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Synlett 2004(3): 473-476  
DOI: 10.1055/s-2004-815426
LETTER
© Georg Thieme Verlag Stuttgart · New York

Diols as Building Blocks in Solid-Phase Synthesis of Polyamine Toxins by Fukuyama-Mitsunobu Alkylation

Christian A. Olsena, Matthias Wittb, Jerzy W. Jaroszewskia, Henrik Franzyk*a
a Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, 2100 Copenhagen, Denmark
Fax: +4535306441; e-Mail: hf@dfuni.dk;
b Bruker Daltonik GmbH, Fahrenheitstrasse 4, 28359 Bremen, Germany
Further Information

Publication History

Received 30 October 2003
Publication Date:
26 January 2004 (online)

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Abstract

Philanthotoxin-433 (PhTX-433) is a polyamine wasp toxin that antagonizes certain ionotropic receptors. In the present work three analogues of PhTX-433 were synthesized in good overall yields (27-31%) employing a Fukuyama-Mitsunobu strategy on solid phase. Primary diols were used as building blocks in solid-phase synthesis of polyamines for the first time. Furthermore, experiments with sterically congested alcohols indicated that incorporation of such structures by the solid-phase Fukuyama-Mitsunobu approach is not possible.

Key words

polyamines - philanthotoxins - Fukuyama-Mitsunobu alkylation - diols - solid-phase synthesis

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For example, Aldrich 2003: 4-Amino-1-butanol, ı 19.30 /
1 g; 1,4-butanediamine, ı 30.50 / 25 g; 1,4-butanediol,
ı 27.00 / 1 L.

