[56210-72-1]  · C16H19N  · (-)-(S,S)-a,a“-Dimethyldibenzylamine  · (MW 225.36)

(starting material for the formation of chiral amide reagents; useful in the stereospecific deprotonation of prochiral ketones, and as a chirality transfer agent in the reactions of prochiral enolates; stereoselective conjugate addition of organometallic reagents to unsaturated carbonyl systems1)

Physical Data: (free base): bp 103-105 °C/0.5 mmHg;2 [a]D -157° (c 2.4, EtOH);1a -197.3° (c 3.65, benzene);1b -187.9° (c 6.87, benzene);3 -171.6° (c 6.71, chloroform).4 (HCl salt): mp >300 °C; [a]D -84.1° (c 3, EtOH);1a -72.1° (c 2.94, EtOH).1b

Solubility: readily sol common organic solvents (ether, THF, chloroform, etc.); insol H2O.

Form Supplied in: available commercially.

Analysis of Reagent Purity: diastereomeric purity can be assessed by the 1H NMR chemical shift of the methyl groups,1a and by GC analysis.5 Optical purity can be assessed by derivatization with (R)-(-)-1-(1-naphthyl)ethyl isocyanate and 1H NMR analysis of the product.4

Preparative Methods: minor improvements to the original catalytic hydrogenation procedure6 have been described (eq 1).1a This method provides (S,S)-(-)-(1) with an optical purity of only 70%. Enantiomerically pure (S,S)-(-)-(1) can be obtained by recrystallization of the hydrochloride salt of this enriched material from water1b or the benzoate salt from isopropanol.3 A chemical reduction procedure has also been described that yields optically active (S,S)-(1) with 74% enantiomeric excess (eq 2).2 A significant improvement to the former procedures is the diastereoselective hydrogenation of imines catalyzed by rhodium/chiral diphosphines, which yields (S,S)-(1) with an optical purity of 99.4% (eq 3).5

Purification: the free base can be distilled. The HCl salt can be recrystallized from water, which removes diastereomeric impurities. The benzoate salt can be recrystallized from isopropanol.

Handling, Storage, and Precautions: no special precautions have been noted in the literature. The free base is a clear distillable liquid that should be stored under an inert atmosphere to prevent air oxidation. Long term storage may lead to some coloration of the material.


In most cases the (R,R) and (S,S) enantiomers of (1) possess similar synthetic applications. References to both enantiomers have been incorporated into this article, under the heading of (S,S). The equations depict the actual enantiomer used in each publication.

Asymmetric Deprotonation/Protonation of Ketones.

Lithium amides of chiral amines have been used for performing asymmetric deprotonations of symmetrically substituted (prochiral) ketones.7,8 The resulting optically active enols or enol derivatives (most frequently enol silanes) are highly versatile synthetic intermediates. Particularly useful for this purpose are chiral amines possessing C2 symmetry, such as (1). For example, reaction of 4-t-butylcyclohexanone with the lithium amide of (R,R)-(1) (readily prepared in situ by treatment of (1) with n-Butyllithium) is highly stereoselective; the resulting enol silyl ether possesses an 88% ee (eq 4).9

The most predictable results are obtained with conformationally rigid systems, such as those represented in eqs 5 and 6, which possess axially oriented a-protons.10,11 This minimizes complications resulting from the presence of diastereotopic a-protons, although unexpected modes of deprotonation have been described with related chiral amides, which may involve boat conformations.12 To prevent enolate equilibration (with the resulting loss of stereoselectivity), Corey's internal quench method for enolate trapping with silyl chlorides is frequently used.13 The stereospecificity of this deprotonation is highly dependent on solvent and temperature conditions. Best results are obtained at -100 °C or lower temperatures, with THF as the solvent.

The lithium amide of (S,S)-(1) has been used to convert racemic a-substituted ketones into optically active ketones via sequential deprotonation/asymmetric protonation of rigid prochiral enolates. Enantiomeric enrichment may occur during the protonation step as a result of the tight coordination between the enolate and the lithium amide in the form of diastereomeric complexes (eq 7).14

Alternatively, the enantiomeric enrichment derives from kinetic differences in the rate of deprotonation of the two ketone enantiomers (eq 8).15 Ether is the best solvent for these reactions.

The lithium amide of (1) has also been used to perform the kinetic resolution of racemic lactams by selective kinetic deprotonation of one of the enantiomers, followed by reaction of the partially formed enolates with an electrophile.16 These procedures have not proven to be particularly useful yet, since high enantiomeric purity is only achieved at low conversions of the starting materials (eq 9).17

Stereoselective Alkylation of Prochiral Enolates.

A limited amount of work has demonstrated the potential use of chiral amines in inducing stereoselectivity in the alkylation/carboxylation of prochiral enolates. The selectivity of these reactions, like those described above, is highly dependent on solvent and temperature conditions. The use of ether at -196 °C provides optimal results in a particular system (eq 10).18

Asymmetric Induction in Organometallic Reactions.

A number of chiral amines have been used as nontransferable ligands for the enantioselective conjugate addition of organocopper reagents, with optical yields as high as 95%.19-22 (R,R)-(1) has also been used for this purpose, effecting the conjugate addition of organocopper reagents to enones with moderate to high enantioselectivity (eq 11).23,24 The use of dimethyl sulfide as the solvent for this transformation is critical, since ether solvents produce products of low optical activity.

