Enantioselective reactions asymmetric autocatalysis

As described in the preceding section, asymmetric amplification has been reported in the non-autocatalytic enantioselective addition of dialkylzincs. In asymmetric autocatalysis, amplification of has a more significant role, because the product of the asymmetric autocatalysis itself is capable of acting as the asymmetric autocatalyst. Once the product, i.e. the asymmetric autocatalyst with an enhanced , is formed in the asymmetric autocatalytic reaction, the product catalyzes the formation of itself with higher . From the viewpoint of the molecule, an asymmetric autocatalyst with dominant absolute configuration catalyzes... 

The first asymmetric autocatalysis with amplification of was observed in the automultiplication of a 5-pyrimidyl alkanol 80 (Figure l)169. When (5)-5-pyrimidyl alkanol 80 with as low as 2% is used as the asymmetric autocatalyst for enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde 88, the of the produced pyrimidyl alkanol (and the initial asymmetric autocatalyst) 80 increases to 10% (Figure 1, 1st run). Consecutive asymmetric autocatalyses using 5-pyrimidyl alkanol 80 with 10% have increased its to 57%, 81% and 88% , successively. During the reactions, the major (S)-enantiomer in the initial asymmetric autocatalyst has automultiplied by a factor of 238, while the slightly minor (R)-enantiomer has automultiplied by a factor of only 16. 

Highly enantioselective asymmetric autocatalysis has recently been reported. In such reactions, a trace amount of chiral molecule automultiplies without the assistance of another chiral molecule. Moreover, asymmetric autocatalysis with an amplification of enantiopurity has been reported, that is, the enantiopurity of the initial chiral molecule increases from very low to very high during automultiplication. 

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. 

The results of such a high enantioselectivity in the autocatalytic reaction encouraged us to investigate the enantioselective alkylation utilizing an autocatalyst with a small enantiomeric imbalance of 2% ee. In an earlier study on asymmetric autocatalysis using other compounds as the autocatalyst, the enantiomeric excess of chiral product has always been lower than that of the chiral catalyst. However, in this pyrimidine system, we found for the first time... 

Asymmetric amplification in reactions involving partially resolved chiral auxiliaries is now a well-established phenomenon that is very attractive since it gives improved enantioselectivities witb respect to expectations based upon the ee of the auxiliary. It may have practical application in that enantiomerically pure chiral auxiliaries are not always required for highly selective asymmetric synthesis. Asymmetric amplification is also of fundamental importance in order to achieve efficient asymmetric autocatalysis. Finally, evidence of an asymmetric amplification is a very useful piece of information in mechanistic studies. 

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... 

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. 

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. 

The pyrimidyl alkanol 120 with up to 99% ee is formed with the absolute configuration corresponding to the helical chiraHty of the thiaheHcenes used as chiral inducers. The enantioselectivity observed in this asymmetric reaction may be explained taking into account the coordination of /PraZn to the sulfur atoms of the chiral thiahehcene to form a chiral active zinc species. Since these chiral species react with pyrimidine-5-caibaldehyde 119 in the initial stage of the reaction, a small ee is initially induced. Then, a subsequent asymmetric autocatalysis with an amplification of the ee affords the alkanol, as a zinc alkoxide, with a high ee, which shows the corresponding absolute configuration. 

This is the first example of a highly enantioselective reaction induced by chirality resulting from deuterium substitution of amino acids. In addition, chirally deuterated primary alcohols [52] and chiral amino acid derivatives with partially deuterated substituent such as monodeuterated methyl group (—CDH2) can induce the chirality in asymmetric autocatalysis [53]. 

Carbon-isotope chirality is experimentally difficult to discriminate because the chirality originates from the very small difference between the carbon-12 and carbon-13. Therefore, it has been a question whether isotopically substituted carbon chiral compounds can induce chirality in some enantioselective reactions. To address this problem, we performed asymmetric autocatalysis triggered by a chiral compound arising solely from carbon-isotope substitution. 

In summary, we have described how we find out the asymmetric autocatalysis with amplification of chirality in the reaction between pyrimidine-5-carbaldehyde and i-Pr2Zn. 2-Alkynyl-5-pyrimidyl alkanol is a highly enantioselective asymmetric autocatalyst with greater than 99.5% enantioselectivity for the addition of i-Pr2Zn to the corresponding pyrimidine-5-carbaldehydes. Furthermore, it was found that enantiomeric excess of asymmetric autocatalyst enhances during the reaction. Thus, (5)-pyrimidyl alkanol with as low as ca. 0.00005% ee enhanced its ee to... 

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,... 

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