TETRAHEDRONLETTERS

Tetrahedron Letters 44 (2003) 6107–6110Pergamon

An efficient approach to the synthesis of tri-substitutediminothiazolidenes and their effects on the human

neuroblastoma cell lineMuhammad Saeed,† Muhammad Abbas, Angelica Heinrich and Wolfgang Voelter*

Abteilung fur Physikalische Biochemie des Physiologisch-chemischen Instituts der Universitat Tubingen, Hoppe-Seyler-Strasse 4,D-72076 Tubingen, Germany

Received 17 March 2003; revised 6 June 2003; accepted 10 June 2003

Abstract—Starting from cis-oriented epoxytriflate pentoses 1 and 4, an expeditious route to the chiral thioazolidene derivatives2a–3a and 5a–6a in good yields is described. A minor amount of structural isomers 2b–3b and 5b–6b has also been observed. Thenewly formed compounds show activity against the human neuroblastoma cell line SK-N-LO.© 2003 Elsevier Ltd. All rights reserved.

Substituted thiazolidene derivatives represent importantkey intermediates for the synthesis of numerous phar-macologically active drugs.1–3 Besides, thiazolidenesshow a broad range of biological effects includingprotease inhibition,4,5 anti-tumor,6 platelet GPIIb/IIIareceptor antagonistic,7 anti-HIV,8 anti-diabetic,9,10 orpesticidal activities.11 Moreover, a number of naturalproducts has been reported containing thiazolidene andthiazoline moieties.10,12,13 Thiazolidenes can also beused as precursors to other functionalities.14

In the past, much attention has been given to thesynthesis of substituted thiazoliden-4-ones and non-car-bohydrate organic compounds containing the thiazoli-dene ring because of their pharmaceutical activities.15–18

However, to the best of our knowledge, no sugar-embedded thiazolidene has been reported for its biolog-ical activity. In this communication, we want to presentthe synthesis and biological potential of thiazolideneson carbohydrate scaffoled. Using the chiral synthons,benzyl 2,3-anhydro-4-O-triflyl-�-L-ribopyranoside (1)

Scheme 1. Synthesis of different iminothiazolidene derivatives.

* Corresponding author. E-mail: wolfgang.voelter@uni-tuebingen.de† Present address: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical

Center, Omaha, NE 68198-6805.

0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.doi:10.1016/S0040-4039(03)01457-6

M. Saeed et al. / Tetrahedron Letters 44 (2003) 6107–61106108

Table 1. Formation of thiazolidene derivatives fromepoxytriflates 1 and 4

Product REntry no. YieldaEpoxytriflate

2a1 Ac1 742 1 2b Ac 163 1 3a Ph 63

3b Ph1 6445 5a Ac 6646 5b Ac 9

6a Ph4 4978 4 6b Ph 7

a Yield after acetylation and TLC purification.

Along with the major products, minor amounts of theproducts 2b, 3b, 5b, and 6b were also formed as isshown Scheme 1. Formation of minor compounds maybe accounted for, if one considers the initially formedintermediate as a mixture of structure 7a/8a and 7b/8b,respectively (Scheme 2). Attack of the sulfur atom viapath a leads to the major product 9a or 10a, whereaspath b leads to the formation of minor product 9b or10b, respectively. Acetylation of the mixture leads tothe final products.

The structures of all compounds were elucidated apply-ing MS, 1H and 13C NMR spectroscopy.21 The 13CNMR of all new compounds showed a quaternary

and benzyl 2,3-anhydro-4-O-triflyl-�-D-ribopyranoside(4) for the synthesis of chiral heterocyclic systems is anattractive approach.19 Continuing our research on thesynthesis of carbohydrate-based building blocks, wewant to report here the syntheses of highly functional-ized tri-substituted chiral thiazolidenes.

Starting from the partially blocked carbohydrate tem-plates 1 and 4, a regioselective path to the chiralthiazolidenes 2a–3a and 5a–6a is achieved through aone-pot reaction with thiosemicarbazide (R=H) or 4-phenylthiosemicarbazide (R=Ph) (Scheme 1).20 In atypical reaction, the epoxytriflates (0.5 mmol) in THF(5 mL) were reacted overnight with a solution ofthiosemicarbazide or 4-phenylthiosemicarbazide (0.55mmol) in 1,4-dioxane (10 mL). A strong nucleophilicattack by the sulfur atom and removal of the triflylgroup at C-4 with the simultaneous ring opening of theepoxide by nitrogen led to the formation of thiazoli-dene derivatives 2a–3a and 5a–6a in good yield. Theproducts were isolated after complete acetylation withacetic anhydride in pyridine in good yields (see Table1).

