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Synlett 2004(8): 1371-1374  
DOI: 10.1055/s-2004-825626
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Michael T. Crimmins, Jin She
Department of Chemistry, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA
Fax: +1(919)9622388; e-Mail: crimmins@email.unc.edu;
Further Information

Publication History

Received 30 April 2004
Publication Date:
08 June 2004 (online)

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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.

Key words

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

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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.

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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.

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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.