DOI 10.1007/s10600-014-1148-9 Chemistry of Natural Compounds, Vol. 50, No. 6, December, 2014 [Russian original No. 6, November–December, 2014]
DIELS–ALDER REACTION OF LEVOPIMARIC ACID WITH 2-(2,4-DIOXO-5-THIAZOLIDINYLIDENE)ACETIC ACID
G. F. Vafina,* A. R. Uzbekov, L. V. Spirikhin, and M. S. Yunusov
New derivatives of levopimaric acid containing a thiazolidinedione fragment were synthesized by a Diels–Alder reaction of levopimaric acid and 2-(2,4-dioxo-5-thiazolidinylidene)acetic acid. The new compounds were characterized using elemental analysis and NMR spectroscopy. Keywords: diene synthesis, levopimaric acid, thiazolidinedione fragment. Publications on the synthesis of diene adducts of resin acids have grown dramatically in the last few years. Compounds with antitumor, anti-inflammatory, antiulcer, and antiviral activity were found among diene adducts of levopimaric acid with quinones [1]. Syntheses of thiazole and its derivatives were widely explored because of the large number of natural products and drugs with that heterocycle in their structures [2, 3]. Thiazolidinedione derivatives exhibit anti-inflammatory [4], antibacterial [5], antituberculosis [6], antifungal [7], and anti-HIV [8] activity. The diene synthesis of levopimaric acid and 2-(2,4-dioxo5-thiazolidinylidene)acetic acid seemed interesting with respect to the discovery of new optically active compounds with potential biological activity. In continuation of research on the synthesis of new levopimaric acid derivatives [9, 10], we performed a Diels–Alder reaction of levopimaric acid (1), which occurs in pine sap (~30%), with 2-(2,4-dioxo-5-thiazolidinylidene)acetic acid. The reaction after 17 d was stereoselective and formed two regioisomers 2a and 2b in 81% yield. The ratio of 2a:2b was 7:1 and was established using the integrated intensity of the H-1 singlet in PMR spectra. Unfortunately, we were unable to separate the mixture of regioisomers and isolate pure major isomer 2a. COOH
NH
4b 7
COOH 1
10a 10 8a
COOR a
NR
COOR O
3 12
4 4a
5
O EtOH, 17 days
O
13
O
S
2 1
4' 11
S
S NR 2'
O
COOR
+
O COOR b R = H (2a,b) R = Me (3a,b)
CH2N2, Et 2O
Methylation of the mixture of 2a and 2b by diazomethane produced N-methyl dimethyl esters 3a and 3b in quantitative yield. Purification by column chromatography isolated pure major diester 3a. Structures of all synthesized compounds were established using NMR spectroscopy and elemental analysis. COSY, TOCSY, NOESY, 1H–13C HSQC, 1H–13C HMBC, and 1H–15N HMBC spectra were recorded in order to assign accurately resonances of framework atoms. 13C NMR spectra were interpreted based on DEPT-90 and DEPT-135 experiments [11]. Chemical shifts for protons of corresponding C atoms were established using HSQC spectra. Coupling of geminal and vicinal protons were confirmed by 1H–1H COSY spectra; through-space coupling of protons with geminal and vicinal C atoms, HMBC spectra. Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, 450054, Ufa, Prosp. Oktyabrya, 71, e-mail:
[email protected]. Translated from Khimiya Prirodnykh Soedinenii, No. 6, November–December, 2014, pp. 876–878. Original article submitted June 19, 2014. 0009-3130/14/5006-1009
©2014
Springer Science+Business Media New York
1009
Structures of the regioisomers were determined from couplings in HMBC and HSQC spectra of pure major diester 3a. Thus, according to the HSQC spectrum, H-12 resonated at GH 2.82 ppm and had cross peaks for coupling with C-11 (GC 70.09 ppm) and C-3 (GC 51.95 ppm) in the HMBC spectrum. The resonance for C-11 was coupled with vicinal H-1 (GH 5.45 ppm), H-4a (GH 3.10 ppm), and H-3 (GH 1.73 ppm). The E-location of H-12 and the D-orientation of the carboxymethyl group were consistent with coupling between H-12 and isopropyl methyl proton resonances in the NOESY spectrum. Unfortunately, the configuration of the spiro center could not be determined.
