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Synlett 2009(1): 43-46  
DOI: 10.1055/s-0028-1087387
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Modular Total Synthesis of Lamellarin G Trimethyl Ether

Jhillu S. Yadav*, Kamakolanu Uma Gayathri, Basi V. Subba Reddy, Attaluri R. Prasad
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax: +91(40)27160512; e-Mail: yadavpub@iict.res.in;
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Publication History

Received 17 April 2008
Publication Date:
12 December 2008 (online)

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Abstract

A modular synthesis of the lamellarin G trimethyl ether has been developed based on the application of several reaction ­sequences which include Friedel-Crafts acylation, esterification, haloarylation, and oxidative cyclization. The formation of pyrrolo [2,1-a]isoquinoline core, the key step for the successful completion of lamellarin G trimethyl ether synthesis, is comfortably accomplished through the haloarylation of 3-bromo-4-(3,4-dimethoxy-benzoyl)-6,7-dimethoxy-chroman-2-one which has resulted in exclusive endo product.

Key words

lamellarins - Friedel-Crafts acylation - esterification - bromoarylation - oxidative cyclization

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4-(3,4-Dimethoxyphenyl)-4-oxobut-2-enoic acid (3)
To a solution of veratrole (0.5 g, 3.6 mmol) and maleic anhydride (0.354 g, 3.6 mmol) in anhyd DCE (20 mL) was added anhyd AlCl3 powder (1.042 g, 7.8 mmol) in two portions. The reaction mixture was stirred for 1 h under reflux conditions. The reaction was hydrolyzed by adding 2.08 mL of H2O with vigorous stirring at 0 ˚C, followed by neutralization with concd HCl (0.416 mL). The resulting mixture was extracted with EtOAc and purified by column chromatography on SiO2 to afford 0.72 g (85%) of an acid as yellow solid; mp 178-179 ˚C (lit.¹³a mp 178 ˚C, no range given). ¹H NMR (400 MHz, CDCl3): δ = 7.80 (dd, J = 12.4, 15.2 Hz, 1 H), 7.48 (m, 2 H), 6.88 (dd, J = 4.1, 8.2 Hz, 1 H), 6.67 (dd, J = 6.2, 15.8 Hz, 1 H), 3.88 (s, 6 H). ¹³C NMR (50 MHz, CDCl3 + DMSO): δ = 186.4, 166.1, 150.4, 144.2, 135.3, 130.7, 127.7, 121.6, 114.4, 114.1, 38.8, 37.9. IR (neat): 3327, 2925, 2854, 2676, 2361, 1739, 1701, 1654, 1587, 1516, 1461, 1428, 1286, 1169, 1215, 1025, 938, 898, 766, 670, 612, 583 cm-¹. ESI-MS: m/z = 261 [M+ + 2 + 23], 232, 218, 146, 124, 105. Anal. Calcd for C12H12O5: C, 61.01; H, 5.12. Found: C, 61.02; H, 5.14.

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Experimental Procedure - 4-(3,4-Dimethoxyphenyl)-4-oxobut-2-enoic Acid 3,4-Dimethoxyphenyl Ester (5) To a stirred solution of acid 3 (0.3 g, 1.27 mmol) in anhyd DMF (10 mL) was added DMAP (15.5 mg, 0.127 mmol) and 3,4-dimethoxy phenol (4, 0.19 g, 1.27 mmol). Afterwards, DCC (0.28 g, 1.37 mmol) was added to the above reaction mixture at 0 ˚C and stirred for 5 min at 0 ˚C and then 3 h at 20 ˚C. Precipitated urea was filtered off and the filtrate was washed with 0.5 N HCl, followed by sat. NaHCO3 solution, and then dried over Na2SO4. The solvent was removed by evaporation, and the resulting crude reaction mixture was purified by column chromatography on SiO2 to give 0.42 g (83%) of ester. ¹H NMR (200 MHz, CDCl3): δ = 6.62 (d, J = 8.6 Hz, 3 H), 6.40 (d, J = 2.3 Hz, 3 H), 6.28 (dd, J = 3.1, 8.5 Hz, 2 H), 3.73 (d, J = 7.8 Hz, 12 H). ¹³C NMR (75 MHz, CDCl3): δ = 193.7, 173.6, 162.9, 156.6, 151.1, 149.7, 147.0, 123.3, 114.2, 114.1, 112.5, 110.1, 109.9, 105.8, 100.7, 99.9, 56.5, 56.0, 55.7, 54.1. IR (neat): 3274, 2933, 2854, 1754, 1690, 1647, 1606, 1512, 1442, 1287, 1223, 1161, 1124, 1026, 953, 834, 803, 763, 720, 626 cm-¹. ESI-MS: m/z = 372 [M+]. Anal. Calcd for C20H20O7: C, 64.51; H, 5.41. Found: C, 64.54; H, 5.44.

