Synthesis and Modifications of Alkyne Derivatives of ... - Springer Link

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 10, pp. 1496–1502. © Pleiades Publishing, Ltd., 2016. Original Russian Text © E.V. Tret’yakova, E.V. Salimova, L.V. Parfenova, V.N. Odinokov, 2016, published in Zhurnal Organicheskoi Khimii, 2016, Vol. 52, No. 10, pp. 1503–1508.

Synthesis and Modifications of Alkyne Derivatives of Dihydroquinopimaric, Maleopimaric, and Fumaropimaric Acids E. V. Tret’yakova,* E. V. Salimova, L. V. Parfenova, and V. N. Odinokov Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, pr. Oktyabrya 141, Ufa, 450075 Bashkortostan, Russia *e-mail: [email protected] Received June 22, 2016

Abstract—Reactions of maleopimaric and dihydroquinopimaric acid chlorides with propargyl alcohol and propargylamine afforded new terminal diterpene alkynes, and Sonogashira cross-coupling of the latter with 4-iodonitrobenzene led to the formation of arylalkynyl derivatives of Diels–Alder adducts of levopimaric acid.

DOI: 10.1134/S1070428016100201 Alkyne moiety plays an important role in the design of new medicinals [1, 2]. Triple C≡C bond is present in molecules of many natural compounds and their synthetic analogs possessing various kinds of biological activity, including antitumor, antibacterial, antimicrobial, antifungal, and others [3–5]. Furthermore, the presence of an acetylenic fragment extends the possibilities of structural modifications, so that considerable attention was given to the development of efficient and selective methods for the synthesis of alkynes [6, 7] and their functionalization [8–10]. An efficient approach to the synthesis of functionalized alkynes is based on palladium-catalyzed crosscoupling of aryl halides with terminal alkynes (Sonogashira reaction) [11]. Herein we report the synthesis of alkynyl derivatives of Diels–Alder adducts obtained from levopimaric acid and their functionalization via Sonogashira cross-coupling. Levopimaric acid is an accessible abietane diterpenoid abundant in conifer resin [12]. Due to the presence of conjugated double bond system, levopimaric acid is a versatile reagent for Diels–Alder cycloadditions leading to various derivatives [13, 14] exhibiting valuable biological properties such as antiinflammatory [15], antiulcer [16], antiviral [17], and antitumor activity [18]. Initial maleopimaric and dihydroquinopimaric acids 1 and 2 are readily available via Diels‒Alder reactions of levopimaric acid [19, 20]. The condensation of

maleopimaric and dihydroquinopimaric acid chlorides 3 and 4 [21, 22] with propargylamine hydrochloride on heating in boiling anhydrous chloroform in the presence of triethylamine gave amides 5 and 7 in 95 and 90% yield, respectively. Esters 6 and 8 were obtained in quantitative yield from acid chlorides 3 and 4 and propargyl alcohol in chloroform at room temperature (Scheme 1). The terminal alkyne fragment (≡CH) in 5–8 gave rise to a signal at δ 2.46 (5, 7) or δ 2.23 ppm (6, 8) in their 1H NMR spectra and signals of the triple-bonded carbon atoms in the region δC 71.46– 79.90 ppm of the 13C NMR spectra. Alkaline hydrolysis of maleopimaric acid derivatives 5 and 6 in 15% methanolic potassium hydroxide afforded 85 and 89% of fumaropimaric acid derivatives 9 and 10 (Scheme 1). The COOH protons of 9 and 10 resonated in the 1H NMR spectra at δ 8.50– 8.51 ppm. Compounds 5–10 were brought into Sonogashira cross-coupling with 4-iodonitrobenzene in DMF in the presence of CuI‒PdCl2(PPh3)2 and triethylamine. The reactions were carried out at room temperature (4 h), and the products were the corresponding arylalkynyl derivatives 11–16 which were isolated in 62–89% yield (Scheme 2). Compounds 11–16 displayed in the 1 H NMR spectra aromatic proton signals in the region δ 7.51–8.30 ppm, and aromatic carbon atoms therein resonated at δC 123.63–147.40 ppm in the 13C NMR spectra.

