Ethyl 3-Hydroxybutanoate1,2


[24915-95-5]  · C6H12O3  · Ethyl 3-Hydroxybutanoate  · (MW 132.18) (S)


(chiral building block; stereoselective substitution of the dianion at C-2 by electrophiles3)

Alternate Name: ethyl 3-hydroxybutyrate.

Physical Data: bp 71-73 °C/12 mmHg;2 [a]20D +41.3° (c 1, CHCl3) (97% ee);4 [a]24D -43.6° (c 1.2, CHCl3);1 [a]24D -19.05° (neat) (100% ee).1

Solubility: sol common organic solvents such as ether, THF, n-hexane, CH2Cl2, EtOH, and also in water.

Form Supplied in: colorless liquid.

Analysis of Reagent Purity: NMR and optical rotation ([a]D).

Preparative Methods: reduction of Ethyl Acetoacetate with Baker's Yeast2,4-6 yields the (S)-(+) enantiomer; reduction with Geotrichum candidum4,7 yields the (R)-(-) enantiomer. The (R)-(-) enantiomer was also prepared1 by depolymerization of poly-(R)-3-hydroxybutyric acid (PHB). Both enantiomers can be prepared by chemical reduction using a ruthenium catalyst complexed with (S)- and (R)-BINAP, respectively.8,9 The yeast reduction of ethyl acetoacetate has been varied: in petroleum ether (58%, 94% ee),10 in the presence of ethyl chloroacetate (75%, 99% ee),10,11 immobilized by magnesium alginate and under high concentration of Mg2+ ion (65%, 99% ee),13 immobilized by calcium alginate in organic-water solvent system.14

Chemical reductions with Sodium Borohydride-L-tartaric acid15 ((R)-(-), 65%, 81% ee) and with a chiral oxazaphospholidine-borane complex16 ((R)-(-), 80%, 99% ee) have been published.

Purification: the enrichment of the (S)-(+) enantiomer to 100% enantiomeric purity by means of the 3,5-dinitrobenzoate has been described.2,17

Handling, Storage, and Precautions: should be stored in a refrigerator because of possible transesterification-oligomerization at room temperature.2

Dianion Alkylation.

b-Hydroxy carboxylates can be converted to their corresponding dianions through deprotonation of the hydroxy group and the a-carbon atom.18,19 The so-formed double charged enolates are relatively stable species and can efficiently react with electrophiles in the a-position. The dianions of (3R)- and (3S)-ethyl 3-hydroxybutanoate were prepared3,20 by lithiation with 2 equiv of Lithium Diisopropylamide in THF at -50 to -70 °C and 1 equiv of an alkyl halide was added, often in the presence of HMPA at -75 to 0 °C. The usual yield is 70-90%, and the stereoselectivity is generally better than 95:5 in favor of the anti isomer (eq 1).

Alkylations with Iodomethane,3,21-24 Allyl Bromide,3,20 Benzyl Bromide,3 n-butyl bromide,20 dimethylallyl bromide,25 Benzyl Chloromethyl Ether,26,27 (S)-2-methylbutyl iodide,29 and (benzene)Mn(CO)3+PF629 have been reported.

The mechanistic explanation for the ~20:1 stereoselection is the formation of a chelate as depicted in (1), where the approach of the electrophile is more favorable anti to the sterically more demanding Me (or alkyl) group.

This method of dianion alkylation is an important and reliable preparative way to control the vicinal stereochemistry; the method is especially valuable, because both (R) and (S) starting materials are commercially available, although quite expensive, or may be easily prepared.

Dianion Amination.

The electrophilic amination has been carried out with the synthetic equivalent of [NH2+], i.e. Di-t-butyl Azodicarboxylate (TBAD) (eq 2).30,31 The initially formed 94:6 mixture of the a-hydrazino-b-hydroxy ester was transformed into the a-amino-b-hydroxy derivative,30 and was also used in the total synthesis of an amino sugar.32

Reaction of the Dianion with Imines: Formation of b-Lactams.

The dianions of (R)- and (S)-ethyl 3-hydroxybutyrate have been added to different imines, yielding in one step the b-lactam, a precursor for, e.g. thienamycin (eq 3).33-37

A very clean and highly stereoselective reaction has been achieved with the Zn/Li dianion and N-trimethylsilylphenylpropargylidene imine and the corresponding cinnamylidene imine (eq 4). Only one isomer was observed out of the four possible in yields of 85% and 78%, respectively.38

Other Esters and General Remarks.

The dianion chemistry of 3-hydroxy esters is of a very broad utility and synthetic importance.39 Beside the cases above, a large variety of alkylations of 3-hydroxy ester dianions has been reported, e.g. (S)-dialkyl 2-hydroxysuccinate (malate)40-42 and other examples.3,43-45 It is of major importance to realize that a second alkylation allows the enantioselective preparation of a quaternary carbon center.3,20,46-48 This is obviously also the case when cyclic analogs, such as (1R,2S)-ethyl 2-hydroxycyclohexanecarboxylates (eq 5), 95:5 de),49 are alkylated by means of the dianion.49-51

Related Reagents.

(R)-2-t-Butyl-6-methyl-4H-1,3-dioxin-4-one; Di-t-butyl Azodicarboxylate; Ethyl Acetoacetate.

