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Synthesis of new N-tetrasubstituted derivatives of R,R-tartaric acid and their use as chiral ligands in oxidation catalysts/R,R-viinhappe N-tetraasendatud derivaatide suntees ja kasutamine kiraalsete ligandidena oksudatsiooni katalusaatorites.


Asymmetric catalysis is one of the most important areas of synthetic organic chemistry [1]. In recent years many outstanding results in this field have been achieved. A remarkable example is the highly enantioselective epoxidation of allylic alcohols using the Sharpless catalyst [2]. The asymmetric Baeyer-Villiger oxidation has been neglected for a long time. Positive promising results in this field have been obtained only recently [3, 4].

A number of tartaric acid derivatives have been examined as substitutes for tartrate esters in the asymmetric catalysis. N,N'-alkyl-R,R-tartramides have been used as enantiomerically pure chiral auxiliaries in different catalysts [5-7]. Aminoalcohols have been also used as chiral auxiliaries in asymmetric oxidations (e.g. in dihydroxylation [8, 9]).

In this paper we report the synthesis of different N-containing tartaric acid derivatives: N,N,N',N'-tetraaryl-R,R-tartramides 4 and 5, N,N,N',N'-tetrabenzyl 1,4-amino-S,S-2,3-butanediol 7, and their acetals (2, 3, and 6). Also, the results of preliminary experiments on Baeyer-Villiger oxidation of ketones using synthesized compounds as chiral ligands in the asymmetric catalysts are presented.


N,N,N',N'-tetraaryl-R,R-tartramides 4 and 5 were prepared from 2,3-O-isopropylidene-R,R-tartryl chloride 1 by aminolysis of the corresponding secondary amines (Scheme 1). The preparation of 2,3-O-isopropylidene-R,R-tartryl chloride involves a certain problem because of labile acetal group in the molecule. However, the acid chloride 1 was successfully synthesized from (+)-dimethyl-2,3-O-isopropylidene-R,R-tartrate [10] according to a method suggested by Choi et al. [11].


In order to obtain N,N,N',N'-tetrabenzyl-1,4-amino-S,S-2,3-butanediols 6 and 7 we tried the reduction of N,N,N',N'-tetrabenzyl-2,3-O-isopropylidene R,R-tartramide 3 with various reducing agents. The mixed reducing agent LiAl[H.sub.4]-Al[Cl.sub.3] and Al[H.sub.3] [12] reduced 3 in good yield (Table 1, Nos. 2, 3). A mild reduction of 3 with diborane [13] resulted in amine 6 in high yield (Table 1, No. 1). LiAl[H.sub.4] alone did not give the target amine (Table 1, No. 4). After the removal of the protecting group (Scheme 2) we obtained N,N,N',N'-tetrabenzyl-1,4-amino-S,S-2,3-butanediol 7 in good yield.


The behaviour of new synthesized compounds (2-7) as ligands in metalcatalyzed Baeyer-Villiger oxidation was checked. Often a stoichiometric amount of the catalyst is required for Baeyer-Villiger oxidation of ketones [14, 15]. However, in some cases excellent catalytic processes have been developed with moderate to good enantioselectivity (up to 95% ee) [4, 16].

Two different oxidative systems were investigated on Baeyer-Villiger oxidation of cyclic ketones (Scheme 3).


We found that the copper(II)triflate/aldehyde/[O.sub.2] system with an N-containing chiral ligand in a catalytic amount (5-10 mol% of catalyst) oxidizes ketones 9-12 into lactones 13-16, correspondingly, with moderate yield (Scheme 4, Table 2, Nos. 1, 2, 6-14). Only in one case, with substrate 9, a certain enantioselectivity was achieved (26% ee, Table 2, No. 1). The isolated yield of lactone 13 was, however, very low (5%). The catalytic activity of the complex depends considerably on the aldehyde used (Table 2, Nos. 6, 9). Oxidation of ketone 11 with molecular oxygen in the presence of various ligands 2-8, copper(II)triflate, and aldehyde led to racemic lactone 15. In the case of a titanium based catalyst, a stoichiometric amount of the catalyst was required (Table 2, Nos. 4, 5). Poor to moderate diastereodifferentiation (9 and 37% ee; kinetic resolution) with moderate yield was obtained.