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SYNTHESIS AND MODIFICATIONS OF ALKYNE DERIVATIVES

1497

Scheme 1. 19

Me

18

17

Me

20 11

13

Me 9

2 3

1 4

21

10

6

22

O

H

5

H

Me

14

Me

O

12

23 15 16

O

24

8 7

Me

(COCl)2 CHCl3, 2 h

H

Me

OH

HC≡CCH2NH2 · HCl CHCl3, Et3N, 60°C, 6 h or HC≡CCH2OH CHCl3, 22°C, 2 h

O H

O

Me

O

Me

Me

O H

O H

Me

Cl

O

O

1

O

Me

O

X 2'

1'

3

3'

CH

5, 6

Me

O

Me

OH

Me

15% KOH/MeOH 65°C, 1 h

OH H H

Me

O

X

O

CH 9, 10

17

Me

16

15

Me

12

18 11

13

10b

14

Me

9 8

10

6a

7

19

H

Me O

4b

10a

20

H 6

5

H

Me

1 12a 4a 4

H

Me

O 2 3

H

O H

Me

H

Me

O HC≡CCH2NH2 · HCl CHCl3, Et3N, 60°C, 6 h or HC≡CCH2OH CHCl3, 22°C, 2 h

Me

(COCl)2 CHCl3, 2 h

OH

H

H H

Me

Cl

O

H

O

X

O 4

H

Me

O

O 2

Me

CH 7, 8

5, 7, 9, X = NH; 6, 8, 10, X = O.

In summary, we have synthesized arylalkynyl derivatives of Diels–Alder adducts of levopimaric acid by selective palladium-catalyzed cross-coupling of new alkynyl derivatives of maleopimaric, fumaropimaric, and dihydroquinopimaric acids with 4-iodonitrobenzene. EXPERIMENTAL The 1H and 13C NMR spectra were recorded on Bruker AM-300 (300 and 75.5 MHz, respectively) and Bruker Avance III spectrometers (500.13 and 125.47 MHz, respectively) using a PABBO 5-mm Z-gradient probe (298 K); the chemical shifts were measured relative to tetramethylsilane as internal standard. The melting points were determined on a Boetius hot stage. Sorbfil plates (Sorbpolimer, Russia) were used for thin-layer chromatography (chloroform–ethyl

acetate, 40 : 3); the chromatograms were developed by treatment with a 10% solution of sulfuric acid, followed by heating for 2–3 min at 100–120°C. Column chromatography was performed with neutral alumina (KhromLab, Russia). Maleopimaric acid (1) [19], dihydroquinopimaric acid (2) [20], and acid chlorides 3 [21] and 4 [22] were synthesized by known methods. Compounds 5 and 7 (general procedure). A solution of 0.1 g (1.1 mmol) of propargylamine hydrochloride in 5 mL of anhydrous chloroform and 0.25 mL (1.7 mmol) of triethylamine were added with stirring to a solution of 0.43 g (1 mmol) of acid chloride 3 or 4 in 15 mL of anhydrous chloroform. The mixture was refluxed for 2 h, cooled, washed with 5% aqueous HCl (3 × 20 mL) and water (2 × 100 mL), and dried over CaCl2. The solvent was evaporated, and the residue was purified by alumina column chromatography using methylene chloride as eluent.

RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 10 2016

TRET’YAKOVA et al.

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Scheme 2. Me

5, 6

Me

4-O2NC6H4I PdCl2(PPh3)2 CuI, Et3N, DMF

H

Me

O H

Me

Me

O

Me

O

7, 8

O

Me


H H

Me

X

H

H

O

X

O

O

NO2

NO2 13, 14

11, 12

Me

O

Me

9, 10

OH

Me


OH H H

Me

O

X

O NO2 15, 16

11, 13, 15, X = NH; 12, 14, 16, X = O.

