4-(1-Methylethyl)-3-(1-oxoethyl)-2-thiazolidinethione

[102979-45-7]  · C8H13NOS2  · (MW 203.32)

(chiral auxiliary for asymmetric alkylation and acetate aldol additions)

Solubility: soluble in most organic solvents.

Form Supplied in: yellow oil.

Handling, Storage, and Precautions: no special precautions necessary.

Synthesis of the Chiral Thiazolidinethione Auxiliary1

Typical procedure to synthesize the chiral auxiliary involves reducing the corresponding amino acid to the amino alcohol, followed by conversion to the thiazolidinethione. Most commonly, sodium borohydride/iodine is utilized for reduction of the amino acid to the amino alcohol.1,2 Subsequent formation of the thiazolidinethione is performed by heating with carbon disulfide in 1 M aqueous KOH solution.1,3

Methods of N-Acylation

Thiazolidinethiones are readily converted to the N-acetyl derivative through acylation with acetyl chloride. This conversion can be accomplished either via the lithium salt of the thiazolidinethione or by using triethylamine.4

This transformation can also be performed using the thiazolidinethione, acetic acid, dimethylaminopyridine (DMAP), and dicyclohexylcarbodiimide (DCC) at room temperature.4b

Enolization of N-Acylthiazolidinethiones

Formation of the tin(II) enolate is most commonly performed in methylene chloride with tin triflate (Sn(OTf)2) and N-ethylpiperidine. The tin enolates are most commonly used because of their wide generality. Enolization of N-acylthiazolidinethiones to their titanium enolates has also been accomplished.5 Typically, treatment of the N-acetylthiazolidinethione with titanium tetrachloride and Hunig's base readily effects enolization. The titanium enolates appear to be somewhat less general than the tin (II) enolates and give the best results with a,b-unsaturated aldehydes.

Enolate Alkylation

Alkylation of chiral N-acetylthiazolidinethiones by cyclic acyl iminium ions through the tin (II) enolate readily occurs to afford syn products in >93% de (eqs 3 and 4).6,7

Acetate Aldol Reactions

The tin enolates of acetylthiazolidinethiones readily react with aldehydes to form the syn (secondary hydroxyl syn to the alkyl group on the thiazolidinethione) aldol adducts with high stereoselectivity. The source of this high selectivity has been proposed to be the result of a highly ordered chelated transition state.1

Reaction with a wide variety of aldehydes results in efficient conversion to the desired aldol adducts. Syn-aldol adducts are always formed selectively, therefore using either (R) or (S) auxiliary may allow access to either enantiomer of the resultant alcohol. Addition of the tin enolate of N-acetylthiazolidinethiones to aliphatic aldehydes gives the aldol adduct in high yields and stereoselectivities (eqs 5-7).8-10

Aldol additions of N-acetylthiazolidinethiones with a,b-unsaturated aldehydes proceed efficiently with high levels of stereocontrol (eqs 8-14). The tin(II) enolization conditions are also mild enough to accommodate most protecting groups.11-15

Aldol additions of N-acetylthiazolidinethiones under titanium enolization conditions have also been performed.5

Cleavage of the Chiral Auxiliary

N-acetylthiazolidinethiones are readily cleaved to a variety of products. Subjecting aldol products to sodium borohydride or diisobutylaluminum hydride yields the alcohol or aldehyde, respectively (eqs 15, 16).16,8

Conversion to the carboxylic acid is readily achieved through the use of imidazole followed by citric acid (17).7

Cleavage of the thiazolidinethione directly to the beta-Ketophosphonate ester can be performed with lithiated dimethyl methylphosphonate (18).14


1. Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.; Inoue, T.; Hashimoto, K., J. Org. Chem. 1986, 51, 2391.
2. McKennon, M. J.; Meyers, A. I., J. Org. Chem. 1993, 58, 3568.
3. Delaunay, D.; Toupet, L.; Le Corre, M., J. Org. Chem. 1995, 60, 6604.
4. (a) Nagao, Y.; Dai, W.; Ochiai, M.; Shiro, M., J. Org. Chem. 1989, 54, 5211. (b) Nagao, Y.; Dai, W.; Ochiai, M.; Tsukagoshi, S.; Fujita, E., J. Org. Chem. 1990, 55, 1148. (c) Crimmins, M. T.; Chaudhary, K., Org. Lett. 2000, 2, 775.
5. (a) Crimmins, M. T.; Emmitte, K. A., Org. Lett. 1999, 1, 2029. (b) Gonzalez, A.; Aiguade, J.; Urpi, F.; Vilarrasa, J., Tetrahedron Lett. 1996, 37, 8949.
6. Matsunaga, H.; Kumagai, T.; Inoue, Y.; Nagao, Y., Heterocycles 1994, 39, 859.
7. Nagao, Y.; Kumagai, T.; Nagase, Y.; Tamai, S.; Inoue, Y.; Shiro, M., J. Org. Chem. 1992, 57, 4232.
8. Sano, S.; Kobayashi, Y.; Kondo, T.; Takebayashi, M.; Maruyama, S.; Fujita, T.; Nagao, Y., Tetrahedron Lett. 1995, 36, 2097.
9. Paquette, L. A.; Zuev, D., Tetrahedron Lett. 1997, 38, 5115.
10. Sugiyama, H.; Yokokawa, F.; Shioiri, T., Org. Lett. 2000, 2, 2149.
11. Romo, D.; Rzasa, R. M.; Shea, H. A.; Park, K.; Langenhan, J. M.; Sun, L.; Akhiezer, A.; Liu, J., J. Am. Chem. Soc. 1998, 120, 12237.
12. Cuzzupe, A.; Hutton, C. A.; Lilly, M. J.; Mann, R. K.; Rizzacasa, M. A.; Zammit, S. C., Org. Lett. 2000, 2, 191.
13. Efremov, I.; Paquette, L. A., J. Am. Chem. Soc. 2000, 122, 9324.
14. Astles, P. C.; Thomas, E. J., J. Chem. Soc. Perkin Trans 1. 1997, 845.
15. Arai, M.; Morita, N.; Aoyagi, S.; Kibayashi, C., Tetrahedron Lett. 2000, 41, 1199.
16. Nagao, Y.; Kawabata, K.; Seno, K.; Fujita, E., J. Chem. Soc. Perkin 1. 1980, 2470.

Michael T. Crimmins & Kleem Chaudhary

University of North Carolina at Chapel Hill, NC, USA



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