Alkanols, enantioselective 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 of Pyrimidyl Alkanol... 

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

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. 

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

We have demonstrated the enantioselective synthesis of near-enantiopure compounds by asymmetric photodegradation of racemic pyrimidyl alkanol 2c by circularly polarized light followed by asymmetric autocatalysis. This is the first example of asymmetric autocatalysis triggered directly by a chiral physical factor CPL. 

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. 

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. 

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. 

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. 

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. 

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... 

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. 

We found asymmetric autocatalysis of pyrimidyl alkanol 1 [1-10], Pyrimidyl alkanol 1 acts as asymmetric autocatalyst in the enantioselective addition of diisopropylzinc (/-Pr2Zn) to pyrimidine-5-carbaldehyde 2 to produce more of itself with the same absolute configuration [11] of >99.5% enantiomeric excess (ee) in a yield of >99% (Scheme 1) [12]. Thus, pyrimidyl alkanol 1 automultiplies in... 

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. 

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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