The glassware was dried in an oven and cooled under argon atmosphere. Toluene was distilled over sodium under argon atmosphere and THF was distilled over LiAl[H.sub.4]. The dried solvents were stored under dry argon. Commercial reagents, dibenzylamine (Aldrich, 97%), (+)-dimethyl-R,R-tartrate (Merck, 99%), 2,2-dimethoxypropane (Aldrich, 98%), p-TsOH (Reachim), [B.sub.2][H.sub.6] (Lancaster 1M solution in THF), AlLi[H.sub.4] (Reachim), Al[Cl.sub.3] (Aldrich, 98%), and acetonitrile (Fisher Scientific, HPLC grade) were used without purification. [K.sub.2]C[O.sub.3] (Reachim) was freshly dried and diphenylamine (Reachim) was recrystallized from petrolether. (+)-Dimethyl-2,3-O-isopropylidene-R,R-tartrate was prepared via a published procedure [10]. For flash-column chromatography 40-100 [micro]m KKC 120 silica gel was used. A Pye Unicam PU 4500 gas chromatograph (GC) (Philips) equipped with a flame ionization detector and an Alltech ECONO-CAP EC-5, 15 m x 0.53 mm ID x 1.2 [micro]m was utilized for all GC analyses. The system was operated using helium as the carrier gas with a linear velocity of 10 mL/min. The injector and detector temperatures were set at 120 and 250 [degrees]C respectively. HPLC was performed with an instrument of Shimadzu LC-10AT VP with a system controller SCL-10A and a UV-VIS detector SPD-10A VP ([lambda] = 254 nm), FCV-10AL VP at ambient temperature. The column was Symmetry C18 5 ?m, 4.6 x 250 mm; and the mobile phase used was acetonitrile/[H.sub.3]P[O.sub.4], [H.sub.2]O 0.5 mL/L, TEA, pH = 7.0, with a program that runs 60% C[H.sub.3]CN for 10 min and during 20 min the mobile phase was changed to 100% C[H.sub.3]CN.

New compounds were characterized by [sup.1]H and [sup.13]C NMR spectroscopy with an AMX500 MHz Bruker instrument. The optical rotations were measured with a polarimeter Polamat A.


To the solution of (+)-dimethyl-R,R-tartrate (45.5 mmol) in toluene (100 mL) 2,2-methoxypropane (95.6 mmol) and p-TsOH (5 mol%) were added. The reaction mixture was kept at 60-70[degrees]C for 3 h. After azeotropic distillation (toluene-methanol) with a Vigreux column (15 cm) at 64[degrees]C the reaction mixture was stirred for 4 h and it was left overnight at room temperature. To the reaction mixture (1.05 g) [K.sub.2]C[O.sub.3] was added and the mixture was stirred for 1 h at room temperature. After filtration and concentration the crude product (purity 86.3% by GC) was distilled under vacuum at 115-122 [degrees]C (2-3 mmHg). The yield of the product was 85.2% with 97.4% purity by GC.

[sup.1]H NMR (CD[Cl.sub.3]) [delta] (ppm): 1.35 s (-C[H.sub.3]); 3.71 s (-O-C[H.sub.3]); 4.67 s (-CH-).

[sup.13]C NMR (CD[Cl.sub.3]) [delta] (ppm): 25.92 (-C[H.sub.3]); 52.34 (-O-C[H.sub.3]); 76.64 (-CH-); 113.41 (tert-C); 169.69 (C=O).