12-Isopropyl-6,10-dimethyl-1,3-dioxo-N-(prop-2yn-1-yl)-3b,11-ethenohexadecahydrophenanthro[1,2-c]furan-6-carboxamide (5). Yield 0.42 g (95%), mp 100‒102°C. 1H NMR spectrum (CDCl3), δ, ppm: 0.55 s (3H, C20H3), 0.90 d (3H, C18H3, J = 6.9 Hz), 0.96 d (3H, C19H3, J = 7.0 Hz), 1.18 s (3H, C21H3), 1.21‒1.91 m (14H, 1-H, 2-H, 3-H, 5-H, 6-H, 7-H, 9-H, 11-H), 2.23 s (1H, 3′-H), 2.45 d (1H, 17-H, J = 8.4 Hz), 2.62 d.t (1H, 16-H, J = 3.0, 14.0 Hz), 2.90 d (1H, 15-H, J = 8.4 Hz), 3.08 d (1H, 12-H, J = 8.4 Hz), 3.98 d.d (2H, 1′-H, J = 18.4, 1.72 Hz), 5.49 s (1H, 14-H), 6.15 br.s (1H, NH). 13 C NMR spectrum (CDCl 3 ), δ C, ppm: 15.59 (C 20 ), 16.68 (C 19 ), 17.00 (C2), 19.95 (C18), 20.54 (C19), 20.98 (C6), 27.15 (C11), 29.56 (C1′), 32.70 (C17), 34.65 (C7), 35.65 (C12), 36.61 (C3), 37.68 (C10), 37.75 (C1), 40.33 (C8), 45.61 (C15), 46.62 (C4), 49.64 (C5), 53.05 (C9), 53.06 (C16), 71.46 (C3′), 79.90 (C2′), 125.17 (C14), 148.00 (C13), 171.14 (C23), 172.91 (C24), 178.27 (C22). Found, %: C 74.00; H 8.54; N 3.00. C27H35NO4. Calculated, %: C 74.11; H 8.06; N 3.20. 13-Isopropyl-7,10a-dimethyl-1,4-dioxo-N-(prop2-yn-1-yl)-4b,12-ethenohexadecahydrochrysene-7carboxamide (7). Yield 0.41 g (90%), mp 120‒122°C. 1 H NMR spectrum (CDCl 3 ), δ, ppm: 0.57 s (3H, C18H3), 0.75–0.89 m (2H, 6-H), 1.00 d (3H, C16H3, J =

6.9 Hz), 1.02 d (3H, C17H3, J = 6.9 Hz), 1.18 s (3H, C19H3), 1.20–1.66 m (12H, 5-H, 6a-H, 8-H, 9-H, 10-H, 10b-H, 11-H), 2.18 s (1H, 4a-H), 2.25 s (1H, 3′-H), 2.35 t (1H, 15-H, J = 6.2 Hz), 2.40–2.50 m (4H, 2-H, 3-H), 2.75 br.s (1H, 12a-H), 3.2 br.s (1H, 12-H), 4.15 d.d (2H, 1′-H, J = 17.2, 1.82 Hz), 5.30 s (1H, NH), 5.54 s (1H, 14-H). 13C NMR spectrum (CDCl3), δC, ppm: 15.88 (C19), 16.70 (C18), 16.98 (C9), 19.89 (C17), 20.53 (C16), 21.23 (C6), 27.75 (C11), 29.69 (C1′), 32.89 (C15), 34.66 (C3), 36.76 (C5), 36.99 (C8), 37.88 (C12), 38.12 (C10), 38.16 (C10a), 38.98 (C4b), 41.22 (C2), 46.72 (C7), 49.92 (C6a), 54.85 (C10b), 55.85 (C4a), 60.58 (C12a), 71.57 (C3′), 79.80 (C2′), 125.47 (C14), 149.48 (C13), 178.55 (C20), 208.91 (C1), 210.16 (C4). Found, %: C 75.10; H 8.14; N 3.30. C29H39NO3. Calculated, %: C 77.47; H 8.74; N 3.12. Compounds 6 and 8 (general procedure). A solution of 0.09 mL (1.5 mmol) of propargyl alcohol in 5 mL of anhydrous chloroform was added to a solution of 0.43 g (1 mmol) of 3 or 4 in 15 mL of anhydrous chloroform. The mixture was stirred for 2 h, washed with a 15% aqueous solution of NaHCO3 (3 × 20 mL) and with water (2 × 100 mL), and dried over CaCl2. The solvent was evaporated, and the residue was purified by alumina column chromatography using methylene chloride as eluent.



