1570 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 6
J ames et al.
Observed m/z 713.2811. Anal. Calcd for C33H40N6O12‚1.0 H2O:
(2S ,3S )-3-(N 2-(N -B e n zy lo x y c a r b o n y lis o le u c y lg lu -
t a m ylt h r eon yl)-N1-ca r b oxym et h ylh yd r a zin oca r b on yl)-
oxir a n e-2-ca r boxylic Acid Eth yl Ester (Cbz-Ile-Glu -Th r -
AAsp -(2S,3S)-EP -COOEt, 27c). 1H NMR (DMSO-d6): 0.8 (m,
6H, Ile CH3), 1-1.2 (m, 4H, Thr CH3 and Ile CH2), 1.2 (t, 3H,
OCH2CH3), 1.4 (m, 1H, Ile CH2), 1.6-1.8 (m, 2H, CH Ile and
Glu CH2), 1.8-1.9 (m, 1H, Glu CH2), 2.1-2.3 (m, 2H, Glu CH2),
3.5 (d, 1H, epoxy), 3.85-4.05 (m, 3H, NCH2COOH and CH-
OH), 4.1 (d, 1H, epoxy), 4.1-4.3 (m, 3H, OCH2CH3 and R-H),
4.3-4.45 (m, 2H, R-H), 4.6 (m, 1H, NH), 4.9 (m, 1H, NH), 5.05
(m, 2H, Cbz), 7.30-7.40 (m, 5H, Ph), 7.80 (m, 1H, NH), 8.1
(m, 1H, NH), 11.00 (m, COOH). HRMS (FAB) Calcd for
C, 54.21; H, 5.68; N, 11.34. Found: C, 54.24; H, 5.79; N, 10.50.
(2R,3R)-3-(N2-(N-Ben zyloxyca r b on ylleu cylglu t a m yl-
th r eon yl)-N1-car boxym eth ylh ydr azin ocar bon yl)oxir an e-2-
ca r boxylic Acid Eth yl Ester (Cbz-Leu -Glu -Th r -AAsp -
1
(2R,3R)-EP -COOEt, 26c). H NMR (DMSO-d6): 0.82 (t, 6H,
Leu CH3), 1.0 (d, 3H, Thr CH3), 1.2 (t, 3H, OCH2CH3), 1.4 (m,
2H, Leu CH2), 1.6 (m, 1H, CH Leu), 1.78 (m, 1H, Glu CH2),
1.9 (m, 1H, Glu CH2), 2.25 (m, 2H, Glu), 3.5 (s, 1H, epoxy),
3.9-4.0 (m, 1H, R-H), 4.0-4.1 (m, 3H, NCH2COOH, epoxy),
4.1-4.2 (m, 3H, OCH2CH3 and CH-OH), 4.32-4.41 (m, 2H,
R-H), 5.05 (m, 2H, Cbz), 7.30-7.40 (m, 5H, Ph), 7.45 (d, 1H,
NH), 7.80 (m, 1H, NH), 8.05 (m, 1H, NH), 11.00 (m, COOH).
HRMS (FAB) Calcd for C31H44N5O14: 710.28848. Observed m/z
710.29480. Anal. Calcd for C31H43N5O14‚H2O: C, 51.17; H, 6.19;
N, 9.63. Found: C, 51.33; H, 6.02; N, 9.66.
C
31H44N5O14: 710.28848. Observed m/z 710.29205. Anal. Calcd
for C31H43N5O14‚2H2O: C, 49.93; H, 6.31; N, 9.40. Found: C,
49.71; H, 6.12; N, 9.42.