EXPERIMENTAL PMR and 13C NMR spectra were recorded in CDCl3 or C6D6 on a Bruker Avance-III 500 MHz pulsed spectrometer at operating frequency 500.13 (1H) and 125.47 MHz (13C). Chemical shifts in 13C NMR and PMR spectra were given in ppm vs. tetramethylsilane (TMS) internal standard. Two-dimensional correlation spectra were recorded using the standard library of instrument pulse sequences. IR spectra were recorded from thin layers on a Shimadzu instrument. Elemental analysis was performed on a Euro EA 3000 analyzer. Optical rotation angles were measured on a PerkinElmer 341 polarimeter (O 589 nm) at 20°C. Melting points were uncorrected and were measured on a Boetius apparatus. NMR and IR spectra were recorded on equipment at the Khimiya CCU, IOC, USC, RAS. Elemental analyses of all synthesized compounds agreed with those calculated. The course of reactions was monitored by TLC on Sorbfil PTSKh-AF-A plates using CHCl3–MeOH (10:1). 2-(2,4-Dioxo-5-thiazolidinylidene)acetic acid was prepared from maleic anhydride and thiourea in two steps [12]. Physicochemical data of the synthesized dienophile agreed with the literature values. We used Pinus sylvestris sap containing ~30% levopimaric acid that was collected in spring 2012 near Nizhnii Novgorod. The levopimaric acid content in the sap was determined by GC from the ratio of methyl esters of total resin acids that were prepared via methylation of the sap by an excess of diazomethane. The yields of reaction products were determined based on starting dienophile. (4bS,8R)-2-Isopropyl-4b,8-dimethyl-2c,4c-dioxo-4,4a,4b,5,6,7,8,8a,9,10-decahydro-3H-spiro[3,10aethanophenanthren-11,5c-[1,3]-thiazolidine]-8,12-dicarboxylic Acid (2a) and (4bS,8R)-2-Isopropyl-4b,8-dimethyl-2c,4cdioxo-4,4a,4b,5,6,7,8,8a,9,10-decahydro-3H-spiro[3,10a-ethanophenanthren-12,5c-[1,3]-thiazolidine]-8,11-dicarboxylic Acid (2b). C25H33NO6S. Pine sap (7.5 g) in EtOH (100 mL) was treated with 2-(2,4-dioxo-5-thiazolidinylidene)acetic acid (1.3 g) and stored in the dark at room temperature for 17 d. The solvent was vacuum distilled (water aspirator). The residue was crystallized from Et2O–petroleum ether (40–70°C). Yield 81%. IR spectrum (Q, cm–1): 3164, 1746, 1697, 1462, 1378, 1328, 1279, 1209, 1198, 1163. 13C NMR spectrum of major acid 2a (ÑDCl 3, G, ppm): 16.21 (q, Ìå), 16.42 (q, Ìå), 16.71 (t, Ñ-6), 19.68 (q, Ìå), 19.77 (q, Ìå), 20.94 (t, Ñ-9), 21.09 (t, Ñ-5), 29.72 (t, Ñ-4), 32.14 (d, Ñ-13), 35.11 (d, Ñ-12), 36.49 (t, Ñ-7), 37.41 (t, Ñ-10), 37.74 (s, C-4b), 46.40, 46.67 (s, C-8, 10a), 48.77 (d, Ñ-8à), 51.43 (d, Ñ-3), 55.06 (d, Ñ-4à), 71.21 (s, Ñ-11), 123.50 (d, Ñ-1), 149.78 (s, Ñ-2), 172.05 (s, C-4c), 173.67 (s, C-2c), 177.69 (s, Ñ-12-ÑÎÎ), 182.27 (s, Ñ-8-ÑÎÎ). 