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3-Bromo-4-(3,4-Dimethoxybenzoyl)-6,7-dimethoxy-chroman-2-one (6) The ester (0.2 g, 0.53 mmol) was treated with NBS (0.1 g, 0.59 mmol) and Sm(OTf)3 (0.032 g, 0.053 mmol) in MeCN at 20 ˚C to produce 0.22 g (93%) of 6, as an exclusively endo-cyclized product. ¹H NMR (200 MHz, CDCl3): δ = 7.23 (s, 1 H), 7.18 (s, 1 H), 6.83 (s, 1 H), 6.54 (s, 2 H), 6.05 (s, 1 H), 5.09 (s, 1 H), 3.80 (m, 12 H). ¹³C NMR (75 MHz, CDCl3): δ = 202.6, 166.5, 149.9, 146.5, 143.7, 135.7, 116.8, 114.9, 106.9, 103.6, 100.6, 99.7, 95.5, 94.6, 56.8, 56.7, 56.5, 56.2, 56.0. IR (neat): 3422, 2925, 2853, 2361, 1713, 1657, 1593, 1507, 1455, 1406, 1204, 1035, 977, 846, 798, 760, 666, 593 cm-¹. ESI-MS: m/z = 450 [M+], 490 [M+ + 39], 423, 403, 375, 336, 306, 285, 258, 229, 208, 142. Anal. Calcd for C20H19BrO7: C, 53.23; H, 4.24. Found: C, 53.26; H, 4.22.

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13-(3,4-Dimethoxy-phenyl)-2,3,10,11-tetramethoxy-7,8-dihydro-5-oxa-6b-aza-dibenzo[ a , i ]fluoren-6-one (Lamellarin G Trimethyl Ether, 1) The bromide 6 (0.05 g, 0.11 mmol) was added to 6,7-dimethoxy-1,2,3,4-tetrahydro isoquinoline (0.51 g, 2.22 mmol) and K2CO3 (0.10 g, 0.73 mmol) in MeCN (3 mL) with continuous stirring under aerobic conditions. The mixture was stirred under reflux for 2 h, and then the reaction mixture was quenched with H2O and extracted with EtOAc (3 × 10 mL) and purified by column chromatography on SiO2 to afford 0.038 g (63%) of lamellarin G trimethyl ether as white solid; mp 238-239 ˚C (lit.¹¹ mp 239.1-240 ˚C). ¹H NMR (300 MHz, CDCl3): δ = 7.05 (m, 3 H), 6.88 (s, 1 H), 6.75 (s, 1 H), 6.69 (s, 1 H), 6.64 (s, 1 H), 4.78 (m, 2 H), 3.92 (s, 3 H), 3.88 (s, 3 H), 3.87 (s, 3 H), 3.84 (s,
3 H), 3.46 (s, 3 H), 3.34 (s, 3 H), 3.10 (t, J = 6.6 Hz, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 155.4, 149.7, 148.9, 148.8, 148.6, 147.2, 146.1, 145.5, 135.8, 128.0, 127.9, 126.7, 123.7, 120.1, 114.7, 114.0, 113.6, 111.8, 111.1, 110.2, 108.6, 104.4, 100.3, 56.2, 56.1, 56.0, 55.8, 55.4, 55.0, 42.4, 28.5. IR (neat): 3420, 2930, 1705, 1512, 1488, 1460, 1438, 1415, 1270, 1240, 1214, 1166, 1045, 752 cm-¹. ESI-MS: m/z = 543 [M+]. Anal. Calcd for C31H29NO8: C, 68.50; H, 5.38; N, 2.58. Found: C, 68.48; H, 5.36; N, 2.54.