(2S,3S)-3-(N2-(N-Ben zyloxyca r bon ylisoleu cylglu ta m yl-
th r eon yl)-N1-car boxym eth ylh ydr azin ocar bon yl)oxir an e-2-
ca r boxylic Acid Ben zyl Ester (Cbz-Ile-Glu -Th r -AAsp -
(2S,3S)-EP -COOCH2P h , 27d ). 1H NMR (DMSO-d6): 0.8 (m,
6H, Ile CH3), 0.9-1.2 (m, 4H, Thr CH3 and Ile CH2), 1.3-1.5
(m, 1H, Ile CH2), 1.6-1.8 (m, 2H, CH Ile and Glu CH2), 1.8-
2.0 (m, 1H, Glu CH2), 2.2-2.3 (m, 2H, Glu CH2), 3.55 (d, 1H,
epoxy), 3.9-4.0 (m, 3H, NCH2COOH and CH-OH), 4.05 (d, 1H,
epoxy), 4.2 (m, 1H, R-H), 4.4 (m, 2H, R-H), 4.95 (m, 1H, NH),
5-5.05 and 5.1-5.2 (m, 4H, Cbz), 7.20-7.40 (m, 10H, Ph), 7.80
(m, 1H, NH), 8.1 (m, 1H, NH), 11.00 (m, COOH). HRMS (FAB)
Calcd for C36H46N5O14: 772.30413. Observed m/z 772.30898.
Anal. Calcd for C36H45N5O14‚H2O: C, 54.75; H, 5.96; N, 8.87.
Found: C, 54.97; H, 5.80; N, 8.91.
(2R ,3R )-3-(N 2-(N -B e n zy lo x y c a r b o n y lis o le u c y lg lu -
t a m ylt h r eon yl)-N1-ca r b oxym et h ylh yd r a zin oca r b on yl)-
oxir a n e-2-ca r boxylic Acid Ben zyl Ester (Cbz-Ile-Glu -
Th r -AAsp -(2R,3R)-EP -COOCH2P h , 27d ). 1H NMR (DMSO-
d6): 0.7-0.9 (m, 6H, Ile CH3), 0.9-1.2 (m, 4H, Thr CH3 and
Ile CH2), 1.4 (m, 1H, Ile CH2), 1.6-1.8 (m, 2H, CH Ile and
Glu CH2), 1.8-2.0 (m, 1H, Glu CH2), 2.2-2.35 (m, 2H, Glu
CH2), 3.55-3.6 (d, 1H, epoxy), 3.8-4.0 (m, 3H, NCH2COOH
and CH-OH), 4.05 (d, 1H, epoxy), 4.15 (m, 1H, R-H), 4.3-4.5
(m, 2H, R-H), 4.9-5.1 and 5.1-5.3 (m, 4H, Cbz), 7.20-7.50
(m, 10H, Ph), 7.7-7.9 (m, 1H, NH), 8-8.15 (m, 1H, NH), 11.00
(m, COOH). HRMS (FAB) Calcd for C36H46N5O14: 772.30413.
Observed m/z 772.30837. Anal. Calcd for C36H45N5O14‚H2O: C,
54.75; H, 5.96; N, 8.87. Found: C, 54.51; H, 5.82; N, 8.82.
(2R,3R)-2-(2-Ben zylca r ba m oyl)-3-(N2-(N-ben zyloxyca r -
bon ylisoleu cylglu ta m ylth r eon yl)-N1-ca r boxym eth ylh y-
dr azin ocar bon yl)oxir an e (Cbz-Ile-Glu -Th r -AAsp-(2R,3R)-
EP -CONHCH 2P h , 27g). 1H NMR (DMSO-d6): 0.7-0.9 (m,
6H, Ile CH3), 0.9-1.15 (m, 4H, Thr CH3 and Ile CH2), 1.4 (m,
1H, Ile CH2), 1.65-1.8 (m, 2H, CH Ile and Glu CH2), 1.8-2.0
(m, 1H, Glu CH2), 2.2-2.3 (m, 2H, Glu CH2), 3.5 (d, 1H, epoxy),
3.8-4.0 (m, 3H, NCH2COOH and CH-OH), 4.03 (d, 1H, epoxy),
4.1-4.2 (m, 1H, R-H), 4.3-4.4 (m, 2H, NHCH2Ph), 4.4 (m, 2H,
R-H), 4.9-5.1 (m, 2H, Cbz), 7.15-7.40 (m, 10H, Ph), 7.85 (m,
1H, NH), 8.05 (m, 1H, NH), 11.00 (m, COOH). HRMS (FAB)
Calcd for C36H47N6O13: 771.32011. Observed m/z 771.33322.
