Asymmetric autocatalysis high enantioselectivity

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. 

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]. 

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. 

Highly Enantioselective Asymmetric Autocatalysis of Pyrimidyl 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... 

Scheme 4 Highly enantioselective asymmetric autocatalysis of pyrimidyl alkanol in enantioselective z -Pr2Zn addition...

We reasoned that chiral organic compounds with low ee induced by CPL can act as a chiral trigger in the enantioselective addition of z -Pr2Zn to pyrimidine-5-carbaldehyde, and that the subsequent asymmetric autocatalysis of pyrimidyl alkanol, formed in situ, amplifies its ee to produce highly enantioenriched pyrimidyl alkanol with an absolute configuration corresponding to that of the handedness of the CPL. 

Scheme 17 Highly enantioselective asymmetric autocatalysis using chiral co-crystals...

We investigated highly enantioselective asymmetric autocatalysis of a chiral compound induced by the isotopic enantiomer of a primary alcohol-a-d (Scheme 22) [118]. The correlation between the absolute configurations of the obtained pyrimidyl alkanol and the isotopic chiral compound is reproducible, thus the small isotope chirality can be recognized by asymmetric autocatalysis. 

We found that inorganic helical structures such as helical silica serve as chiral triggers for asymmetric autocatalysis (Scheme 23). In the presence of helical silica, the enantioselective addition of z-P Zn to 2-alkynylpyrimidine-5-carbaldehyde 11 was examined. In the presence of right-handed helical silica, (S)-5-pyrimidyl alkanol 12 was formed [123]. In contrast, in the presence of left-handed helical silica, (S)-5-pyrimidyl alkanol 12 with high ee was obtained. These results clearly show that asymmetric auto catalysis can discriminate the helical structure in artificially tuned inorganic silica. 

Scheme 23 Helical silica-induced highly enantioselective asymmetric autocatalysis of chiral pyrimidyl alkanol...

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... 

Highly enantioselective asymmetric syntheses of pyridyl by addition of organometallic reagents to aldehydes, autocatalysis by the formed chiral adduct 04YGK673. 

Shibata T, Morioka H, Hayase T, Choji K, Soai K (1996) Highly enantioselective catalytic asymmetric auto-multiplication of chiral pyrimidyl alcohol. J Am Chem Soc 118 471-472 Soai K, Kawasaki T (2006) Discovery of asymmetric autocatalysis with amplification of chirality and its implication in chiral homogeneity of biomolecules. Chirality 18 469-478 Szostak JW (2010) On the origins of primitive cells from nutrient intake to elongation encapsulated nucleotides. Angew Chem 49 3738-3750 Szostak JW et al (2001) Synthesizing life. Nature 409 387-390... 

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. 

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]. 

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... 

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