Figure 1. Cytotoxic effect of a mixture of thiazolidenes 9aand 9b on the human neuroblastoma cell line SK-N-LO.

Scheme 2. Proposed mechanism of the formation of major and minor product.

M. Saeed et al. / Tetrahedron Letters 44 (2003) 6107–6110 6109

carbon resonance at about 144–146 ppm, indicative forthe external immine (C�N) bond formation. Completeacetylation of products was confirmed by their methylresonances around 19–28 ppm and carbonyl resonancesaround 165–175 ppm for each compound. The structureof compound 2a was also unambiguously confirmed byX-ray crystallography.22

A mixture of compounds 9a and 9b (R=H) was sub-jected to the human neuroblastoma cell line SK-N-LOto test its cyototoxicity.23 The thiazolidene sampleshowed a survival effect for the neuroblastoma cell linecomparable to doxorubicin (Fig. 1).

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18. Tierney, J. J. Heterocyclic Chem. 1989, 26, 997.19. (a) Saeed, M.; Abbas, M.; Abdel-Jalil, R. J.; Zahid, M.;

Voelter, W. Tetrahedron Lett. 2003, 44, 315; (b) Saeed,

M.; Abdel-Jalil, R. J.; Voelter, W.; El-Abadelah, M. M.Chem. Lett. 2001, 7, 660; (c) Abdel-Jalil, R. J.; Saeed, M.;Voelter, W. Tetrahedron Lett. 2001, 42, 2435.

20. For the references on the use of thiosemicarbazide asnucleophile, see: (a) Kryl’sky, D. V.; Shikhaliev, Kh. S.;Pigarev, V. V.; Solovyev, A. S. Chem. Heterocyclic Comp.(New York, US) 2002, 38, 992; (b) Deshmukh, R. S.;Berad, B. N. Indian J. Heterocyclic Chem. 2002, 12, 153;(c) Zou, J.-P.; Zeng, R.-S.; Lu, Z.-E.; Chen, K.-Q. TrendsHeterocyclic Chem. 2001, 7, 107–116; (d) Janaca, M.;Necas, M.; Zak, Z.; Prihoda, J. V. Polyhedron 2001, 20,2823; (e) Mirskova, A.; Levkovskaya, G.; Guseva, S.Phos. Sulfur and Silicon and their Related Elements 1994,95 and 96, 463; (f) Shainyn, B. A.; Indyukova, L. N.;Kalikhaman, I. D.; Mirskova, A. N. Zhurnal Organich-eskoi Khimii 1986, 22, 639.

