3-Pyridyl alkanol, enantioselective asymmetric

Pyridyl alkanol [41], diol [42], and ferrocenyl alcohol [43] were the first asymmetric autocatalysts found by Soai and co-workers in the enantioselective alkylation of pyridine-3-carbaldehyde, dialdehyde, and ferrocenecarbaldehyde, respectively, with dialkylzincs. 

Fu reported the enantioselective addition of diphenylzinc to ketones catalyzed by chiral amino alcohol 6, and observed a slight asymmetric amplification [13]. Bolm also reported asymmetric amplification in enantioselective alkylations using diethylzinc promoted by a chiral 2-pyridyl alkanol 7 and (1-hydroxy sulfoximine 8 (Scheme 9.6) [14,15]. 

In the course of the continuing study [9a,b] on the enantioselective addition of dialkylzincs to aldehydes by using chiral amino alcohols such as diphenyl(l-methyl-2-pyrrolidinyl)methanol (45) (DPMPM) [48] A. A -dibutylnorephedrine 46 (DBNE) [49], and 2-pyrrolidinyl-l-phenyl-1-propanol (47) [50] as chiral catalysts, Soai et al. reacted pyridine-3-carbaldehyde (48) with dialkylzincs using (lS,2/ )-DBNE 46, which gave the corresponding chiral pyridyl alkanols 49 with 74-86% ee (Scheme 9.24) [51]. The reaction with aldehyde 48 proceeded more rapidly (1 h) than that with benzaldehyde (16 h), which indicates that the product (zinc alkoxide of pyridyl alkanol) also catalyzes the reaction to produce itself. This observation led them to search for an asymmetric autocatalysis by using chiral pyridyl alkanol. 

One of the reasons that the enantioselectivity of 5-pyrimidyl alkanol is higher than that of 3-pyridyl alkanol may be due to the presence of symmetry in the pyrimidine ring. When the bond between the asymmetric carbon and the pyridine ring rotates, conformational isomers of pyridyl alkanol will be formed (Figure 9.2). However, with pyrimidyl alkanol, the rotation does not form conformational isomers. Thus, the reduced number of possible conformational isomers may enable 5-pyrimidyl alkanol to serve as a highly enantioselective asymmetric autocatalyst. 

The introduction of a carbamoyl group to the 5-position of chiral 3-pyridyl alkanol enhances its efficacy as asymmetric autocatalyst. (S)-5-Carbamoyl-3-pyridyl alkanols 61 are automulti-plied with up to 86% ee in the enantioselective addition of i-Pr2Zn to 5-carbamoyl-3-pyridine-carbaldehyde 60 (Scheme 9.32) [60]. The enantioselectivity depends on the structure of the substituent on the nitrogen atom of the amide. A bulky t-Pr substituent is efficient for achieving high enantioselectivity. The amplification of the enantiopurity of 61 to a certain degree is also observed [61]. 

We found that chiral 5-pyrimidyl alkanol, 3-quinolyl alkanol and 5-carbamoyl-3-pyridyl alkanol are highly enantioselective asymmetric autocatalysts for the addition of z-Pr2Zn to the corresponding aldehydes, respectively. Among these, 2-alkynyl-5-pyrimidyl alkanol is a highly efficient asymmetric auto-... 

Soai K, Niwa S, Hori H Asymmetric self-catalytic reaction — Self-production of chiral l-(3-pyridyl)alkanols as chiral self-catalysts in the enantioselective addition of dialkylzinc reagents to pyridine-3-carbaldehyde. J Chem Soc Chem Common 1990, (l4) 982-983. 

As described in the preceding sections, we already had experience on the enantioselective alkylation of aldehydes with dialkylzincs and the enantioselective synthesis of 3-pyridyl alkanol. In 1990, we found the first asymmetric autocatalysis of (5)-3-pyridyl alkanol 6 in the enantioselective addition of i-Pr2Zn to pyridine-3-carbaldehyde 7 to produce more of itself of 35% ee with the same S configuration (Scheme 6) [24]. Although the ee of product 6 decreased compared to that of the initial catalyst, the newly formed predominant enantiomer of the product is the same with that of asymmetric autocatalyst 6. We claim that this is the first asymmetric autocatalysis, that is, catalytic replication of chiral compound with the generation of new stereogenic centers. 

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