Although (1) itself has not been shown to be useful in the stereospecific 1,2-addition of organometallic reagents to carbonyl compounds, closely related amines, such as (R)-(a-methoxymethylbenzyl)-(S)-(a-methylbenzyl)amine, have been used to direct the addition of organolithium reagents to benzaldehyde with up to 95% stereoselectivity (eq 12).25

Enantioselective Conjugate Additions.

(R,R)-(1) has been used in the synthesis of (R)-b-aminobutanoic acid. The conjugate addition of the lithium amide of (R,R)-(1) to (E)-methyl crotonate proceeds with complete diastereoselectivity. Catalytic reduction of the benzyl groups results in the formal stereospecific 1,4-addition of an amino group to an unsaturated ester (eq 13).26 Although (1) has not been used extensively for this type of transformation, a variety of other chiral amines have been used for similar purposes.8,27,28

Chiral Auxiliary.

(R,R)-(1) has been used as a chiral auxiliary to direct the stereochemistry of addition of a nucleophile to an acrylate moiety. Almost complete stereoselectivity is achieved in the addition of cyclopentanecarboxylic acid lithium dianion to the a-substituted acrylate substrate (eq 14).29 This methodology allows stereochemical control at the a-position of a b-amino ester and thus complements the methodology described above26 for the stereoselective formation of b-substituted b-amino esters.

Other Enantioselective Reactions.

Enantioselective epoxide elimination by chiral bases has been demonstrated.30 More recently, the enantioselective [2,3]-Wittig rearrangement of a 13-membered propargylic allylic ether has been performed using the lithium amide of (R,R)-(1) as the base for deprotonation (eq 15).4 For this particular substrate, THF is a better solvent than ether, although pentane produces better results in a related transformation (eq 16).4 In fact, a change in solvent in this type of reaction has been shown to lead to a reversal of the stereoselectivity of the transformation.4

1. (a) Eleveld, M. B.; Hogeveen, H.; Schudde, E. P. JOC 1986, 51, 3635. (b) Yoshida, T.; Harada, K. BCJ 1972, 45, 3706.
2. Periasamy, M.; Devasagayaraj, A.; Satyanarayana, N.; Narayana, C. SC 1989, 19, 565.
3. Raban, M.; Yamamoto, G. JOC 1975, 40, 3093.
4. Marshall, J. A.; Lebreton, J. JACS 1988, 110, 2925.
5. Lensink, C.; de Vries, J. G. TA 1993, 4, 215.
6. Overberger, C. G.; Marullo, N. P.; Hiskey, R. G. JACS 1961, 83, 1374.
7. Simpkins, N. S. CI(L) 1988, 387.
8. Cox, P. J.; Simpkins, N. S. TA 1991, 2, 1.
9. Cain, C. M.; Cousins, R. P. C.; Coumbarides, G.; Simpkins, N. S. T 1990, 46, 523.
10. Honda, T.; Kimura, N.; Tsubuki, M. TA 1993, 4, 21.
11. Bunn, B. J.; Cox, P. J.; Simpkins, N. S. T 1993, 49, 207.
12. Sobukawa, M.; Nakajima, M.; Koga, K. TA 1990, 1, 295.
13. Corey, E. J.; Gross, A. W. TL 1984, 25, 495.
14. Hogeveen, H.; Zwart, L. TL 1982, 23, 105.
15. Eleveld, M. B.; Hogeveen, H. TL 1986, 27, 631.
16. Coggins, P.; Simpkins, N. S. SL 1991, 515.
17. Coggins, P.; Simpkins, N. S. SL 1992, 313.
18. Hogeveen, H.; Menge, W. M. P. B. TL 1986, 27, 2767.
19. Bertz, S. H.; Dabbagh, G.; Sundararajan, G. JOC 1986, 51, 4953.
20. Dieter, R. K.; Tokles, M. JACS 1987, 109, 2040.
21. Dieter, R. K.; Lagu, B.; Deo, N.; Dieter, J. W. TL 1990, 31, 4105.
22. Ahn, K.-H.; Klassen, R. B.; Lippard, S. J. OM 1991, 9, 3178.
23. Rossiter, B. E.; Eguchi, M. TL 1990, 31, 965.
24. Rossiter, B. E.; Eguchi, M.; Miao, G.; Swingle, N. M.; Hernández, A. E.; Vickers, D.; Fluckiger, E.; Patterson, R. G.; Reddy, K. V. T 1993, 49, 965.
25. Eleveld, M. B.; Hogeveen, H. TL 1984, 25, 5187.
26. Davies, S. G.; Ichihara, O. TA 1991, 2, 183.
27. Seebach, D.; Estermann, H. TL 1987, 28, 3103.
28. Rudolf, K.; Hawkins, J. M.; Loncharich, R. J.; Houk, K. N. JOC 1988, 53, 3879.
29. Barnish, I. T.; Corless, M.; Dunn, P. J.; Ellis, D.; Finn, P. W.; Hardstone, J. D.; James, K. TL 1993, 34, 1323.
30. Whitesell, J. K.; Felman, S. W. JOC 1980, 45, 755.

Juan C. Jaen

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

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