An Improved Procedure for Asymmetric Aldol Additions with N-Acyl Oxazolidinones, Oxazolidinethiones and Thiazolidinethiones

Abstract

Asymmetric aldol additions using chlorotitanium enolates of N-acyl oxazolidinones, oxazolidinethiones and thiazoli­dinethiones proceed with high diastereoselectivity for the ‘Evans syn’ product using one equivalent of titanium tetrachloride, one equivalent of diisopropylethylamine and one equivalent of N-methyl-2-pyrrolidinone. Typical selectivities of 94:6 to >98:2 were obtained using N-propionyl oxazolidinones, oxazolidinethiones and thiazolidinethiones at 0 °C with stoichiometric amounts of aldehyde. Glycolate imides also gave high selectivities and high yields using this procedure.

aldol reactions - asymmetric synthesis - titanium enolates - imides - glycolates

References

1a Walker MA. Heathcock CH. J. Org. Chem.  1991,  56:  5747 

1b Arya P. Qin H. Tetrahedron  2000,  56:  917 

1c Ager DJ. Prakash I. Schaad DR. Aldrichimica Acta  1997,  30:  3 

1d Velazquez F. Olivo HF. Curr. Org. Chem.  2002,  6:  303 

1e Evans DA. Shaw JT. Actualité Chimique  2003,  35 

For selected examples see:

2a Evans DA. Kaldor SW. Jones TK. Clardy J. Stout TJ. J. Am. Chem. Soc.  1990,  112:  7001 

2b Evans DA. Gage JR. Leighton JL. J. Am. Chem. Soc.  1992,  114:  9434 

2c Evans DA. Ng HP. Rieger DL. J. Am. Chem. Soc.  1993,  115:  11446 

2d Evans DA. Fitch DM. J. Org. Chem.  1997,  62:  454 

2e Evans DA. Kim AS. Metternich R. Novack VJ. J. Am. Chem. Soc.  1998,  120:  5921 

2f Crimmins MT. King BW. J. Am. Chem. Soc.  1998,  120:  9084 

2g Crimmins MT. King BW. J. Org. Chem.  1996,  61:  4192 

2h Crimmins MT. Katz JD. Washburn DG. Allwein SP. MacAtee LF. J. Am. Chem. Soc.  2002,  124:  5661 

3 Evans DA. Bartroli J. Shih TL. J. Am. Chem. Soc.  1981,  103:  2127 

4 Evans DA. Rieger DL. Bilodeau MT. Urpi F. J. Am. Chem. Soc.  1991,  113:  1047 

5a Nerz-Stormes M. Thornton ER. J. Org. Chem.  1991,  56:  2489 

5b Bonner MP. Thornton ER. J. Am. Chem. Soc.  1991,  113:  1299 

6a Yan T.-H. Tan C.-W. Lee H.-C. Lo H.-C. Huang T.-Y. J. Am. Chem. Soc.  1993,  115:  2613 ; and references therein

6b Yan T.-H. Hung A.-W. Lee H.-C. Chang C.-S. Liu W.-H. J. Org. Chem.  1995,  60:  3301 

7a Nagao Y. Hagiwara Y. Kumagai T. Ochiai M. Inoue T. Hashimoto K. Fujita E. J. Org. Chem.  1986,  51:  2391 

7b Hsiao C.-N. Liu L. Miller MJ. J. Org. Chem.  1987,  52:  2201 

8a Crimmins MT. King BW. J. Am. Chem. Soc.  1998,  120:  9084 

8b Crimmins MT. Chaudhary K. Org. Lett.  2000,  2:  775 

9 Crimmins MT. King BW. Tabet EA. Chaudhary K. J. Org. Chem.  2001,  66:  894 

10a Zhang W. Carter RG. Yokochi AFT. J. Org. Chem.  2004,  69:  2569 

10b Crimmins MT. McDougall PJ. Org. Lett.  2003,  5:  591 

10c Ambhaikar NB. Snyder JP. Liotta DC. J. Am. Chem. Soc.  2003,  125:  3690 

10d Guz NR. Phillips AJ. Org. Lett.  2002,  4:  2253 

11

Typical Procedure for Formation of Evans syn Adducts from N -Propionylimides 1a, 1b, and 1c. To a dry round-bottom flask under argon was added 1.00 mmol of the appropriate N-acyloxazolidinone, N-acyloxazolidinethione, or N-propionylthiazolidinethione, and 10 mL CH₂Cl₂. After cooling to 0 °C, TiCl₄ (0.115 mL, 1.05 mmol) was added dropwise and the solution was allowed to stir for 15 min. Diisopropylethylamine (0.191 mL, 1.10 mmol) was added dropwise to the mixture and the solution was allowed to stir for 40 min. 1-Methyl-2-pyrrolidinone (0.096 mL, 1.00 mmol for N-acyloxazolidinone and N-acyloxazolidinethione; 0.192 mL, 2.00 mmol for N-propionylthiazolidinethione) was added at 0 °C and the mixture was stirred for an additional 10 min. Freshly distilled aldehyde (1.10 mmol) was then added directly to the enolate. The reaction was allowed to stir for 1-2 h followed by addition of half-sat. NH₄Cl. The organic layer was separated and the aqueous layer extracted twice with CH₂Cl₂. The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The initial product mixture was analyzed by ¹H NMR followed by purification by column chromatography.

12a Crimmins MT. Choy AL. J. Org. Chem.  1997,  62:  7548 

12b Crimmins MT. Choy AL. J. Am. Chem. Soc.  1999,  121:  5663 

12c Crimmins MT. Tabet EA. J. Am. Chem. Soc.  2000,  122:  5473 

12d Crimmins MT. King BW. Zuercher WJ. Choy AL. J. Org. Chem.  2000,  65:  8499 

12e Crimmins MT. Emmitte KA. Choy AL. Tetrahedron  2002,  58:  1817 

13

The use of 2.5 equiv of diisopropylethylamine for N-glycolylimides (compared to the use of 1.1 equiv of diisopropylethylamine forN-propionyl imides) improved the levels of conversion in the aldol reaction.

14

Typical Procedure for Formation of Evans syn Adducts from N -Glycolylimides. To a dry round-bottom flask under argon was added 1.00 mmol of the appropriate N-acyloxazolidone, N-acyloxazolidinethione, or N-propionylthiazolidinethione, and 10 mL CH₂Cl₂. After cooling to -78 °C, TiCl₄ (0.115 mL, 1.05 mmol) was added dropwise and the solution was allowed to stir for 15 min. Diisopropylethylamine (0.434 mL, 2.50 mmol) was added dropwise to the mixture and the solution was allowed to stir for 1-2 h. 1-Methyl-2-pyrrolidinone (0.096 mL, 1.00 mmol) was added at -78 °C and the mixture was stirred for an additional 10 min. Freshly distilled aldehyde (2.00-4.00 mmol) was then added directly to the enolate. The reaction was allowed to stir for 1-2 h at -78 °C and then warmed to -40 °C for 1-2 h followed by addition of half-sat. NH₄Cl. The organic layer was separated and the aqueous layer extracted twice with CH₂Cl₂. The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The initial product mixture was analyzed by ¹H NMR followed by purification by column chromatography.