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CC BY-ND-NC 4.0 · SynOpen 2017; 01(01): 0059-0062
DOI: 10.1055/s-0036-1588519
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Chain Length of Amphipathic-Type Thioesters Dramatically Affects Reactivity in Aqueous Amidation Reactions with Cysteine Esters

Ikumi Otomo
a   Department of Chemistry, Rikkyo University, Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan   eMail: chkkuroda@rikkyo.ac.jp
,
Kanna Watanabe
a   Department of Chemistry, Rikkyo University, Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan   eMail: chkkuroda@rikkyo.ac.jp
,
Chiaki Kuroda*
a   Department of Chemistry, Rikkyo University, Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan   eMail: chkkuroda@rikkyo.ac.jp
,
Kenichi Kobayashi*
b   Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, Noshio, Kiyose, Tokyo 204-8588, Japan   eMail: kenichik@my-pharm.ac.jp
› InstitutsangabenThis work was partly supported by the Strategic Research Foundation Grant-aided Projects for Private Universities from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.
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Publikationsverlauf

Received: 10. Juli 2017

Accepted after revision: 11. Juli 2017

Publikationsdatum:
01. August 2017 (online)

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Abstract

The reaction of five amphipathic-type thioesters, CH3(CH2) m COS(CH2) n COONa (m + n = 12), with cysteine hexyl, butyl, and ethyl esters were studied in aqueous medium. Compounds with the thioester group in close proximity to the carboxylate moiety (m = 10, n = 2) afforded amides in almost quantitative yield, whereas no reaction proceeded by using compounds with the thioester group distant from the carboxylate. In contrast, no clear difference in yield was observed among the five amphipathic-type thioesters upon reaction with valine hexyl ester. The results indicate that the reaction is affected by both the position of the thioester group and the hydrophilic/hydrophobic properties of the amino acid side chain.

