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Synlett 2011(1): 84-88  
DOI: 10.1055/s-0030-1259098
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Concise and Convergent Synthesis of Luotonin B and E

Manoj Balu Wagha, R. Shankara, U. K. Syam Kumar*a, C. H. Gillb
a Technology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Hyderabad 500049, India
Fax: +91(40)23045439; e-Mail: syam_kmr@yahoo.com;
b Dr. Babasaheb Ambedkar University, Aurangabad, Maharashtra 431004, India
Further Information

Publication History

Received 31 August 2010
Publication Date:
10 December 2010 (online)

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Abstract

A concise and highly convergent practical synthesis of topoisomerase 1 inhibitor luotonin B was developed in a one-pot process in excellent yields. The C and D rings of luotonin B was constructed by cascade cyclizations of 2-cyanoquinoline-3-aldehyde or 2-cyanoquinoline-3-hemiacetal with methylanthranilate under acidic conditions. The luotonin B was then converted into luotonin E by an acid-catalyzed etherification reaction.

Key words

luotonin A - B and E alkaloids - camptothecin - 2-cyanoquinoline-3-aldehyde - 2-cyanoquinoline-3-acetal - methyl anthranilate - cascade cyclization

15

To a suspension of 2-cyanoquinoline-3-acetal (9, 1 g, 0.004 mol, 1 equiv) in AcOH (10 mL), methyl anthranilate (0.7 g, 0.005 mol, 1.05 equiv) was added, and the reaction mixture was heated to reflux for a period of 12-14 h. The reaction mass was then cooled, the precipitated product was filtered off, and further purified by column chromatography using EtOAc and hexane (7:3) to yield the lutonin B. The filtrate was diluted with H2O, and extracted with EtOAc, and dried. Concentration and purification by column chromatography yielded 11.

16

To a suspension of cyanoaldehyde (1 g, 0.5 mmol, 1 equiv) in AcOH (10 mL) and Ac2O (0.2 mL), methyl anthranilate (0.554 g, 0.71 mmol, 1.5 equiv) was added, and the reaction mixture was heated to reflux for a period of 12-14 h. The reaction mass was then cooled to r.t., and precipitated product was filtered off. The mother liquor was then diluted with H2O, and extracted with EtOAc. The precipitated product mixture and the EtOAc extracts were combined together, concentrated under vacuum. The product was then purified by column chromatography using EtOAc and hexane (7:3), and pure luotonin B was isolated as white to off-white solid in 0.890 g, 54% of yield. Also 12% of 11 was also isolated from the column.

17

Methyl-2-(11-oxo-11,13-dihydroquinolino[2′,3′:3,4]-pyrrolo[2,1- b ]quinazolin-13-yl)amino benzoate (11) Yield 20%; mp 312-314 ˚C. ¹H NMR (400 MHz, CDCl3):
δ = 3.80 (s, 3 H), 6.77 (t, J = 7.2 Hz, 1 H), 7.26 (s, 1 H), 7.27 (s, 1 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.52 (t, J = 6.8 Hz, 1 H), 7.69 (t, J = 7.6 Hz, 1 H), 7.80-7.97 (m, 4 H), 8.1 (d, J = 8.0 Hz, 1 H), 8.34 (dd, J = 1.6, 7.8 Hz, 1 H), 8.48 (s, 1 H) 8.52 (d, J = 8.8 Hz, 1 H), 8.85 (d, J = 9.6 Hz, 1 H). ¹³C NMR (400 MHz, CDCl3): δ = 51.8, 68.4, 112, 113.6, 117.6, 122.4, 126.7, 127.6, 128.4, 128.6, 128.8, 129.1, 130.8, 131.2, 131.7, 132.2, 132.6, 134.4, 134.6, 148.0, 149.0, 150.0, 150.4, 151.4, 160.6, 168.9. MS: m/z (%) = 435 [M + 1], 302.2, 137.1. Anal Calcd for C26H18N4O3: C, 71.88; H, 4.18; N, 12.90. Found: C, 71.86; H, 4.15; N, 12.87.