Prop-2-yn-1-yl 12-isopropyl-6,10-dimethyl-1,3dioxo-3b,11-ethenohexadecahydrophenanthro[1,2-c]furan-6-carboxylate (6). Yield 0.43 g (98%), mp 118‒120°C. 1H NMR spectrum (CDCl3), δ, ppm: 0.50 s (3H, C20H3), 0.85 d (3H, C18H3, J = 6.9 Hz), 0.90 d (3H, C19H3, J = 7.0 Hz), 1.12 s (3H, C21H3), 1.21–1.81 m (14H, 1-H, 2-H, 3-H, 5-H, 6-H, 7-H, 9-H, 11-H), 2.25 d (1H, 17-H, J = 8.4 Hz), 2.43 s (1H, 3′-H), 2.62 d.t (1H, 16-H, J = 3.0, 14.0 Hz), 2.90 d (1H, 15-H, J = 8.4 Hz), 3.08 d (1H, 12-H, J = 8.4 Hz), 4.50 d.d (2H, 1′-H, J = 10.9, 1.55 Hz), 5.50 s (1H, 14-H). 13C NMR spectrum (CDCl3), δC, ppm: 15.50 (C20), 16.66 (C19), 16.88 (C2), 19.94 (C18), 20.54 (C19), 21.49 (C6), 27.16 (C11), 29.56 (C1′), 32.71 (C17), 34.60 (C7), 35.62 (C12), 36.37 (C3), 37.63 (C10), 37.87 (C1), 40.38 (C8), 45.62 (C15), 49.29 (C4), 52.05 (C5), 53.02 (C9), 53.11 (C16), 74.65 (C3′), 77.88 (C2′), 125.13 (C14), 148.07 (C13), 171.11 (C23), 172.11 (C24), 177.64 (C22). Found, %: C 75.10; H 8.10. C27H34O5. Calculated, %: C 73.94; H 7.81. Prop-2-yn-1-yl 13-isopropyl-7,10a-dimethyl-1,4dioxo-4b,12-ethenohexadecahydrochrysene-7-carboxylate (8). Yield 0.43 g (96%), mp 139–141°C. 1 H NMR spectrum (CDCl 3 ), δ, ppm: 0.57 s (3H, C18H3), 0.75–0.89 m (2H, 6-H), 1.03 d (3H, C16H3, J = 6.9 Hz), 1.09 d (3H, C17H3, J = 6.9 Hz), 1.18 s (3H, C19H3), 1.18‒1.74 m (12H, 5-H, 6a-H, 8-H, 9-H, 10-H, 10b-H, 11-H), 2.20 br.s (2H, 4a-H, 12a-H), 2.45 s (1H, 3′-H), 2.50 t (1H, 15-H, J = 6.2 Hz), 2.50‒2.55 m (4H, 2-H, 3-H), 3.21 br.s (1H, 12-H), 4.65 s (2H, 1′-H), 5.51 s (1H, 14-H). 13C NMR spectrum (CDCl3), δC, ppm: 14.27 (C19), 15.96 (C18), 16.70 (C9), 16.98 (C17), 19.89 (C16), 20.53 (C6), 21.60 (C11), 27.85 (C1′), 32.42 (C 15 ), 34.50 (C 3 ), 36.21 (C 5 ), 36.99 (C 8 ), 37.88 (C 12 ), 38.52 (C 10 ), 38.99 (C 10a), 41.58 (C 4b ), 46.63 (C2), 50.11 (C7), 54.67 (C6a), 55.88 (C10b), 60.53 (C4a), 60.60 (C 12a), 74.60 (C 3′), 77.94 (C 2′), 125.44 (C 14 ), 149.54 (C13), 177.70 (C20), 208.84 (C1), 210.04 (C4). Found, %: C 75.60; H 8.90. C29H38O4. Calculated, %: C 77.30; H 8.50. Compounds 9 and 10 (general procedure). Compound 5, 0.44 g (1 mmol), or 6, 0.45 g (1 mmol), was dissolved in 5 mL of methanol, 10 mL of a 15% solution of potassium hydroxide in methanol was added, and the mixture was refluxed for 1 h. The mixture was cooled to room temperature and poured into 100 mL of 10% aqueous HCl. The precipitate was filtered off, washed with water until neutral washings, and dried in air. The product was purified by column chromatography on aluminum oxide using methylene chloride as eluent.

