Chiral initiators, enantioselective asymmetric autocatalysis

We describe highly enantioselective asymmetric autocatalysis with amplification of chirality and asymmetric autocatalysis initiated by chiral triggers. Asymmetric autocatalysis correlates between the origin of chirality and the homochirality of organic compounds. We also describe spontaneous absolute asymmetric synthesis in combination with asymmetric autocatalysis. 

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. 

When enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde 89 was examined, simple 2-butanol with low (ca 0.1%) induces a tiny chirality in the initially produced alkanol 81 and the value of the finally obtained alkanol becomes higher (73-76%) due to the asymmetric autocatalysis (Table 2). Note that the value can be further amplified by subsequent asymmetric autocatalysis, as described in the preceding section. Various chiral compounds have been proved to act as chiral initiators. 

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. 

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. 

As described in the preceding sections, we already had experience on the enantioselective alkylation of aldehydes with dialkylzincs and the enantioselective synthesis of 3-pyridyl alkanol. In 1990, we found the first asymmetric autocatalysis of (5)-3-pyridyl alkanol 6 in the enantioselective addition of i-Pr2Zn to pyridine-3-carbaldehyde 7 to produce more of itself of 35% ee with the same S configuration (Scheme 6) [24]. Although the ee of product 6 decreased compared to that of the initial catalyst, the newly formed predominant enantiomer of the product is the same with that of asymmetric autocatalyst 6. We claim that this is the first asymmetric autocatalysis, that is, catalytic replication of chiral compound with the generation of new stereogenic centers. 

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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