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Synlett 2004(14): 2533-2536  
DOI: 10.1055/s-2004-834821
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of DNA-Interactive Pyrrolo[2,1-c][1,4]benzodiazepines by Employing Polymer-Supported Reagents: Preparation of DC-81

Ahmed Kamal*, K. Laxma Reddy, V. Devaiah, N. Shankaraiah
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Fax: +91(40)27193189; Fax: +91(40)27160512; e-Mail: ahmedkamal@iict.res.in; e-Mail: ahmedkamal@ins.iictnet.com;
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Publication History

Received 21 July 2004
Publication Date:
20 October 2004 (online)

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Abstract

Polymer-supported reagents have been utilized for the generation of combinatorial library of substituted pyrrolo[2,1-c][1,4]benzodiazepine derivatives that provides a clean and efficient preparation and does not require conventional purification techniques like chromatography. This methodology involves intra molecular aza-Wittig reaction and has been extended for the synthesis of the natural product DC-81 in good overall yields.

Key words

polymer-supported reagents - combinatorial library - pyrrolo[2,1-c][1,4] benzodiazepines

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Preparation of Compound 5g: N-Cyclohexylcarbodiimide, N′-methyl polystyrene (0.66 mmol, 1.30 mmol/g) was added to a dry reaction vessel. The 2-azido-4-benzoxy-5-methoxy benzoic acid (4g, 150 mg, 0.50 mmol) in CH2Cl2 (5 mL) was added to the dry resin and the resulting mixture was stirred at r.t. After 5 min, prolinol (34 mg, 0.33 mmol) in CH2Cl2 (2 mL) was added and the stirring continued at r.t. for 12 h. The resin was removed by filtration and washed with CH2Cl2. Evaporation of the filtrate provided 5g in 98% yield. 1H NMR (200 MHz, CDCl3): δ = 1.65-1.90 (3 H, m), 2.15-2.20 (1 H, m), 3.25-3.36 (2 H, m), 3.69-3.86 (2 H, m), 3.84 (3 H, s), 4.28-4.37 (1 H, m), 4.75 (1 H, br s), 5.18 (2 H, s), 6.67 (1 H, s), 6.83 (1 H, s), 7.28-7.46 (5 H, m). MS (EI): m/z = 382 [M+].

14

Preparation of Compound 6g: 6-(Methylsulfinyl)hexa-noyl methyl polystyrene (0.52 mmol, 2.20 mmol/g) was swollen in CH2Cl2 (5 mL) at r.t. for 15 min and then cooled to -50 °C. Oxalyl chloride (0.52 mmol, 66 mg) in CH2Cl2
(1 mL) was added dropwise. After 1 h at that temperature, azido alcohol (5g, 100 mg, 0.26 mmol) in CH2Cl2 (1 mL) was added, and the mixture was stirred for 3 h before the addition of Et3N (0.78 mmol, 79 mg). The mixture was allowed to warm to r.t. and stirred overnight. The resin was removed by filtration and washed with CH2Cl2. The filtrate was washed three times with H2O. The organic phases was dried (Na2SO4) and evaporated to afford 6g in 95% yield. 1H NMR (200 MHz, CDCl3): δ = 2.14-2.24 (2 H, m), 3.35-3.49 (2 H, m), 3.89 (3 H, s), 4.09-4.15 (2 H, m), 4.60-4.65 (1 H, m), 5.14-5.20 (2 H, m), 6.69 (1 H, s), 7.32-7.47 (6 H, m), 9.69 (1 H, d, J = 2.33 Hz). MS (EI): m/z = 380 [M+].

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Preparation of Compound 7g: Triphenylphosphine polystyrene (0.9 mmol, 3 mmol/g) was suspended in anhyd CH2Cl2 (10 mL) and the azido aldehyde (6g, 70 mg, 0.18 mmol) was added, the suspension was stirred for 4 h at r.t. The resin was removed by filtration and washed with CH2Cl2. Evaporation of the filtrate to afford 6g in 96% yield. 1H NMR (400 MHz, CDCl3): δ = 2.09-2.26 (2 H, m), 3.38-3.80 (5 H, m), 3.87 (3 H, s), 4.98-5.15 (2 H, m), 6.74 (1 H, s), 7.08-7.42 (6 H, m), 7.50 (1 H, d, J = 2.97 Hz). MS (EI): m/z = 336 [M+].

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Preparation of Compound 8: To a solution of compound 7g (50 mg, 0.15 mmol) in absolute EtOH (3 mL) was added 10% Pd/C (75 mg) under nitrogen atmosphere. 1,4-Cyclo-hexadiene (120 mg, 1.50 mmol) was added drop wise to the solution. The resulting solution was stirred at r.t. for 2.5 h. The reaction mixture was filtered and evaporated to afford 8 in 91% yield. 1H NMR (400 MHz, CDCl3): δ = 2.01-2.10
(2 H, m), 2.30-2.36 (2 H, m), 3.55-3.61 (1 H, m), 3.70-3.74 (1 H, m), 3.79-3.87 (1 H, m), 3.96 (3 H, s), 6.41 (-OH, br s), 6.90 (1 H, s), 7.52 (1 H, s), 7.67 (1 H, d, J = 4.4 Hz). MS (EI): m/z = 246 [M+]. [α]26 D +296 (c 0.02, CHCl3); lit. [18] [α]22 D +135 (c 0.2, CHCl3).