(S)-4-Benzyl-2,2,5,5-tetramethyloxazolidine

[144899-42-3]  · C14H21NO  · (S)-4-Benzyl-2,2,5,5-tetramethyloxazolidine  · (MW 219.33)

(chirality-controlling auxiliary1)

Physical Data: colorless liquid; IR,2 1H NMR,1 and 13C NMR2 spectra are available.

Solubility: very sol in most organic solvents; decomposition occurs in protic solvents.

Handling, Storage, and Precautions: decomposes on silica gel column chromatography; recommended not to be stored for a long time.

Introduction.

(S)-4-Benzyl-2,2,5,5-tetramethyloxazolidine is used as a chirality-controlling auxiliary. Its amide derivatives preferentially occupy the syn conformation1 so that one of the p-facial reaction sites of the amide moiety becomes sterically less hindered. This chiral auxiliary will be especially useful for the asymmetric reactions which have to be performed in the absence of metallic additives.

Preparation and Stability.

Since N-unsubstituted oxazolidines are labile to hydrolysis, they should be transformed immediately after preparation to amide derivatives, which show much higher stability. Thus reaction of (S)-3-amino-2-methyl-4-phenyl-2-butanol3 with acetone in the presence of a catalytic amount of p-Toluenesulfonic Acid produces (S)-4-benzyl-2,2,5,5-tetramethyloxazolidine. N-Acylation using acryloyl, cinnamoyl, and propanoyl chloride (Et3N, -78 °C) gives the corresponding amides. The N-crotonoyl derivative is better obtained by the crotonoylation of (S)-3-amino-2-methyl-4-phenyl-2-butanol followed by acetalization with (Me)2C(OMe)2.

Unsaturated Amides.

Cycloaddition of (S)-3-acryloyl-4-benzyl-2,2,5,5-tetramethyloxazolidine with Benzonitrile Oxide proceeds smoothly at 0 °C to provide the corresponding oxazolidine in a 93:7 diastereomer ratio (eq 1),4 which is quantitatively reduced with Lithium Triethylborohydride to give the isoxazoline-5-methanol derivative without loss of enantiomeric purity. A single diastereomer of isoxazoline can be obtained when 3-acryloyl-2,2-dimethyl-4-diphenylmethyloxazolidine is employed.4

Conjugate additions of organocuprates to (S)-4-benzyl-3-crotonoyl-2,2,5,5-tetramethyloxazolidine in the presence of Chlorotrimethylsilane (1.2 equiv) also proceed in a highly diastereoselective manner (eq 2) to give, after the acid-catalyzed hydrolytic removal of the chiral auxiliary, optically pure carboxylic acids with b-chirality.5

Amide Enolates.

The lithium (Z)-enolate can be generated from (S)-4-benzyl-3-propanoyl-2,2,5,5-tetramethyloxazolidine and Lithium Diisopropylamide in THF at -78 °C. Its alkylations6 take place smoothly in the presence of Hexamethylphosphoric Triamide with high diastereoselectivity (eq 3), and its Michael additions7 to a,b-unsaturated carbonyl compounds are also exclusively diastereoselective (eq 4). Synthetic applications have been made in the aldol reactions of the titanium (Z)-enolates of a-(alkylideneamino) esters.8


1. Kanemasa, S.; Onimura, K. T 1992, 48, 8631.
2. IR (neat) 3350, 2950, 1410, 1360, 1100, and 800 cm-1; 13C NMR (CDCl3) d = 23.21, 27.37, 28.52, 29.60, 35.95, 67.04, 80.66, 92.75, 128.48, 128.62, 128.71, and 139.00.
3. (S)-3-Amino-2-methyl-4-phenyl-2-butanol is available from (S)-phenylalanine and MeMgI (4 equiv): diethyl ether, rt, 5 h, 58%.
4. Kanemasa, S.; Onimura, K. T 1992, 48, 8645.
5. Kanemasa, S.; Suenaga, H.; Onimura, K. JOC 1994, in press.
6. Kanemasa, S.; Ueno, K.; Kikkawa, T.; Onimura, K. Unpublished results.
7. Nomura, M.; Kanemasa, S.; Yoshinaga, S. Unpublished results.
8. Kanemasa, S.; Mori, T.; Tatsukawa, A. TL 1993, 34, 8293.

Shuji Kanemasa

Kyushu University, Kasuga, Japan



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