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Experimental procedures and characterization of philanthotoxins (9a-c, Scheme [3] ): Functionalized trityl resin 4 (170 mg, 0.176 mmol) was suspended in THF (1 mL). Diol 3 (277 mg, 0.88 mmol, 5 equiv) in CH2Cl2 (1 mL), PMe3 (0.95 mL, 0.95 mmol, 6 equiv; 1.0 M in THF) and ADDP (222 mg, 0.88 mmol, 5 equiv) in CH2Cl2 (1 mL) were added, and the mixture was shaken at r.t. under N2 for 3 h. The resin was drained and washed with DMF, CH2Cl2, MeOH and CH2Cl2 (3 ×), and then the procedure was repeated two times, shaking for 16 h during the last repetition. The resin was then treated with TBAF (278 mg, 0.88 mmol, 5.0 equiv) in THF (3 mL) for 1 h at 50 °C, and washed with DMF, CH2Cl2, MeOH and CH2Cl2 (3 ×) to give resin 6. The resin 6 was then suspended in THF (1 mL), diamine 2 (368 mg, 0.88 mmol, 5 equiv) in CH2Cl2 (1 mL), PBu3 (0.34 mL, 0.95 mmol, 6 equiv) in THF (1 mL) and ADDP (222 mg, 0.88 mmol, 5 equiv) in CH2Cl2 (1 mL) were added, and the mixture was shaken at r.t. under N2 for 3 h. The resin was drained and washed with DMF, CH2Cl2, MeOH and CH2Cl2 (3 ×). The above procedure was repeated two times, shaking for 16 h during the last repetition. After washing, the resin was treated with TBAF (278 mg, 0.88 mmol, 5.0 equiv) in THF (3 mL) for 1 h at 50 °C, cooled to r.t., and washed with DMF, CH2Cl2, MeOH and CH2Cl2
(3 ×) to give resin 7. Attachment of the (S)-cyclohexyl-alanine residue was accomplished by suspending the resin in DMF (1 mL), and adding DIEA (80 µL, 0.46 mmol, 2.6 equiv), HODhbt (29 mg, 0.177 mmol, 1 equiv) in DMF (1 mL), and (S)-N α-Fmoc-Cha-OPfp (295 mg, 0.528 mmol, 3 equiv) in DMF (2 mL). The mixture was agitated at r.t. under N2 for 2 h. The resin was drained and washed with DMF, CH2Cl2, MeOH and CH2Cl2 (3 ×), and then the coupling procedure was repeated. The resulting resin was treated with 20% piperidine in DMF (2 mL) for 10 min at r.t., washed with DMF (3 ×), treated again with 20% piperidine in DMF (2 mL) for 10 min, and washed with DMF, CH2Cl2, MeOH and CH2Cl2 (3 ×). After removal of the Fmoc group, the resin was suspended in DMF (1 mL) and acylated by treatment with DIEA (80 µL, 0.46 mmol, 2.6 equiv) and HODhbt (29 mg, 0.177 mmol, 1 equiv) in DMF (1 mL), and a carboxylic acid Pfp ester (3 equiv) in DMF (2 mL) under N2 for 2 h. The resin was drained and washed with DMF, CH2Cl2, MeOH and CH2Cl2 (3 ×). The acylation procedure was repeated to give resin 8a, 8b or 8c. The resin was then treated with DBU (131 µL, 0.88 mmol, 5 equiv) in DMF (1 mL) and 2-mercaptoethanol (124 µL, 1.76 mmol, 10 equiv) in DMF (1 mL) for 2.5 h, and was then drained and washed with DMF (3 ×). This treatment was repeated for 10 min, and a colorless drain confirmed that deprotection was complete. The resin was washed with DMF, CH2Cl2, MeOH and CH2Cl2 (3 ×), and the product was cleaved off with TFA-CH2Cl2-triisopropylsilane-H2O (47.5:47.5:2.5:2.5; 2 mL) at r.t. for 2 h. The filtrate was combined with the MeOH (2 × 5 mL) and CH2Cl2 (2 × 5 mL) washings, and concentrated in vacuo. The residue was purified by RP-18 VLC [H2O-MeCN-TFA (95:5:0.1, 90:10:0.1, 85:15:0.1 and 80:20:0.1)], to give 9a-c.
Philanthotoxin 9a: Yield: 44 mg (31%). 1H NMR (400 MHz, CD3OD): δ = 0.77-1.32 (m, 6 H), 1.52-1.70 (m, 11 H), 2.08 (br p, J = 7.5 Hz, 4 H, 2 × CH2), 2.90-3.28 (m, 12 H, CH2N), 3.56 (d, J gem = 14.2 Hz, 1 H, CH2Ph), 3.59 (d, J gem = 14.2 Hz, 1 H, CH2Ph), 4.28 (m, 1 H, H-α), 7.24-7.36 (m, 5 H, Ar-H). 13C NMR (100 MHz, CD3OD): δ = 26.6, 26.7, 27.9, 29.7, 29.8, 29.9, 30.0, 35.6, 37.4, 37.9, 40.3, 41.7, 42.8, 46.1, 48.0, 48.5 (2 × C), 51.0, 55.6, 130.5, 132.2
(2 × C), 132.7 (2 × C), 139.6, 176.9, 177.9. HRMS: m/z calcd [C27H48N5O2]+: 474.38025; found: 474.38006.
Philanthotoxin 9b: Yield: 41 mg (28%). 1H NMR (400 MHz, CD3OD): δ = 0.86-1.39 (m, 10 H), 1.54-1.73 (m, 18 H), 2.11 (m, 6 H, 3 × CH2), 2.89-3.24 (m, 12 H, CH2N), 4.31 (m, 1 H, H-α). 13C NMR (100 MHz, CD3OD): δ = 24.4, 24.6, 25.7, 27.5 (2 × C), 27.6 (4 × C), 27.8 (2 × C), 33.5, 34.3, 34.5, 35.2, 35.7, 37.3, 38.0, 39.5, 40.5, 45.1, 45.9, 46.3 (2 × C), 53.0, 175.8, 176.0. HRMS: m/z calcd [C27H54N5O2]+: 480.42720; found: 480.42686.
Philanthotoxin 9c: Yield: 37 mg (27%). 1H NMR (400 MHz, CD3OD): δ = 0.95 (t, J = 7.4 Hz, 3 H, CH3), 0.86-1.43 (m, 6 H), 1.52-1.87 (m, 13 H), 2.05-2.19 (br m, 4 H), 2.24 (m, 2 H, CH2CO), 2.85-3.45 (m, 12 H), 4.24 (t, J = 7.7 Hz, 1 H, H-α). 13C NMR (100 MHz, CD3OD): δ = 15.0, 21.3, 25.2 (2 × C), 26.4, 28.2, 28.4, 28.5, 34.3 (2 × C), 35.9 (2 × C), 36.5, 37.8, 38.8, 39.7, 40.2, 41.3, 46.6, 47.0, 53.9, 176.6, 177.4. HRMS: m/z calcd [C23H48N5O2]+: 426.38025; found: 426.37984.

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Pfp esters were obtained in 85-97% isolated yield. Conditions were as described by Olsen et al. [14]