13C NMR spectrum of minor acid 2b (ÑDCl , G, ppm): 16.54 (q, Ìå), 16.10 (t, Ñ-6), 21.95 (t, Ñ-9), 22.39 (t, Ñ-5), 31.00 (t, 3 Ñ-4), 32.34 (d, Ñ-13), 36.11 (t, Ñ-7), 36.50 (d, Ñ-11), 37.52 (t, Ñ-10), 39.32 (s, C-4b), 44.71 (d, Ñ-8à), 46.36, 46.66 (s, C-8, 10a), 49.55 (d, Ñ-3), 56.59 (d, Ñ-4à), 75.17 (s, Ñ-12), 119.36 (d, Ñ-1), 151.53 (s, Ñ-2), 171.32 (s, C-4c), 174.52 (s, C-2c), 176.33 (s, Ñ-11-ÑÎÎ), 182.72 (s, Ñ-8-ÑÎÎ). Dimethyl (4bS,8R)-2-isopropyl-3c,4b,8-trimethyl-2c,4c-dioxo-4,4a,4b,5,6,7,8,8a,9,10-decahydro-3H-spiro[3,10aethanophenanthren-11,5c-[1,3]-thiazolidene]-8,12-dicarboxylate (3a), C28H39NO6 S, was prepared by diazomethane methylation of the mixture of 2a and 2b. The yield was quantitative. Dimethyl ester 3a was isolated pure by column chromatography over silica gel using CHCl3–MeOH (50:1). Yield after purification, 79%. Rf 0.73, mp 65–66°C, [D]20 D +94q (c 1.9, CHCl3). IR spectrum (Q, cm–1): 1744, 1720, 1168, 1458, 1427, 1369, 1287, 1244, 1192, 1105, 1022, 762. 1Í NMR spectrum (Ñ6D6, G, ppm, J/Hz): 0.42 (3Í, s, Ìå), 0.62 (1Í, td, J = 13.1, 3.5, Í-10àõ), 0.97 (1Í, m, Í-9eq), 0.98 (3H, d, J = 6.0, Ìå), 1.0 (3H, d, J = 6.0, Ìå), 1.12 (1H, dd, J = 13.1, 2.7, H-10eq), 1.20 (3Í, s, Ìå), 1.20–1.23 (1H, m, H-6eq), 1.25–1.36 (2H, m, H-9ax, 6ax), 1.41 (1H, m, Í-5eq), 1.49 (1H, ddd, J = 12.8, 3.2, 3.0, H-7eq), 1.55 (1H, ddt, J = 12.4, 3.0, 1.8, 1.8, H-4eq), 1.73 (1H, dd, J = 10.1, 4.7, H-3), 1.76–1.87 (3H, m, H-7ax, 8ax, 4ax), 2.20 (1H, sept, J = 6.5, H-13), 2.39 (1H, ddd, J = 12.1, 10.1, 1.9, H-5ax), 2.73 (3H, s, N-Me), 2.82 (1H, br.s, Í-12), 3.10 (1Í, s, Í-4à), 3.32, 3.34 (6Í, s, ÑÎÎÌå), 5.45 (1Í, s, Í-1). 13Ñ NMR spectrum (Ñ6D6, G, ppm): 16.84 (q, Ìå), 17.00 (q, Ìå), 17.23 (t, Ñ-6), 20.01 (q, Ìå), 20.13 (q, Ìå), 21.49 (t, Ñ-9), 21.65 (t, Ñ-5), 27.53 (q, N-Me), 30.32 (t, Ñ-4), 32.58 (d, Ñ-13), 35.81 (d, Ñ-12), 36.96 (t, Ñ-7), 37.70 (t, Ñ-10), 38.19 (s,
1010
C-4b), 47.24, 47.31 (s, C-8, 10a), 49.45 (d, Ñ-8à), 51.40, 51.62 (q, 2ÑÎÎÌå), 51.95 (d, Ñ-3), 55.44 (d, Ñ-4à), 70.09 (s, Ñ-11), 124.62 (d, Ñ-1), 149.47 (s, Ñ-2), 170.00 (s, C-4c), 171.37 (s, C-2c), 176.04 (s, Ñ-12-ÑÎÎÌå), 178.24 (s, Ñ-8-ÑÎÎÌå). Dimethyl (4bS,8R)-2-isopropyl-3c,4b,8-trimethyl-2c,4c-dioxo-4,4a,4b,5,6,7,8,8a,9,10-decahydro-3H-spiro[3,10aethanophenanthren-12,5c-[1,3]-thiazolidene]-8,11-dicarboxylate (3b) was not isolated pure. 1Í NMR spectrum (Ñ6D6, G, ppm): 5.55 (1Í, s, Í-1). 13Ñ NMR spectrum (ÑDCl3, G, ppm): 15.78 (q, Ìå), 16.56 (q, Ìå), 16.92 (t, Ñ-6), 17.61 (q, Ìå), 18.36 (q, Ìå), 21.45 (t, Ñ-9), 22.10 (t, Ñ-5), 27.48 (q, N-Me), 29.55 (t, Ñ-4), 32.48 (d, Ñ-13), 35.39 (d, Ñ-11), 36.97 (t, Ñ-7), 37.66 (t, Ñ-10), 38.43 (s, C-4b), 46.68, 46.78 (s, C-8, 10a), 48.66 (d, Ñ-8à), 51.46, 51.64 (q, 2ÑÎÎÌå), 51.88 (d, Ñ-3), 54.85 (d, Ñ-4à), 73.40 (s, Ñ-12), 126.85 (d, Ñ-1), 151.50 (s, Ñ-2), 170.84 (s, C-4c), 171.44 (s, C-2c), 175.99 (s, Ñ-11-ÑÎÎÌå), 178.81 (s, Ñ-8-ÑÎÎÌå).
ACKNOWLEDGMENT The work was supported financially by a grant of the RF President for Leading Scientific Schools No. NSh-1700.2014.3 and RAS Presidium Basic Research Program No. 8P.
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