaction product is autocatalytically amplified and has a chiral C-atom at the isopropyl group...

Direct asymmetric autocatalysis amplified the slight excess of one enantiomer, leading to the enantiopure compound by reaction with diisopropylzinc. It is widely accepted that enantiomerically enriched products must form from achiral precursors merely because of statistical fluctuations. Usually, however, enantiomeric enrichment by fluctuations is very low. Thus, an amplification process of enantiomeric enrichment is required. Detailed kinetic analysis revealed that autocatalysis and inhibition are the major players in asymmetric autocatalytic synthesis. It turned out that tetramers serve as catalyst in the Soai reaction. The transition state for the Soai reaction implicates two molecules of pyrimidine alcohols or alcoxides as the dimeric catalysts and one molecule of prochiral aldehyde substrate (Buono and Blackmond 2003). Further kinetic studies using different ratios of substrate and reagent showed that a tetramer template is used. 

Recently it has been shown that optically active quartz crystals as asymmetric inductors become very effective in autocatalytic enantioselective reactions. Soai et al. have shown that in asymmetric autocatalysis, the action of small amounts of chiral reaction products (involved in the reaction cycle) may enhance the enantioselective excess by a factor of 94 after introduction of an intermediate into the reaction. Optically active synthetic quartz crystals were used in this reaction with ratios of 1 1.9 quartz to aldehyde and 1 2.2 quartz to diisopropyl-zinc. 

Furthermore, the absolute asymmetric syntheses have been extended for reactions taking place in solution, where chiral supramolecular clusters are formed as intermediate templates. In particular, consideration should be given to the remarkable absolute autocatalytic Soai reaction in the synthesis of alcohols, where minute enantiomeric fluctuations are ampHfied from achiral reactants into products of single handedness [100, 101]. Tsogoeva and Mauksch reported absolute asymmetric transformations in the Mannish and aldol condensation reactions [102-104]. The same authors also proposed that similar spontaneous... 

In 1995 Soai et al. discovered a reaction that remains so far essentially the only straightforward example of a chemical process that leads to amplification of the catalyst chirality (Scheme 2.15). Intensive research of the properties of this entirely new phenomenon showed that it features numerous unique properties interesting both from the theoretical and practical points of view. Thus, the Soai reaction offers the possibility of bringing the optical purity of the catalyst/product to almost absolute perfection by repeated runs,i inducing the initial chirality of the sample by microscopic amounts of chiral compounds, " and even of generating scalemic samples from nonchiral precursors. " ... 

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... 

Soai et al.115 found that (.S j-pyrimidyl alcohol 141 (20% mol, 94.8% ee) catalyzed its own synthesis in a reaction between the corresponding aldehyde 140 and diisopropyl zinc. The product eventually reached 48% yield and 95.7% ee (Scheme 8-57). In a similar manner, when the reaction was carried out starting from 20% of the (S)-141 with only 2% ee, the first cycle gave the alcohol in 10% ee. Subsequent reaction cycles increased the ee up to 88%. 

In the course of the continuing study [9a,b] on the enantioselective addition of dialkylzincs to aldehydes by using chiral amino alcohols such as diphenyl(l-methyl-2-pyrrolidinyl)methanol (45) (DPMPM) [48] A. A -dibutylnorephedrine 46 (DBNE) [49], and 2-pyrrolidinyl-l-phenyl-1-propanol (47) [50] as chiral catalysts, Soai et al. reacted pyridine-3-carbaldehyde (48) with dialkylzincs using (lS,2/ )-DBNE 46, which gave the corresponding chiral pyridyl alkanols 49 with 74-86% ee (Scheme 9.24) [51]. The reaction with aldehyde 48 proceeded more rapidly (1 h) than that with benzaldehyde (16 h), which indicates that the product (zinc alkoxide of pyridyl alkanol) also catalyzes the reaction to produce itself. This observation led them to search for an asymmetric autocatalysis by using chiral pyridyl alkanol. 

It is explicit in the definition and formulation of NLEs that an enantio-selective reaction where the product catalyses its own formation will be subject to the same rules autocatalysis can hence both breed and amplify chirality (Fig. 2). Up to late 1995 examples were lacking, until the work of Soai... 

The conformational distinction between homo- and heterochiral dimers indicates why a bulky dialkylzinc may be important in limiting the scope of amplifying auto catalysis the Soai prescription remains unique. Since it is the product of reaction that is also the catalyst, a further question needs to be addressed. In the conventional Oguni-Noyori reaction discussed earlier [60-71] the zinc alkoxide product normally plays no further part in the proceedings because it forms a stable cubic tetramer [81-87]. There are scattered exceptions in zinc-mediated catalysis, arising when the product structure is conducive to its further involvement [88,89]. 

Soai and co-workers have developed additions of diisopropylzinc to 2-alkynylpyrimidyl-5-carbaldehydes. The resulting alcohol allows a practically perfect asymmetric autocatalysis.216 Recently, they reported that an efficient amplification by a catalyst with as low as 10 5%ee gives practically enantiomerically pure (>99.5%ee) product in only three consecutive cycles.217 The product formed in situ with enhanced ee serves as an asymmetric autocatalyst. Thus, addition of diisopropylzinc to the carbaldehyde 64 in presence of 20 mol% of the alkanol (61-65 with 10 s% ee gives after 1.5 h (6)-65 with 57% ee. A new addition of the mixture diisopropylzinc/carbaldehyde 64 to the reaction... 

Whereas the Soai system does not develop intrinsic spontaneous asymmetry (the ee in an undoped Soai system, which pretends to do so, is not statistical, and therefore the appearance of asymmetry is attributed to the action of a chiral impurity [15]), Asakura et al. report random variations of ee values (up to 4- or — 25-30%) in the creation of asymmetry by chiral autocatalysis in the reaction of a trinuclear Co complex with ammonium bromide [142]. The authors propose a stochastic model. The reactions quickly reach a state of supersaturation of the racemic chiral product, and enantiopure autocatalytic clusters of 10 and more product molecules are formed, which tips the reaction to one enantiomeric side. 

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