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K. Ersmark et al. / Bioorg. Med. Chem. 11 (2003) 3723–3733
(2R,3R,4R,5R)-N1,N6-Bis[(1R)-2-methyl-1-(methylcarb-
amoyl)propyl]- 2,5- di(benzyloxy) -3,4-dihydroxyhexane-
1,6-diamide (3b). The title compoundwas prepared
according to Method I, using 57 mg (0.16 mmol) of
bislactone 2a (stirring 9 h at room temperature and15 h
at reflux). Purification by flash chromatography
(CH2Cl2/CH3OH, 20:1–10:1) gave the title compound
3b (52 mg, 53%) as a white solid: [a]2D2 +48.1ꢄ (c 0.53,
(2R,3R,4R,5R)-N1,N6-Bis[(1S)-2-methyl-1-(methylcarb-
amoyl)propyl]-2,5-di(allyloxy)-3,4-dihydroxyhexane-1,6-
diamide (3c). The title compoundwas preparedaccord-
ing to MethodII, using 179 mg (0.71 mmol) of bislac-
tone 2b andtotally 9 mL dry CH 2Cl2 (reflux 21 h). The
crude product was suspended in H2O (5 mL), filtered,
dissolved in CHCl3/CH3OH, 9:1 (20 mL) andfiltered
through a padof silica (1.5 cm). The padwas further
washedwith CHCl 3/MeOH, 9:1 (30 mL). Concentration
of the filtrate under reduced pressure gave product 3c
(243 mg, 67%) as a white solid: [a]2D2 +8.4ꢄ (c 0.44,
1
CHCl3/CH3OH, 10:1); H NMR (CDCl3/CD3OD, 4:2)
d 7.36–7.22 (m, 10H), 4.62 (d, J=11.13 Hz, 2H), 4.49
(d, J=11.13 Hz, 2H), 4.23 (d, J=6.06 Hz, 2H), 4.13
(app s, 4H), 2.71 (s, 6H), 2.14 (dh, J=6.06, 6.89 Hz,
2H), 0.92 (d, J=6.89 Hz, 6H), 0.86 (d, J=6.89 Hz, 6H);
13C NMR (CDCl3/CD3OD, 4:2) d 172.9, 172.8, 137.4,
129.1, 128.0, 128.7, 80.0, 73.4, 71.8, 58.9, 31.1, 26.3,
1
CHCl3/CH3OH, 10:1); H NMR (CDCl3/CD3OD, 4:2)
d 5.91 (dddd, J=2.80, 5.61, 10.35, 17.24 Hz, 2H), 5.31
(ddd, J=1.94, 3.67, 17.24 Hz, 2H), 5.21 (ddd, J=1.32,
2.80, 10.35 Hz, 2H), 4.22 (d, J=5.40 Hz, 2H), 4.18–4.01
(m, 6H), 3.95 (XX0 part of AA0XX0, 2H), 2.71 (s, 6H), 2.27
(dh, J=5.40, 6.89 Hz, 2H), 0.94 (d, J=6.89 Hz, 6H), 0.87
(d, J=6.89 Hz, 6H); 13C NMR (CDCl3/CD3OD, 4:2) d
172.7, 172.5, 134.0, 118.6, 80.5, 72.4, 72.3, 58.7, 30.4,
26.3,19.8, 17.6. Anal. calcdfor C 24H42N4O8: C, 56.01; H,
8.23; N, 10.89. Found: C, 56.0; H, 8.3; N, 10.7.
.
19.6, 17.9. Anal. calcdfor C 32H46N4O8 1/2H2O: C,
61.62; H, 7.60; N, 8.98. Found: C, 61.3; H, 7.4; N, 8.7.
(2S,3S,4S,5S)-N1,N6-Bis[(1S)-2-methyl-1-(methylcarb-
amoyl)propyl] - 2,5- di(benzyloxy) -3,4-dihydroxyhexane-
1,6-diamide (3e). The title compoundwas prepared
according to Method I, using 51 mg (0.14 mmol) of
bislactone 2c (stirring 10 h at room temperature and13
h at reflux). Purification by flash chromatography
(EtOAc/CH3OH, 50:1–10:1) provided product 3e (49
mg, 55%) as a white solid: [a]2D2 ꢀ47.4ꢄ (c 0.53, CHCl3/
(2R,3R,4R,5R)-N1,N6-Bis[(1R)-2-methyl-1-(methylcarb-
amoyl)propyl]-2,5-di(allyloxy)-3,4-dihydroxyhexane-1,6-
diamide (3d). The title compoundwas preparedaccord-
ing to MethodII, using 39 mg (0.71 mmol) of bislactone
2b andtotally 4 mL dry CH 2Cl2 (reflux 30 h). Purifica-
tion by SP-HPLC (CHCl3) gave ꢄproduct 3d (68 mg,
1
CH3OH, 10:1); H NMR (CDCl3/CD3OD, 4:2) d 7.36–
7.23 (m, 10H), 4.62 (d, J=11.22 Hz, 2H), 4.49 (d,
J=11.22 Hz, 2H), 4.23 (d, J=6.02 Hz, 2H), 4.01 (app s,
4H), 2.71 (s, 6H), 2.15 (dh, J=6.02, 6.89 Hz, 2H), 0.92
(d, J=6.89 Hz, 6H), 0.87 (d, J=6.89 Hz, 6H); 13C
NMR (CDCl3/CD3OD, 4:2) d 172.9, 172.7, 137.3,
129.1, 128.9, 128.7, 80.0, 73.4, 71.7, 58.9, 31.1, 26.3,
1
86%) as a white solid: [a]2D1 +73.1 (c 0.50, CHCl3); H
NMR (CDCL3/CD3OD, 4:2) d 5.89 (dddd, J=2.89,
5.86, 10.35, 17.24 Hz, 2H), 5.28 (ddd, J=1.57, 3.13,
17.24 Hz, 2H), 5.19 (ddd, J=1.32, 2.80, 10.35 Hz, 2H),
4.24 (d, J=6.02 Hz, 2H), 4.14–3.97 (m, 4H), 3.95 (app s,
4H), 2.72 (s, 6H), 2.16 (dh, J=6.02, 6.85 Hz, 2H), 0.93
(d, J=6.85 Hz, 6H), 0.88 (d, J=6.85 Hz, 6H); 13C
NMR (CDCL3/CD3OD, 4:2) d 172.9, 172.7, 134.0,
118.9, 79.8, 72.4, 71.6, 58.8, 31.0, 26.2, 19.6, 17.8. Anal.
