(2R,3R)-Dipivaloyltartaric Acid

[65259-81-6]  · C14H22O8  · (2R,3R)-Dipivaloyltartaric Acid  · (MW 318.36)

(chiral auxiliary for enantioselective protonation (deracemization) and asymmetric transformation; starting material for synthesis of chiral succinimides and polyhydroxy compounds)

Alternate Name: (2R,3R)-DPTA.

Physical Data: mp 135 °C; [a]25D -24.2° (1.7, dioxane).1

Solubility: sol Et2O, THF, aq NaHCO3 solution; insol cold H2O.

Preparative Method: hydrolysis of the corresponding anhydride obtained by heating (2R,3R)-tartaric acid and pivaloyl chloride at 120-140 °C for 4 h.1 Drying: over P2O5 in vacuo, controlled by 1H NMR and optical rotations.

Handling, Storage, and Precautions: the anhydrous solid can be stored at rt in the absence of moisture. It is retrievable from its basic solution (10 % aq NaHCO3), after acidification (HCl), with a quantitative yield.2 On heating it transforms into an anhydride with elimination of one molecule of water.

Chiral Auxiliary Used for Enantioselective Protonation (Kinetic Control).

(2R,3R)-Dipivaloyltartaric acid has been essentially used for enantioselective protonations.3 Surprisingly, for the creation of the chirality during the formation of the C-H linkage, this type of reaction has received attention only recently, unlike enantioselective hydrogenations or enantioselective reductions with hydride anion, widely used in asymmetric syntheses. (2R,3R)-DPTA was the first protonating reagent leading to appreciable enantioselections (up to 80 %) when applied to different classes of substrates such as enamines,4 enolates of functionalized esters,5 and carbonyl compounds.4 At the present time, high enantioselectivities have also been reached with other protonating agents,6 but often limited to one target molecule.

The first reported experiments concerned the protonation of enamines with (2R,3R)-DPTA leading, after hydrolysis of the iminium salts formed in situ, to optically active carbonyl compounds.7 Starting from the (Z)- and (E)-morpholino enamines of 2-phenylpropanal, it was possible to establish, in spite of modest results (ee 13-18%), that the protonation step was kinetically controlled: the (Z)- and (E)-isomers led to 2-phenylpropanal with a reverse configuration, excluding an equilibrium of the intermediate diastereoisomeric salts (eq 1).7

The protonation of lithium enolates of Schiff bases of racemic a-amino esters leads, after the workup, to a-amino acids of (S) configuration with ee as high as 70% (eq 2).2,5,8,9

A first set of experiments, the study of the protonation of enolates obtained from benzaldehyde Schiff bases and Lithium Diisopropylamide, showed that the asymmetric induction was not significantly affected by the size of the R moiety of the amino acid (R = Me, Et, i-Pr, n-Bu, t-Bu, Ph; ee = 44-56%).2,9 The two main factors improving the enantioselection were the Ar substituent of the Schiff base and the lithium amide used for the deprotonation.5,8,10 The following results (Table 1) indicate clearly that the enantioselectivity increases with the electron-donating power of substituents para to the Schiff base (eq 3),5 leading to 70% ee with the Schiff base of p-methoxybenzaldehyde derived from phenylglycine.9

The favorable effect of electron-donating substituents X, interpreted as the structure of the enolate becomes more rigid due to the increase of the coordination between the lithium and the nitrogen atoms, was confirmed on a series of a-amino acids.9

The enantioselectivity was dramatically affected by the structure of the lithium amide used for the deprotonation, indicating that the secondary amine liberated during the metalation step participates in the protonation step.3,8,10 The utilization of chiral lithium amides allowed higher enantioselections than with classical LDA (eq 4) (Table 2).8,10

The crucial role of the secondary liberated amine was also reported in experiments involving deprotonation with lithium (R)-N-ethyl(1-phenylethyl)amide and reprotonation at -70 °C with 2R,3R, racemic, and meso-DPTA, yielding, respectively, 70, 39, and 24% ee of the (S)-enantiomer. In the two last cases, significant inductions were obtained with the sole secondary chiral amine as chiral inductor in the medium.8 Since these first results, chiral lithium amides have been widely used for asymmetric synthesis.

Owing to the importance of the amine, probably acting as a ligand of lithium or a proton carrier [ammonium salt of (2R,3R)-DPTA],3,10 a process was proposed allowing the introduction of different amines and consequently a modification of the selectivity of the protonation: after deprotonation of a Schiff base of methyl valinate with Lithium Hexamethyldisilazide (LHMDS), the liberated HMDS was replaced by a more basic primary, secondary, or tertiary amine prior to the addition of (2R,3R)-DPTA (eq 5) (Table 3). In some cases, higher ee were observed compared to the classical procedure with LHMDS (34% ee) or LDA (47% ee).10

Enantioselective protonation of lithium dienolates obtained from Schiff bases of methyl a-aminobutenoates was carried out using (2R,3R)-DPTA, in order to synthesize vinylglycine by deconjugation (ee 36%).9 Protonation of a cyclic lithium enolate derived from mandelic acid with (2R,3R)-DPTA was reported to occur with a low ee.6b

