Pyrimidyl alkanols

Another practically perfect asymmetric catalysis has been observed in reactions using (2-alkynyl-5-pyrimidyl)alkanols as the catalyst. The asymmetric autocatalysis shown in Scheme 8-59 gives the corresponding product in high yield with over 99% ee.116... 

When (5)-2-a]kynyl-5-pyrimidyl alkanol 2c with >99.5% ee was employed as an asymmetric autocatalyst, (5)-2c with >99.5% ee composed of both the newly formed 2c and the initially used 2c was obtained. The yield of the newly formed 2c was >99%. To make use of the advantage of asymmetric autocatalysis—that the structures of the asymmetric autocatalyst and the product are the same—the 2c obtained in the first round was used as an asymmetric autocatalyst for the following round. Again, the product (5)-2c and the initial autocatalyst had an ee of >99.5% and the yield of the newly formed (S)-2c was >99%. The product 2c was therefore used as an asymmetric autocatalyst for the following round. Even after the 10th round, the yield of 2c was >99% and the ee was >99.5%. Thus, 2-aIkynyl-5-pyrimidyl alkanol 2c served as a virtually perfect asymmetric autocatalyst. Moreover, the amount of (S)-2c automultiplied by a factor of 60 million during the 10 rounds ... 

Asymmetric autocatalysis using (5)-pyrimidyl alkanol 2a with only 2% ee afforded (5)-2a with an increased ee of 10%, [Eq. (9.4)]. The (5)-2a obtained with 10% ee was then used as an asymmetric autocatalyst for the following asymmetric autocatalysis. (5)-Pyrimidyl alkanol 2a with an increased ee of 57% was obtained. The subsequent consecutive asymmetric autocatalysis and the use of that product as an asymmetric autocatalyst for the following round gave (5)-pyrimidyl alkanol 2a with 81 % and 88% ee, respectively. Thus, the overall process was the asymmetric autocatalysis of (5)-2a starting from a low ee of 2% with significant amplification of chirality to 88% ee, with the increase in the amount without need for other chiral auxiliary. ° This stands as the first example of an asymmetric autocatalysis with amplification of ee. In addition, one-pot asymmetric autocatalysis of pyrimidyl alkanol 2b also significantly increased the chirality from 0.28 to 87% ee. ... 

As described, pyrimidyl alkanols 2 act as highly efficient asymmetric autocatalysts with significant amplification of chirality. 3-Quinolyl alkanoland 5-carbamoyl-3-pyridyl alkanol also serve as efficient asymmetric autocatalysts with amplification of chirality. 

In the presence of (P)-hexahelicene with very low (0.13%) ee as a chiral trigger, the reaction between aldehyde Ic and -Pr2Zn gave (5)-pyrimidyl alkanol 2c with 56% ee. When (M)-hexahelicene with 0.54% ee was used instead of (P)-hexahelicene, K)-2c with 62% ee was formed. 

Irradiation of CPL to racemic alkylidenecyclohexanone induces a small enantiomeric imbalance, which triggers the subsequent asymmetric autocatalysis to afford highly enantioenriched pyrimidyl alkanol 2c with the absolute configuration corre-... 

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. 

P-cocrystal, (/ )-pyrimidyl alkanol 2c with high enantioenrichment is formed, while M-cocrystal affords (5)-2c with high enantioenrichment [Eq. (9.10)]. ... 

We thought that when i-Pr2Zn was treated with pyrimidine-5-carbaldehyde without adding any chiral substance, extremely slight enantioenrichment would be induced statistically in the initially formed zinc alkoxide of the pyrimidyl aUca-nol, and that the subsequent amplification of chirality by asymmetric autocatalysis would afford the pyrimidyl alkanol with detectable enantioenrichment [Eq. (9.11)]. Indeed, we found that pyrimidyl alkanol with an ee that is above the detection level was formed.Pyrimidine-5-carbaldehyde was reacted with /-Pr2Zn, and the resulting pyrimidyl alkanol was used as an asymmetric autocatalyst for the subsequent asymmetric autocatalysis. The consecutive asymmetric autocatalysis afforded pyrimidyl alkanol of either 5 or 7 configuration with enantiomeric enrichment above the detection level. °... 