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12-Isopropyl-4b,8-dimethyl-8-[(prop-2-yn-1-yl)carbamoyl]-3,10a-ethenotetradecahydrophenanthrene-1,2-dicarboxylic acid (9). Yield 0.39 g (85%), mp 135–137°C. 1H NMR spectrum (CDCl3), δ, ppm: 0.45 s (3H, C21H3), 0.89 d (3H, C18H3, J = 6.9 Hz), 0.92 d (3H, C19H3, J = 7.0 Hz), 1.10 s (3H, C20H3), 1.21–1.91 m (14H, 1-H, 2-H, 3-H, 5-H, 6-H, 7-H, 9-H, 11-H), 2.23 s (1H, 3′-H), 2.45 d (1H, 12-H, J = 8.4 Hz), 2.62 d.t (1H, 17-H, J = 3.0, 14.0 Hz), 2.90 d (1H, 16-H, J = 8.4 Hz), 3.08 d (1H, 15-H, J = 8.4 Hz), 3.98 d.d (2H, 1′-H, J = 18.4, 1.72 Hz), 5.50 s (1H, 14-H), 6.15 br.s (1H, NH), 8.51 br.s (2H, OH). 13 C NMR spectrum (CDCl 3 ), δ C, ppm: 15.59 (C 20 ), 16.68 (C21), 17.00 (C2), 20.95 (C18), 20.54 (C19), 20.98 (C6), 27.15 (C11), 29.56 (C1′), 32.70 (C17), 34.65 (C7), 35.65 (C12), 36.61 (C3), 37.68 (C10), 37.75 (C1), 40.33 (C8), 45.61 (C15), 46.62 (C4), 49.64 (C16), 53.05 (C5), 53.06 (C 9 ), 73.54 (C 3′), 78.99 (C 2′), 123.87 (C 14 ), 147.60 (C13), 176.11 (C23), 177.85 (C24), 179.30 (C22). Found, %: C 71.02; H 7.00; N 3.30. C27H37NO5. Calculated, %: C 71.18; H 8.19; N 3.07. 12-Isopropyl-4b,8-dimethyl-8-[(prop-2-yn-1-yloxy)carbonyl]-3,10a-ethenotetradecahydrophenanthrene-1,2-dicarboxylic acid (10). Yield 0.41 g (89%), mp 141–143°C. 1H NMR spectrum (CDCl3), δ, ppm: 0.51 s (3H, C 21 H 3 ), 0.89 d (3H, C 18 H 3 , J = 6.9 Hz), 0.92 d (3H, C19H3, J = 7.0 Hz), 1.18 s (3H, C20H3), 1.21–1.81 m (14H, 1-H, 2-H, 3-H, 5-H, 6-H, 7-H, 9-H, 11-H), 2.25 d (1H, 12-H, J = 8.4 Hz), 2.43 s (1H, 3′-H), 2.62 d.t (1H, 17-H, J = 3.0, 14.0 Hz), 2.90 d (1H, 16-H, J = 8.4 Hz), 3.08 d (1H, 15-H, J = 8.4 Hz), 4.50 d.d (2H, 1′-H, J = 10.9, 1.55 Hz), 5.51 s (1H, 14-H), 8.50 br.s (2H, OH). 13C NMR spectrum (CDCl3), δC, ppm: 15.10 (C20), 16.73 (C21), 16.92 (C2), 19.54 (C18), 20.54 (C19), 21.49 (C6), 27.16 (C11), 28.99 (C1′), 32.71 (C17), 34.60 (C7), 35.62 (C12), 36.37 (C3), 37.63 (C10), 37.87 (C1), 40.38 (C8), 47.00 (C15), 49.29 (C4), 52.05 (C16), 53.02 (C5), 53.11 (C9), 75.32 (C3′), 77.18 (C2′), 125.13 (C14), 148.07 (C13), 176.91 (C23), 177.94 (C24), 178.99 (C22). Found, %: C 69.02; H 8.40. C27H36O6. Calculated, %: C 71.03; H 7.95. Compounds 11–16 (general procedure). Terminal alkyne derivative 5–10, 1.0 mmol, and 4-iodonitrobenzene, 0.25 g (1 mmol), were dissolved in 30 mL of DMF, and 0.02 g (0.11 mmol) of copper(I) iodide, 0.07 g (0.06 mmol) of PdCl 2 (PPh 3 ) 2 , and 0.16 mL (1.1 mmol) of triethylamine were added in succession under argon. The mixture was stirred for 4 h at room temperature, washed with 5% aqueous HCl (3 × 20 mL) and water (2 × 100 mL), and dried over CaCl 2 . The


