Ethyl-3-hydroxybutanoate

Optically pure a, . (R)-3-hydroxybutanoates can be obtained by alcoholysis of poly-(R)-3-hydroxybutanoate, a fermentation product of fructose by Alcaligones eutrophus.4 (S)-Ethyl 3-hydroxybutanoate in 84-87% ee can be synthesized in 57-67% yield on a decagram-scale by an Organic Syntheses procedure6 using bakers yeast reduction of ethyl 3-oxobutanoate with the aid of sucrose.7 In order to obtain enantioselectivity as high as 95-97% ee, the substrate concentration should be kept below 1 g/L.6... 

The silyl ketene acetal 2, prepared from ethyl 3-hydroxybutanoate, undergoes a similar condensation with benzylideneaniline but with syn-selectivity. The product cyclizes to a cis-fl-lactam (4). 

T Kometani, H Yoshii, Y Takeuchi, R Matsuno. Large-scale preparation of (S)-ethyl 3-hydroxybutanoate with a high enantiomeric excess through baker s yeast-mediated bioreduction. JFerm Bioeng 76 33-37, 1993. 

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. 

Optically active ethyl 3-hydroxybutanoate is a very useful chiral building block for natural product synthesis. Some applications are shown in Table I. Alkylation of doubly deprotonated ethyl 3-hydroxybutanoate gives branched structures of the following type ... 

NATURAL PRODUCTS FROM (S)- OR (R)-ETHYL 3-HYDROXYBUTANOATE The Skeleton of Ethyl 3-Hydroxybutanoate is Indicated by Heavy Lines... 

Dieter Seebach, Marius A. Sutter, Roland H. Weber, and Max F. Ziger 1 YEAST REDUCTION OF ETHYL ACETOACETATE (S)-(+)-ETHYL 3-HYDROXYBUTANOATE... 

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). 

Ethyl 3-Hydroxybutanoate as a Building Block for Sulcatol and Pityol. 

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 %). 

Related Reagents. (25, 45)-3-Benzoyl-2-r-butyl-4-methyl-l,3-oxazolidin-5-one (,S )-4-Benzyl-2-oxazolidinone (R,R)-2-t-Butyl-5-methyl-l,3-dioxolan-4-one 10,2-(2amphorsultam 10-Dicyclohexylsulfonamidoisobomeol (R,/J)-2,5-Dimethylboro-lane Ethyl 3-Hydroxybutanoate 2-Hydroxy-l,2,2-triphenyl-ethyl Acetate (5)-4-Benzyl-2-oxazolidinone (RJi)-l,2-Dipheny 1-1,2-diaminoethane NA( -Bis[3,5-bis(trifluoromethyl)-benzenesulfonamide] 2,2,6-Trimethy 1-4//-1,3-dioxin-4-one. 

In this experiment we will use the enzymes found in baker s yeast to reduce ethyl acetoacetate to 5( + )-ethyl 3-hydroxybutanoate. This compound is a very useful synthetic building block. At least eight chiral natural product syntheses are based on this hydroxyester. ... 

The optical purity of the product can be determined by measuring the optical rotation in a polarimeter. The specific rotation, [a], of 5( + )-ethyl 3-hydroxybutanoate has been reported to vary from +31.3° to +41.7° in chloroform. The specific rotation, [a] , of 37.2° (chloroform, C 1.3) corresponds to an enantiomeric excess of 85%. 

The nmr experiment is easily accomplished by adding 20-mg increments of tris[3-(heptafluoropropylhydroxymethylene)-( + )-campharato]-europium(III) shift reagent (Aldrich 16,474-7) to a solution of 30 mg of pure, dry ethyl 3-hydroxybutanoate in 0.3 mL of carbon tetrachloride. ... 

The 3,5-dinitrobenzoates of a racemic mixture of R- and 5-ethyl 3-hydroxybutanoate, like almost all racemates, crystallize together to give... 

ToO.5 g of the 5(+)-ethyl 3-hydroxybutanoate in a 25 mL round-bottomed flask fitted with condenser add 0.875 g of pure 3,5-dinitrobenzoyl chloride and 5 mL of pyridine. Reflux the mixture for 15 min and then transfer it with a Pasteur pipette to 20 mL of water in an Erlenmeyer flask. Remove the solvent from the crystals and shake the crystals with 10 mL of 5% sodium carbonate solution to remove dinitrobenzoic acid. Remove the bicarbonate... 

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. 

What can you say about the purity of the reduction product whose H nmr spectrum is illustrated in Fig. 1 Assign the peaks of ethyl 3-hydroxybutanoate to specific protons in the molecule. 

Figure VII. Capillary GC-separation of (R)-(+)-MTPA-derivatives of ethyl 3-hydroxybutanoate obtained by yeast reduction and after isolation from passion fruit and mango.

Reformatsky reaction. The Reformatsky reaction is normally conducted at reflux temperatures in benzene or benzene-ether as solvent. Rathke and Lindert2 studied the Reformatsky reaction of acetaldehyde and ethyl bromoacetate under various conditions the yield of ethyl 3-hydroxybutanoate obtained in benzene at... 

Ethylcyclohexene, 209 Ethyl diazoacetate, 137, 138—139, 210 Ethyl dibromoacetate, 26, 28, 236 Ethyl dichloroacetate, 26 Ethyl tram,cis,irans-3,1 l-dimethyl-7-ethyl-trideca-2,6,10-trienoate, 110 Ethyl diphenylphosphonite, 139—140 Ethylene chlorohydrin, 272 Ethylenediamine, 57 Ethylene dibromide, 159 Ethylene glycol, 274 Ethyleneketals, 140 Ethylene oxide, 140 Ethyl farnesoate, 110 Ethyl 3-hexenoate, 236 Ethyl 3-hydroxybutanoate, 310 Ethyl 3-hydroxy-3-methylbutyrate, 118 9-Ethylidenefluorene, 35 Ethylidene iodide, 141... 

Reaction of the dianion derived from ethyl 3-hydroxybutanoate with trimethylsilyl imine... 

And although mixtures of many volatile chemicals are the rule, a single chemical may instead furnish the dominant aroma. Thus, ethyl-2-methyl butyrate smells unmistakably like apple. A popcorn smell is provided by methyl-2-peridylketone. A marshmallow taste is given by adding ethyl-3-hydroxybutanoate. There is a constituent called hexanal (an aldehyde) that smells like freshly cut grass. On the other hand, body odor is approximated by 3-methyl-butanoic acid. (It may be noted that butyric acid smells like rancid butter and is considered an anticancer agent.)... 

The enantioselective hydrogenation of methyl or ethyl 3-oxobutanoate to give methyl or ethyl 3-hydroxybutanoate is a model reaction for the preparation of 3-hydroxyalkanoic acids, ail important class of compounds which comprise key intermediates in the synthesis of natural products and in the biosynthesis and metabolism of fatty acids. 

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