Pyrimidine-5-carbaldehyde, addition

Abstract The addition of diisopropylzinc to prochiral pyrimidine carbaldehydes (Soai reaction) is the only known example of spontaneous asymmetric synthesis in organic chemistry. It serves as a model system for the spontaneous occurrence of chiral asymmetry from achiral initial conditions. This review describes the possible kinetic origin of specific experimental features of this reaction. It is shown that generic kinetic models, including enantioselective autocatalysis and mutual inhibition between the enantiomers,... 

The first experimental invention of spontaneous asymmetric synthesis was achieved only a little more than a decade ago in an organic reaction system by Soai and coworkers [9-15]. The Soai reaction (Scheme 1) comprises the addition of diisopropylzinc to prochiral pyrimidine carbaldehydes yielding isopropylzinc alkoxides that, after hydrolysis, are usually converted into stable chiral pyrimidyl alkanols. 

It is noteworthy that, as early as 1929, Shibata and Tsuchida reported a kinetic resolution of rac-3,4-dihydroxyphenylalanine by selective oxidation of one enantiomer using a chiral cobalt complex [Co(en)3NH3Cl]Br2 as a catalyst [46,47]. Figure 12 shows a highly enantioselective addition of diisopropy-Izinc to 2-(ferf-butylethynyl)pyrimidine-5-carbaldehyde via an autocatalytic process in the presence of a chiral octahedral cobalt complex with ethylenedi-... 

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. 

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. 

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... 

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). 

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. 

The next investigation focused on the substituent effect at the pyrimidine ring, especially at the 2-position. The asymmetric autocatalysis in the addition reaction of z-P Zn to pyrimidine-5-carbaldehyde was examined using enantiomerically enriched (S)-2-methyl-l-(5-pyrimidyl)-propan-l-ol 10. The treatment of the corresponding 2-methylpyrimidine-5-carbaldehyde 9 with z-P Zn in the presence of autocatalyst 10 with > 99.5% ee resulted in highly... 

Kinetic analysis of asymmetric autocatalysis was performed to study the reaction mechanism of asymmetric autocatalysis. The relationship between the reaction time and the yields of the product was investigated [67]. The i-P Zn addition to pyrimidine-5-carbaldehyde 11 was performed in the presence of enantiomerically pure autocatalyst, the reaction being monitored by HPLC using naphthalene as an internal standard. The plots shown in Fig. 4(a) constitute S-shaped curves that are characteristic of an autocatalytic reaction. The relationship between time, yield and enantiomeric excess was also measured in the asymmetric autocatalysis with amplification of ee using high to low ee of pyrimidyl alkanol as the catalyst (Fig. 4b) [68]. Portions of the reaction mixture were quenched periodically and analyzed by chiral HPLC. When pyrimidyl alkanols with high to good ee are used as the asymmetric autocatalyst, the observed values of yield and ee were well matched to our simulated... 

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... 

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. 

In addition, we performed the asymmetric autocatalysis in the presence of an achiral silica gel under achiral conditions, the enantioenriched pyrimidyl alkanol 12 is generated from the reaction between 2-alkynylpyrimidine-5-carbaldehyde 11 and z-P Zn in conjunction with the subsequent asymmetric autocatalysis [104]. The reaction of pyrimidine-5-carbaldehyde 11 with... 

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. 

Highly enantioselective asymmetric autocatalytic reactions have been reported using chiral pyrimidyl-lla,b and quinolylalkanols (Scheme 12.2).Uc (5)-2-methyl-l-(2-methyl-5-pyrimidyl)-l-propanol (14b, 99.9% ee) autocatalyses the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde to afford 14b itself of the same configuration with 98.2% ee.ll Moreover 14a shows asymmetric autocatalytic reaction with amplification of ee. Thus, starting from (5)-14a with only 2% ee, four successive autocatalytic reactions afford (5)-14a with 88% ee.ub... 

Soai K., Sato I., Shibata T., Komiya S., Hayashi M., Matsueda Y., Imamura H., Hayase T., Morioka H., Tabira H., Yamamoto J. and Kowata Y. (2003) Asymmetric synthesis of pyrimidyl alkanol without adding chiral substances by the addition of diisopropylzinc to pyrimidine-5-carbaldehyde in conjunct-tion with asymmetric autocatalysis, Tetrahedr. Asymm. 14, 185-188. 

A rather unconventional use of tetrathiaheHcene (P)-72 has been reported (2006TA2050). These 7-TH systems, without any functional groups, can act as chiral inducers in a chiral amphfication process related to the addition of diisopropylzinc to the pyrimidine-5-carbaldehyde 119 (Scheme 35). 

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... 

As we had expected, the first asymmetric autocatalysis of pyrimidyl alkanol in the addition of -Pr2Zn to pyrimidine-5-carbaldehyde gave a promising result. We refined the reaction conditions and ee became near 90% ee. Moreover, amplification of ee was observed in the reaction. Starting from pyrimidyl alkanol with 2% ee, consecutive asymmetric autocatalysis using the product of one round as asymmetric autocatalyst for the next round afforded alkanol with 88% ee (see Scheme 1). At this stage, we found the first asymmetric autocatalysis with amplification of chirality. These results were published in Nature in 1995 [11]. 

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... 

The chiral organosilica materials were successfully used to induce enantiose-lective synthesis in conjunction with asymmetric autocatalyzed addition of diiso-propylzinc to pyrimidine-5-carbaldehyde to generate 5-pyrimidyl alkanol with up to 96% ee [49]. 

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