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solvent was evaporated, and the product was isolated by alumina column chromatography using methylene chloride as eluent. 12-Isopropyl-6,10-dimethyl-1,3-dioxo-N-[3-(4-nitrophenyl)prop-2-yn-1-yl]-3b,11-ethenohexadecahydrophenanthro[1,2-c]furan-6-carboxamide (11). Yield 0.43 g (78%), mp 138‒140°C. 1H NMR spectrum (CDCl3), δ, ppm: 0.53 s (3H, C20H3), 0.91 d (3H, C18H3, J = 6.9 Hz), 0.96 d (3H, C19H3, J = 7.0 Hz), 1.20 s (3H, C21H3), 1.22–1.90 m (14H, 1-H, 2-H, 3-H, 5-H, 6-H, 7-H, 9-H, 11-H), 2.45 d (1H, 17-H, J = 8.4 Hz), 2.60 d.t (1H, 16-H, J = 3.0, 14.0 Hz), 2.87 d (1H, 15-H, J = 8.4 Hz), 3.05 d (1H, 12-H, J = 8.4 Hz), 4.00 d.d (2H, 1′-H, J = 18.4, 1.72 Hz), 5.50 s (1H, 14-H), 6.15 br.s (1H, NH), 7.55 s (1H, Harom), 7.80 d (1H, Harom, J = 10.9 Hz), 8.19 m (1H, Harom), 8.30 d (1H, Harom, J = 10.9 Hz). 13C NMR spectrum (CDCl3), δC, ppm: 15.59 (C20), 16.68 (C19), 17.00 (C2), 19.95 (C18), 20.54 (C19), 20.98 (C6), 27.15 (C11), 29.56 (C1′), 32.70, (C17), 34.65 (C7), 35.65 (C12), 36.61 (C3), 37.68 (C10), 37.75 (C1), 40.33 (C8), 45.61 (C15), 46.62 (C4), 49.64 (C5), 53.05 (C9), 53.06 (C16), 84.29 (C3′), 87.13 (C 2′), 123.63 (C arom), 123.95 (C arom), 125.17 (C 14 ), 129.18 (Carom), 131.88 (Carom), 137.33 (Carom), 147.10 (C arom ), 148.00 (C 13 ), 171.14 (C 23 ), 172.91 (C 24 ), 178.27 (C 22 ). Found, %: C 72.02; H 7.04; N 5.20. C33H38N2O6. Calculated, %: C 70.95; H 6.86; N 5.01. 3-(4-Nitrophenyl)prop-2-yn-1-yl 12-isopropyl6,10-dimethyl-1,3-dioxo-3b,11-ethenohexadecahydrophenanthro[1,2-c]furan-4-carboxylate (12). Yield 0.49 g (89%), mp 158–160°C. 1H NMR spectrum (CDCl3), δ, ppm: 0.51 s (3H, C20H3), 0.85 d (3H, C18H3, J = 6.9 Hz), 0.90 d (3H, C19H3, J = 7.0 Hz), 1.20 s (3H, C21H3), 1.22–1.61 m (14H, 1-H, 2-H, 3-H, 5-H, 6-H, 7-H, 9-H, 11-H), 2.25 d (1H, 15-H, J = 8.4 Hz), 2.78 d (1H, 16-H, J = 8.4 Hz), 3.18 d (1H, 12-H, J = 8.4 Hz), 4.80 d.d (2H, 1′-H, J = 19.8, 35.6 Hz), 5.59 s (1H, 14-H), 7.51 s (1H, Harom), 7.60 d (1H, Harom, J = 10.9 Hz), 7.90 m (1H, Harom), 8.20 d (1H, Harom, J = 10.9 Hz). 13C NMR spectrum (CDCl3), δC, ppm: 16.74 (C20), 16.93 (C19), 16.99 (C2), 19.94 (C18), 20.57 (C19), 21.57 (C6), 27.14 (C11), 32.76 (C17), 34.91 (C7), 35.63 (C12), 36.32 (C3), 37.70 (C10), 37.96 (C1), 40.43 (C8), 45.66 (C15), 47.22 (C1′), 49.55 (C4), 52.50 (C5), 53.03 (C9), 53.33 (C16), 84.19 (C3′), 88.63 (C 2′), 123.63 (C arom), 123.65 (C arom), 124.95 (C 14 ), 128.98 (Carom), 132.61 (Carom), 138.67 (Carom), 147.40 (C arom ), 148.28 (C 13 ), 171.04 (C 23 ), 172.70 (C 24 ), 177.68 (C 22 ). Found, %: C 72.02; H 7.04; N 5.20. C33H37NO7. Calculated, %: C 70.82; H 6.66; N 2.50.

