Synthesis And Biocatalytic Reduction Of 2-Fluoroallyl Alcohols

Fluoroalcohols are a kind of alcohols contaning fluorine atoms. Because of their unique property, fluoroalcohols as potential intermediates have received much attention in recent years. However, the methods reported for preparing fluorinated primary alcohols with one fluorine atom, especially for introducing a fluorine-containing stereocenter are still few. Therefore, it is necessary to develop new synthetic approaches to chiral primary alcohols with a fluorine-containing stereocenter. In this dissertation, we focous our attention on the study of asymmetric bioreduction of 2-fluoroallyl alcohols mediated by baker's yeast. By this reaction, chiral fluoroalcohols with high enantioselectivity are obtained.In order to understand the bioreduction mechanism of substituted allyl alcohols, reduction of 2-alkyl-3-arylallyl alcohols mediated by baker's yeast has been studied in chapter 2. Firstly, the reaction conditions of bioreduction involving pH value, reaction time, concentration of the substrate and the amount of baker's yeast, have been optimized. Next, the effects of the substituents at both 2-position and 3-position of allyl acohols were investigated. The results showed that with the increase of the size of the substituents at 2-position of allyl acohols, the reaction rate decreased sharply. An obvious increase of the reaction rate has been observed when a phenyl group was replaced by a furyl group at 3-position of allyl alcohols, indicating that the reaction was more favorable with the increase of electron density on C=C bond.Bioreduction of 2-fluorosubstituted cinnamyl alcohols has been studied in chapter 3. As the atomic radius of fluorine is near to that of hydrogen and less effect on electron density on C=C bond,2-fluorocinnamyl alcohol was almost completely converted into saturated alcohol with 81% ee within 48 h, whereas the conversion of 2-bromocinnamyl alcohol was only 5% due to the large size and electron-withdrawing property of bromine. The electronic property of substituents on benzene ring could also affect the bioreduction of 2-fluorosubstituted cinnamyl alcohols. The decrease in electron density on benzene ring 2-fluoro-3-(4-fluorophenyl)-2-propen-1-ol were reduced into their corresponding saturated alcohols with 92% ee and 82% ee within 48 h, respectively, but only 27% of 2-fluoro-3-(4-chlorophenyl)-2-propen-1-ol was converted. In addition, all of the saturated primary alcohols formed from the bioreduction of 2-fluorosubstituted cinnamyl alcohols mediated by baker's yeast were assigned to be (S)-configuration by analysis of rotation degree and NMR spectra, which is consistent with the stereoselectivity reported previously.In order to broaden the substrate spectrum, the configuration effect of C=C bond and bioreduction of a series of (Z)-3-alkyl-2-fluoro-2-propen-l-ols mediated by baker's yeast have been studied. Firstly, the bioreduction of (Z)-and (E)-2-fluoro-3-(4-methoxyphenyl)-2-propen-1-ol were performed respectively. (Z)-isomer could be almost completely converted into saturated alcohols within 48h, whereas (E)-isomer couldn't be reduced by baker's yeast even the reaction time was prolonged to one week. In order to confirm this remarkable difference in reactivity between (E)-and (Z)-isomers, 2-fluoro-4-methyl-2-penten-1-ol (E:Z=1:9) was also tested. The same difference in reactivity was observed. Only (Z)-isomer could be readily reduced into (S)-2-fluoro-4-methyl-pentan-1-ol with 91% ee after 48 h, and (E)-isomer was totally remained in the reaction mixture. As a result, the configuration of the substrate played a crucial role in the reduction of 2-fluoroallyl alcohols mediated by baker's yeast. In addition, the results showed that the reaction rate of (Z)-3-alkyl-2-fluoro-2-propen-l-ols decreased sharply with the increase of the alkyl chain length.6-chloro-2-fluoro-2-hexen-1-ol and 2-fluoro-2-octen-1-ol were consumed completely after bioreduction of baker's yeast within 48 h, and corresponding saturated alcohols were formed with 91%ee and 92% ee respectively. With the alkyl chain length increasing (R=n-C11H23),2-fluoro-2-tetradecen-1-ol was hardly reduced.