Chiral initiators

The opposite case is also worthy of consideration. cis-2,3>Epoxybutane is a meso compound but the two halves of the molecule, and particularly the two O—CH(CH3) bonds, are not equivalent but enantiotopic. Ring opening polymerization occurring selectively on one of the bonds converts the R, S) monomer into a succession of monomer units (R, / )—(/ , R)— and so on, or —(5, S)—(S, S)— and so on. A chiral initiator can effect an enantiotopic differentiation (281) and thus give rise to an optically active polymer with an excess of (R, R) or (S, S) units (81, 82). 

Some chiral initiators have structures such that alternate monomer placements occur with opposite faces of the monomer to yield the syndiotactic polymer. This is syndioselective polymerization proceeding with catalyst site control and is usually observed only with some homogeneous initiators, both traditional Ziegler-Natta and metallocene. 

Polymerization of the bulky monomer chloral yields an optically active product when one uses a chiral initiator, e.g., lithium salts of methyl (+)- or (—)-mandelate or (R)- or (S)-octanoate [Corley et al., 1988 Jaycox and Vogl, 1990 Qin et al., 1995 Vogl, 2000], The chiral initiator forces propagation to proceed to form an excess of one of the two enantiomeric helices. The same driving force has been observed in the polymerization of triphenyl-methyl methacrylate at —78°C in toluene by initiating polymerization with a chiral complex formed from an achiral initiator such as n-butyllithium and an optically active amine such as (+)-l-(2-pyrrolidinylmethyl)pyrrolidine [Isobe et al., 2001b Nakano and Okamoto, 2000 Nakano et al., 2001]. Such polymerizations that proceed in an unsymmetrical manner to form an excess of one enantiomer are referred to as asymmetric polymerizations [Hatada et al., 2002]. Asymmetric polymerization has also been observed in the radical... 

Chiral compounds can be used as chiral initiators of asymmetric autocatalysts. In the presence of a chiral initiator, an enantiomeric imbalance is induced in the initially formed... 

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 place of the above-mentioned chiral organic compounds, chiral inorganic substrates have been examined as chiral initiators. Quartz (Si02) exhibits both dextrorotatory (d) and levorotatory (Z) enantiomorphs that exist in nature. Quartz is considered as one of the origins of chirality of organic compounds186. 

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

Metal complexes which initiate rac-LA ROP with a high degree of stereocontrol are currently an area of major research interest and have the potential to produce a spectrum of different materials [19, 21], Much attention focuses on iso-selectivity as this can enable production of PLA of good thermal resistance (isotactic, stereoblock or even stereocomplex PLA). There are two mechanisms by which an initiator can exert iso-selectivity in rac-LA ROP (1) an enantiomorphic site control mechanism or (2) a chain end control mechanism. Enantiomorphic site control occurs using chiral initiators (Fig. 6) it is the chirality of the metal complex which... 

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... 

Indeed, in the presence of L-leucine with only 2% ee as a chiral initiator, the reaction of 2-methylpyrimidine-5-carbaldehyde 9 with i-Pr2Zn produced (iC-pyrimidyl alkanol 10 with an enhanced ee of 21% (Scheme 11) [74,81]. In contrast, when D-leucine with 2% ee was used as a chiral initiator, (S)-10 with an increased ee of 26% was obtained. As described in the preceding section, the ee of the obtained pyrimidyl alkanol can be amplified significantly by consecutive asymmetric auto catalysis to achieve homochirality. 

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. 

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. 

Chiral Hydrocarbons Act as Chiral Initiators (S-Indudng Enantiomer)... 

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. 

Furthermore, the generality of the effect of isotopic enantiomers in chiral initiation was exemplified using chiral tolyl methanol-a-d, 2,2-naphthyl... 

Highly sensitive chiral discrimination of amino acids with low ee was described. Amino acids with low ee act as a chiral initiator of asymmetric autocatalysis. In the presence of amino acids with low ee, pyrimidine-5-carbaldehyde was treated with z-P Zn to produce chiral pyrimidyl alkanol with the absolute configuration correlated with that of the amino acid by the consecutive asymmetric autocatalysis with amplification of ee. In addition, direct examination of extraterrestrial chirality was performed using meteorites by applying the asymmetric autocatalysis as the chiral sensor. The results indicated the presence of some chiral factor in the meteorites other than known organic compounds such as amino acids. 

Spontaneous asymmetric synthesis has been envisaged by theoretical models for more than 50 years [1-7]. This process features the generation and amplification of optical activity during the course of a chemical reaction. It stands in contrast to asymmetric procedures, such as stoichiometric resolution, conglomerate crystallization, or chiral chromatography, in which the optical activity can be increased but no additional chiral product is formed [8]. It is also different from classical asymmetric synthesis, in which new chiral product is obtained but the resulting enantiomeric excess (ee) is usually less than or, at most, equal to that of the chiral initiator or catalyst1. 

As listed In Tables 2 and 3, not only the initially added pyrimidyl alkanol but also a wide variety of other chiral substances can act as chiral initiators in the Soai reaction [42-63]. All the experiments reported below have been reproduced several times and were performed by using alternately the R and S enantiomer of the additives to confirm the inversion of the outcome. 

Table 2 Soluble chiral additives in the Soai reaction that act as chiral initiators...

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