[2627-86-3]  · C8H11N  · (S)-a-Methylbenzylamine  · (MW 121.20)

(resolving agent for carboxylic acids;7-11 determination of enantiomeric purity of carboxylic acids;16,17 stereospecific reactions of carbonyl compounds;18 reductive amination of carbonyl compounds29,30)

Physical Data: bp 187 °C; d 0.940 g cm-3; [a]D -39° (neat).

Solubility: readily sol all organic solvents.

Form Supplied in: both enantiomers are commercially available.

Analysis of Reagent Purity: the enantiomeric purity of the reagent can be assessed by NMR analysis of the corresponding Mosher's amide.4 Chiral complexing reagents (such as 1,1-binaphthyl-2,2-diylphosphoric acid) have also been used in the direct NMR analysis of the reagent.5,6

Preparative Methods: racemic a-methylbenzylamine has been resolved utilizing chiral acids such as tartaric acid1 and (S)-(-)-carbamalactic acid,2 among others. Several stereospecific syntheses have been reported.3

Handling, Storage, and Precautions: stable at rt for extended periods of time when stored under nitrogen.

Resolving Reagent for Carboxylic Acids and Other Types of Compounds.

A large number of carboxylic acids have been resolved via their diastereomeric salts with (S)- or (R)-a-methylbenzylamine (1). The ready availability of both enantiomers of (1) guarantees access to both enantiomers of the desired acid. Compounds (2)-(6) are representative examples of acids obtained in high enantiomeric purity.7-11 Alternatively, racemic carboxylic acids have been resolved by covalent derivatization with (1) and separation of the resulting diastereomeric amides by physical means such as chromatography (eq 1)12 or fractional crystallization (eq 2).13

Racemic compounds other than carboxylic acids have also been resolved by reaction with enantiomerically pure (1) and separation of the corresponding diastereomeric mixtures by physical methods. For example, reaction of a racemic b-substituted g-butyrolactone with (1) yields a mixture of hydroxy amides, which can be separated by fractional recrystallization and chromatography (eq 3).14 Amide hydrolysis regenerates the chiral hydroxy acids, which spontaneously cyclize to produce the chiral lactones.

The displacement of a variety of leaving groups by (1) produces diastereomeric mixtures of amines, which can be separated into diastereomerically pure secondary amines and, following reductive removal of the a-methylbenzyl group, serve as a source of chiral primary amines (eq 4).15

Reagent for the Determination of Enantiomeric Purity of Carboxylic Acids.

Amine (1) is frequently used as a derivatizing reagent for determining the enantiomeric purity of carboxylic acids by HPLC, with limits of detection often as low as 1%. Most commonly used coupling methods include use of dehydrating agents such as 1,3-Dicyclohexylcarbodiimide (eq 5)16 and the mixed anhydride method (eq 6).17

Stereospecific Reactions of Carbonyl Compounds.

One of the most frequent uses of both enantiomers of reagent (1) is in promoting the stereospecific reaction of carbonyl compounds via the corresponding chiral imines. The transfer of chirality from (1) to the newly formed bonds is generally most effective in cyclization reactions. Some examples are the Lewis acid-catalyzed cyclization of o-unsaturated aldehyde imines to produce amines of high enantiomeric purity (eq 7),18 the enantioselective synthesis of g,d-unsaturated aldehydes via the aza-Claisen rearrangement of derivatives of (1) (eq 8),19 and the asymmetric Lewis acid-catalyzed aza-Diels-Alder reaction of aldehyde imines with electron-rich dienes (eq 9).20

Enantiomerically pure disubstituted b-lactams are also available by cyclization of acyclic intermediates containing (1) as a chiral appendage, which is later removed by catalytic hydrogenation (eq 10).21

Examples of highly stereoselective acyclic reactions include the Zr-mediated coupling of aldehydes with imines of (1) to produce chiral amino alcohol derivatives (eq 11),22 and the addition of cyanide to aldimines of (1) to yield intermediates that can be elaborated into enantiomerically pure a-amino acids (eq 12).23

Another frequent use of (1) and its enantiomer is the stereospecific conjugate addition of carbonyl compounds to a,b-unsaturated systems. Most published examples contain chiral imine derivatives of cyclic ketones, which add to a,b-unsaturated esters and ketones in a highly stereoselective manner (eqs 13 and 14).24,25 When the ketone is not symmetrically substituted, reaction usually occurs at the most substituted a-position, including those cases where the ketone is a-substituted by oxygen (eq 15).26 High stereoselectivity can also be achieved when the Michael acceptor is other than an unsaturated ketone or ester, such as a vinyl sulfone (eq 16).27 Intramolecular variations of this transformation have also been described (eq 17).28

Stereospecific Reductive Amination of Carbonyl Compounds.

Catalytic or chemical reduction of chiral imines derived from (1) often proceeds with high diastereoselectivity. Reductive removal of the a-methylbenzyl group yields chiral primary amines (eqs 18 and 19).29,30

Removable Chiral Appendage.