Figure 9.2. Histogram of the absolute configuration and the enantiomeric excess of pyrimidyl alkanol 2c.

Spontaneous absolute asymmetric synthesis is described in the formation of enantiomerically enriched pyrimidyl alkanol from the reaction of pyrimidine-5-car-baldehyde and /-Pr2Zn without adding chiral substance in combination with asymmetric autocatalysis. The approximate stochastic distribution of the absolute conhgurations of the product pyrimidyl alkanol strongly suggests that the reaction is a spontaneous absolute asymmetric synthesis. 

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. 

The asymmetric autocatalysis of 2-f-butylethynyl-5-pyrimidyl alkanol 82 starting from extremely low has been reported170. When (5)-2-f-butylethynyl-5-pyrimidyl alkanol 82 with only ca 0.00005% (S isomer R isomer = ca 50.000025 49.999975) is used as an initial asymmetric autocatalyst, the first round of reaction gives pyrimidyl alkanol 82 with an increased of 57% (Figure 2). The product is used as an asymmetric autocatalyst for the second run, affording the pyrimidyl alkanol 82 with an enhanced ... 

The mechanism of the asymmetric autocatalysis with amplification of has been examined experimentally by us171 and other groups172. It is basically understood that the aggregation of the isopropylzinc alkoxide of 5-pyrimidyl alkanol is involved in the reaction. Kinetic analysis of the reaction shows that the reaction is second order in the isopropylzinc alkoxide of 5-pyrimidyl alkanol171. 

In the absence of any chiral factors, the probability of the formation of S- and 77-enantiomers is 1 to 1. However, the numbers of the resulting two enantiomers are not exactly the same in almost all cases. Mislow197 described the inevitability of small enantiomeric enrichment in absolute asymmetric synthesis. According to the statistics, it is expected that a fluctuation in the ratio of the S- and 77-enantiomers becomes more and more likely as the numbers in the enantiomer mixture become smaller198. Thus, if the asymmetric autocatalysis is initiated without adding any chiral substance, small fluctuations of enantiomers produced in the initial stage could be enhanced by consecutive asymmetric autocatalytic reaction of pyrimidyl alkanol with amplification of chirality. 

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]. 

Moreover, when these alkanols with low ee are utilized as asymmetric autocatalysts, 5-pyrimidyl alkanol 28 [48], 3-quinolyl alkanol [49],and 5-carbamoyl-3-pyridyl alkanols [50] with higher ees were obtained. The successive reactions were performed in order to make the best use of the autocatalysis, that is, the products of one round served as the asymmetric autocatalysts for the next. In the case of pyrimidyl alkanol, staring from (S)-alkanol 28a with only 2% ee, the ee reached almost 90% after four rounds [48] without the assistance of any other chiral auxiliary (Scheme 14). 2-Alkynyl-5-pyrimidyl alkanol 28b [5] and 2-... 

Chiral isopropylzinc alkoxide 50 of pyrimidyl alkanol formed in situ from the chiral pyrimidyl alkanol and i-Pr2Zn is considered to be an initial actual asymmetric autocatalyst, which automultiplies itself by catalyzing the addition of i-Pr2Zn to aldehyde 48 (Scheme 9.25). 

Thus, chiral pyrimidyl alkanol, ferrocenyl alkanol and diol are asymmetric autocatalysts, although the enantiopurities of the newly formed products are moderate. 

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). 

Chiral pyrimidyl alkanol reacts with i-Pr2Zn to form chiral isopropylzinc alkoxide 57, which serves as the true asymmetric autocatalyst to multiply itself with the same configuration in the addition reaction of i-Pr2Zn to pyrimidine-5-carbaldehyde 55 (Scheme 9.29). 

---