Anal. Calcd for C36H46N6O13‚1.25H2O: C, 54.51; H, 6.12; N,
10.60. Found: C, 54.30; H, 6.04; N, 10.36.
(2R ,3R )-3-(N 2-(N -B e n zy lo x y c a r b o n y lis o le u c y lg lu -
t a m ylt h r eon yl)-N1-ca r b oxym et h ylh yd r a zin oca r b on yl)-
oxir a n e-2-ca r boxylic Acid Eth yl Ester (Cbz-Ile-Glu -Th r -
AAsp -(2R,3R)-EP -COOEt, 27c). 1H NMR (DMSO-d6): 0.8 (m,
6H, Ile CH3), 1.0 (d, 3H, Thr CH3), 1-1.2 and 1.4 (m, 2H, Ile
CH2), 1.2 (t, 3H, OCH2CH3), 1.65-1.8 (m, 2H, CH Ile and Glu
CH2), 1.8-2.0 (m, 1H, Glu CH2), 2.1-2.3 (m, 2H, Glu CH2),
3.5 (d, 1H, epoxy), 3.8-4.0 (m, 3H, NCH2COOH and CH-OH),
4.05 (d, 1H, epoxy), 4.1-4.23 (m, 3H, OCH2CH3 and R-H), 4.3-
4.45 (m, 2H, R-H), 5.05 (m, 2H, Cbz), 7.30-7.40 (m, 5H, Ph),
7.80 (m, 1H, NH), 8.1 (m, 1H, NH), 11.00 (m, COOH). HRMS
(2S,3S)-3-(N2-(N-Ben zyloxyca r b on ylleu cylglu t a m yl-
th r eon yl)-N1-car boxym eth ylh ydr azin ocar bon yl)oxir an e-2-
ca r boxylic Acid Eth yl Ester (Cbz-Leu -Glu -Th r -AAsp -
1
(2S,3S)-EP -COOEt, 26c). H NMR (DMSO-d6): 0.85 (t, 6H,
Leu CH3), 1.05 (d, 3H, Thr CH3), 1.2 (t, 3H, OCH2CH3), 1.4
(m, 2H, Leu CH2), 1.6 (m, 1H, CH Leu), 1.77 (m, 1H, Glu CH2),
1.9 (m, 1H, Glu CH2), 2.3 (m, 2H, Glu CH2), 3.5 (s, 1H, epoxy),
3.9-4.1 (m, 4H, NCH2COOH, epoxy, R-H), 4.1-4.3 (m, 3H,
OCH2CH3 and CH-OH), 4.3-4.4 (m, 2H, R-H), 4.95 (m, 1H,
NH), 5.02 (m, 2H, Cbz), 7.30-7.40 (m, 5H, Ph), 7.50 (d, 1H,
NH), 7.78 (m, 1H, NH), 8.05 (m, 1H, NH), 11.00 (m, COOH).
HRMS (FAB) Calcd for C31H44N5O14: 710.28848. Observed m/z
710.28450. Anal. Calcd for C31H43N5O14‚1.25H2O: C, 50.85; H,
6.22; N, 9.57. Found: C, 50.74; H, 6.27; N, 9.67.
(2S,3S)-3-(N2-(N-Ben zyloxyca r b on ylleu cylglu t a m yl-
th r eon yl)-N1-car boxym eth ylh ydr azin ocar bon yl)oxir an e-2-
ca r boxylic Acid Ben zyl Ester (Cbz-Leu -Glu -Th r -AAsp -
(2S,3S)-EP -COOCH2P h , 26d ). 1H NMR (DMSO-d6): 0.7-0.9
(t, 6H, Leu CH3), 0.9-1.1 (d, 3H, Thr CH3), 1.3-1.5 (m, 2H,
Leu CH2), 1.6-1.7 (m, 1H, CH Leu), 1.7-1.8 (m, 1H, Glu CH2),
1.8-2.0 (m, 1H, Glu CH2), 2.2-2.35 (m, 2H, Glu CH2), 3.6 (s,
1H, epoxy), 3.9-4.1 (m, 4H, NCH2COOH, epoxy, R-H), 4.1-
4.3 (m, 1H, CH-OH), 4.3-4.4 (m, 2H, R-H), 4.95 (m, 1H, NH),
4.95-5.05 and 5.1-5.3 (m, 4H, Cbz), 7.20-7.50 (m, 10H, Ph),
7.78 (m, 1H, NH), 8.05 (m, 1H, NH), 11.00 (m, COOH). HRMS
(FAB) Calcd for
C36H46N5O14: 772.30413. Observed m/z
772.30610. Anal. Calcd for C36H46N5O14‚H2O: C, 54.75; H, 5.96;
N, 8.87. Found: C, 54.78; H, 5.94; N, 8.87.