1. Seebach, D.; Züger, M. HCA 1982, 65, 495.
2. Seebach, D.; Suter, M. A.; Weber, R. H.; Züger, M. F. OSC 1984, 7, 215.
3. Fráter, G.; Müller, U.; Günther, W. T 1984, 40, 1269.
4. Wipf, B.; Kupfer, E.; Bertazzi, R.; Leuenberger, H. G. W. HCA 1983, 66, 485.
5. Deol, B. S.; Ridley, D. D.; Simpson, G. W. AJC 1976, 29, 2459.
6. Fráter, G. HCA 1979, 62, 2825.
7. Buisson, D.; Azerad, R.; Sanner, C.; Larcheveque, M. Biocatalysis 1992, 5, 249.
8. (a) Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.; Kumobayashi, H.; Akutagawa, S. JACS 1987, 109, 5586. (b) Kitamura, M.; Tokunaga, M. Ohkuma, T.; Noyori, R. OS 1993, 71, 1.
9. Keck, G. E.; Murry, J. A. JOC 1991, 56, 6606.
10. Jayasingh, L. Y.; Smallridge, A. J.; Trewhella, M. A. TL 1993, 34, 3949.
11. Nakamura, K.; Kawai, Y.; Ohno, A. TL 1990, 31, 267.
12. Nakamura, K.; Kawai, Y.; Nakajima, N.; Ohno, A. JOC 1991, 56, 4778.
13. Nakamura, K.; Kawai, Y.; Oka, S.; Ohno, A. TL 1989, 30, 2245.
14. Naoshima, Y.; Nishiyama, T.; Munakata, Y. CL 1989, 1517.
15. Yatagai, M.; Ohnuki, T. JCS(P1) 1990, 1826.
16. Brunel, J.-M.; Pardigon, O.; Faure, B.; Buono, G. CC 1992, 287.
17. Hungerbühler, E.; Seebach, D.; Wasmuth, D. HCA 1981, 64, 1467.
18. Herrmann, J. L.; Schlessinger, R. H. TL 1973, 2429.
19. Kraus, G. A.; Taschner, M. J. TL 1977, 4575.
20. Fráter, G. HCA 1979, 62, 2825.
21. Suter, M. A.; Seebach, D. LA 1983, 939.
22. Mori, K.; Ebata, T. T 1986, 42, 4413; Mori, K.; Takikawa, H. T 1990, 46, 4473.
23. Brooks, D. W.; Kellog, R. P. TL 1982, 23, 4991.
24. Keck, G. E.; Kachensky, D. F.; Enholm, E. J. JOC 1985, 50, 4317.
25. Kramer, A.; Pfander, H. HCA 1982, 65, 293.
26. Hatakeyama, S.; Ochi, N.; Numata, H.; Takano, S. CC 1988, 1202.
27. Ireland, R. E.; Wardle, R. B. JOC 1987, 52, 1780.
28. Caldwell, C. G.; Rupprecht, K. M.; Bondy, S. S.; Davis, A. A. JOC 1990, 55, 2355.
29. Miles, W.; Smiley, P. M.; Brinkman, H. R. CC 1989, 1987.
30. Guanti, G.; Banfi, L.; Narisano, E. T 1988, 44, 5553.
31. Genet, J. P.; Juge, S.; Mallart, S. TL 1988, 29, 6765.
32. Guanti, G.; Banfi, L.; Narisano, E.; Riva, R. TL 1992, 33, 2221.
33. (a) Georg, G. I. TL 1984, 25, 3779. (b) Georg, G. I.; Gill, H. S.; Gerhardt, C. TL 1985, 26, 3903.
34. (a) Ha, D.-C.; Hart, D. J.; Yang, T.-K. JACS 1984, 106, 4819. (b) Hart, D. J.; Ha, D.-C. TL 1985, 26, 5493.
35. (a) Chiba, T.; Nagatsuma, M.; Nakai, T. CL 1984, 1927. (b) Chiba, T.; Nakai, T. CL 1985, 651.
36. Hatanaka, M.; Nitta, H. TL 1987, 28, 69.
37. Cainelli, G.; Panunzio, M.; Basile, T.; Bongini, A.; Giacomini, D.; Martelli, G. JCS(P1) 1987, 2637.
38. Oguni, N.; Ohkawa Y. CC 1988, 1376.
39. Seebach, D.; Roggo, S.; Zimmermann, J. In Stereochemistry of Organic and Bioorganic Transformations; Bartmann, W.; Sharpless, K. B. Eds.; Verlag Chemie: Weinheim, 1987; Vol. 17, p 85-126.
40. Seebach, D.; Wasmuth, D. HCA 1980, 63, 197.
41. Grossen, P.; Herold, P.; Mohr, P.; Tammer, C. HCA 1984, 67, 1625.
42. Miller, M. J., Bajwa, J. S.; Mattingly, P. G.; Peterson, K. JOC 1982, 42, 4928.
43. Still, W. C.; Romero, A. G. JACS 1986, 108, 2105.
44. Jones, A. B.; Yamaguchi, M.; Patten, A.; Danishefsky, S. J.; Ragan, J. A.; Smith, D. B.; Schreiber, S. L. JOC 1989, 54, 17.
45. Katsuki, T.; Hanomoto, T.; Yamaguchi, M. CL 1989, 117.
46. Fráter, G. TL 1981, 22, 425.
47. Uno, T.; Watanabe H.; Mori, K. T 1990, 46, 5563.
48. Wasmuth, D.; Arigoni, D.; Seebach, D. HCA 1982, 65, 344.
49. Fráter, G. HCA 1980, 63, 1383.
50. Fráter, G.; Günther, W.; Müller, U. HCA 1989, 72, 1846.
51. Kitahara, T.; Touhara, K.; Watanabe, H.; Mori, K. T 1989, 45, 6387.

Georg Fráter

Givaudan-Roure Research Ltd, Duebendorf, Switzerland

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