A Concise and Convergent Synthesis of Luotonin B and E

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.

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

References and Notes

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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.