(2S,3S)-2-(2-P h en eth ylca r ba m oyl)-3-(N2-(N-ben zyloxy-
ca r bon ylleu cylglu ta m ylth r eon yl)-N1-ca r boxym eth ylh y-
dr azin ocar bon yl)oxir an e (Cbz-Leu -Glu -Th r -AAsp-(2S,3S)-
EP -CONHCH2CH2P h , 26h ). 1H NMR (DMSO-d6): 0.83 (t,
6H, Leu CH3), 1.00 (m, 3H, Thr CH3), 1.40 (m, 2H, Leu CH2),
1.60 (m, 1H, Leu CH), 1.75 and 1.90 (d of m, 2H, Glu CH2),
2.23 (m, 2H, Glu CH2), 2.71 (t, 2H, CH2Ph), 3.32 (s, 2H, AAsp
CH2), 3.43 and 3.52 (d, 2H, epoxy), 3.92 (b, 2H, R-H), 4.02 (b,
1H, R-H), 4.19 (m, 1H, Thr CH), 4.34 (m, 2H, NCH2), 4.99 (s,
2H, Z), 7.15-7.35 (m, 10H, Ph), 7.40 (d, 1H, NH), 7.78 (b, 1H,
NH), 8.00 (b, 1H, NH), 8.15 (s, 1H, NH), 8.20 (b, 1H, NH),
10.80 (b, 2H. COOH). HRMS (FAB) Calcd for C37H49N6O13
:
785.3358. Observed m/z 785.3400. Anal. Calcd for C37H48N6O13‚
H2O: C, 55.35; H, 6.28; N, 10.47. Found: C, 54.96; H, 6.13; N,
10.21.
(2S,3S)-2-(1-Ben zylca r b a m oylet h ylca r b a m oyl)-3-(N2-
(N-b en zyloxyca r b on ylleu cylglu t a m ylt h r eon yl)-N1-ca r -
boxym eth ylh yd r a zin oca r bon yl)oxir a n e (Cbz-Leu -Glu -
Th r -AAsp-(2S,3S)-EP -CO-Ala-NHBzl, 26j). 1H NMR (DMSO-
d6): 0.83 (t, 6H, Leu CH3), 0.99 (d, 3H, Thr CH3), 1.25 (d, 3H,
Ala CH3), 1.39 (m, 2H, Leu CH2), 1.60 (m, 1H, Leu CH), 1.75
and 1.90 (d of m, 2H, Glu CH2), 2.24 (m, 2H, Glu CH2), 3.32
(s, 2H, AAsp CH2), 3.56 and 3.64 (d, 2H, epoxy), 3.95 (b, 1H,
R-H), 4.02 (b, 2H, R-H), 4.19 (m, 1H, R-H), 4.26 (d, 1H, Thr
CH), 4.35 (m, 2H, CH2Ph), 4.99 (s, 2H, Z), 7.15-7.35 (m, 11H,
Ph and NH), 7.40 (d, 1H, NH), 7.75 (b, 1H, NH), 8.05 (d, 1H,
NH), 8.45 (m, 2H, NH), 10.85 (b, 2H. COOH). HRMS (FAB)
(FAB) Calcd for
C31H44N5O14: 710.28848. Observed m/z
710.28779. Anal. Calcd for C31H43N5O14‚1H2O: C, 51.17; H,
6.19; N, 9.63. Found: C, 51.07; H, 6.10; N, 9.55.
(2S,3S)-2-(1-Ben zylca r b a m oylet h ylca r b a m oyl)-3-(N2-
(N-ben zyloxycar bon ylisoleu cylglu tam ylth r eon yl)-N1-car -
b oxym et h ylh yd r a zin oca r b on yl)oxir a n e (Cb z-Ile-Glu -
Calcd for C39H52N7O14
:
842.3572. Observed m/z 842.3336.
Anal. Calcd for C39H51N7O14‚H2O: C, 54.48; H, 6.21; N, 11.40.
Found: C, 53.83; H, 5.96; N, 11.10.