Modular Total Synthesis of Lamellarin G Trimethyl Ether

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

References and Notes

• 1 Davidson BS. Chem. Rev.  1993,  93:  1771 
• 2 Anderson RJ. Faulkner DJ. Cun-Heng H. Van Duyne GD. Clardy J. J. Am. Chem. Soc.  1985,  107:  5492 
• 3 Davis RH. Carroll AR. Pierens GK. Quinn RJ. J. Nat. Prod.  1999,  62:  419 
• 4a Carroll AR. Bowden BF. Coll JC. Aust. J. Chem.  1993,  46:  489 
• 4b Reddy RMV. Faulkner DJ. Venkateswarlu Y. Rao MR. Tetrahedron  1997,  53:  3457 
• 5 Reddy RMV. Rao MR. Rhodes D. Hansen MST. Rubins K. Bushman FD. Venkateswarlu Y. Faulkner DJ. J. Med. Chem.  1999,  42:  1901 
• 6a Quesada AR. Garcia Gravalos MD. Fernandez Puentes JL. Br. J. Cancer  1996,  74:  677 
• 6b Quesada AR, Garcia Gravalos MD, and Fernandez Puentes JL. inventors; WO 9701336 A1  970116.  ; Chem. Abstr. 1996, 126, 166474
• 6c Boger DL. Boyce CW. Labroli MA. Sehon CA. Jin Q. J. Am. Chem. Soc.  1999,  121:  54 
• 6d Boger DL. Soenen DR. Boyce CW. Hedrick MP. Jin Q. J. Org. Chem.  2000,  65:  2479 
• 7a Heim A. Terpin A. Steglich W. Angew. Chem., Int. Ed. Engl.  1997,  36:  155 
• 7b Peschko C. Winklhofer C. Steglich W. Chem. Eur. J.  2000,  6:  1147 
• 8 Gupton JT. Clough SC. Miller RB. Lukens JR. Henry CA. Kanters RPF. Sikorski JA. Tetrahedron  2003,  59:  207 
• 9a Banwell MG. Hockless DCR. Flynn BL. Longmore RW. Rae D. Aust. J. Chem.  1999,  52:  755 
• 9b Banwell MG. Flynn BL. Hamel E. Hockless DCR. Chem. Commun.  1997,  207 
• 9c Liu J.-H. Yang Q.-C. Mak TCW. Wong HNC. J. Org. Chem.  2000,  65:  3587 
• 10 Iwao M. Takeuchi T. Fujikawa N. Fukuda T. Ishibashi F. Tetrahedron Lett.  2003,  44:  4443 
• 11 Handy ST. Zhang Y. Bregman H. J. Org. Chem.  2004,  69:  2362 
• 12a Ploypradith P. Petchmanee T. Sahakitpichan P. Litvinas ND. Ruchirawat S. J. Org. Chem.  2006,  71:  9440 
• 12b Ruchirawat S. Mutarapat T. Tetrahedron Lett.  2001,  42:  1205 
• 12c Ploypradith P. Jinaglueng W. Pavaro C. Ruchirawat S. Tetrahedron Lett.  2003,  44:  1363 
• 13a Ridley CP. Reddy MVR. Rocha G. Bushman FD. Faulkner DJ. Bioorg. Med. Chem.  2002,  10:  3285 
• 13b Cironi P. Manzanares I. Albericio F. Alvarez M. Org. Lett.  2003,  5:  2959 
• 13c Fernandez D. Ahaidar A. Danelon G. Cironi P. Marfil M. Perez O. Cuevas C. Albericio F. Joule JA. Alvarez M. Monatsh. Chem.  2004,  135:  615 
• 13d Marfil M. Albericio F. Alvrez M. Tetrahedron  2004,  60:  8659 
• 13e Tardy C. Facompre ML. Laine W. Baldeyrou B. Garcia-Gravalos D. Francesch A. Mateo C. Pastor A. Jimenez JA. Manzanares I. Cuevas C. Bailly C. Bioorg. Med. Chem.  2004,  12:  1697 
• 13f Zhang Y. Handy ST. Bregman H. American Chemical Society 228^th National Meeting (August 2004, Philadelphia, PA)
• 13g Nyerges M. Toke L. Tetrahedron Lett.  2005,  46:  7531 
• 13h Ploypradith P. Kagan RK. Ruchirawat S. J. Org. Chem.  2005,  70:  5119 
• 13i Schroter S. Bach T. Synlett  2005,  1957 
• 13j Yang G. Wang AL. Chen HL. You YC. Chin. J. Org. Chem.  2005,  25:  641 
• 13k Fujikawa N. Ohta T. Yamaguchi T. Fukuda T. Ishibashi F. Iwao M. Tetrahedron  2006,  62:  594 
• 13l Fürstner A. Domostoj MM. Scheiper B. J. Am. Chem. Soc.  2006,  128:  8087 
• 13m Peschko C. Winklhofer C. Terpin A. Steglich W. Synthesis  2006,  3048 
• 13n Worayuthakarn R. Thasana N. Ruchirawat S. Org. Lett.  2006,  8:  5845 
• 13o Thasana N. Worayuthakarn R. Kradranrat P. Hohn E. Young LR. Ruchirawat S. J. Org. Chem.  2007,  72:  9379 
• 13p Toth J. Nedves A. Dancso A. Blasko G. Tőke L. Nyerges M. Synthesis  2007,  1003 
• 13q Tóth J. Varadi L. Dancso A. Blasko G. Tõke L. Nyerges M. Synlett  2007,  1259 
• 14a Baddeley G. Makar SM. Ivanson MG. J. Chem. Soc.  1953,  3969 
• 14b Grummitt O. Becker EI. Miesse C. Org. Synth., Coll. Vol. III  1955,  109 
• 16 Neises B. Steglich W. Angew. Chem., Int. Ed. Engl.  1978,  17:  522 
• 18 Hajra S. Maji B. Karmkar A. Tetrahedron Lett.  2005,  46:  8599 
• 20a Casagrande C. Invernizzi A. Ferrini R. Ferrari GG. J. Med. Chem.  1968,  11:  765 
• 20b Alberola A. Ortega AG. Sadaba ML. Sanudo C. Tetrahedron  1999,  55:  6555 

15

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.

17

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.

19

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.

21

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.