21. Data for compound 2a: colorless crystals, mp 187°C;yield 74%. [� ]D=+167.3 (c 1, CH2Cl2); 1H NMR (250MHz, CDCl3): �=7.33–7.20 (m, 5H), 5.22 (s, 1H), 4.81(br. s, 1H), 4.78 (br. s, 1H), 4.62 (d, J=11.1 Hz, 1H,CHHPh), 4.39 (d, J=11.1 Hz, 1H, CHHPh), 4.06 (m,1H), 4.37–3.61 (m, 2H), 2.50 (s, 3H), 2.08 (s, 3H), 2.00 (s,6H); 13C NMR (62.8 MHz, CDCl3): �=183.0, 174.5,169.5, 169.2, 135.5 (5×C), 95.5 (C-1), 70.2 (CH2Ph), 65.5(C-2), 58.3 (C-4), 58.1 (C-5), 35.2 (C-3), 27.7, 26.5, 23.1and 20.8 (4×CH3). FAB-MS: m/z 464.1435 [M+1]+, calcdC21H26N3O7S (464.1491). Data for 2b: colorless oil; yield16%; [� ]D=+15.3 (c 1, CH2Cl2); 1H NMR (250 MHz,CDCl3): �=7.30–7.18 (m, 5H), 5.22 (s, 1H), 4.99 (br. s,1H), 4.76 (br. s, 1H), 4.56 (d, J=11.1 Hz, 1H, CHHPh),4.36 (d, J=11.1 Hz, 1H, CHHPh), 4.00 (m, 1H), 3.72–3.29 (m, 2H), 2.06 (s, 6H), 1.97 (s, 3H), 1.37 (s, 3H); 13CNMR (62.8 MHz, CDCl3): �=183.0, 177.5, 169.4, 164.5,136.4 (5×C), 95.8 (C-1), 70.6 (CH2Ph), 66.2 (C-2), 61.7(C-4), 59.2 (C-5), 35.2 (C-3), 27.6, 24.9, 21.8 and 20.9(4×CH3); FAB-MS: m/z 464.1440 [M+1]+, calcdC21H26N3O7S (464.1491). Data for compound 3a: color-less oil; 1H NMR (250 MHz, CDCl3): �=7.45–6.78 (m,10H), 4.81 (s, 1H), 4.75 (s, 1H), 4.66 (d, J=11.6 Hz, 1H),4.47 (d, J=11.6 Hz, 1H), 4.30 (br. s, J=5.47 Hz, 1H),3.92–3.56 (m, 3H), 2.52 (s, 3H), 2.18 (s, 3H), 1.74 (s, 3H);13C NMR (62.8 MHz, CDCl3): �=95.7 (C-1), 70.1 (C-2),66.5 (CH2Ph), 59.1 (C-3), 59.0 (C-5), 35.1 (C-3), 26.9,23.4 and 20.8 (3×CH3); FAB-MS: m/z 498.1665 [M+1]+,calcd C25H27N3O6S (497.1699). Data for compound 5a:colorless oil; [� ]D=+67.0 (c 1, CH2Cl2); 1H NMR (250MHz, CDCl3): �=7.33–7.20 (m, 5H), 5.22 (s, 1H), 4.99(br. s, 1H), 4.76 (br. s, 1H), 4.56 (d, J=11.1 Hz, 1H,CHHPh), 4.36 (d, J=11.1 Hz, 1H, CHHPh), 4.00 (m,1H), 3.72–3.29 (m, 2H), 2.06 (s, 6H, 2×CH3), 1.97 (s, 3H,CH3), 1.37 (s, 3H, CH3); 13C NMR (62.8 MHz, CDCl3):�=94.1 (C-1), 70.1 (CH2Ph), 70.0 (C-2), 58.9 (C-4), 58.8(C-5), 41.5 (C-3), 27.3, 25.4, 23.9 and 20.7 (4×CH3);FAB-MS: m/z 464.1440 [M+1]+, calcd C21H26N3O7S(464.1491). Data for compound 6a: colorless oil; 1HNMR (250 MHz, CDCl3): �=7.48–6.71 (m, 10H), 5.19(m, 1H), 5.06 (m, 1H), 4.70 (d, J=11.6 Hz, 1H), 4.47 (d,J=11.6 Hz, 1H), 4.33 (m, 1H), 4.15–4.00 (m, 2H), 3.67–3.40 (m, 1H), 2.52 (s, 3H), 2.20 (s, 3H), 1.72 (s, 3H); 13CNMR (62.8 MHz, CDCl3): �=94.4 (C-1), 70.8 (C-2), 70.0(CH2Ph), 60.2 (C-3), 59.2 (C-5), 42.1 (C-3), 26.1, 23.7 and20.8 (3×CH3); FAB-MS: m/z 498.1651 [M+1]+, calcdC25H27N3O6S (497.1699).

M. Saeed et al. / Tetrahedron Letters 44 (2003) 6107–61106110

22. Selected bond lengths (A� ) and bond angles of 2a; (°);S(1)�C(6) 1.738(7); N(1)�C(5) 1.474(9); S(1)�C(1)1.814(8); N(1)�C(6) 1.388(9); C(1)�C(5) 1.523(11);N(3)�C(11) 1.419(10); N(3)�C(9) 1.411(9); N(2)�C(13)1.399(9); O(2)�C(4) 1.437(8); C(6)�S(1)�C(1) 91.6(3);C(6)�N(1)�C(5) 114.8(5); N(3)�C(11)�C(12) 118.7(7);N(3)�C(9)�C(10) 116.1(7); C(3)�O(3)�C(15) 111.6(5);C(6)�N(1)�N(3) 115.9(5); C(5)�C(1)�C(2) 112.6(6).

23. The assay was based on the mitochondrial conversion ofa yellow colored tetrazolium salt, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) into a pur-ple formazan, which was spectrophotometricallyquantified using an ELISA plate reader. Since reductionof MTT can only occur in metabolically active cells, thelevel of activity was taken as a measure of the viability ofthe cells. 200 �L of cell suspension (5.0×105 cells/mL)were placed into a 96-well microtiter plate and incubatedovernight at 37°C, 5% CO2 and 100% humidity. Thethiazolidene compound or doxorubicin was added assolution (10 �L) in PBS (phosphate buffer saline) andcells were incubated further for 48 h under the sameconditions. The cell culture medium was removed and100 �L of MTT solution was added and the microtiterplate was further incubated for 3 h. Treatment with 100�L of isopropanol solution resulted in the dissolution ofcrystalline formazan to a clear purple solution which wasmeasured with a reference wavelength at 550 nm and testwavelength at 630 nm. The absorbance of control wastaken as 100% survival. Detailed results will be presentedelsewhere as a full paper.