Key words

thioesters - amides - amino acids - micelles - hydrophobic effects
 

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  • 9 Compounds 6 and 9 were prepared by TfOH-catalyzed esterification of cysteine or valine, respectively, with 1-hexanol. Compound 17 was prepared in the same way with 1-butanol. Compound 15 is commercially available as the hydrochloride, and HCl was removed by the addition of NaOH/MeOH, followed by recrystallization (H2O/MeCN).
  • 10 In a typical experiment, thioester 1 (44.3 mg, 0.142 mmol) was added to a stirred mixture of 6 (59.5 mg, 0.290 mmol) in water (6 mL), and the mixture was heated to reflux for 6 h. The mixture was diluted with water, extracted with EtOAc, and the organic layer washed with aqueous NaHCO3 solution and dried over Na2SO4. Filtration and evaporation of the solvent afforded 7 (53.8 mg, 0.139 mmol, 98%). In the same manner, 2 (50.4 mg, 0.162 mg) was reacted with 6 (72.5 mg, 0.354 mmol) to afford 8 (56.9 mg, 0.158 mmol, 98%). Reaction of 2 (20.8 mg) and 9 (32.2 mg) afforded 11 (13.8 mg, 58 %) after silica gel column chromatography (hexane/EtOAc); 3 (15.7 mg) and 9 (27.1 mg) afforded 12 (12.0 mg, 73%); 4 (13.3 mg) and 9 (21.9 mg) afforded 13 (7.0 mg, 55%); 5 (97.7 mg) and 9 (131.2 mg) afforded 14 (38.9 mg, 46%); 1 (63.2 mg) and 17 (73.4 mg) afforded 18 (64.9 mg, 89%); 2 (28.1 mg) and 17 (33.5 mg) afforded 19 (29.0 mg, 96%, refluxing for 12 h)
  • 11 Compound 7: Mp 65.6–67.5 °C; IR (KBr): 3324, 1736, 1670 cm–1; 1H NMR (CDCl3): δ = 0.88 (t, J = 6.5 Hz, 3 H, CH3), 0.90 (t, J = 6.2 Hz, 3 H, CH3), 1.22–1.39 (m, 22 H, 11×CH2), 1.57–1.73 (m, 4 H, 2×CH2), 2.25 (t, J = 7.5 Hz, 2 H, NHCOCH 2), 3.17 (dd, J = 5.2, 14.0 Hz, 1 H, CHHSH), 3.23 (dd, J = 4.9, 14.0 Hz, 1 H, CHHSH), 4.08–4.24 (m, 2 H, COOCH2), 4.86 (td, J = 5.0, 7.1 Hz, 1 H, CONHCH), 6.47 (d, J = 7.2 Hz, 1 H, NH); 13C NMR (CDCl3): δ = 14.0, 14.1, 22.5, 22.7, 25.5, 28.4, 29.3, 29.3, 29.4, 29.5, 29.6, 29.6 (2C), 31.3, 31.9, 36.5, 41.0, 51.7, 66.2, 170.6, 173.1; MS (FAB): m/z = 388 [M+H]+, 119; HRMS-FAB: m/z [M+H]+ calcd for C21H42NO3S: 388.2885; found: 388.2883
  • 12 Compound 8: Mp 71.4–73.0 °C; IR (KBr): 3313, 1731, 1644 cm–1; 1H NMR (CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H, CH3), 0.90 (t, J = 6.8 Hz, 3 H, CH3), 1.23–1.38 (m, 18 H, 9×CH2), 1.59–1.70 (m, 4 H, 2×CH2), 2.26 (app. t, J = 7.5 Hz, 2 H, NHCOCH 2), 3.17 (dd, J = 5.3, 14.0 Hz, 1 H, CHHSH), 3.24 (dd, J = 5.0, 14.0 Hz, 1 H, CHHSH), 4.09–4.21 (m, 2 H, COOCH2), 4.86 (td, J = 5.0, 7.3 Hz, 1 H, CONHCH), 6.51 (d, J = 7.2 Hz, 1 H, NH); 13C NMR (CDCl3): δ = 14.0, 14.1, 22.5, 22.7, 25.5 (2C), 28.4, 29.3 (2C), 29.4, 29.5, 31.3, 31.9, 36.5, 40.9, 51.7, 66.2, 170.6, 173.1; MS (FAB): m/z = 360 [M+H]+, 119; HRMS-FAB: m/z [M+H]+ calcd for C19H38NO3S: 360.2572; found: 360.2569
  • 13 Compound 11: Oil; IR (neat): 3308, 1742, 1651, 1539 cm–1; 1H NMR (CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H, CH3), 0.89 (t, J = 6.8 Hz, 3 H, CH3), 0.90 (d, J = 6.9 Hz, 3 H, CH3), 0.94 (d, J = 6.9 Hz, 3 H, CH3), 1.23–1.40 (m, 18 H, 9×CH2), 1.58–1.69 (m, 4 H, 2×CH2), 2.10–2.22 (m, 1 H, CH(CH3)2), 2.23 (app. t, J = 7.6 Hz, 2 H, NHCOCH 2), 4.07–4.18 (m, 2 H, COOCH2), 4.59 (dd, J = 8.7, 4.8 Hz, 1 H, CHiPr), 6.00 (br d, J = 8.7 Hz, 1 H, NH); 13C NMR (CDCl3): δ = 13.9, 14.1, 17.7, 18.9, 22.5, 22.6, 25.5, 25.7, 28.5, 29.2 (2C), 29.3, 29.4, 31.3, 31.4, 31.8, 36.8, 56.7, 65.4, 172.4, 173.0; MS (EI, 70 eV): m/z = 355 [M+], 226; HRMS: m/z [M+] calcd for C21H41NO3: 355.3086; found: 355.3090
