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Synlett 2003(12): 1826-1829  
DOI: 10.1055/s-2003-41477
LETTER
© Georg Thieme Verlag Stuttgart · New York

l-α-Methylhomoisoserine: A New Versatile Building Block for Peptide and Depsipeptide Modification [1]

Gábor Radicsa, Beate Kokscha, Salah M. El-Kousyb, Jan Spenglera, Klaus Burger*a
a Department of Organic Chemistry, University of Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Fax: +49(341)9736599; e-Mail: burger@organik.chemie.uni-leipzig.de;
b Faculty of Science, Minufiya University, Shebin El-Kom, Egypt
Further Information

Publication History

Received 20 June 2003
Publication Date:
19 September 2003 (online)

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Abstract

An efficient access to l-α-methylhomoisoserine derivatives starting from l -citramalic acid is described. The new compounds are GABA derivatives and represent new, versatile building blocks for peptide and depsipeptide modification.

Keywords

citramalic acid - hexafluoroacetone - γ-amino-α-hydroxy-α-methylbutyric acid - Wolff rearrangement - Arndt-Eistert synthesis - Curtius rearrangement - amino acid hydroxamates

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    (2 S)-4- tert -Butyloxycarbonylamino-2-hydroxy-2-methyl-butanoic acid methyl ester (10a): A solution of 9a (200 mg, 0.52 mmol) in dry MeOH (15 mL) was heated for 72 h. When the reaction was complete (TLC control), the solvent was evaporated in vacuo and the remaining residue purified by column chromatography (eluent: CHCl3-MeOH, 20:1, Rf = 0.32). Yield: 0.63 mg (49%) 9a, colorless oil; [a]D = -4.2 (c 0.48, MeOH). 1H NMR (CDCl3): d = 1.35 (s, 3 H, CH3), 1.36 [s, 9 H, C(CH3)3], 1.74 (m, 1 H, CH2CH2), 2.01 (m, 1 H, CH2CH2), 2.97 (s, 1 H, OH), 3.10 (m, 1 H, NCH2), 3.20 (m, 1 H, NCH2), 3.72 (s, 3 H, OCH3), 4.83 (br s, 1 H, NH). 13C NMR (CDCl3): d = 26.60, 28.36, 36.21, 39.15, 52.89, 74.75, 83.39, 155.97, 177.48. MS (ESI): m/z = 270.13119 [M + Na]+ 270.13144, calcd: 270.13119; [2 M + Na]+ 517.27351, calcd: 517.27317.

  • 18b

    (2S)-4- tert- Butyloxycarbonylamino-2-hydroxy-2-methyl-butan-hydroxamate ( 10b): To a stirred solution of 9a (200 mg, 0.52 mmol) in DMF, HCl·NH2OH (40 mg, 0.58 mmol) and propylene oxide (34 mg, 0.58 mmol) were added. After 24 h the reaction was complete (TLC control). The solvent was evaporated in vacuo and the residue purified by column chromatography (eluent: CHCl3-MeOH 10:1, Rf = 0.11). Yield: 88 mg (67%) 10b, white hygroscopic solid; [α]D = -3.0 (c 0.5, MeOH). 1H NMR (DMSO-d 6): δ = 1.22 (s, 3 H, CH3), 1.35 [s, 9 H, C(CH3)3], 1.56 [m, 1 H, CH2CH2], 1.75 (m, 1 H, CH2CH2), 2.83 (m, 1 H, NCH2), 3.01 (m, 1 H, NCH2), 5.14 (s, 1 H, OH), 6.59 (br s, 1 H, NH), 8.59 (br s, 1 H, NHOH), 10.29 (br s, 1 H, NHOH). 13C NMR (DMSO-d 6): δ = 26.42, 28.16, 35.65, 39.90, 73.18, 77.27, 155.33, 171.67. MS (ESI): m/z = [M + Na]+ 271.12670; calcd 271.12644; [2 M + Na]+ 519.26389; calcd 519.26366.

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16

( 5S )-5-(2-Isocyanatoethyl)-5-methyl-2,2-bis(trifluoro-methyl)-1,3-dioxolan-4-one ( 8): To a solution of acid chloride 7 (3.94 g, 11.98 mmol) in anhyd toluene (20 mL) trimethylsilyl azide (1.52 g, 13.18 mmol) was added with stirring, then the reaction mixture was heated (85 °C, bath temperature). After 12 h the reaction was complete (19F NMR analysis), the solvent was evaporated in vacuo and the residue distilled under reduced pressure. Yield: 2.59 g (70%) 8, yellow oil, bp 34-38 °C/0.34 mbar; [α]D = -6.8 (c 1.33, CH2Cl2). 1H NMR (CDCl3): δ = 1.66 (s, 3 H, CH3), 2.17 (br t, 2 H, 3 J = 7 Hz, NHCH2CH 2 ), 3.59 (m, 2 H, NHCH 2 ). 13C NMR (CDCl3): δ = 22.33, 37.38 38.54, 80.59, 97.37 (sept., J = 35.9 Hz), 119.32 (q, J = 288.0 Hz), 122.83, 169.87.
19F NMR (CDCl3): δ = -81.14 (m, 6 F, 2 × CF3). MS (EI): m/z (%) = 307 [M]+(3), 238 (28), 169 (14), 72 (66), 56 (100).