Even in reactions that proceed with moderate stereoselectivity, incorporation of a chiral moiety such as (1) frequently provides an opportunity to easily separate diastereomeric products. For example, the introduction of (1) into an imidazolone structure allows the easy separation of diastereomers by chromatography. Reductive removal of the chiral appendage and imidazolone hydrolysis provides a synthesis of optically pure a-amino acids (eq 20).31 In another example, even though the conjugate addition of (1) to methyl crotonate proceeds with low stereoselectivity, the diastereomeric conjugates are easily separated by chromatography and elaborated to provide optically active b-amino esters (eq 21).32 Similarly, cycloaddition of the aldimine of (1) with a substituted ketene produces a mixture of b-lactams, which can be separated by chromatography as a source of optically active b-lactams (eq 22).33

Miscellaneous Uses.

Substituted derivatives of (1), e.g. (7), react with a,b-unsaturated carbonyl systems in a highly stereoselective manner to produce chiral b-aminocarbonyl compounds.34 The lithium amides of a different type of substituted derivatives, e.g. (8), have been used to deprotonate symmetrical ketones, usually cyclic, in a highly stereoselective manner.35

1. Newman, P. Optical Resolution Procedures for Chemical Compounds; O.R.I.C., Manhattan College: New York, 1978; Vol. 1, pp 79-82.
2. Brown, E.; Viot, F.; Le Floc'h, Y. TL 1985, 26, 4451.
3. (a) Wu, M.-J.; Pridgen, L. N. JOC 1991, 56, 1340. (b) Hua, D. H.; Miao, S. W.; Chen, J. S.; Iguchi, S. JOC 1991, 56, 4.
4. Dale, J. A.; Dull, D. L.; Mosher, H. S. JOC 1969, 34, 2543.
5. Shapiro, M. J.; Archinal, A. E.; Jarema, M. A. JOC 1989, 54, 5826.
6. Parker, D.; Taylor, R. J. T 1987, 43, 5451.
7. Kappe, C. O.; Uray, G.; Roschger, P.; Lindner, W.; Kratky, C.; Keller, W. T 1992, 48, 5473.
8. Yamamoto, M.; Hayashi, M.; Masaki, M.; Nohira, H. TA 1991, 2, 403.
9. Dharanipragada, R.; Nicolas, E.; Toth, G.; Hruby, V. TL 1989, 30, 6841.
10. Hoffmann, N.; Scharf, H.-D. TA 1991, 2, 977.
11. Ornstein, P. L.; Arnold, M. B.; Augenstein, N. K.; Paschal, J. W. JOC 1991, 56, 4388.
12. Chung, J. Y. L.; Wasicak, J. T.; Arnold, W. A.; May, C. S.; Nadzan, A. M.; Holladay, M. W. JOC 1990, 55, 270.
13. Gong, B.; Chen, W.; Hu, B. JOC 1991, 56, 423.
14. (a) Taguchi, T.; Kawara, A.; Watanabe, S.; Oki, Y.; Fukushima, H.; Kobayashi, Y.; Okada, M.; Ohta, K.; Iitaka, Y. TL 1986, 27, 5117. (b) Ishibashi, F.; Taniguchi, E. CL 1986, 1771.
15. Nilsson, B. M.; De Boer, P.; Grol, C. J.; Hacksell, U. Chirality 1992, 4, 367.
16. Hoffman, R. V.; Kim, H.-O. T 1992, 48, 3007.
17. Compagnone, R. S.; Rapoport, H. JOC 1986, 51, 1713.
18. Sakane, S.; Maruoka, K.; Yamamoto, H. T 1986, 42, 2203.
19. Bailey, P. D.; Harrison, M. J. TL 1989, 30, 5341.
20. Hattori, K.; Yamamoto, H. T 1993, 49, 1749.
21. (a) Kawabata, T.; Itoh, K.; Hiyama, T. TL 1989, 30, 4837. (b) Kawabata, T.; Sumi, K.; Hiyama, T. JACS 1989, 111, 6843.
22. Ito, H.; Taguchi, T. Hanzawa, Y. TL 1992, 33, 4469.
23. Saito, K.; Harada, K. TL 1989, 30, 4535.
24. (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.
25. (a) Pfau, M.; Revial, G.; Guingant, A.; d'Angelo, J. JACS 1985, 107, 273. (b) Revial, G. TL 1989, 30, 4121.
26. (a) Desmaële, D. T 1992, 48, 2925. (b) Desmaële, D.; d'Angelo, J. TL 1989, 30, 345.
27. Pinheiro, S.; Guingant, A.; Desmaële, D.; d'Angelo, J. TA 1992, 3, 1003.
28. d'Angelo, J.; Ferroud, C. TL 1989, 30, 6511.
29. (a) Bringmann, G.; Künkel, G.; Geuder, T. SL 1990, 253. (b) Van Niel, J. C. G.; Pandit, U. K. T 1985, 41, 6005. (c) Bringmann, G.; Geisler, J.-P. TL 1989, 30, 317.
30. Farkas, E.; Sunman, C. J. JOC 1985, 50, 1110.
31. Amoroso, R.; Cardillo, G.; Tomasini, C. TL 1990, 31, 6413.
32. Estermann, H.; Seebach, D. HCA 1988, 71, 1824.
33. Kobayashi, Y.; Takemoto, Y.; Kamijo, T.; Harada, H.; Ito, Y.; Terashima, S. T 1992, 48, 1853.
34. Davies, S. G.; Ichihara, O. TA 1991, 2, 183.
35. Cain, C. M.; Cousins, R. P. C.; Coumbarides, G.; Simpkins, N. S. T 1990, 46, 523.

Juan C. Jaen

Parke-Davis Pharmaceutical Research, Ann Arbor, MI, USA

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