Asymmetric autocatalysis chiral initiators

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. 

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. 

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. °... 

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. 

TABLE 2. Asymmetric autocatalysis initiated by various organic and metal complex chiral initiators... 

TABLE 3. Asymmetric autocatalysis in reaction of 87 initiated by chiral inorganic crystals, inorganic-organic hybrid materials and chiral cocrystals of achiral compounds... 

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. 

Indeed, chiral (,V)-pyrimidyl alkanol 56b with only 0.28% ee was automultiplied by a factor of ca. 100 in quantity (92%) with significant amplification of enantiopurity (87.0% ee) in a one-pot reaction by three portion-wise additions of 2-methylpyrimidine-5-carbaldehyde (56b) and i-Pr2Zn (Table 9.4, Run 1) [57]. As shown in Figure 9.4, the initially slightly predominant (.S )-56b was multiplied by a factor of 189, whereas the initially slightly minor (R)-56b was multiplied by a factor of only 13 (Figure 9.4). Even when (R)-56b with enantiopurity as low as 0.18% ee was used as the asymmetric autocatalyst, (R)-56b with 83.9% ee was obtained in 84% yield through one-pot asymmetric autocatalysis (Run 2). 

Derivatization of 2-substituted 5-pyrimidyl alkanol 12 expanded the applicable compounds for asymmetric autocatalysis with amplification of chirality. The capabilities of chiral amplification were clarified by the use of an autocatalyst with low ee value. The n-butylethynyl derivative 13 (Fig. 3), including initial catalyst, with 21% ee was formed by one round of reaction using 13... 

As shown in Scheme 9, various organic compounds can act as a chiral initiator of asymmetric auto catalysis. 2-Methylpyrimidine-5-carbaldehyde 9 was subjected to the addition of z-Pr2Zn in the presence of chiral butan-2-ol, methyl mandelate and a carboxylic acid [74], When the chiral alcohol, (S)-butan-2-ol with ca. 0.1% ee was used as a chiral initiator of asymmetric autocatalysis, (S)-pyrimidyl alkanol 10 with 73% ee was obtained. In contrast, (,R)-butan-2-ol with 0.1% ee induced the production of (A)-10 with 76% ee. In the same manner, methyl mandelate (ca. 0.05% ee) and a chiral carboxylic acid (ca. 0.1% ee) can act as a chiral initiator of asymmetric autocatalysis, therefore the S- and IC enantiomers of methyl mandelate and carboxylic acid induce the formation of (R)- and (S)-alkanol 10, respectively. Chiral propylene oxide (2% ee) and styrene oxide (2% ee) also induce the imbalance of ee in initially forming the zinc alkoxide of the pyrimidyl alkanol in the addition reaction of z-Pr2Zn to pyrimidine-5-carbaldehyde 11 [75]. Further consecutive reactions enable the amplification of ee to produce the highly enantiomerically enriched alkanol 12 (up to 96% ee) with the corresponding... 

Scheme 9 Asymmetric autocatalysis initiated with chiral organic compounds...

Hexahelicene is a chiral hydrocarbon with a helical structure. We found that (P)-hexahelicene with 0.13% ee, a lower ee than that induced by CPL [3,80], acts as a chiral initiator for asymmetric autocatalysis (Scheme 11). The reaction between pyrimidine-5-carbaldehyde 11 and i-Pr2Zn gave (S)-pyrimidyl alkanol 12 with 56% ee [83]. On the other hand, when (M)-hexahelicene with 0.54% ee was used instead of (P)-hexahelicene, (P)-12 with 62% ee was formed. As already described, these ee can be enhanced by further asymmetric autocatalysis. Thus, the chirality of CPL has been correlated with that of alkanol 12 with high ee by using hexahelicene as the chiral source of asymmetric auto catalysis. 

Asymmetric Autocatalysis Utilizing Enantiomorphous Inorganic Crystals as an Initial Source of Chirality... 

