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S. Kumar et al. / Tetrahedron 63 (2007) 2084–2092
the residue was dissolved in H2O (10 mL), acidified with 1 N
KHSO4 to pH 4 and extracted with ethyl acetate. The com-
bined organic extracts were washed with brine, dried over
Na2SO4 and concentrated. Column chromatography with
CH2Cl2/EtOAc (1:1), then CH2Cl2/MeOH (50:1) afforded
acid 20 (73 mg, 75%, two rotamers): mp 76–79 ꢀC; [a]D
ꢁ16 (c 0.50, CHCl3); IR (neat) n 3381, 2976, 1706, 1606,
1507, 1390, 1365, 1272, 1246, 1139, 1098, 980, 887, 851,
42.9, 40.8, 36.9, 32.3, 31.3; MS (ESI) m/z 373 [M+H]+;
HRMS calcd for C14H25N6O6 (M+H) 373.1836, found
373.1805.
4.1.16. (2S,400S)-2-[30-(300-tert-Butoxycarbonyl-200,200-di-
methyl-oxazolidin-400-yl)-propylamino]-succinic acid
di-tert-butyl ester (24). This compound was prepared ac-
cording to the same procedure described for 7 starting from
L-Asp(OtBu)2 23 (3.51 g, 14.33 mmol), aldehyde 22 (3.34 g,
13.03 mmol) and sodium triacetoxyborohydride (3.85 g,
18.24 mmol). Flash column chromatography with heptane/
ethyl acetate (4:1 then 2:1) gave 5.37 g (85%, two rotamers)
of 24 as a yellow oil: [a]D +16 (c 0.50, CHCl3); IR (neat)
n 2976, 1727, 1692, 1454, 1386, 1364, 1255, 1144, 1086,
1
811 cmꢁ1; H NMR (500 MHz, CD3OD) d 5.25–4.88 (m,
2H), 4.10–3.90 (m, 2H), 3.86 (d, J¼5.9 Hz, 1H), 3.62–
3.52 (m, 1H), 3.50–3.38 (m, 1H), 2.31–2.16 (m, 2H),
1.98–1.88 (m, 1H), 1.78–1.63 (m, 2H), 1.58, 1.57 (2s, 9H),
1.49 (s, 9H), 1.48 (s, 3H), 1.44 (s, 6H); 13C NMR
(125 MHz, CD3OD) d 176.5, 176.1, 164.4, 161.6, 156.2,
156.0, 155.9, 85.4, 81.6, 81.2, 79.9, 66.2, 65.6, 47.1, 46.9,
44.5, 44.4, 43.8, 42.9, 33.7, 31.2, 30.9, 28.9, 28.8, 28.7,
28.5; MS (ESI) m/z 523 [M+Na]+; HRMS calcd for
C23H40N4O8Na(M+Na) 523.2744, found 523.2740.
1
942, 845, 805 cmꢁ1; H NMR (300 MHz, CDCl3) d 3.97–
3.68 (m, 3H), 3.48–3.39 (m, 1H), 2.79–2.39 (m, 4H), 1.47,
1.45 (2s, 27H), 1.89–1.24 (m, 10H); 13C NMR (75 MHz,
CDCl3) d 173.0, 170.1, 152.1, 151.8, 93.6, 93.1, 81.2,
80.6, 79.8, 79.3, 67.1, 66.7, 58.6, 57.6, 57.3, 48.0, 39.4,
31.5, 30.7, 28.5, 28.1, 27.6, 27.0, 26.8, 24.6, 23.3; MS
(ESI) m/z 487 [M+H]+, 509 [M+Na]+; HRMS calcd for
C25H47N2O7 (M+H) 487.3383, found 487.3395.
4.1.14. (2S,200S,300S)-2-(20-{[100-tert-Butoxycarbonyl-300-
(2000-N,N0-bis(tert-butoxycarbonyl)-guanidino-ethyl)-pyr-
rolidine-200-carbonyl]-amino}-acetylamino)-succinic
acid di-tert-butyl ester (21). To a solution of acid 20
(115 mg, 0.23 mmol) and L-Gly–Asp (OtBu)2 (76 mg,
0.25 mmol) in CH2Cl2 (10 mL) were added EDC (52 mg,
0.27 mmol) and HOBt (36 mg, 0.27 mmol) and the reaction
mixture was stirred at room temperature under Ar for 24 h.
Water was added and the reaction mixture was extracted
with CH2Cl2. The organic extracts were washed with 1 N
KHSO4, H2O, saturated NaHCO3, brine, successively, dried
over Na2SO4 and evaporated under reduced pressure. Flash
column chromatography with CH2Cl2/ethyl acetate (1:1),
then CH2Cl2/MeOH (50:1) gave 155 mg of 21 (86%): mp
68–70 ꢀC; [a]D +32 (c 0.25, CHCl3); IR (neat) n 2976,
4.1.17. (2S,400S)-2-[[30-(300-tert-Butoxycarbonyl-200,200-
dimethyl-oxazolidin-400-yl)-propyl]-(9H-fluoren-9-yl-
methoxycarbonyl)-amino]-succinic acid di-tert-butyl
ester (25). This compound was prepared according to the
same procedure described for 8 starting from 24 (4.77 g,
9.81 mmol). Flash column chromatography with CH2Cl2/
ethyl acetate (4:1 then 2:1) gave 5.80 g (83%, two rotamers)
of 25 as white foam: [a]D ꢁ14 (c 0.62, CHCl3); IR (neat)
n 2976, 2932, 1727, 1692, 1477, 1451, 1421, 1388, 1364,
1246, 1208, 1146, 1081, 1013, 943, 919, 844, 806 cmꢁ1
;
1H NMR (300 MHz, CDCl3) d 7.76 (d, J¼7.1 Hz, 2H),
7.67–7.51 (m, 2H), 7.45–7.23 (m, 4H), 4.81–4.15 (m, 4H),
3.98–3.62 (m, 3H), 3.54–2.21 (m, 4H), 1.47, 1.43, 1.40
(3s, 27H), 1.75–1.16 (m, 10H); 13C NMR (75 MHz,
CDCl3) d 170.5, 170.1, 169.1, 155.7, 155.5, 152.1, 151.7,
143.9, 141.3, 127.7, 127.1, 125.1, 125.0, 124.7, 120.0,
93.7, 93.2, 82.0, 81.7, 81.0, 80.8, 80.0, 79.5, 67.5, 67.1,
66.8, 66.7, 66.5, 58.8, 57.8, 57.5, 57.1, 48.9, 47.4, 47.3,
37.0, 36.5, 31.0, 30.1, 28.5, 28.1, 27.9, 27.7, 26.9, 25.9,
25.3, 24.6, 23.2; MS (ESI) m/z 731 [M+Na]+; HRMS calcd
for C40H56N2NaO9 (M+Na) 731.3884, found 731.3896.