N,N,N',N'-tetraphenyl-2,3-O-isopropylidene R,R-tartramide 2

To the solution of chloride 1 (3.68 mmol) in THF (2 mL) a solution of diphenylamine (19.08 mmol) in THF (5 mL) was added dropwise at 0[degrees]C. The reaction mixture was refluxed for 1 h and stirring was continued for 4 days at room temperature. After work-up the organic layer was dried on MgS[O.sub.4] and concentrated with rotavap. The crude product was purified by flash-column chromatography on silica gel (petrolether:ethylacetate 15:1). The preparative yield of the product was 66% (purity of the product was 99.2% by HPLC).

[sup.1]H NMR (CD[Cl.sub.3]) [delta] (ppm): 1.22 s (-C[H.sub.3]); 5.01 s (-CH-); 7.15-7.37 (exchange broadened arom.).

[sup.13]C NMR (CD[Cl.sub.3]) [delta] (ppm): 26.23 (-C[H.sub.3]); 76.59 (-CH-); 112.57 (tert-C); 126.7-129.2 and 142.0 (exchange broadened arom.); 168.35 (-C=O).

N,N,N',N'-tetrabenzyl-2,3-O-isopropylidene R,R-tartramide 3

To the solution of chloride 1 (1.1 mmol) in THF (2.5 mL) a solution of dibenzylamine (3.3 mmol) in THF (1.5 mL) was added dropwise at 0[degrees]C. The reaction mixture was stirred for 1.5 h at room temperature. After filtration and concentration with rotavap, the product was purified by flash-column chromatography on silica gel (petroether : ethylacetate 10:1). The preparative yield of the product was 88% (purity of the product was 85% by HPLC).

[sup.1]H NMR (CD[Cl.sub.3]) [delta] (ppm): 1.48 s (-C[H.sub.3]); 5.59 s (-CH-); 4.48 d and 4.63 d, 4.68 d and 4.73 d (2 C[H.sub.2]-Ph).

[sup.13]C NMR (CD[Cl.sub.3]) [delta] (ppm): 26.41 (-C[H.sub.3]); 47.49 and 49.65 (2-C[H.sub.2]Ph); 76.06 (-OCH); 112.42 (tert-C); 127.55 and 128.09 (ortho), 128.60 and 128.77 (meta), 127.36 and 127.69 (para), 136.28 and 136.61 (s); 168.83 (C=O).

General procedure for deprotection [17]

To the solution of the corresponding 2,2-dimethyl-1,3-dioxolanes in C[H.sub.3]CN (40 mL) 6 N [H.sub.2]S[O.sub.4] (20 mL) was added. After refluxing for 1.5 h the reaction was stopped by adding ice-cold water and the mixture was extracted with EtOAc (4 x 15 mL). The organic layer was collected and concentrated with rotavap. After flash-column chromatography on silica gel (petrolether : ethylacetate 5 : 3) the corresponding product was obtained.

N,N,N',N'-tetraphenyl R,R-tartramide 4

The deprotection of N,N,N',N'-tetraphenyl-2,3-O-isopropylidene R,R-tartramide 2 gave 83% yield of white crystals with 84% purity by HPLC.

[[[alpha]].sub.546.sup.21[degrees]C] = -133 (c = 1.646, DMF).

[sup.1]H NMR (CD[Cl.sub.3]) [delta] (ppm): 4.12 s (O-CH); 4.25 (OH); 7.1-7.3 m (exchange broadened arom.).

[sup.13]C NMR (CD[Cl.sub.3]) [delta] (ppm): 69.90 (HO-CH); 126.33 (2), 126.68 (1), 128.13 (3), 129.07 (2), 129.87 (2), 140.42 (s), 142.75 (s) (arom.); 170.75 (C=O). Aromatic carbon atoms showed at room temperature exchange broadening between E and Z phenyl groups. Equivalence of phenyl groups occurred at temperatures above 60[degrees]C.

N,N,N',N'-tetrabenzyl R,R-tartramide 5

The deprotection of N,N,N',N'-tetrabenzyl-2,3-O-isopropylidene R,R-tartramide 3 gave 85% yield of white crystals with 95% purity by HPLC. [[[alpha]].sub.546.sup.21.5[degrees]C] = 13.3 (c = 2.15 EtOAc).

