Soai autocatalysis

One striking example mentioned in this final chapter requires us to bend the term racemate, to include very near racemates that contain a very small enantiomeric excess. Enrichment of such samples by direct crystallization-based methods would typically only be attempted by committed optimists. In such a situation, we could synthesize more of the excess enantiomer preferentially if we had an appropriately asymmetric autocatalytic reaction - our initial excess enantiomer could replicate at the expense of the other. Preparatively, this is the effective separation of the enantiomers we used at the outset. Such a system has its physical realization in the Soai autocatalysis in which a very small enantiomeric excess of a pyrimidyl alcohol is amplified over several cycles to give an almost enantiopure sample of the alcohol (Scheme 1.10) [19]. 

Soai et al. established highly enantioselective asymmetric autocatalysis in the asymmetric isopropylation of pyrimidine-5-carbaldehyde 27 (Scheme 14) [44], quinoline-3-carbaldehyde [45], and 5-carbamoylpyridine-3-carbaldehyde [46]. Among these, 2-alkynyl-5-pyrimidyl alkanol is a practically perfect asymmetric autocatalysis [47]. When 0.2 equivalents of 2-alkynyl-5-pyrimidyl alkanol 28b with >99.5% ee was employed as an asymmetric autocatalyst in the isopropylation of 2-alkynylpyrimidine-5-carbaldehyde 27b, it automultiplies in a yield of >99% without any loss of ee (>99.5% ee). When the product was used as an asymmetric autocatalyst for the next run, pyrimidyl alkanol 28b with >99.5% ee was obtained in >99%. Even after tenth round, pyrimidyl alkanol 28b with >99.5% ee was formed in a yield of >99% [47]. 

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. 

Soai K, Shibata T (1999) Asymmetric autocatalysis and biomolecular chirality In Palyi G, Zucchi C, Caglioti L (eds) Advances in biochirality, chap 11. Elsevier, Oxford, p 125... 

Soai K Shibata T (2000) Asymmetric amplification and autocatalysis In Ojima I (ed) Catalytic asymmetric synthesis, 2nd ed, chap 9. Wiley-VCH, New York, p 699... 

Soai K, Sato I, Shibata T (2004) Asymmetric autocatalysis and the origin of homochirality of biomolecules. In Malhotra SV (ed) Methodologies in asymmetric catalysis. J Am Chem Soc, Washington, DC, p 85... 

Fig. 3 Basis of the Soai amplifying autocatalysis illustrated by a two-stage procedure...

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 key NMR observations (i) that the proportion of homo- and heterochiral dimers is near-equal, and (ii) that their interconversion by a dissociative process is rapid compared to catalytic turnover, preclude the possibility of a monomer autocatalyst. In Kagan s classification, monomer catalysis with a positive NLE may only arise when there is an unequal concentration of homo- and heterochiral oligomers, in favour of the heterochiral form, which acts as a reservoir for the deficient enantiomer. NMR results show that the resting state for Soai s autocatalysis is an equal mixture of homo-and heterochiral species, predominantly dimeric. The lack of ground-state stereo-discrimination requires that the number of chiral entities in the resting state must be less than or equal to the number in the enantioselectivity-determining transition state, else there is no possibility of the vital non-linear effect. Even after the publication of these results in late 2004, their consequences are not always applied. For recent discussions where a monomeric catalyst for Soai s system is permitted or promoted, see [91-93]. 

Abstract The addition of diisopropylzinc to prochiral pyrimidine carbaldehydes (Soai reaction) is the only known example of spontaneous asymmetric synthesis in organic chemistry. It serves as a model system for the spontaneous occurrence of chiral asymmetry from achiral initial conditions. This review describes the possible kinetic origin of specific experimental features of this reaction. It is shown that generic kinetic models, including enantioselective autocatalysis and mutual inhibition between the enantiomers,... 

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. 

The presence of N-atoms in the aromatic part of the aldehyde appears essential for chiral amplification. With only one nitrogen, such as in the case of 3-pyridine carbaldehyde, autocatalytic kinetics but no chiral amplification effect has been observed [24,25]. In the case of 3-quinoline carbaldehyde, i.e., in the presence of two nucleophilic centers, autocatalysis as well as moderate chiral amplification were reported [26,27]. Highest amplification capacity is observed in the presence of two N-atoms in the aromatic part of the aldehyde, where for the substituent at the 2-position the amplification capacity increases H < CH3 < f- Bu - C=C -, i.e., with the size and rigidity of this group. So far, detailed studies that could relate the given observations to the possible mechanism of chiral amplification in Soai s reaction are still to be carried out. 

