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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
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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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( 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).

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( 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.

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[(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.

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[(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.