[sup.1]H NMR (CD[Cl.sub.3]) [delta] (ppm): 4.40 d, 4.47 d, 4.67 d, and 4.78 d (-C[H.sub.2]-Ph); 4.79 s (HO-CH-); 7.14-7.34 m (arom.).

[sup.13]C NMR (CD[Cl.sub.3]) [delta] (ppm): 48.47 and 49.32 (-C[H.sub.2]-Ph); 70.19 (HO-CH-); 126.70, 127.62 (para), 127.86 (para), 128.36, 128.68, 129.01, 135.48 (s), 136.10 (s) (arom.); 171.69 (C=O).

1,4-amino-N,N,N',N'-tetrabenzyl-2,3-O-isopropylidene-S,S-2,3-butanediol 6 (Table 1)

[sup.1]H NMR (CD[Cl.sub.3]) [delta] (ppm): 1.28 s (-C[H.sub.3]), 2.48 and 2.59 m (-N-C[H.sub.2]-CHO-); 3.55 d and 3.60 d (J = 13.9 Hz) (-C[H.sub.2]-Ph), 3.83 m (-CH-O-), 7.18-7.32 m (arom.).

[sup.13]C NMR (CD[Cl.sub.3]) [delta] (ppm): 27.16 (-C[H.sub.3]), 55.32 (-N-C[H.sub.2]-CHO-), 58.73 (-N-C[H.sub.2]-Ph), 78.50 (-C[H.sub.2]-CH-O), 108.66 (tert-C), 126.79 (para), 128.10 (meta), 128.90 (ortho), and 139.25 (s) (arom.).

1,4-amino-N,N,N',N'-tetrabenzyl-S,S-2,3-butanediol 7

Deprotection of 1,4-amino-N,N,N',N'-tetrabenzyl-2,3-O-propylidene-S,S-2,3-butanediol 6 gave 99% yield of white crystals with 93% purity by HPLC.

[[[alpha]].sub.546.sup.21.5[degrees]C] = -11.8 (c = 1.52, DMF).

[sup.1]H NMR (CD[Cl.sub.3]) [delta] (ppm): exchange broadened spectrum: 2.55 and 2.65 m (-OCH-C[H.sub.2]-N-); 3.50 and 3.79 m (N-C[H.sub.2]-Ph); 3.65 m (-CHO); 7.2-7.4 m (arom.).

[sup.13]C NMR (CD[Cl.sub.3]) [delta] (ppm): exchange broadened spectrum: 56.43 (-OCH - C[H.sub.2]-N); 59.01 (-C[H.sub.2]-Ph); 69.32 (HO-CH-); 127.40 (para), 128.46 (meta), 129.32 (ortho); 138.05 (s) (arom.).

General oxidation procedure with a copper(II)triflate/aldehyde/[O.sub.2] system

To a solution of chiral ligand (0.05 eq) in C[H.sub.2][Cl.sub.2] (0.01 M) copper(II)triflate (0.05 eq) was added and the mixture was stirred for 3 h at room temperature. Then ketone (1 eq) and aldehyde (3 eq) were added. The mixture was stirred under an oxygen atmosphere for 2-4.5 days. The reaction was quenched with a saturated solution of NaHC[O.sub.3] and the aqueous layer was extracted three times with C[H.sub.2][Cl.sub.2]. The organic phase was dried over MgS[O.sub.4]. After the removal of the solvent, the crude product was chromatographed on silica gel. The enantiomeric excesses for lactones were determined by HPLC with the column Daicel ODH (4.6 x 250 mm).


The preliminary results of the Baeyer-Villiger oxidation reaction were promising. The easily prepared new derivatives of tartaric acid with titanium and copper complexes show a good ability to catalyze the Baeyer-Villiger oxidation reaction. However, moderate enantioselectivity was achieved only in one case with the catalytic Cu(II) system and with stoichiometric Ti-system. The other metals as well as other oxidation systems should be tested together with the synthesized chiral ligands.