The potassium (Z)-enediolate obtained from racemic benzoin and Potassium Hydride when treated with (2R,3R)-DPTA affords (S)-benzoin with 80% ee (optically pure after one recrystallization in methanol).11 In the reaction conditions, the enediolate is first O-protonated, then the resulting enediol slowly tautomerizes at low temperature into optically active benzoin with a high enantioselectivity. In the cases of incomplete tautomerization the residual enediol was immediately oxidized to benzil by the oxygen of the air during the workup. It was shown that the tautomerization of the enediol was hindered by the presence of an excess of (2R,3R)-DPTA (eq 6).11

Finally, the configuration of the protonation product is predictable using the L Rule. The prochiral substrate is represented according to the letter L, where the vertical line represents the C=C bond and the horizontal line the C-X bond (X = nucleophilic atom). In such a case, protonation with (2R,3R)-DPTA is favored on the L-face, i.e. on the side of the reader. As an example, the protonation of a lithium enolate of a Schiff base of an a-amino ester, leading to the (S)-enantiomer, is given in eq 7.3

In enantioselective protonations, the final optically active product is generally chemically identical to the starting racemic material, precursor of the prochiral substrate on which the protonation is carried out. That is why the term deracemization was proposed for this type of process.3,4,12 In a deracemization, the protonation step is kinetically controlled. Therefore a deracemization differs from an asymmetric transformation in which the reactions are thermodynamically controlled.3,4

Chiral Auxiliary Used for Asymmetric Transformations (Thermodynamic Control).

Racemic N-benzyl-N-methyl-a-amino propiophenone mixed with (2R,3R)-DPTA in acetone or dichloromethane leads with 90% yield to the corresponding salt of the (S)-amino ketone, which was reduced over Palladium on Carbon to a mixture of ephedrine (80%) and pseudo-ephedrine (20%) (eq 8).13

Starting Material for Asymmetric Syntheses.

(3R,4R)-Dipivaloyltartaric anhydride, the direct precursor of (2R,3R)-DPTA, has been used as starting material for the synthesis of (3R,4R)-dipivaloyltartrimide,14 its N-chloro and N-bromo derivatives (eq 9)15, and epimeric (3R,4R)-dipivaloyl-5-alkyl lactones (eq 10), which are valuable intermediates for access to optically active polyhydroxy compounds.16

1. Duhamel, L.; Plaquevent, J. C. OPP 1982, 14, 347.
2. Duhamel, L.; Plaquevent, J. C. JACS 1978, 100, 7415.
3. Duhamel, L.; Duhamel, P.; Launay, J. C.; Plaquevent, J. C. BSF(2) 1984, 421.
4. Duhamel, L.; Plaquevent, J. C. BSF(2) 1982, 69.
5. Duhamel, L.; Plaquevent, J. C. BSF(2) 1982, 75.
6. (a) Fuji, K. JACS 1985, 107, 6404. (b) Gerlach, U.; Hunig, S. AG(E) 1987, 26, 1283. (c) Fehr, C.; Galindo, J. JACS 1988, 110, 6909. (d) Piva, O.; Pete, J. P. TL 1990, 31, 5157. (e) Potin, D.; Williams, K.; Rebeck, J. AG(E) 1991, 29, 1420. (f) Matsumoto, K.; Otha, H. TL 1991, 32, 4729. (g) Vedejs, E.; Lee, N. JACS 1991, 113, 5483. (h) Kumar, A.; Salumkhe, R. V.; Ramkrishna, A. R.; Suneel, Y. D. CC 1991, 485. (i) Reymond, J. L.; Janda, K. D.; Lerner, R. A. JACS 1992, 114, 2257.
7. Duhamel, L.; Plaquevent, J. C. TL 1977, 2285.
8. Duhamel, L.; Plaquevent, J. C. TL 1980, 21, 2521.
9. Duhamel, L.; Duhamel, P.; Fouquay, S.; Jamal Eddine, J.; Peschard, O.; Plaquevent, J. C.; Ravard, A.; Solliard, R.; Valnot, J. Y.; Vincens, H. T 1988, 44, 5495.
10. Duhamel, L.; Fouquay, S.; Plaquevent, J. C. TL 1986, 27, 4975.
11. Duhamel, L.; Launay, J. C. TL 1983, 24, 4209.
12. Duhamel, L. CR(C) 1976, 282, 125.
13. Noi, Y.; Ogura, S. Jap. Patent 63 91 352, 1988 (CA 1989, 110, 7832w).
14. Duhamel, L.; Herman, T.; Angibaud, P. SC 1992, 22, 735.
15. Duhamel, L.; Plé, G.; Angibaud, P.; Desmurs, J. R. SC 1993, 22, 2473.
16. (a) Jacob, M. Diplôme d'Etudes Approfondies, Rouen, 1992. (b) Jacob, M.; Fernandez, A. M. to be published.

Lucette Duhamel

University of Rouen, Mont-Saint-Aignan, France

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.