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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.

INTRODUCTION

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.

RESULTS AND DISCUSSION

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].

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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.

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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).

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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.

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EXPERIMENTAL

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.

(+)-Dimethyl-2,3-O-isopropylidene-R,R-tartrate

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).

CONCLUSION

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

REFERENCES

[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; kkallas@chemnet.ee

(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; lopp@chemnet.ee
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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