Ethyl 3-hydroxybutanoate enantiomers

In addition, a sample of (S)-hydroxyester of 85% e.e. was converted to the optically pure (R)-enantiomer under similar conditions. It is also possible to interconvert short chain 2-methyl-3-oxoalkanoates effecting an overall stereo-inversion of the C-2 centre. On prolonged exposure to G. candidum, syn (2R, 3S) ethyl 2-methyl-3-hydroxybutanoate 11 was converted, via the 3-oxoester 12, to the anti (2S,3S) compound 11 with an e.e. of 97% in around 23 h (Scheme 6). 

For example, oily ( + )-ethyl (7 )-4,4,4-trifluoro-3-hydroxybutanoate (2) is obtained with 45% cc from ethyl 4.4,4-trifluoro-3-oxobutanoate (1). The 3,5-dinitrobenzoate of 2 shows the phase diagram of a racemic compound with an eutectic composition of 35 15. This allows the isolation of a limited quantity of the pure crystalline enantiomer, which is then reconverted into 2 by transesterification in ethanol13. 

The procedure of enriching the (S) —(+)-enantiomer to 100% enantiomeric excess by the previously described crystallization method 1s tedious.4 It provides optically pure ethyl (S)-(+)-3-(3, 5 -dlnltro-benzoyloxy)butanoate of [ ]q5 +26.3° (chloroform, a 2), which after cleavage gives enantiomerically pure ( )-(+)-ethyl 3-hydroxybutanoate of [< ](j5 + 43.5° (chloroform, a 1.0). This optically pure compound has recently become commercially available from Fluka AG, CH-9470 Buchs (Switzerland), but it is very expensive. After submission and checking of this procedure, it was shown that the ee of the product can be increased to >95% by working under aerobic conditions and by adding the ketoester more slowly. 

Preparaton of the Enantiomers of Ethyl 3-Hydroxybutanoate. Reduction of ethyl acetoacetate with yeast yields ethyl (S)-3-hydroxybutanoate (15) as shown in Figure 4 (12-14). Purification of crude 15 as its crystalline 3,5-dinitrobenzoate gives (S)-15 of 100% e.e. (14,15). 

When the enantioselective reduction of ethyl 4-chloroacetoacetate was carried out with alcohol dehydrogenase from Candida parapsilosis, the other enantiomer was produced ethyl (P)-4-chloro-3-hydroxybutanoate [134]. This product is a key intermediate in a synthesis of (R)-carnitine. In this case a substrate coupled approach was chosen. The enzyme also has a strong oxidation activity for 2-propanol, which was therefore selected as the cosubstrate. The situation is depicted in Fig. 3.50. Under optimized conditions, the yield of (R)-ethyl-4-chloro-3-hydroxy-butanoate reached 36.6 g L-1 (> 99% ee, 95% yield) on a 30 L scale. 

Ethyl 3-hydroxybutanoate, isolated from yellow passion fruit, mainly consisted of the (S)-enantiomer (82 %), comparable to the product, obtained by yeast reduction of the corresponding 3-ketoacid ester (see above). In contrast, ethyl 3-hydroxybutanoate in purple passion fruit and mango mainly consisted of the (R)-enantiomer (69 % and 78 %). 

Treatment of the derivative with excess acidified ethanol will regenerate 100% ee 5(+)-ethyl 3-hydroxybutanoate. If several crops of crude product are pooled, distillation at reduced pressure (see Chapter 7) can give chemically pure ethyl 3-hydroxybutanoate (bp 71-73° at 12 mm). Both the R and S enantiomers have the same boiling points, so the optical purity will not be changed by distillation. 

In 1984 Isaksson et al. in Sweden separated the enantiomers 88 and 88 by chromatography over a triacetylcellulose column. Their 88 and 88 were of >98% ee, and showed [a]o24 -44.3 0.7 (pentane) and +44.6 0.7 (pentane), respectively. They questioned the higher rotation values of our 88 and 88, since we employed ethyl (S)-3-hydroxybutanoate of only 92% ee as our starting material. They said The reason for this is not clear to us. 66 Apparently, they thought that our starting material with 92% ee should have generated 88 and 88 of 92% ee. 

The volatile component of the mandibular secretion of Andrena haemorrhoa F. contains 2,7-dimethyl-l,6-dioxaspiro[4.6]undecane. All four thermodynamically stable stereoisomers of the Spiro acetal pheromone have been prepared using the two enantiomers of ethyl lactate (which supplies the 2-methyl substituent via butyrolactone 51) and the two enantiomers of 3-hydroxybutanoate (which supplies the 7-methyl via iodide 52). Scheme 8 shows the synthesis of the (2S, 5S, 7/ )-isomer 55. The overall yield in the sequence is 9%, and the purity of the final product is 97% [18]. 

Day 2 of fhe experiment is used to isolate the chiral ethyl 3-hydroxybutanoate. After this has been isolated, each student s product is analyzed by chiral gas chromatography and polarimetry to determine the percentages of each of the enantiomers. As an optional experiment (Experiment 28B), the products can also be analyzed by NMR using a chiral shift reagent to determine the percentages of each of the enantiomers present in the ethyl 3-hydroxybutanoate produced in the chiral reduction. 