Received 24 April 2001


[1.] Katsuki, T. Epoxidation of allylic alcohols. In Comprehensive Asymmetric Catalysis II (Jacobsen, E. N., Phaltz, A. & Yamamoto, H., eds.). Springer, Berlin, 1999, 621-648.

[2.] Gao, Y., Hanson, R. M., Klunder, J. M., Ko, S. Y., Masamune, H. & Sharpless, K. B. Catalytic asymmetric epoxidation and kinetic resolution: Modified procedures including in situ derivatization. J. Am. Chem. Soc., 1987, 109, 5765-5780.

[3.] Strukul, G. Transition metal catalysis in the Baeyer-Villiger oxidation of ketones. Angew. Chem. Int., Ed. Engl., 1998, 37, 1198-1209.

[4.] Bolm, C. & Beckmann, O. Baeyer-Villiger reaction. In Comprehensive Asymmetric Catalysis II (Jacobsen, E. N., Phaltz, A. & Yamamoto, H., eds.). Springer, Berlin, 1999, 803-810, and references cited therein.

[5.] Gawronski, J., Gawronska, K. & Rychlewska, U. Conformational disparity of (R,R)-tartaric acid esters and amides. Tetrahedron Lett., 1989, 30, 6071-6074.

[6.] Lu, L. D.-L., Johnson, R. A., Finn, M. G. & Sharpless, K. B. Two new asymmetric epoxidation catalysts. Unusual stoichiometry and inverse enantiofacial selection. J. Org. Chem., 1984, 49, 728-731.

[7.] Johnson, R. A. & Sharpless, K. B. Addition reactions with formation of carbon-oxygen bonds: ii) Asymmetric methods of epoxidation. In Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Vol. 7 (Trost, B. M. & Fleming, I., eds.). Pergamon Press, Oxford, 1991, 389-436.

[8.] Haines, A. H. Addition reactions with formation of carbon-oxygen bonds: (iii) Glycol forming reactions. In Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Vol. 7 (Trost, B. M. & Fleming, I., eds.). Pergamon Press, Oxford, 1991, 437-448.

[9.] Fleischer, R. & Braun, M. 2-Amino-1,2,2-triphenylethanol: A novel chiral reagent containing the diphenylaminomethyl group. Enantioselective addition of diethylzinc to benzaldehyde. Synlett, 1998, 1441-1443.

[10.] Molander, G. A. & McWilliams, J. C. Mild preparation of allylic tartaramide acetals in DMF. Tetrahedron Lett., 1996, 37, 7197-7200.

[11.] Choi, H.-J., Kwak, M.-O. & Song, H. Efficient synthetic method for L-tartaramides by aminolysis of reactive 2,3-O-isopropylidene-L-tartaryl chloride. Synth. Commun., 1997, 27, 1273-1280.

[12.] Yoon, N. M. & Brown, H. C. Selective reductions. XII. Explorations in some representative applications of aluminium hydride for selective reductions. J. Am. Chem. Soc., 1968, 90, 2927-2938.

[13.] Brown, H. C. & Heim, P. Diborane as a mild reducing agent for the conversion of primary, secondary, and tertiary amides into the corresponding amines. J. Am. Chem. Soc., 1964, 86, 3566-3567.

[14.] Lopp, M., Paju, A., Kanger, T. & Pehk, T. Asymmetric Baeyer-Villiger oxidation of cyclobutanones. Tetrahedron Lett., 1996, 37, 7583-7586.

[15.] Bolm, C. & Beckmann, O. Zirkonium-mediated asymmetric Baeyer-Villiger oxidation. Chirality, 2000, 12, 523-525.

[16.] Bolm, C., Schlingloff, G. & Weickhardt, K. Optically active lactones from a Baeyer-Villiger-type metal-catalyzed oxidation with molecular oxygen. Angew. Chem., Int. Ed. Engl., 1994, 33, 1848-1849.