17

( 5S ) - 5-(2- tert- Butyloxycarbonylamino)ethyl-5-methyl-2,2-bis(trifluoromethyl)-1,3-dioxolan-4-one ( 9a): A solution of 8 1.0 g (3.25 mmol) in t-BuOH(5 mL) was heated (60 °C, bath temperature) for 3 h. After evaporation of the solvent the residue was purified by column chromatography (eluent: CH2Cl2, Rf = 0.11). Yield: 868 mg (70%) 9a, mp 49-51 °C; [α]D = -4.0 (c 1, CH2Cl2). 1H NMR (CDCl3): δ = 1.43 (s, 9 H, C(CH3)3), 1.65 (s, 3 H, CH3), 2.07 (m, 2 H, CH2), 3.29 (m, 1 H, NCH2), 3.44 (m, 1 H, NCH2), 4.70 (m, 1 H, NH). 13C NMR (CDCl3): δ = 22.02, 28.35, 35.11, 37.48, 79.77, 81.13, 97.08 (sept., J = 35.7 Hz), 119.16 (q, J = 288.5 Hz), 155.72, 170.22.
19F NMR (CDCl3): δ = -81.23 (m, 6 F, 2 × CF3). MS (EI) m/z (%) = 381 [M]+ (2), 367 (5), 328 (16), 282 (14), 59 (93), 57 (100).
9b: A solution of 8 (2.0 g, 6.51 mmol) and benzyl alcohol (739 mg, 6.84 mmol) in anhyd CHCl3 (10 mL) was heated under reflux for 12 h. Purification: column chromatography (eluent: CH2Cl2, Rf = 0.32). Yield: 2.01 g (74%) 9b, colorless oil.
9c: A solution of 8 (2.0 g, 6.51 mmol) and 9-fluorenylmethanol (1.34 g, 6.84 mmol) in CHCl3 (10 mL) was heated under reflux for 12 h. Purification: column chromatography (eluent: CH2Cl2, Rf = 0.30). Yield: 3.50 g (76%) 9c, mp 75-78 °C.

25

[(2S)-4-(9-Fluorenylmethyl)oxycarbonylamino-2-hydroxy-2-methyl-butyryl]-phenylalanine tert- butyl ester ( 11b): To a stirred solution of 9c (200 mg, 0.40 mmol) in DMF (2 mL) HCl·NH2-Phe-Ot-Bu (123 mg, 0.48 mmol) and propylene oxide (28 mg, 0.48 mmol) were added. After 48 h at 30-40 °C the reaction was complete (TCL control). The solvent was evaporated in vacuo and the residue was purified by column chromatography (eluent: CHCl3-MeOH 10:1, Rf = 0.36). Yield: 56% (124 mg) 11b; mp 129 °C; [α]D = -4 (c 0.75, MeOH). 1H NMR (DMSO-d 6): δ = 1.30 (s, 3 H, CH3), 1.34 (s, 9 H, C(CH3)3), 1.58 (m, 1 H, CH2), 1.79 (m, 1 H, CH2), 2.77 (m, 1 H, NCH2), 3.02 (m, 3 H, NCH2, CH2-Phe), 4.20 (t, 3 J = 6.8 Hz, 1 H, CH), 4.26 (d, 3 J = 6.8 Hz, 2 H, CH2-Fmoc), 4.41 (dt, 3 J = 7.2 Hz, 3 J = 7.1 Hz, 1 H, CH-Phe), 5.46 (br s, 1 H, OH), 7.07 (br t, 3 J = 5.0 Hz, 1 H, NH), 7.14-7.29 (m, 5 H, H-Ar), 7.64 (d, 3 J = 9.0 Hz, 1 H, NH), 7.32-7.88 (m, 8 H, H-Fmoc). 13C NMR (DMSO-d 6): δ = 27.44, 27.48, 35.88, 36.69, 39.67, 46.64, 53.18, 65.12, 79.68, 80.84, 119.98, 125.03, 126.36, 126.91, 127.47, 128.03, 129.08, 136.92, 140.60. 143.80, 155.77, 170.12, 174.82. MS (ESI) m/z = [M + H]+ 559.28079, calcd.: 559.28026; [M + Na]+ 581.26252, calcd: 581.26221; [2 M + Na]+ 1139.53588, calcd: 1139.53520.

26

[(2S)-4-(9-Fluorenylmethyl)oxycarbonylamino-2-hydroxy-2-methyl-butyryl]-azaglycine methyl ester ( 12b): To a stirred solution of 9c (200 mg, 0.40 mmol) in DMF (2 mL) NH2NHCO2Me (36 mg, 0.40 mmol) was added. After 24 h the reaction was complete (TLC control). DMF was evaporated in vacuo and the residue was purified by column chromatography (eluent: CHCl3-MeOH 10:1, Rf = 0.38) and then lyophilized. Yield: 87% (147 mg) 12b; mp 75-77 °C; [α]D = -3 (c 1.0, MeOH). 1H NMR (DMSO-d 6): δ = 1.26 (s, 3 H, CH3), 1.63 (m, 1 H, CH2), 1.84 (m, 1 H, CH2), 2.99 (m, 1 H, NCH2), 3.19 (m, 1 H, NCH2), 3.57 (s, 3 H, OCH3), 4.21 (m, 3 H, CH, CH2-Fmoc), 5.48 (br s, 1 H, OH), 5.54 (br s, 1 H, OH), 7.16 (br s, 1 H, NH), 7.32-7.87 (m, 8 H, Aryl-H Fmoc), 8.95 (br s, 1 H, NH), 9.46 (br s, 1 H, NH). 13C NMR (DMSO-d 6): δ = 26.42, 35.80, 40.12, 46.64, 51.68, 65.17, 73.25, 119.90, 125.08, 126.94, 127.48, 140.60, 143.83, 155.85, 156.47, 174.77. MS (ESI) m/z = [M + Na]+ 450.16395, calcd 450.16356; [2 M + Na]+ 877.33696, calcd: 877.33789.