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DOI: 10.1055/s-2002-32976
Highly Versatile Synthesis of Polyamines by Ns-strategy on a Novel Trityl Chloride Resin
Publication History
Publication Date:
25 July 2002 (online)
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Abstract
A solid-phase synthesis of polyamines on 4-alkoxytrityl chloride resin 5 is described. By alkylation of nitrobenzenesulfonamide 8 with alkyl halide 7 prepared from the resin 5, spermine bound resin 10 was efficiently synthesized. Condensation of 10 and tyrosine derivative followed by deprotection and cleavage from the resin afforded highly pure philanthotoxin-343 (4).
Key words
polyamines - solid-phase synthesis - 2-nitrobenzenesulfonamide - 4-alkoxytrityl chloride resin - philanthotoxin-343
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References
The sulfonamide 8 was readily prepared from 1,3-diaminopropane, see ref. [5b]
11N-Butyryl-O-acetyl-l-tyrosine-p-nitrophenyl ester 11 was prepared from N-Boc-l-tyrosine in four steps: (i)p-nitrophenol, WSCD·HCl, CH2Cl2 (93%);(ii) Ac2O, pyridine (quant.);(iii) TFA, CH2Cl2;(iv) butyryl chloride, Et3N, CH2Cl2 (88%, 2 steps).
12While amide formation of N-acyl-amino acids is often accompanied in racemization, no appreciable racemization took place during the condensation of p-nitrophenyl ester 11 with primary amine as demonstrated in the following experiments. Condensation reaction with 11 and (S)-(-)-α-methylbenzylamine gave a single isomer. However, treatment of DCC with corresponding carboxylic acid of 11 and (S)-(-)-α-methylbenzylamine gave a 1:1 mixture of the diastereomers.
14The resin 5 could be recycled by treatment with SOCl2/CH2Cl2 (1:9) after cleavage of the substrates.
16Synthetic Procedure for the Polymer Bound Spermine (10). To a suspension of the freshly prepared resin 5 (1.40 g, 0.90 mmol/g) and 1,3-diaminopropane (0.60 mL, 7.20 mmol) in anhyd CH2Cl2 (12.5 mL) was added i-Pr2NEt (1.20 mL, 6.87 mmol) at r.t. under an argon atmosphere. After shaking for 16 h, the resin was filtered, washed with 10% H2O in THF, THF, and ether, and then dried in vacuo for 8 h to give the resin (1.71 g). To a suspension of the above resin (1.71 g) and 2-nitrobenzenesulfonyl chloride (1.80 g, 8.12 mmol) in anhyd CH2Cl2 (12.5 mL) was added 2,4,6-collidine (2.00 mL, 15.2 mmol) at r.t. under an argon atmosphere. After shaking for 16 h, the resin was filtered, washed with 10% H2O in THF, THF, and ether, and then dried in vacuo for 7 h to give the resin 6 (1.86 g). To a suspension of the above resin 6 (1.38 g) and 1,4-dibromobutane (3.00 mL, 25.3 mmol) in DMF (10.0 mL) was added K2CO3 (1.80 g, 13.0 mmol) at 60 °C. After stirring for 16 h, the mixture was then cooled to r.t. Then the resin was filtered, washed with 10% H2O in THF, THF, and ether, and then dried in vacuo for 8 h to give the resin 7 (1.43 g). To a suspension of the above resin 7 (1.26 g) and 8 (1.30 g, 3.79 mmol) in DMF (10.0 mL) was added K2CO3 (1.75 g, 12.7 mmol) at 60 °C. After stirring for 16 h, the mixture was then cooled to r.t. Then the resin was filtered, washed with 10% H2O in THF, THF, and ether, and