Chiral gas chromatography will provide a direct measure of amounts of each stereoisomer present in your chiral ethyl 3-hydroxybutanoate sample. A Varian CP-3800 equipped with an Alltech Cyclosil B capillary column (30 m, 0.25-mm ID, 0.25 /xm) provides an excellent separation of (R) and (S)-enantiomers. Set the FID detector at 270°C and the injector temperature at 250°C, with a 50 1 split ratio. Set the column oven temperature at 90°C and hold at that temperature for 20 minutes. The helium flow rate is 1 mL/min. The compounds elute in the following order ethyl (S)-3-hydroxybutanoate (14.3 min) and the (R)-enantiomer (15.0 min). Any remaining ethyl acetoacetate present in the sample will produce a peak with a retention time of 14.1 minutes. Your observed retention times may vary from those given here, but the order of elution will be the same. Calculate the percentages of each of the enantiomers from the chiral gas chromatography results. Usually, about 92-94% of the (S)-enantiomer is obtained from the reduction. 

Fill a 0.5-dm polarimeter cell with your chiral hydroxyester (about 2 mL required). You may need to combine your product with material obtained by one other student in order to have enough material to fill the cell. Determine the observed optical rotation for the chiral material. Your instructor will show you how to use the polarimeter. Calculate the specific rotation for your sample using the equation provided in Technique 23. The concentration value, c, in the equation is 1.02 g/mL. Using the published value for the specific rotation of ethyl (S)-(-l-)-3-hydroxybutanoate of [ d ] = +43.5°, calculafe fhe optical purity (enantiomeric excess) for your sample (see Technique 23, Section 23.5). Report the observed rotation, the calculated specific rotation, the optical purity (enantiomeric excess), and the percentages of each of the enantiomers to the instructor. How do the percentages of each of the enantiomers calculated from the polarimeter measurement compare to the values obtained from chiral gas chromatography ... 

In Experiment 28A, the yeast reduction of ethyl acetoacetate forms a product that is predominantly the (S)-enantiomer of ethyl 3-hydroxybutanoate. In this part of the experiment, we will use NMR to determine the percentages of each of the enantiomers in the product. The 300 MHz proton NMR spectrum of racemic ethyl 3-hydroxybutanoate is shown in Figure 1. The expansions of fhe individual patterns from Figure 1 are shown in Figure 2. The methyl protons (HJ appear as a doublet at 1.23 ppm, and the methyl protons (H, ) appear as a triplet at 1.28 ppm. The methylene protons (H and H ) are diastereotopic (nonequivalent) and appear at 2.40 and 2.49 ppm (each a doublet of doublefs). The hydroxyl group appears at about 3.1 ppm. The quartet at 4.17 ppm results from the methylene protons (HJ split by the protons (Hjj).The methane proton (H ) is buried under the quartet at about 4.2 ppm. 

This experiment requires the use of a high-field NMR spectrometer in order to obtain sufficient separation of peaks for the two enantiomers. The chiral shift reagent does cause some peak broadening, so care should be taken not to add too much of this reagent to the chiral ethyl 3-hydroxybutanoate sample. A 0.035-g sample of the chiral material and 8-11 mg of chiral shift reagent should be sufficient to give good results. 

Would you expect to see a difference in retention times for the ethyl (S)-3-hydroxybutanoate and the (R)-enantiomer on gas chromatography columns described in Technique 22 ... 

FIGURE 7.19 The structures of the enantiomers in a racemic mixture of ethyl 3-hydroxybutanoate. 

The following chiral reagents were employed for diastereomer formation before sample application and chromatography on silica gel or silica gel G TLC plates (L)-leucine Af-carboxyanhydride for D,L-dopa-carboxyl- " C separated with ethyl acetate/formic acid/water (60 5 35) mobile phase and detected by ninhydrin [7 f 0.38 (d)/0.56 (l)] [43] Af-trifluoroacetyl-L-prolyl chloride for D,L-amphetamine separated with chloroform/methanol (197 3) and detected by sulfuric acid/formaldehyde (10 1) (Rf 0.49 (d)/0.55 (l)) [44] Af-benzyloxycarbonyl-L-prolyl chloride for D,L-methamphetamine separated with n-hexane/ethyl acetate/acetonitrile/diisopropyl ether (2 2 2 1) and detected by sulfuric acid/formaldehyde (10 1) [/ f 0.57 (l)/0.61 (d)] [44] (l/ ,2/ )-(-)-l-(4-nitrophenyl)-2-amino-1,3-propanediol (levobase) and its enantiomer dextrobase for chiral carboxylic acids separated with chloroform/ethanol/acetic acid (9 1 0.5) and detected under UV (254 nm) light R[ values 0.63 and 0.53 for 5- and / -naproxen, respectively) [45] (5)-(4-)-a-methoxyphenylacetic acid for R,S-ethyl-4-(dimethylamino)-3-hydroxybutanoate (carnitine precursor) with diethyl ether mobile phase [/ f 0.55 R)/0J9 (5)] [46] and (5)-(4-)-benoxaprofen chloride with toluene/acetone (100 10, ammonia atmosphere) mobile phase and fluorescence visualization (Zeiss KM 3 densitometer 313 nm excitation, 365 nm emission) (respective R values of R- and 5-isomers of metoprolol, oxprenolol, and propranolol were 0.24/0.28, 0.32/0.38, and 0.32/0.39) [47]. 

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