[17.] Saravanan, P., Chandrasekhar, M., Anand, V. & Singh, V. K. An efficient method for deprotection of acetals. Tetrahedron Lett., 1998, 39, 3091-3092.

Kaja ILMARINEN (a), Kadri KRIIS (a), Anne PAJU (a), Tonis PEHK (b), and Margus LOPP (b,c)

(a) Institute of Chemistry, Tallinn Technical University, Akadeemia tee 15, 12618 Tallinn, Estonia;

(b) National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, Estonia

(c) Department of Chemistry, Tallinn Technical University, Ehitajate tee 5, 19086 Tallinn, Estonia;
Table 1. The reduction of N,N,N',N'-tetrabenzyl-2,3-O-isopropylidene
R,R-tartramide 3

Entry Reducing agent Solvent

1 [B.sub.2][H.sub.6] THF
2 Al[H.sub.3] [Et.sub.2]O, THF
3 LiAl[H.sub.4]-Al[Cl.sub.3] [Et.sub.2]O, THF
4 LiAl[H.sub.4] THF

 Temperature, Yield of
Entry [degrees]C Time, h amine 6, %

1 60 1.5 94
2 0 1.5 70
3 0 1.5 86
4 0 1.0 *

* Only amide-cleavage products were detected.

Table 2. The results of Baeyer-Villiger oxidation of ketones
9-12 by using chiral ligands 2-8 *

 Chiral Metal
Entry Substrate Oxidant ligand compound

1 9 PhCHO, [O.sub.2] 3 [Cu(OTf).sub.2]
2 10 PhCHO, [O.sub.2] 6 [Cu(OTf).sub.2]
3 10 PhCHO, [O.sub.2] 2 [Cu(OTf).sub.2]
4 *** 10 t-BuOOH 5 [Ti(O-iPr).sub.4]
5 *** 10 t-BuOOH 8 [Ti(O-iPr).sub.4]
6 11 PhCHO, [O.sub.2] 3 [Cu(OTf).sub.2]
7 11 PhCHO, [O.sub.2] 5 [Cu(OTf).sub.2]
8 11 PhCHO, [O.sub.2] 8 [Cu(OTf).sub.2]
9 11 t-BuCHO, [O.sub.2] 3 [Cu(OTf).sub.2]
10 11 t-BuCHO, [O.sub.2] 2 [Cu(OTf).sub.2]
11 11 t-BuCHO, [O.sub.2] 4 [Cu(OTf).sub.2]
12 11 t-BuCHO, [O.sub.2] 5 [Cu(OTf).sub.2]
13 11 t-BuCHO, [O.sub.2] 7 [Cu(OTf).sub.2]
14 12 t-BuCHO, [O.sub.2] 3 [Cu(OTf).sub.2]

 Amount of Enantiomeric excess
Entry catalyst Yield, % ee **

1 5 mol% 5 26%
2 5 mol% 43 Rac + regio-isomers
3 1.0 eq 7 Rac + regio-isomers
4 *** 1.4 eq 16 37%
5 *** 1.5 eq 12 9%
6 10 mol% 12 Rac
7 10 mol% 19 Rac
8 10 mol% 19 Rac
9 10 mol% 52.5 Rac
10 10 mol% 30 Rac
11 10 mol% 31 Rac
12 10 mol% 24 Rac
13 10 mol% 33.5 Rac
14 10 mol% 46 Rac

* For the experimental procedure see [16]; the oxidation process
was terminated after a sufficient amount of products for analysis
was obtained;

** The ee values were determined by HPLC with the column Daicel
ODH (4.6 x 250 mm);

*** For the experimental procedure see [14].
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Author:Ilmarinen, Kaja; Kriis, Kadri; Paju, Anne; Tonis, Pehk; Lopp, Margus
Publication:Estonian Academy of Sciences: Chemistry
Date:Sep 1, 2001
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