calcdfor C 24H42N4O8: C, 56.01; H, 8.23; N, 10.89.
Found: C, 55.7; H, 8.1; N, 10.8.
.
19.6, 17.9. Anal. calcdfor C 32H46N4O8 11/2H2O: C,
59.89; H, 7.70; N, 8.73. Found: C, 59.6; H, 7.3; N, 8.4.
(2S,3S,4S,5S)-N1,N6-Bis[(1R)-2-methyl-1-(methylcarb-
amoyl)propyl] - 2,5- di(benzyloxy) -3,4-dihydroxyhexane-
1,6-diamide (3f). The title compoundwas prepared
according to Method I, using 51 mg (0.15 mmol) of
bislactone 2c (stirring 21 h at room temperature and11
h at reflux). Purification by SP-HPLC (CHCl3 to
CHCl3/CH3OH, 50:1) gave product 3f (42 mg, 47%) as
a white solid: [a]D22 +3.9ꢄ (c 0.58, CHCl3/CH3OH, 10:1);
1H NMR (CDCl3/CD3OD, 4:2) d 7.37–7.24 (m, 10H),
4.65 (d, J=11.55 Hz, 2H), 4.58 (d, J=11.55 Hz, 2H), 4.21
(d, J=5.57 Hz, 2H), 4.14 (AA0 part of AA0XX0, 2H), 4.05
(XX0 part of AA0XX0, 2H), 2.69 (s, 6H), 2.24 (dh, J=5.57,
6.85 Hz, 2H), 0.90 (d, J=6.85 Hz, 6H), 0.82 (d, J=6.85
Hz, 6H); 13C NMR (CDCl3/CD3OD, 4:2) d 172.6, 172.4,
137.4, 129.1, 128.8, 128.6, 80.7, 73.4, 72.3, 58.7, 30.5, 26.3,
(2S,3S,4S,5S)-N1,N6-Bis[(1S)-2-methyl-1-(methylcarb-
amoyl)propyl]-2,5-di(allyloxy)-3,4-dihydroxyhexane-1,6-
diamide (3g). The title compoundwas preparedaccord-
ing to MethodII, using 17 mg (0.067 mmol) of bislac-
tone 2dandtotally 4 mL dry CH
2Cl2 (reflux 50 h).
Purification by SP-HPLC (CHCl3 to CHCl3/CH3OH,
50:1) gave product 3g (26 mg, 75%) as a white solid:
[a]2D1 ꢀ73.1ꢄ (c 0.50, CHCl3); 1H NMR (CDCl3/
CD3OD, 4:2) d 5.89 (dddd, J=2.89, 5.90, 10.35, 17.24
Hz, 2H), 5.28 (ddd, J=1.53, 3.09, 17.24 Hz, 2H), 5.19
(ddd, J=1.32, 2.80, 10.35 Hz, 2H), 4.24 (d, J=6.02 Hz,
2H), 4.14–3.98 (m, 4H), 3.96 (app s, 4H), 2.72 (s, 6H),
2.16 (dh, J=6.06, 6.85 Hz, 2H), 0.93 (d, J=6.85 Hz,
6H), 0.89 (d, J=6.85 Hz, 6H); 13C NMR (CDCl3/
CD3OD, 4:2) d 173.0, 172.8, 134.1, 118.9, 79.8, 72.4,
71.7, 58.8, 31.1, 26.3, 19.6, 17.8. Anal. calcdfor
.
19.8, 17.7. Anal. calcdfor C 32H46N4O8 1/2H2O: C, 61.62;
H, 7.60; N, 8.98. Found: C, 61.3; H, 7.4; N, 8.7.
General procedure for preparation of the compounds 3c–d,
3g–h
.
C24H42N4O8 1/4H2O: C, 55.53; H, 8.25; N, 10.79.
Found: C, 55.3; H, 8.1; N, 10.5.
Method II. Bislactone 2b or 2d was dissolved in dry
CH2Cl2 under a nitrogen atmosphere. Four equivalents
of d- or l-valine methylamide in dry CH2Cl2 was added
andthe reaction mixture was stirredat reflux for 21–50
h. Concentration under reduced pressure and different
workup procedures gave the pure products 3c–d, 3g–h.
(2S,3S,4S,5S)-N1,N6-Bis[(1R)-2-methyl-1-(methylcarb-
amoyl)propyl]-2,5-di(allyloxy)-3,4-dihydroxyhexane-1,6-
diamide (3h). The title compoundwas preparedaccord-
ing to MethodII, using 47 mg (0.19 mmol) of bislactone