1
1672, 1608, 1392, 1365, 1248, 1141, 846 cmꢁ1; H NMR
(500 MHz, CD3OD) d 4.51–4.44 (m, 1H), 3.86–3.61 (m,
5H), 3.46–3.35 (m, 2H), 2.63 (dd, J¼6.8, 9.6 Hz, 0.5H),
2.54 (d, J¼5.2 Hz, 1H), 2.45 (dd, J¼5.9, 10.4 Hz, 0.5H),
2.20–1.95 (m, 2H), 1.79–1.62 (m, 1H), 1.60–1.46 (m, 2H),
1.37, 1.30, 1.28, 1.24 (4s, 45H); 13C NMR (125 MHz,
CD3OD) d 175.4, 175.1, 171.2, 171.0, 170.8, 170.3, 164.4,
161.6, 156.1, 155.9, 155.8, 85.2, 83.1, 83.0, 82.4, 82.2,
81.5, 81.3, 79.8, 67.3, 51.1, 50.9, 47.6, 47.0, 44.3, 43.9,
43.5, 43.3, 42.8, 38.4, 38.3, 33.1, 31.4, 30.3, 28.9,
28.7, 28.4, 28.3, 28.2; MS (ESI) m/z 807 [M+Na]+;
HRMS calcd for C37H64N6O12Na (M+Na) 807.4480, found
807.4449.
4.1.18. (2S,40S)-2-[(40-tert-Butoxycarbonylamino-40-car-
boxy-butyl)-(9H-fluoren-9-ylmethoxycarbonyl)-amino]-
succinic acid di-tert-butyl ester acid (26). This compound
was prepared according to the same procedure described for
9 starting from 25 (5.10 g, 7.20 mmol). Flash column chro-
matography with heptane/ethyl acetate (4:1 then 2:1) gave
4.03 g (82%, two rotamers) of 26 as white crystals: mp
56–57 ꢀC; [a]D ꢁ28 (c 0.55, CHCl3); IR (neat) n 2975,
1698, 1478, 1450, 1422, 1392, 1366, 1246, 1148, 1014,
844 cmꢁ1; 1H NMR (300 MHz, CDCl3) d 10.05 (br s, 1H),
7.81–7.69 (m, 2H), 7.64–7.50 (m, 2H), 7.43–7.25 (m, 4H),
5.40 (d, J¼6.6 Hz, 0.5H), 5.24 (d, J¼7.5 Hz, 0.5H), 4.80–
4.65 (m, 0.5H), 4.63–4.40 (m, 1.5H), 4.38–4.01 (m, 3H),
3.54–2.21 (m, 4H), 1.47, 1.44, 1.41, 1.39 (4s, 27H), 1.95–
1.13 (m, 4H); 13C NMR (75 MHz, CDCl3) d 176.5, 176.1,
170.8, 170.3, 169.1, 156.1, 155.8, 155.6, 143.9, 143.7,
141.4, 127.7, 127.1, 125.1, 124.9, 124.6, 120.0, 82.2, 82.0,
81.2, 81.0, 79.9, 67.7, 66.9, 58.6, 57.8, 53.2, 48.3, 47.4,
4.1.15. (2S,200S,300R)-2-(20-{[300-(2000-Guanidino-ethyl)-
pyrrolidine-200-carbonyl]-amino}-acetylamino)-succinic
acid (3). To a solution of 21 (100 mg, 0.12 mmol) in CH2Cl2
(3 mL) was added TFA (3 mL) at 0 ꢀC, then the reaction
mixture was stirred at room temperature for 4 h. The sol-
vents were evaporated and the residue was dried under vac-
uum to give compound 3 (52 mg, 83%): mp 84–86 ꢀC; [a]D
+51 (c 0.26, MeOH); IR (neat) n 3209, 3084, 1658, 1650,
1
1633, 1555, 1422, 1179, 1128, 1042, 837 cmꢁ1; H NMR
(500 MHz, CD3OD) d 4.73 (t, J¼5.6 Hz, 1H), 4.13 (d,
J¼16.6 Hz, 1H), 3.93 (d, J¼9.3 Hz, 1H), 3.85 (d,
J¼16.6 Hz, 1H), 3.47–3.27 (m, 4H), 2.88–2.77 (m, 2H),
2.46–2.35 (m, 1H), 2.34–2.20 (m, 1H), 2.13–2.02 (m, 1H),
1.84–1.66 (m, 2H); 13C NMR (125 MHz, CD3OD)
d 174.2, 174.0, 171.0, 170.0, 158.7, 65.4, 50.4, 47.0, 43.3,