The results of Soai and coworkers [35] as well as those of Singleton and Vo [36] suggest the occurrence of mirror-symmetry breaking in the Soai reaction, which is a rare phenomenon that is basically limited to a few crystallization processes [37]. Under certain kinetic conditions, chiral autocatalysis... 

Commenting their discovery of the first case of chiral autocatalysis in organic chemistry, Soai et al. stated that it seems conceivable that the [Soai] reaction. .. may be an example of the scheme proposed by Frank [9]. Indeed, the so-called Frank model that has been developed in 1953 predicts the spontaneous amplification of an initial enantiomeric excess by means of a simple set of coupled differential equations [1] ... 

We have given kinetic insight into a number of experimental features of the Soai reaction. It was shown that chiral amplification and mirror-symmetry breaking are driven by a reaction network that contains enantioselective autocatalysis and mutual inhibition as the essential ingredients. In this sense, the Soai reaction moves the early concepts of Frank forward into experimental reality. Taking into account the formation of isopropylzinc alkoxide dimers, an evaluation of the parameter space in which amplification and symmetrybreaking are observed indicates that the heterochiral dimers display a higher thermodynamic stability and have to be formed faster than the homochiral ones. The necessity of such sensitive interplay may explain why such reactions systems are so scarce. 

Keywords Flow trajectory Homochirality Nonlinear autocatalysis Recycling Soai reaction... 

In all the cases considered, auto catalytic processes must be present, whether linear or nonlinear. To understand the actual mechanism of autocatalysis for the Soai reaction, identification of the process at a molecular level is necessary, but is out of scope of the present review. 

Soai K, Kawasaki T (2008) Asymmetric Autocatalysis with Amplification of Chirality. 284 1-33... 

Examples of asymmetric autocatalysis are difficult to find. Only quite recently have Soai et al. shown that a catalyzed diorganozinc addition to aldehydes may be... 

K. Soai, T. Shibata, Asymmetric Amplification and Autocatalysis, in Catalytic Asymmetric Synthesis (I. Ojima, Ed.), Wiley-VCH, New York, 2nd ed., 2000, 699-726. 

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. 

In 1995, Soai and coworkers reported a highly enantiose-lective asymmetric autocatalysis of pyrimidyl alkanol in the enantioselective addition reaction of I-Pr2Zn to pyrimidine-5-carboxaldehyde (equation 63). When a 5-pyrimidyl alkanol with a small enantiomeric excess such as 5x10 % is added to j-Pr2Zn and pyrimidine-5-carboxaldehyde, then the reaction... 

Soai, K. Shibata, T. Sato, I. Enantioselective Automultiplication of Chiral Molecules by Asymmetric Autocatalysis, Acc. Chem. Res. 2000,55, 382-390. 

Soai, K. Asymmetric Autocatalysis and Biomolecular Chirality, Adv. Biochirality, Palyi, G. Zucchi, C. Caglioti, L., Eds. Elsevier Amsterdam, The Netherlands, 1999. 

Soai has reported the remarkable example of asymmetric autocatalysis in carbonyl-addition reactions of diisopropylzinc [40- 3, 45]. Usually, zinc alkoxide forms an inactive tetramer. However, the use of pyridyl aldehyde as a substrate to give pyridyl alcohol product can loop the catalytic cycle without formation of the inac-... 

Soai et al. discovered and developed asymmetric autocatalysis (Figure 9), in which the structures of the chiral catalyst (5)-54 and the chiral product (5)-54 are the same after the addition of diisopropylzinc to aldehyde 53. Consecutive asymmetric autocatalysis starting with (S)-54 of 0.6% ee amplifies its ee, and yields itself as the product with >99.5% ee. Even chiral inorganic crystals, such as quartz or sodium chlorate, act as chiral inducers in this reaction. Soai et alls asymmetric autocatalysis gives us an insight to speculate on the early asymmetric reactions on this planet Earth. However, it can be argued whether such strictly anhydrous organometallic reactions are possible under the nonartificial conditions or not. 

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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