then dried in vacuo for 4 h to give the resin 9 (1.36 g). Confirmation of the structure of the spermine skeleton of 9 was performed by following acidic cleavage from the resin. To a mixture of the resulting resin 9 (60.0 mg) in CH2Cl2 (2.5 mL) was added TFA (10 µL, 0.130 mmol) at r.t. After shaking for 5 min, the resin was filtered and washed with MeOH:CH2Cl2 (1:2). The combined washings were evaporated with benzene and dried in vacuo to provide N 1-Alloc-N 4,N 8-di-Ns-spermine (23.5 mg, 91% from 5) as the TFA salt. 1H NMR (400 MHz, DMSO-d 6): δ = 1.23 (2 H, m), 1.36 (2 H, m), 1.56 (2 H, m), 1.78 (2 H, m), 2.72 (2 H, m), 2.90 (2 H, m), 3.15-3.32 (8 H, m), 4.44 (2 H, d, J = 6.0 Hz), 5.19 (2 H, dd, J = 10.8 Hz, 16.8 Hz), 5.89 (1 H, m), 7.19 (1 H, m), 7.78-8.00 (10 H, m). 13C NMR (100 MHz, DMSO-d 6): δ = 24.8, 25.0, 28.4, 36.5, 37.7, 44.7, 45.2, 46.8, 47.1, 64.2, 116.9, 124.3, 124.4, 129.6, 129.6, 131.6, 131.7, 132.4, 132.5, 133.8, 134.5, 134.6, 147.5. MS: m/z = 657 (MH+); HR MS: Found 657.2032 (MH+). Calcd 657.2013 (C26H37N6O10S2, MH+). To a suspension of the resin 9 (220 mg) and Pd(PPh3)4 (100 mg, 0.087 mmol) in anhyd DMF or THF (2.5 mL) was added pyrrolidine (0.25 mL, 3.02 mmol) at r.t. under an argon atmosphere. After shaking for 16 h, the resin was filtered, washed with 10% H2O in THF, THF, and ether, and then dried in vacuo for 8 h to give the resin 10 (217 mg).
17Synthetic Procedure for Philanthotoxin-343 (4). To a suspension of the resin 10 (217 mg) in CH2Cl2 (2.5 mL) was added 11 (168 mg, 0.405 mmol) at r.t. After shaking for 2 d, the resin was filtered, washed with 10% H2O in THF, THF, and ether, and then dried in vacuo for 4 h to give the resin 12 (316 mg). To a suspension of 12 (64 mg) in MeOH (1.0 mL) was added K2CO3 (60 mg, 0.434 mmol) at r.t. After shaking for 16 h, the resin was filtered, washed with 10% H2O in THF, THF, and ether, and then dried in vacuo for 4 h to afford the resin (60 mg). To a suspension of the above resin (50 mg) and 2-mercaptoethanol (30 µL, 0.426 mmol) in DMF (1.0 mL) was added DBU (60 µL, 0.402 mmol) at r.t. After shaking for 6 h, the resin was filtered, washed with 10% H2O in THF, THF, and ether, and then dried in vacuo for 3 h to give the resin (41 mg). To a mixture of the resulting resin in CH2Cl2 (2.5 mL) was added TFA (30 µL, 0.389 mmol) at r.t. After shaking for 5 min, the resin was filtered and washed with MeOH:CH2Cl2 (1:2). The combined washings were evaporated with benzene and dried in vacuo to provide Philanthotoxin-343(4) (18.0 mg, 75% from 5) as the TFA salt. [α]D +5.1 (c 0.14, CH3OH). 1H NMR (400 MHz, CD3OD): δ = 0.77 (3 H, t, J = 7.5 Hz), 1.46 (2 H, q, J = 7.5 Hz), 1.70 (6 H, m), 1.99 (2 H, t, J = 8.0 Hz), 2.09 (2 H, dt, J = 7.5 Hz, J = 2.0 Hz), 2.75-3.21 (14 H, m), 4.28 (1 H, t, J = 7.6 Hz), 6.61 (2 H, d, J = 8.5 Hz), 6.95 (2 H, d, J = 8.5 Hz). 13C NMR (100 MHz, D2O): δ = 13.4, 19.7, 23.6, 24.5, 26.1, 36.7, 36.9, 37.3, 38.0, 45.3, 45.7, 45.8, 47.8, 56.6, 116.3, 129.0, 131.3, 155.3, 174.7, 178.0. IR: 722, 799, 837, 1133, 1202, 1433, 1517, 1678, 2965 cm-1. MS: m/z = 436 (MH+); HR MS: Found 436.3264 (MH+). Calcd 436.3288 (C23H42O3N5, MH+).