· (MW 135.23)
(chiral reagent for the resolution of racemic acids and aldehydes; chiral directing group for the enantioselective conjugate addition of ketones)
Alternate Names: (+)-amphetamine; d-amphetamine; dexamphetamine; dextroamphetamine.
Physical Data: bp 200-203 °C; d 0.913 g cm-3; [a]19D +38° (benzene); mp (HCl salt) 154-155 °C.3
Solubility: readily sol all common organic solvents and acids; slightly sol water.
Form Supplied in: the free base (1) is a colorless liquid. A number of salts of (1) and its enantiomer (including the hydrochloride and sulfate) are commercially available.
Preparative Methods: enantiomerically pure (1) can be obtained by resolution of racemic (1) with (+)-tartaric acid.4 Several highly stereospecific syntheses have been described.5
Analysis of Reagent Purity: enantiomeric and chemical purity of the reagent can be assayed by GC or HPLC analysis of its (S)-(-)-a-Methoxy-a-(trifluoromethyl)phenylacetic Acid amide.3,6
Handling, Storage, and Precautions: the reagent is a central stimulant and should be handled with gloves in a well-ventilated hood. Both the free base and its salts are stable at room temperature for extended periods of time.
Reagent for the Resolution of Carboxylic Acids.
Reagent (1) and its enantiomer have been used, although not as extensively as the more common (S)-a-Methylbenzylamine, as resolving agents for carboxylic acids via fractional crystallization of the corresponding diastereomeric salts.7 Examples of acids resolved this way include (2)-(6).8-10 Additional examples, such as mandelic, hydratopic, and a-aryloxypropionic acids, can be found in the literature.11,12
Resolution of Asymmetric Aldehydes.
The resolution of the aldehyde-containing natural product (±)-gossypol has been accomplished by chromatographic separation of (7), the diastereomeric condensation product between (1) and gossypol hexaacetate.13 Other chiral primary amines commonly used for the resolution of aldehydes and ketones by physical separation of diastereomeric imines include 2-amino-1-butanol, a-methylbenzylamine, and Betti's base (8).14,15
Stereoselective Synthesis of Biaryl Compounds.
The best known application of (1) to the asymmetric oxidative coupling of phenolic compounds is the copper(II)-catalyzed synthesis of 1,1´-binaphthyl-2,2´-diol in greater than 95% ee (eq 1).16,17
Enantioselective Conjugate Additions.
The use of chiral imines for the enantioselective conjugate addition of carbonyl compounds to a,b-unsaturated systems is well established, mostly with imines derived from a-methylbenzylamine.18-20 Recently, (1) has been used to effect the Michael addition of a 4-piperidone to acrylonitrile and methyl acrylate (eq 2).21
- 1. Leithe, W. CB 1932, 65, 660.
- 2. (a) Karrer, P.; Ehrhardt, K. HCA 1951, 34, 2202. (b) Smith, H. E.; Cook, S. L.; Warren, M. E., Jr. JOC 1964, 29, 2265.
- 3. Buckley, T. F., III; Rapoport, H. JACS 1981, 103, 6157.
- 4. (a) Ernst, R. E.; O'Connor, M. J.; Holm, R. H. JACS 1968, 90, 5735. (b) &CCbreve;ervinka, O.; Kroupová, E.; B&ebreve;lovský, O. CCC 1968, 33, 3551.
- 5. (a) Denmark, S. E.; Weber, T.; Piotrowski, D. W. JACS 1987, 109, 2224. (b) Rangaishenvi, M. V.; Singaram, B.; Brown, H. C. JOC 1991, 56, 3286.
- 6. Dale, J. A.; Dull, D. L.; Mosher, H. S. JOC 1969, 34, 2543.
- 7. Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates and Resolutions; Wiley: New York, 1981.
- 8. Wilen, S. H. Tables of Resolving Agents and Optical Resolutions; Univ. of Notre Dame Press: Notre Dame, IN, 1972.
- 9. Fredga, A. ACS 1969, 23, 2216.
- 10. Buttrey, J. D.; Jones, A. S.; Walker, R. T. T 1975, 31, 73.
- 11. Beckett, A. H.; Choulis, N. H. JPS 1966, 55, 1155.
- 12. Leclercq, M.; Jacques, J. BSF(2) 1975, 2052.
- 13. Kai, Z. D.; Kang, S. Y.; Ke, M. J.; Jin, Z.; Liang, H. CC 1985, 168.
- 14. Wilen, S. H. Top. Stereochem. 1971, 6, 107.
- 15. Betti, M. OSC 1941, 1, 381.
- 16. Brussee, J.; Jansen, A. C. A. TL 1983, 24, 3261.
- 17. Trost, B. M.; Murphy, D. J. OM 1985, 4, 1143.
- 18. (a) Ambroise, L.; Chassagnard, C.; Revial, G.; d'Angelo, J. TA 1991, 2, 407. (b) d'Angelo, J.; Revial, G.; Volpe, T.; Pfau, M. TL 1988, 29, 4427.
- 19. (a) Pfau, M.; Revial, G.; Guingant, A.; d'Angelo, J. JACS 1985, 107, 273. (b) Revial, G. TL 1989, 30, 4121.
- 20. (a) Desmaële, D. T 1992, 48, 2925. (b) Desmaële, D.; d'Angelo, J. TL 1989, 30, 345.
- 21. Gaidarova, E. L.; Grishina, G. V. SL 1992, 89.
Juan C. Jaen
Parke-Davis Pharmaceutical Research, Ann Arbor, MI, USA
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