Amplification autocatalysis

CHIRAL AMPLIFICATION, CHIRAL AUTOCATALYSIS, AND THE ORIGIN OF NATURAL CHIRALITY... 

In the 45 years since its proposal, Frank s autocatalytic mechanism (Section 11.3, above) has spawned numerous theoretical refinements including consideration of such factors as reversibility, racemization, environmental noise, and parity-violating energy differences. [100,101] In contrast to the above examples of stereospecific autocatalysis by the SRURC, however, none of these theoretical refinements is supported by experimental evidence. While earlier attempts to validate the Frank mechanism for the autocatalytic amplification of small e.e.s in other experimental systems have generally been unsuccessful, several recent attempts have shown more promising results. [102,104]... 

ASYMMETRIC AUTOCATALYSIS WITH AMPLIFICATION OF CHIRALITY AND ORIGIN OF CHIRAL HOMOGENEITY OF BIOMOLECULES... 

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. 

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. ... 

ASYMMETRIC AUTOCATALYSIS AND ITS ROLE IN THE ORIGIN AND AMPLIFICATION OF CHIRALITY... 

Thus, a slight enantiomeric imbalance in compounds induced by CPL was correlated for the first time to an organic compound with very high ee by asymmetric autocatalysis with amplification of chirality. Moreover, various chiral organic compounds such as 1,1-binaphthyl,[2.2]paracyclophanes, and primary alka-nols due to deuterium substitution have been found to serve as chiral triggers in asymmetric autocatalysis. 

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. °... 

As described, asymmetric autocatalysis with amplification of chirality is a powerful tool to correlate the origin of chirality with highly enantioenriched organic compounds. 

Nowadays, this chemistry includes a wide range of applications. The organozinc compounds employed in the enantioselective addition include dialkylzincs, dialkenylzincs, dialkynylzincs, diarylzincs and the related unsymmetrical diorganozincs. Electrophiles have been expanded to aldehydes, ketones and imines. Asymmetric amplification has been observed in the enantioselective addition of organozincs. Recently, asymmetric autocatalysis, i.e. automultiplication of chiral compounds, has been created in organozinc addition to aldehydes. 

As described in the preceding section, asymmetric amplification has been reported in the non-autocatalytic enantioselective addition of dialkylzincs. In asymmetric autocatalysis, amplification of has a more significant role, because the product of the asymmetric autocatalysis itself is capable of acting as the asymmetric autocatalyst. Once the product, i.e. the asymmetric autocatalyst with an enhanced , is formed in the asymmetric autocatalytic reaction, the product catalyzes the formation of itself with higher . From the viewpoint of the molecule, an asymmetric autocatalyst with dominant absolute configuration catalyzes... 

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 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. 

Meanwhile, asymmetric autocatalysis of 3-quinolyl alkanol 84-86167,173 and 5-carbamoyl-3-pyridyl alkanol 77174 also proceed with amplification of . Quinolyl alkanols 84 with 9% increases its to 88%173 and the of 5-carbamoyl-3-pyridyl alkanol 77 increased from 14% to 87%174. 

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. 

Indeed, the reaction of pyrimidine-5-carbaldehydes and i-Pr2Zn without the addition of any chiral substance and the subsequent asymmetric autocatalysis with amplification of... 

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