The achiral inorganic ionic sodium chlorate (NaClOs) and sodium bro-mate (NaBrOs) crystallize in enantiomeric forms belonging to the P2i3 space group for which the same crystal structures exhibit opposite optical rotation [89]. The levo-(Z) and dextrorotatory (d) crystals can be obtained in equal proportions [90]. The chiral ionic crystals of NaClOs and NaBrC>3 were subjected to asymmetric autocatalysis as the initial seed of chirality to study the correlation between the organic compound with high ee and the chiral inorganic crystal composed of achiral ionic components. 

Scheme 14 Asymmetric autocatalysis utilizing inorganic crystals as an initial source of chirality...

A mechanistic consideration is as follows the initial reaction of aldehyde 11 and z-Pr2Zn proceeded on the chiral surface of the crystal so that a small enantiomeric excess was induced. Then, subsequent asymmetric autocatalysis with an amplification of chirality produced alkanol 12 in high enantiomeric excess and with the corresponding absolute configuration. Further mechanistic details are now under investigation. 

Thus, we have developed a method for the detection of the absolute configuration of amino acids with low enantioenrichment. We thought that the absolute configuration of amino acids can be determined by detecting the absolute configuration of the produced pyrimidyl alkanol with high enantiomeric excess by asymmetric autocatalysis using amino acids as chiral initiators (Scheme 18). 

Next, asymmetric autocatalysis initiated by amino acids with low ee was examined. When L-alanine with ca. 10% ee was used as the chiral initiator, the obtained alkanol 12 with 94% ee possessed the S-configuration [99]. Even when the ee was as low as ca. 1% and ca. 0.1% ee, the configuration of the formed 12 was the S-configuration. On the other hand, asymmetric autocatalysis in the presence of D-alanine with low ee gave (R)-12. Similarly, the chirality of methionine, histidine and valine with low ee was also recognized and turned into the amplified ee of the 5-pyrimidyl alkanol. 

We found that the chirality of the saturated quaternary hydrocarbon was successfully discriminated using asymmetric autocatalysis [108]. The asymmetric autocatalysis initiated by the chiral (. -quaternary hydrocarbon using pyrimidine-5-carbaldehyde 11 and z-Pr2Zn produced (S)-pyrimidyl alkanol 12 with 97% ee and 93% yield. In contrast, asymmetric autocatalysis in the presence of the (S)-quaternary hydrocarbon produced (J )-alkanol 12 with 94% ee in 91% yield. These stereochemical correlations were found to be reproducible (Scheme 20). 

In addition, saturated tertiary hydrocarbons [108] also act as a chiral source of asymmetric autocatalysis to give the pyrimidyl alkanol, with the absolute configurations corresponding to that of the chiral alkanes (Scheme 21). The correlation between the absolute configuration of the hydrocarbon and that of the obtained alkanol is reproducible. Therefore, the asymmetric autocatalysis is sufficiently applicable as a chiral sensor for saturated tertiary hydrocarbons. Various chiral hydrocarbons with zr-electrons such as 1,1 -binaphthyls [110], helicenes [82], olefins [83], allenes [111], and [2.2]paracy-clophanes [112,113] serve as chiral initiators in this asymmetric autocatalysis. 

Asymmetric Autocatalysis Initiated by Isotopically Chiral Primary Alcohols... 

Asymmetric Autocatalysis Initiated by Heterogeneous Chiral Substances... 

Chiral organic crystals composed of achiral compounds such as hippuric acid act as the initial source of chirality of asymmetric autocatalysis to produce the highly enantiomerically pure product. In this reaction, chiral organic crystals are utilized as a chiral inducer, not as a reactant. Therefore, these results are the realization of the process in which the crystal chirality of achiral organic compounds induces asymmetry in another organic compound whose chirality was amplified to produce a large amount of enantiomerically pure organic compound, pyrimidyl alkanol in conjunction with asymmetric autocatalysis. 

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