Pyrimidine-5-carbaldehyde

Pyrimidine-5-carbaldehyde, 2-amino-4,6-dichloro-synthesis, 3, 71 Pyrimidinecarbaldehydes derivatives, 3, 79 oxidation, 3, 79 oximes... 

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-... 

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. °... 

The pyrido[2,3- pyrimidinones 380 and 381 were thermally obtained from boiling the ethyl acrylate derivatives 378 and 379, respectively, with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and EtNHPd in THF (Scheme 13) <2001W02001055148, 2004USP2004009993>. The acrylates were obtained from reaction of the corresponding pyrimidine-5-carbaldehyde with (carbethoxymethylene)triphenylphosphorane. On the other hand, acrylate 382 was converted into 383 via aza-Wittig cyclization (Equation 32) <1997LA1619>. 

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... 

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]. 

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. 

When 2-(ferf-bulylethynyl)pyrimidine-5-carbaldehyde 11, instead of the 2-methyl derivative 9, was subjected to reaction with z-P Zn in the presence of chiral leucine, highly enantioenriched pyrimidyl alkanol 12 with the absolute configuration corresponding to that of chiral leucine was also obtained. But it should be noted that the resulting alkanol 12 showed the opposite enan-tioselectivity to that of alkanol 10, i.e., L-leucine induces the production of (S)-alkanol 12 and D-leucine induces (R)-12, respectively [82]. The asymmetric amplification of 12 with an alkynyl substituent is more significant than that of the 2-methyl derivative 10 to increase to 96% ee (Scheme 11). 

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. 

When pyrimidine-5-carbaldehyde 11 was treated with z-Pr2Zn in the presence of powdered [CD(+)260]-crystal, (S)-pyrimidyl alkanol with 73% ee was obtained in 88% yield (Scheme 16). On the other hand, in the presence of [CD(-)260]-crystal, the opposite enantiomer (R)-12 with 89% ee was isolated in 89% yield. When the crystals, grown from the stirred methanol solution of hippuric acid using each enantiomorph of hippuric acid as the seed crystal, were used in asymmetric autocatalysis, the same correlation between the chirality of crystal and the product 12 was observed with excellent reproducibility. It should be noted that nearly enantiopure (S)- and (K)-pyrimidyl alkanols 12 with > 99.5% ee were obtained by consecutive asymmetric autocatalysis [64], In this system, after the enantiomorphs of the crystal induced the chirality of an external organic compound, the subsequent asymmetric autocatalysis gave a greater amount of enantiomerically amplified product. 

The reaction of pyrimidine-5-carbaldehyde 7 and 2-methylpyrimidine-5-carbaldehyde 9 with z-P Zn without adding a chiral substance produced enantioenriched (S)- or ( )-pyrimidyl alkanol 8 and 2-methylpyrimidyl alkanol 10, respectively [102]. 

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... 

We have demonstrated the stochastic formation of (S)- and (,R)-5-pyrimidyl alkanol 12 from pyrimidine-5-carbaldehyde 11 and i-V Zn without the intervention of a chiral auxiliary. Even in the reactions performed in toluene alone, stochastic behavior of the formation of (S)- and (A)-12 was observed in the presence of achiral silica gel. We believe that the approximate stochastic behavior in the formation of alkanols fulfils one of the conditions necessary for chiral symmetry breaking by spontaneous absolute asymmetric synthesis. 

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). 

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