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

[102831-92-5]  · C9H15NOS2  · (MW 217.34)

(versatile chiral auxiliary for asymmetric alkylation and propionate aldol additions)

Solubility: soluble in most organic solvents.

Form Supplied in: yellow crystalline solid.

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 carried out by heating with carbon disulfide in 1 M aqueous KOH solution (1).1,3

Methods of N-Acylation

Thiazolidinethiones are readily converted to the N-propionyl derivative through acylation with propionyl chloride. This conversion takes place either via the lithium salt of the thiazolidinethione or by using triethylamine (2).4

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

Enolization of N-Acylthiazolidinethiones

Formation of the tin(II) enolate is most commonly carried out in methylene chloride with tin triflate [Sn(OTf)2] and N-ethylpiperidine. Titanium enolates are typically prepared by enolization of N-acylthiazolidinethiones by exposure to titanium tetrachloride and an amine base [e.g. (-)-sparteine, TMEDA, or Hunig's base].4c,5,6

Enolate Alkylation

Alkylation of chiral N-propionylthiazolidinethione by cyclic acyl imines through the tin (II) enolate readily occurs to afford syn products in 82% de (3).7

Propionate Aldol Additions: syn-Aldols

The titanium enolates of N-propionylthiazolidinethione readily react with aldehydes to form the syn-aldol adducts with high diastereoselectivity.4c Reaction with a wide variety of aldehydes results in efficient conversion to the desired aldol adducts. Access to either the Evans syn- or non-Evans syn-aldol adduct can be achieved simply by varying the amount of amine base used. The use of 1 equiv of amine results in the non-Evans syn via a highly ordered transition state. Addition of 2 equiv of (-)-sparteine [or 1 equiv of (-)-sparteine and 1 equiv of N-methylpyrrolidinone] produces the Evans syn-aldol adduct through a standard Zimmerman-Traxler transition state (4).

Propionate Aldol Additions: Anti-Aldols

Chiral thiazolidinethione-derived titanium enolates can be used in substitution reactions with dimethyl acetals to produce anti-aldol adducts with high diastereoselectivity.6 This reaction affords enantiopure anti a-methyl-b-alkoxy carbonyl compounds in a wide range of acetals (5).

Diasteroselectivities range from 81:19 to 99:1 depending on the acetal used.

Cleavage of the Chiral Auxiliary

The thiazolidinethione is readily cleaved to a variety of products. Subjecting aldol products to sodium borohydride or diisobutylaluminum hydride yields the alcohol or aldehyde, respectively (6).4c,6,8

Conversion to Weinreb amide, ester, carboxylic acid or amide is also easily accomplished under mild conditions.4c,6


1. Nagao, Y.; Hagiwara, Y.; Kumagai, T.; Ochiai, M.; Inoue, T.; Hashimoto, K., J. Org. Chem. 1986, 51, 2391-2393.
2. McKennon, M. J.; Meyers, A. I., J. Org. Chem. 1993, 58, 3568-3571.
3. Delaunay, D.; Toupet, L.; Le Corre, M., J. Org. Chem. 1995, 60, 6604-6607.
4. (a) Nagao, Y.; Dai, W.; Ochiai, M.; Shiro, M., J. Org. Chem. 1989, 54, 5211-5217. (b) Nagao, Y.; Dai, W.; Ochiai, M.; Tsukagoshi, S.; Fujita, E., J. Org. Chem. 1990, 55, 1148-1156. (c) Crimmins, M. T.; Chaudhary, K., Org. Lett. 2000, 2, 775-777.
5. Gonzalez, A.; Aiguade, J.; Urpi, F.; Vilarrasa, J., Tetrahedron Lett. 1996, 37, 8949-8952.
6. Cosp, A.; Romea, P.; Talavera, P.; Urpi, F.; Vilarrasa, J.; Font-Bardia, M.; Solans, X., Org. Lett. 2001, 3, 615-617.
7. Nagao, Y.; Nagase, Y.; Kumagai, T.; Matsunaga, H.; Abe, T.; Shimada, O.; Hayashi, T.; Inoue, Y., J. Org. Chem. 1992, 57, 4243-4249.
8. Nagao, Y.; Kawabata, K.; Seno, K.; Fujita, E., J. Chem. Soc. Perkin 1. 1980, 2470-2473

Michael T. Crimmins & Kleem Chaudhary

University of North Carolina at Chapel Hill, NC, USA



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