  • 14 Compound 12: Oil; IR (neat): 3308, 1740, 1734, 1653, 1541 cm–1; 1H NMR (CDCl3): δ = 0.88 (t, J = 6.9 Hz, 3 H, CH3), 0.90 (t, J = 6.8 Hz, 3 H, CH3), 0.90 (d, J = 6.8 Hz, 3 H, CH3), 0.94 (d, J = 6.9 Hz, 3 H, CH3), 1.23–1.40 (m, 14 H, 7×CH2), 1.55–1.70 (m, 4 H, 2×CH2), 2.10–2.21 (m, 1 H, CH(CH3)2), 2.24 (app. t, J = 7.6 Hz, 2 H, NHCOCH 2), 4.07–4.18 (m, 2 H, COOCH2), 4.58 (dd, J = 8.7, 4.7 Hz, 1 H, CH iPr), 5.92 (br d, J = 8.8 Hz, 1 H, NH); 13C NMR (CDCl3): δ = 14.0, 14.0, 17.7, 18.9, 22.5, 22.6, 25.5, 25.7, 28.5, 29.0, 29.2, 31.3, 31.4, 31.7, 36.8, 56.7, 65.4, 172.3, 173.0; MS (EI, 70 eV): m/z = 327 [M+], 198; HRMS: m/z [M+] calcd for C19H27NO3: 327.2773; found: 327.2769.
  • 15 Compound 13: Oil; IR (neat): 3304, 1742, 1651, 1539 cm–1; 1H NMR (CDCl3): δ = 0.90 (t, J = 6.8 Hz, 6 H, 2×CH3), 0.90 (d, J = 6.9 Hz, 3 H, CH3), 0.94 (d, J = 6.9 Hz, 3 H, CH3), 1.24–1.40 (m, 10 H, 5×CH2), 1.56–1.71 (m, 4 H, 2×CH2), 2.11–2.21 (m, 1 H, CH(CH3)2), 2.24 (app. t, J = 7.7 Hz, 2 H, NHCOCH 2), 4.07–4.19 (m, 2 H, COOCH2), 4.58 (dd, J = 8.9, 4.8 Hz, 1 H, CHiPr), 5.93 (br d, J = 8.8 Hz, 1 H, NH); 13C NMR (CDCl3): δ = 13.9, 14.0, 17.8, 18.9, 22.4, 22.5, 25.4, 25.5, 28.5, 31.3, 31.4 (2C), 36.7, 56.8, 65.4, 172.4, 173.0; MS (EI, 70 eV): m/z = 299 [M+], 170; HRMS: m/z [M+] calcd for C17H33NO3: 299.2460; found: 299.2458
  • 16 Compound 14: Oil; IR (neat): 3308, 1744, 1734, 1653, 1541 cm–1; 1H NMR (CDCl3): δ = 0.90 (t, J = 7.0 Hz, 3 H, CH3), 0.90 (d, J = 6.9 Hz, 3 H, CH3), 0.95 (d, J = 6.9 Hz, 3 H, CH3), 0.96 (t, J = 7.3 Hz, 3 H, CH3), 1.24–1.40 (m, 6 H, 3×CH2), 1.54–1.74 (m, 4 H, 2×CH2), 2.10–2.22 (m, 1 H, CH(CH3)2), 2.23 (app. t, J = 7.5 Hz, 2 H, NHCOCH 2), 4.07–4.19 (m, 2 H, COOCH2), 4.59 (dd, J = 8.8, 4.7 Hz, 1 H, CHiPr), 5.92 (br d, J = 8.2 Hz, 1 H, NH); 13C NMR (CDCl3): δ = 13.7, 14.0, 17.7, 18.9, 19.1, 22.5, 25.5, 28.5, 31.3, 31.4, 38.7, 56.7, 65.4, 172.4, 172.8; MS (EI, 70 eV): m/z = 271 [M+], 142; HRMS: m/z [M+] calcd for C15H29NO3: 271.2147; found: 271.2144
  • 17 Kimura K. Mori M. Matsuo T. Jpn Kokai Tokkyo Koho 53104741, 1978 ; Chem. Abstr. 1979, 90, 28889.
  • 18 Compound 18: Mp 63.0–64.5 °C; IR (KBr): 3310, 1728, 1641, 1545 cm–1; 1H NMR (CDCl3): δ = 0.88 (t, J = 6.7 Hz, 3 H, CH3), 0.94 (t, J = 7.3 Hz, 3 H, CH3), 1.23–1.44 (m, 18 H, 9×CH2), 1.59–1.71 (m, 4 H, 2×CH2), 2.26 (t, J = 7.6 Hz, 2 H, NHCOCH 2), 3.17 (dd, J = 5.2, 14.1 Hz, 1 H, CHHSH), 3.24 (dd, J = 4.8, 14.1 Hz, 1 H, CHHSH), 4.13–4.25 (m, 2 H, COOCH2), 4.86 (td, J = 5.0, 7.2 Hz, 1 H, CONHCH), 6.47 (d, J = 7.3 Hz, 1 H, NH); 13C NMR (CDCl3): δ = 13.7, 14.1, 19.1, 22.7, 25.5, 29.3 (2C), 29.4, 29.5, 29.6 (2C), 30.4, 31.9, 36.5, 40.9, 51.7, 65.9, 170.6, 173.1; MS (EI, 70 eV): m/z = 359 [M+], 200; HRMS: m/z [M+] calcd for C19H37NO3S: 359.2496; found: 359.2489
  • 19 Compound 19: Mp 69.0–71.0 °C; IR (KBr): 3314, 1728, 1641, 1545 cm–1; 1H NMR (CDCl3): δ = 0.88 (t, J = 6.7 Hz, 3 H, CH3), 0.94 (t, J = 7.3 Hz, 3 H, CH3), 1.23–1.44 (m, 14 H, 7×CH2), 1.58–1.75 (m, 4 H, 2×CH2), 2.26 (app. t, J = 7.5 Hz, 2 H, NHCOCH 2), 3.17 (dd, J = 5.0, 14.0 Hz, 1 H, CHHSH), 3.24 (dd, J = 4.9, 14.0 Hz, 1 H, CHHSH), 4.11–4.25 (m, 2 H, COOCH2), 4.86 (td, J = 5.0, 7.3 Hz, 1 H, CONHCH), 6.52 (d, J = 7.1 Hz, 1 H, NH); 13C NMR (CDCl3): δ = 13.6, 14.1, 19.1, 22.6, 25.5, 29.3 (3C), 29.4, 30.4, 31.8, 36.4, 40.9, 51.7, 65.8, 170.6, 173.1; MS (EI, 70 eV) m/z = 331 [M+], 172; HRMS: m/z [M+] calcd for C17H33NO3S: 331.2183; found: 331.2175.