5-Pyrimidyl alkanols, enantioselective

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. 

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... 

The first highly enantioselective asymmetric autocatalytic reaction was achieved in the addition of (-Pr2Zn to pyrimidine-5-carbaldehydes 55 by using chiral 5-pyrimidyl alkanols 56 as asymmetric autocatalysts. When chiral pyrimidyl alkanol 56b with 95% ee was used, it was automultiplied without any loss of enantiopurity to give itself with 96% ee [54], The enantiopu-rity of the newly formed pyrimidyl alkanol 56b reached 98.2% ee when asymmetric autocatalyst 56b with > 99.5% ee was used (Scheme 9.27). 

One of the reasons that the enantioselectivity of 5-pyrimidyl alkanol is higher than that of 3-pyridyl alkanol may be due to the presence of symmetry in the pyrimidine ring. When the bond between the asymmetric carbon and the pyridine ring rotates, conformational isomers of pyridyl alkanol will be formed (Figure 9.2). However, with pyrimidyl alkanol, the rotation does not form conformational isomers. Thus, the reduced number of possible conformational isomers may enable 5-pyrimidyl alkanol to serve as a highly enantioselective asymmetric autocatalyst. 

Then, we discovered that chiral 2-methyl-l-(5-pyrimidyl)propan-l-ol 8 serves as a highly enantioselective asymmetric autocatalyst for the addition of z-Pr2Zn to pyrimidine-5-carbaldehyde 7 (Scheme 4) [60]. In this compound, the formyl group is connected to the symmetric pyrimidine ring instead of the pyridine ring. When highly enantioenriched (S)-pyrimidyl alkanol 8 with 99% ee was employed as an asymmetric autocatalyst, (S)-8 with 95% ee composed of both the newly formed and the initially used 8 was obtained. The yield of the newly formed 8 was calculated to be 67% and the enantiomeric excess was 93% ee. 

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

Scheme 6 Highly enantioselective catalytic asymmetric automultiplication of a chiral pyrimidyl 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 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. 

We found that chiral 5-pyrimidyl alkanol, 3-quinolyl alkanol and 5-carbamoyl-3-pyridyl alkanol are highly enantioselective asymmetric autocatalysts for the addition of z-Pr2Zn to the corresponding aldehydes, respectively. Among these, 2-alkynyl-5-pyrimidyl alkanol is a highly efficient asymmetric auto-... 

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... 

Practically perfect asymmetric autocatalysts of the (2-alkynyl-5-pyrimidyl)alkanol series have been identified. A /-butylalkynyl residue fulfills the role of proper bulkiness and moderate electron-withdrawing power. Quartz also induces enantioselective addition of (-Pr2Zn to this heterocyclic aldehyde, by virtue of its morphological chirality and acidity, which enable differentiation of the enantiofaces of the aldehyde upon coordination with the oxygen and nitrogen atoms. Chiral sodium chlorate crystals have the same effect. ... 

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... 

Catalytic asymmetric synthesis is a major focus in the field of synthetic organic chemistry. In asymmetric catalyses, achiral additives can enhance the enantioselectivity, and achiral cocatalyst can cooperatively participate in the event of enantioface selection. We have reported on the unusual reversal of enantioface selectivity that the two / -affording chiral catalysts cooperate to give the opposite 5 enantiomer. That is, the enantioselective addition of /-Pr2Zn to pyrimidine-5-carbaldehyde 1 was carried out catalyzed by a mixture of two chiral catalysts DMNE and 2-[(l-phenylethyl)amino]-ethanol (PEAE) (Scheme 15) [55]. The reaction using (11 ,2S )-DMNE alone afforded (l )-5-pyrimidyl alkanol 1, and (/ )-PEAE alone also catalyzed the production of (/ )- with the same enantioface selectivity. 

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... 

A reversal in enantioselectivity has been observed by the combination of a chiral diol and achiral alcohols as a chiral initiator in the asymmetric alkylation of a pyrimidine-5-carbaldehyde using diisopropylzinc. (25,35)-Butane-2,3-diol alone induced (R)-pyrimidyl alkanol, while a mixture of the chiral diol and phenol derivatives induced (5)-pyrimidyl alkanol (Scheme 5). 

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