18

Luotonin B (2)
Yield 0.89 g (54%); mp 273-275 ˚C. IR (KBr): 1028, 1266, 1449, 2041, 2945, cm-¹. ¹H NMR (400 MHz, DMSO-d 6):
δ = 6.98 (d, J = 8.4 Hz, 1 H), 7.62-7.66 (m, 2 H), 7.78 (t, J = 7.2 Hz, 1 H), 7.92-7.96 (m, 3 H), 8.23 (d, J = 8.0 Hz, 1 H), 8.28 (dd, J = 3.6 Hz, 8.4 Hz, 2 H), 8.80 (s, 1 H). ¹³C NMR (400 MHz, DMSO-d 6): δ = 80.5, 122.2, 126.1, 127.5, 128.2, 128.3, 128.7, 128.8, 129.6, 131.0, 132.8, 133.8, 134.7, 148.7, 149.1, 150.3, 151.5, 159.4. MS m/z (%) = 302.1 [M + 1], 246.2, 150.1. Anal Calcd for C18H11N3O2: C, 71.75; H, 3.68; N, 13.95. Found: C, 71.77; H, 3.69; N, 13.90.

19

To a solution of luotonin B (0.35 g, 0.16 mol, 1 equiv) in MeOH (3.5 mL, 10 V), Indion resin (0.1 g, 0.01 mmol, 0.1 equiv) was added, and the reaction mixture was heated at 55 ˚C for a period of 6-7 h. The reaction mixture was then cooled, and the resin was filtered off and washed with MeOH (1 mL). The filtrate was concentrated under reduced pressure, and purified on a filter column using EtOAc-hexane (30:70). The product was isolated as a white to off-white solid in 80% (0.29 g) yield.
Luotonin E Yield 0.29 g (80%).; mp 222-224 ˚C. IR (KBr): 1047, 1237, 1300, 1375, 1730, 2985 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 3.60 (s, 3 H), 6.90 (s, 1 H), 7.58 (dt, J = 0.8, 7.6, 11.2 Hz, 1 H), 7.71 (t, J = 6.8 Hz, 1 H), 7.82-7.88 (m, 2 H), 7.99 (d, J = 8.4 Hz, 1 H), 8.09 (d, J = 8.0 Hz, 1 H) 8.41 (dd, J = 1.2, 8.0 Hz, 1 H), 8.47 (d, J = 8.4 Hz, 1 H), 8.5 (s, 1 H). ¹³C NMR (400 MHz, CDCl3): δ = 56.3, 87.0, 122.2, 126.8, 127.8, 128.4, 128.6, 128.8, 130.0, 130.7, 131.3, 133.0, 134.8, 148.9, 150.4, 151.3, 160.7. MS: m/z (%) = 316.2 [M + 1], 279.2, 130.2. Anal Calcd for C19H13N3O2: C, 72.37; H, 4.16; N, 13.33. Found: C, 72.34; H, 4.15; N, 13.35.

20

Tetrahydroluotonin A (20) Yield 190 mg (50%); mp 191-193 ˚C. ¹H NMR (400 MHz, CDCl3): δ = 2.57 (dd, J = 8.0, 14.8 Hz, 1 H), 2.95-3.06 (m, 2 H), 4.03 (dd, J = 4.0, 12.0 Hz, 1 H), 4.33 (dd, J = 6.8, 12 Hz, 1 H), 4.66 (s, 1 H), 4.81 (dd, J = 3.2, 7.8 Hz, 1 H), 6.65 (d, J = 6.7 Hz, 1 H), 6.70 (dd, J = 0.4, 10.6 Hz, 1 H), 7.01 (m, 2 H) 7.45 (m, 1 H), 7.72-7.80 (m, 2 H), 8.29 (d, J = 8.4 Hz, 1 H). ¹³C NMR (400 MHz, CDCl3): δ = 28.5, 31.6, 49.7, 57.6, 114.3, 118.6, 120.0, 121.1, 126.4, 126.7, 127.1, 127.6, 128.8, 134.2, 142.6, 149.2, 159.5, 160.9. MS: m/z (%) = 435 [M + 1], 290.2, 202.2, 186.2. Anal Calcd for C18H15N3O: C, 74.72; H, 5.23; N, 14.52. Found: C, 74.70; H, 5.21; N, 14.57.