Soai reaction, asymmetric autocatalysis

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. 

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,... 

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... 

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 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. 

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. 

This is easily demonstrated in what Soai calls practically perfect asymmetric autocatalysis with the special aldehyde 221 using 20mol% of the previously prepared product 222 as catalyst and enough i-Pr2Zn to allow for the conversion of the catalyst to the zinc alkoxide. There is considerable amplification if the catalyst 222 has 5.5% ee, the product (also 222) is 70% ee. But if enantiomerically pure catalyst is used, the yield and the ee of the product are practically perfect. Each molecule of catalyst produces five molecules of itself as product. The amplification factor is six and if the whole of the product is used in a second reaction with five times as much aldehyde a second batch of 222, 36 times as much, is the product.51... 

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. 

J. M. Brown, I. Gridnev and J. Klankermayer, Asymmetric Autocatalysis with Organozinc Complexes Elucidation of the Reaction Pathway , in Topics in Current Chemistry, ed. K. Soai, Springer GmbH, 2008, vol. 284, Amplification of Chirahty, p. 35. 

In 1953, Frank developed a mathematical model showing that spontaneous asymmetric synthesis is theoretically possible (21). If the chiral product of a catalytic reaction would act as a catalyst for its own formation and at the same time suppress the formation of its enantiomer, a basically enantiopirre product could be formed from near-racemic starling materials. About forty years later, Soai and coworkers provided the first experimental proof for this concept of asymmetric autocatalysis with the alkylation of pyrimidyl aldehydes with diallgrlzinc reagents (Figure 1) (22). 

Figure 1. Asymmetric autocatalysis in the Soai reaction. R =H, Me, C=CtBu.

A transient alkoxyacetal intermediate formed by 1 2 combination of (40) and (41) has been observed by NMR for reaction of /-Pr2Zn with (40) promoted by Soai asymmetric autocatalysis by (41) (Scheme 29)... 

As if this were not enough, Soai et al. [4] also used this system to demonstrate for the first time the asymmetric amplification during autocatalysis that is inherent in the Frank model. Thus 20 mol% of (S)-9b with an ee of only 2% gave, with autocatalysis, (S)-9b with an ee of 10%. In further reaction cycles the enantiomeric excess rose from 10 through 57 to 81 and finally to 88% (Fig. 1). There was a 942-fold increase in the amount of product after four cycles. The asymmetric amplification shown by this simple selfrepli-cating system behaved, in fact, as predicted by the simple, theoretical Frank model. [18]... 

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]. 

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