Synlett 2008(10): 1475-1478  
DOI: 10.1055/s-2008-1078429
LETTER
© Georg Thieme Verlag Stuttgart · New York

N-Substituted Tetronamides as Ambident Nucleophilic Building Blocks for the Synthesis of New 4-Aza-2,3-didehydropodophyllotoxins

David Madec*, Francesco Mingoia, Guillaume Prestat, Giovanni Poli*
Laboratoire de Chimie Organique, FR2769 Institut de Chimie Moléculaire, UPMC Univ Paris 06, UMR CNRS 7611, Case 183, 75005 Paris, France
Fax: +33(1)44277567; e-Mail: giovanni.poli@upmc.fr; e-Mail: david.madec@upmc.fr;
Further Information

Publication History

Received 13 March 2008
Publication Date:
16 May 2008 (online)

Abstract

Aza-analogues of podophyllotoxin were synthesized in two steps from N-substituted tetronamides. The acid-mediated benz­hydrylation of N-substituted tetronamides with a suitably functionalized benzhydrol quantitatively afforded the cyclization precursors. The target pentacyclic 4-aza-2,3-didehydropodo-phyllotoxins were next obtained via an intramolecular copper-mediated Ullmann-type N-arylation.

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1x

Present address: Istituto per lo Studio dei Materiali Nanostrutturati, CNR, Via Ugo La Malfa 153, 90146 Palermo, Italy

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Representative Experimental Procedure for Benzhydrylation Reaction: To a stirred solution of benzhydrol 6 (437 mg, 1.1 mmol, 1.1 equiv) and enamine 4a (189 mg, 1 mmol) in anhyd CH2Cl2 (10 mL) under a N2 atmosphere at r.t. was added BF3×OEt2 (0.380 mL, 3 equiv). The mixture was stirred for 2 h before a sat. aq NaHCO3 solution (10 mL) was added. The aqueous layer was extracted with Et2O (3 × 10 mL). The organic layers were washed with brine (5 mL), dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by flash chromatography (cyclohexane-EtOAc, 7:3) to afford the alkylated product 8a as a white foam (455 mg, 80% yield). 1H NMR (400 MHz, CDCl3): δ = 3.74 (s, 6 H), 3.80 (s, 3 H), 4.05-4.16 (m, 2 H), 4.64-4.79 (d, AB system, J = 15.4 Hz, 2 H), 5.38 (s, 1 H), 5.93 (d, J = 1.3 Hz, 1 H), 6.00 (d, J = 1.3 Hz, 1 H), 6.35 (s, 2 H), 6.65 (s, 1 H), 6.95 (d, J = 7.6 Hz, 2 H), 7.07 (s, 1 H), 7.32-7.28 (m, 3 H). 13C NMR (100 MHz, CDCl3): δ = 46.0, 47.8, 56.3, 61.0, 65.3, 95.8, 101.9, 105.7, 109.6, 113.5, 115.8, 126.6, 128.3, 129.1, 133.3, 136.0, 136.7, 137.1, 147.4, 147.5, 153.7, 163.3, 174.5. IR (neat): 3375, 2930, 2870, 1730, 1625, 1585, 1500, 1475, 1415, 1230, 1120, 1035 cm-1. HRMS (CI): m/z calcd for C28H26O7N79BrNa: 590.07849 and C28H26O7N81BrNa: 592.07692; found: 590.07755 and 592.07560.

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Representative Experimental Procedure for Intramolecular Copper-Mediated N-Arylation Reaction: To a solution of cyclization precursor 8a (217 mg, 0.38 mmol) in anhyd DMF (4 mL) at r.t. were added CuI (87 mg, 0.46 mmol, 1.2 equiv) and Cs2CO3 (311 mg, 0.96 mmol, 2.5 equiv). The resulting mixture was stirred at 90 °C for 16 h. A sat. aq NH4Cl solution (5 mL) was added and the aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The collected organic phases were washed with aq NH3-NH4Cl solution (1:1, 10 mL), brine (3 × 5 mL), and dried over MgSO4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography (cyclohexane-EtOAc, 7:3) to afford aza-analogue 9a as a yellow foam (185 mg, quantitative yield). 1H NMR (400 MHz, CDCl3): δ = 3.82 (s, 9 H), 4.75-4.89 (m, 4 H), 5.08 (s, 1 H), 5.89 (d, J = 1.2 Hz, 1 H), 5.91 (d, J = 1.2 Hz, 1 H), 6.45 (s, 1 H), 6.46 (s, 2 H), 6.59 (s, 1 H), 7.24-7.38 (m, 5 H). 1H NMR (400 MHz, DMSO-d 6): δ = 3.61 (s, 3 H), 3.73 (s, 6 H), 4.94 (s, 1 H), 4.96 (d, AB system, J = 17.4 Hz, 2 H), 5.13 (d, AB system, J = 15.9 Hz, 2 H), 5.87 (d, J = 0.8 Hz, 1 H), 5.95 (d, J = 0.8 Hz, 1 H), 6.53 (s, 2 H), 6.72 (s, 1 H), 6.77 (s, 1 H), 7.29-7.40 (m, 5 H). 13C NMR (100 MHz, DMSO-d 6): δ = 39.8, 48.9, 55.8, 59.9, 65.6, 95.5, 96.7, 101.4, 104.6, 110.0, 119.1, 126.5, 127.6, 128.9, 131.1, 136.0, 136.5, 142.6, 143.5, 146.7, 152.9, 159.9, 172.2. IR (neat): 2935, 2845, 1730, 1645, 1615, 1590, 1505, 1475, 1240, 1190, 1125, 1040 cm-1. HRMS (CI): m/z calcd for C28H25O7NNa: 510.15232; found: 510.15154.

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The cyclization of enolic precursors such as 7 to give 4-oxa-2,3-didehydropodophyllotoxin analogues will be the object of a separate study and will be reported elsewhere.