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Synlett 2008(19): 2989-2992  
DOI: 10.1055/s-0028-1087299
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 2,7-Naphthyridine-Containing Analogues of Luotonin A

Xiangqian Daia, Chen Chenga, Chunyong Dingb, Qizheng Yaob, Ao Zhang*a
a Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. of China
Fax: +86(21)50806035; e-Mail: aozhang@mail.shcnc.ac.cn;
b School of Pharmacy, China Pharmaceutical University, Nanjing 210009, P. R. of China
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Publication History

Received 26 June 2008
Publication Date:
23 October 2008 (online)

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Abstract

A series of luotonin A analogues 7a-d with the N-14 atom moved to position 18 was prepared using an intramolecular aza-hetero-Diels-Alder reaction.

Key words

luotonin A - 2,7-naththyridine - anticancer - intramolecular aza-hetero-Diels-Alder reaction

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General Procedure for the Intramolecular Aza-Diels-Alder Cyclization
To a solution of Ph3PO (837 mg, 2.98 mmol) in anhyd CH2Cl2 (20 mL) at 0 ˚C was added dropwise a solution of Tf2O (0.25 mL, 1.5 mmol) in CH2Cl2 (2 mL). After the mixture was stirred for 15 min at 0 ˚C, a solution of 2-allyl-1-oxo-N-aryl-2,7-naphthyridin-3-carboxamide (13, 1.0 mmol) or 2-propargyl-1-oxo-N-aryl-2,7-naphthyridin-3-carboxamide (16, 1.0 mmol) in CH2Cl2 (20 mL) was dropped slowly. The reaction mixture was stirred at 0 ˚C for 0.5 h, and then at r.t. for 1-5 h. The completion of the reaction was detected by disappearance of the carboxamide substrate 13. A solution of aq Na2CO3 (10%, 10 mL) was added to quench the reaction. The mixture was extracted with CHCl3 (3 × 30 mL). The organic phases were combined, washed with brine, and dried over anhyd Na2SO4. After filtration, the solvent was removed, and the residue was subjected to column chromatography (CH2Cl2-MeOH, 10:1). The cyclization products 7a-c were obtained.
Compound 7a (78%): white solid, mp >210 ˚C. MS (EI): m/z (%) =285(100) [M+]. ¹H NMR (300 MHz, CDCl3-CD3OD): δ = 5.17 (br s, 2 H), 7.47 (m, 3 H), 7.63 (m, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 8.7 Hz, 1 H), 8.27 (s, 1 H), 8.51 (d, J = 5.4 Hz, 1 H), 9.37 (s, 1 H). HRMS: m/z calcd for C18H11ON3: 285.0902; found: 285.0890.
Compound 7b (45%): slightly yellow solid, mp >200 ˚C. MS (EI): m/z (%) = 343(100) [M+]. ¹H NMR (300 MHz, CDCl3-CD3OD): δ = 3.81 (s, 3 H), 5.21 (br s, 2 H), 7.46 (s, 1 H), 7.52 (d, J = 5.4 Hz, 1 H), 8.03 (d, J = 9.0 Hz, 1 H), 8.16 (d, J = 8.4 Hz, 1H), 8.39 (s, 1 H), 8.48 (s, 1 H), 8.54 (d, J = 5.4 Hz, 1 H), 9.39 (s, 1 H). HRMS: m/z calcd for C20H13O3N3: 343.0957; found: 343.0959.
Compound 7c (64%): slightly yellow solid, mp >210 ˚C. MS (EI): m/z (%) = 315(100) [M+]. ¹H NMR (300 MHz, CDCl3-CD3OD): δ = 3.94 (s, 3 H), 5.31 (s, 2 H), 7.19 (s,
1 H), 7.45 (m, 1 H), 7.51 (s, 1 H), 7.58 (d, 1 H, J = 7.6 Hz), 8.06 (d, J = 12.4 Hz, 1 H), 8.25 (s, 1 H), 8.69 (s, 1 H), 9.60 (s, 1 H). HRMS: m/z calcd for C19H13O2N3: 315.1008; found: 315.1017.

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The cycloadducts 7a-c showed extremely poor solubility in regular deuterated solvents (CDCl3, CD3OD, CD3SOCD3, D2O). Their purity (>95%) was further confirmed by HPLC analysis on an Agilent 1100 series LC system (Agilent ChemStation Rev.A.10.02; ZORBAX Eclipse XDB-C8,
4.8 mm × 150 mm, 5 µM, 1.0 mL/min, UV: λ = 254 nm, r.t.) with two solvent systems (MeCN-H2O, and MeOH-H2O).

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Compound 7d (30%): yellow solid, mp 202-204 ˚C. MS (EI): m/z = 341 [M+]. ¹H NMR (300 MHz, CDCl3-CD3OD): δ = 4.90 (d, J = 6.0 Hz, 1 H), 5.35 (s, 2 H), 5.36 (d, J = 6.6 Hz, 1 H), 5.50 (dd, J = 1.2, 17.1 Hz, 1 H), 6.37 (m, 1 H), 7.62 (t, J = 7.2 Hz, 1 H), 7.78 (t, J = 7.2 Hz, 1 H), 7.86 (m, 2 H), 8.23 (d, J = 8.7 Hz, 1 H), 8.28 (s, 1 H), 8.85 (d, J = 5.7 Hz, 1 H), 9.68 (s, 1 H). ¹³C NMR (75 MHz, CDCl3-CD3OD):
δ = 49.7, 76.0, 115.4, 118.9, 119.6, 127.0, 127.6, 127.8, 128.4, 129.8, 130.2, 133.3, 134.2, 134.9, 140.7, 148.8, 150.4, 150.5, 151.7, 158.6. HRMS: m/z calcd for C21H15O2N3: 341.1164; found: 341.1160.