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3.6. N,N-Bis[methyl (2S,4R,5R)-2-amino-4,5-(isopropylidenedioxy)hexanoate-6-yl]-N-benzyloxycar-
bonylamine (7)
1 M HCl (4.47 ml, 4.47 mmol) was added dropwise to a solution of N,N-bis[4-((2R,5S)-
2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazin-5-yl)-(2R,3R)-2,3-(isopropylidenedioxy)butyl]-N-
benzyloxycarbonylamine (0.69 g, 0.89 mmol) in dioxane (4.47 ml) and the solution stirred at ambient
temperature for 10 h. Aqueous ammonia was then added until pH 9 and the mixture extracted with
chloroform (3×25 ml). The combined organic layers were dried (MgSO4), the solvent and the valine
methyl ester distilled off at reduced pressure by bulb-to-bulb distillation (50°C, 0.02 torr); yield: 0.44 g
(85%). 1H NMR (CDCl3): δ 1.32, 1.33, 1.35 (3 s, 12H, (CHO)2C(CH3)2), 1.55 (s, 4H, NH2), 1.55–2.20
(m, 4H, CH2(CHO)2CH2NCO), 3.28–3.56 (m, 2H, C–H), 3.69, 3.71 (s, 6H, OCH3), 3.70–4.00 (m, 8H,
CH2(CHO)2CH2NCO), 5.10 (t, J 3 Hz, 2H, CH2–C6H5), 7.33 (s, 5H, CH2–C6H5). 13C NMR (CDCl3):
δ 27.03, 37.68 (CH2(CHO)2CH2NCO), 50.35 (OCH3), 52.34, 52.57 (C–H), 67.52 (CH2–C6H5), 76.25,
76.43 ((CHO)2C(CH3)2), 80.70, 81.07 ((CHO)2C(CH3)2), 109.18, 109.31 ((CHO)2C(CH3)2), 128.10,
128.17, 128.46, 136.29 (CH2–C6H5), 155.92 (NHCO), 175.51 (C_O).
3.7. N,N-Bis[(2S,4R,5R)-2-fluorenylmethoxycarbonylamino-4,5-(isopropylidenedioxy)hexanoic acid-6-
yl]-N-benzyloxycarbonylamine (9)
2 M LiOH (0.756 ml, 1.512 mmol) was added to a solution of N,N-bis[methyl (2S,4R,5R)-2-
amino-4,5-(isopropylidenedioxy)hexanoate-6-yl]-N-benzyloxycarbonylamine (0.44 g, 0.756 mmol) in
dioxane (3 ml) and the mixture stirred at ambient temperature for 12 h to effect complete hydrol-
ysis of the methyl ester groups. The solution was then cooled to 0°C and 1 M NaHCO3 (2.5 ml,
2.5 mmol) added. A solution of 9-fluorenylmethoxycarbonyl chloride (0.62 g, 2.4 mmol) in diox-
ane (2.5 ml) was added dropwise to the cold solution and the resultant solution stirred at ambient
temperature for 5 h. The solution was then acidified by addition of KHSO4, and the aqueous layer
extracted with chloroform (3×50 ml). The combined organic extracts were washed, dried (MgSO4)
and the solvent distilled off at reduced pressure. The residual product was purified by flash chro-
matography using hexane:Et2O:AcOH (7:4:1); yield 0.45 g (59%) (TLC; RF 0.15). Found: C, 67.32;
H, 6.17; N, 4.37. Calc. for C56H59N3O14: C, 67.25; H, 6.15; N, 4.20%. 1H NMR (CDCl3): δ
1.61 (s, 12H, (CHO)2C(CH3)2), 1.60–2.00 (s, 4H, CH2(CHO)2CH2NCO), 3.28 (m, 2H, C–H), 3.50
(m, 2H, C–H(Fmoc)), 3.75 (m, 4H, CH2(CHO)2CH2NCO), 4.14 (m, 8H, CH2(CHO)2CH2NCO and
CH2–C13H9), 4.98 (t, J 6 Hz, CH2–C6H5), 7.20–7.80 (m, 21H, CH2–C6H5). 13C NMR (CDCl3): δ 27.52,
35.62, 47.41, 50.52, (CH2(CHO)2CH2NCO), 52.35 (C–H), 66.50 (CH2–C13H9), 67.42, (CH2–C6H5),
76.51 ((CHO)2C(CH3)2), 80.09, 80.39 ((CHO)2C(CH3)2), 109.32 ((CHO)2C(CH3)2), 120.86, 125.91,
127.94, 128.38, 128.56, 128.70, 129.16, 137.30, 141.44, 144.38, 144.46 (CH2–C6H5 and CH2–C13H9),
156.36, 156.69, 156.94 (NHCO), 175.32 (C_O).
3.8. (2S,4R,5R)-2-N0-Benzyloxycarbonyl-4,5-(isopropylidenedioxy)lysine methyl ester (10)
(2R,5S)-5-((2R,3R)-(4-Benzyloxycarbonylamino-2,3-(isopropylidenedioxy)butyl)-2,5-dihydro-3,6-
dimethoxy-2-isopropylpyrazine (0.5 g, 1.08 mmol) was dissolved in dioxane (5 ml) and 0.5 M HCl
(4.20 ml, 2.10 mmol) was added dropwise. The mixture was stirred under argon at ambient temperature
for 5 h. Aqueous ammonia was then added until pH=9 and the mixture was extracted with chloroform
(3×25 ml). The combined organic layers were dried (MgSO4), the solvent and the valine methyl ester
1
distilled off at reduced pressure by bulb-to-bulb distillation (25°C, 0.05 torr); yield: 0.40 g (>95%). H