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

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

References

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13

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⁺].

15

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⁺].

16

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).