13-Isopropyl-7,10a-dimethyl-N-[3-(4-nitrophenyl)prop-2-yn-1-yl]-1,4-dioxo-4b,12-ethenohexadecahydrochrysene-7-carboxamide (13). Yield 0.42 g (74%), mp 104–106°C. 1 H NMR spectrum (CDCl3), δ, ppm: 0.52 s (3H, C18H3), 0.80–0.91 (2H, 6-H), 1.02 d (3H, C 16 H 3 , J = 6.9 Hz), 1.04 d (3H, C17H3, J = 6.9 Hz), 1.18 s (3H, C19H3), 1.20–1.66 m (12H, 5-H, 6a-H, 8-H, 9-H, 10-H, 10b-H, 11-H), 2.38– 2.50 m (6H, 12a-H, 2-H, 3-H, 4a-H), 2.75 t (1H, 15-H, J = 6.2 Hz), 3.15 br.s (1H, 12-H), 4.16 d.d (2H, 1′-H, J = 17.2, 1.82 Hz), 5.30 s (1H, NH), 5.55 s (1H, 14-H), 7.57 s (1H, H arom), 7.84 d (1H, H arom, J = 10.9 Hz), 8.23 m (1H, Harom), 8.33 d (1H, Harom, J = 10.9 Hz). 13 C NMR spectrum (CDCl 3 ), δ C, ppm: 14.21 (C 19 ), 15.89 (C18), 16.77 (C9), 16.98 (C17), 19.89 (C16), 20.53 (C6), 21.60 (C11), 27.85 (C1′), 32.42 (C15), 34.50 (C3), 36.21 (C5), 36.99 (C8), 37.88 (C12), 38.52 (C10), 38.99 (C10a), 41.58 (C4b), 46.63 (C2), 50.11 (C7), 54.67 (C6a), 55.88 (C10b), 60.53 (C4a), 60.63 (C12a), 85.09 (C3′), 88.10 (C 2′), 123.88 (C arom), 124.05 (C arom), 125.67 (C14), 129.81 (Carom), 133.81 (Carom), 139.33 (Carom), 145.10 (Carom), 149.48 (C13), 178.55 (C20), 208.91 (C1), 210.16 (C 4 ). Found, %: C 73.02; H 7.14; N 5.20. C35H42N2O5. Calculated, %: C 73.66; H 7.42; N 4.91. 3-(4-Nitrophenyl)prop-2-yn-1-yl 13-isopropyl7,10a-dimethyl-1,4-dioxo-4b,12-ethenohexadecahydrochrysene-7-carboxylate (14). Yield 0.47 g (84%), mp 160–162°C. 1H NMR spectrum (CDCl3), δ, ppm: 0.55 s (3H, C 18 H 3 ), 0.75–0.88 m (2H, 6-H), 1.02 d (3H, C16H3, J = 6.9 Hz), 1.09 d (3H, C17H3, J = 6.9 Hz), 1.18 s (3H, C19H3), 1.18–1.74 m (12H, 5-H, 6a-H, 8-H, 9-H, 10-H, 10b-H, 11-H), 2.20–2.54 m (6H, 12a-H, 4a-H, 2-H, 3-H), 2.79 t (1H, 15-H, J = 6.2 Hz), 3.21 br.s (1H, 12-H), 4.65 s (2H, 1′-H), 5.55 s (1H, 14-H), 7.55 s (1H, H arom ), 7.66 d (1H, H arom , J = 10.9 Hz), 7.78 m (1H, Harom), 8.14 d (1H, Harom, J = 10.9 Hz). 13C NMR spectrum (CDCl3), δC, ppm: 14.28 (C 19 ), 15.66 (C 18 ), 16.70 (C 9 ), 16.98 (C 17 ), 20.00 (C16), 20.53 (C6), 21.60 (C11), 27.85 (C1′), 32.42 (C15), 34.50 (C3), 36.21 (C5), 36.99 (C8), 37.88 (C12), 38.52 (C 10 ), 38.99 (C 10a), 41.58 (C 4b ), 46.65 (C 2 ), 50.11 (C 7 ), 54.67 (C 6a), 55.90 (C 10b ), 60.51 (C 4a), 60.66 (C12a), 84.27 (C3′), 88.03 (C2′), 123.00 (Carom), 123.70 (Carom), 125.54 (C14), 128.80 (Carom), 132.66 (Carom), 138.17 (Carom), 147.40 (Carom), 149.99 (C13), 177.02 (C20), 208.54 (C1), 210.54 (C4). Found, %: C 72.82; H 7.10; N 2.80. C35H41NO6. Calculated, %: C 73.53; H 7.23; N 2.45. 12-Isopropyl-4b,8-dimethyl-4-{[3-(4-nitrophenyl)prop-2-yn-1-yl]carbamoyl}-3,10a-etheno-



tetradecahydrophenanthrene-1,2-dicarboxylic acid (15). Yield 0.36 g (62%), mp 163–165°C. 1H NMR spectrum (CDCl3), δ, ppm: 0.47 s (3H, C21H3), 0.91 d (3H, C 18 H 3 , J = 6.9 Hz), 0.95 d (3H, C 19 H 3 , J = 7.0 Hz), 1.11 s (3H, C20H3), 1.20–1.91 m (14H, 1-H, 2-H, 3-H, 5-H, 6-H, 7-H, 9-H, 11-H), 2.45 d (1H, 12-H, J = 8.4 Hz), 2.62 d.t (1H, 17-H, J = 3.0, 14.0 Hz), 2.90 d (1H, 16-H, J = 8.4 Hz), 3.08 d (1H, 15-H, J = 8.4 Hz), 4.00 d.d (2H, 1′-H, J = 18.4, 1.72 Hz), 5.50 s (1H, 14-H), 6.23 br.s (1H, NH), 7.59 s (1H, Harom), 7.80 d (1H, Harom, J = 10.9 Hz), 8.22 m (1H, Harom), 8.30 d (1H, Harom, J = 10.9 Hz), 8.55 br.s (2H, OH). 13C NMR spectrum (CDCl3), δC, ppm: 15.60 (C20), 16.70 (C21), 17.00 (C2), 20.01 (C18), 20.55 (C19), 21.01 (C6), 27.15 (C11), 29.71 (C1′), 32.81 (C17), 34.71 (C7), 35.45 (C12), 36.65 (C3), 37.71 (C10), 37.75 (C1), 40.40 (C8), 45.63 (C15), 46.71 (C4), 49.69 (C16), 53.02 (C 5 ), 54.06 (C 9 ), 84.29 (C 3′), 87.13 (C 2′), 123.63 (Carom), 123.69 (C14), 124.80 (Carom), 129.28 (Carom), 131.90 (Carom), 137.20 (Carom), 147.50 (Carom), 147.71 (C13), 178.21 (C23), 178.85 (C24), 179.30 (C22). Found, %: C 67.20; H 7.40; N 5.20. C33H40N2O7. Calculated, %: C 68.73; H 6.99; N 4.86. 12-Isopropyl-4b,8-dimethyl-4-{[3-(4-nitrophenyl)prop-2-yn-1-yloxy]carbonyl}-3,10a-ethenotetradecahydrophenanthrene-1,2-dicarboxylic acid (16). Yield 0.38 g (67%), mp 177–179°C. 1H NMR spectrum (CDCl3), δ, ppm: 0.53 s (3H, C21H3), 0.90 d (3H, C 18 H 3 , J = 6.9 Hz), 0.93 d (3H, C 19 H 3 , J = 7.0 Hz), 1.20 s (3H, C20H3), 1.23–1.82 m (14H, 1-H, 2-H, 3-H, 5-H, 6-H, 7-H, 9-H, 11-H), 2.27 d (1H, 12-H, J = 8.4 Hz), 2.46 d (1H, 16-H, J = 8.4 Hz), 2.62 d.t (1H, 17-H, J = 3.0, 14.0 Hz), 3.08 d (1H, 15-H, J = 8.4 Hz), 4.48 d.d (2H, 1′-H, J = 10.9, 1.55 Hz), 5.51 s (1H, 14-H), 7.51 s (1H, Harom), 7.60 d (1H, Harom, J = 10.9 Hz), 7.90 m (1H, Harom), 8.20 d (1H, Harom, J = 10.9 Hz), 8.50 br.s (2H, OH). 13C NMR spectrum (CDCl3), δC, ppm: 15.44 (C20), 16.75 (C21), 16.92 (C2), 19.54 (C18), 20.56 (C19), 21.52 (C6), 27.20 (C 11 ), 28.73 (C 1′), 32.73 (C 17 ), 34.60 (C 7 ), 35.60 (C12), 36.43 (C3), 37.72 (C10), 37.90 (C1), 40.36 (C8), 47.03 (C15), 49.33 (C4), 52.05 (C16), 53.00 (C5), 53.11 (C9), 84.19 (C3′), 88.63 (C2′), 123.63 (Carom), 123.65 (Carom), 125.13 (C14), 128.98 (Carom), 132.61 (Carom), 138.67 (Carom), 147.40 (Carom), 148.07 (C13), 176.91 (C23), 177.94 (C24), 178.99 (C22). Found, %: C 68.10; H 7.20; N 2.20. C33H39NO8. Calculated, %: C 68.61; H 6.80; N 2.42. The spectral studies of compounds 5–15 were performed at the Agidel’ Joint Center, Institute of

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