J. Humljan et al. / Tetrahedron 62 (2006) 10980–10988
10987
NHCH), 9.35 (s, 1H, Ar-NHCO); IR (KBr, cmꢂ1): 3283.9,
1736.5, 1669.9, 1536.0, 1455.0, 1120.9, 753.4; FABMS:
m/z¼488 (M+H).
(m, 1H, CHCO), 7.40–8.00 (m, 11H, Ar-H+2ꢃNH); IR
(KBr, cmꢂ1): 3288.0, 1714.9, 1312.9, 1159.4, 982.5,
765.1, 674.4, 574.8; FABMS: m/z¼486 (M+H)+; Anal.
Calcd for C20H24N2O8S2: C (49.58%), H (4.99%), N
(5.78%). Found: C (49.20%), H (5.10%), N (5.50%).
5.6.2. Dimethyl N-[((2S)-2-{[(E)-3-(1,3-benzodioxol-5-
yl)-2-propenoyl]amino}propyl)sulfonyl]-D-glutamate
(20). Colourless oil (150 mg, 38%): Rf¼0.13 (CHCl3/
acetone¼5/1); [a]D23 +30.0 (c 0.140, MeOH); 1H NMR
(300 MHz, DMSO): d 1.25 (d, 3H, J¼6.8 Hz, CHCH3),
1.73–1.88 (m, 1H, CH2CH2CO), 1.92–2.05 (m, 1H,
CH2CH2CO), 2.38–2.45 (m, 2H, CH2CH2CO), 3.09–3.29
(m, 2H, CH2SO2), 3.58 (s, 3H, COOCH3), 3.66 (s, 3H,
COOCH3), 3.96–4.06 (m, 1H, CHCO), 4.24–4.36 (m, 1H,
CHCH3), 6.07 (s, 2H, OCH2O), 6.41 (d, 1H, J¼15.8 Hz,
CHCHCO), 6.95 (d, 1H, J¼7.9 Hz, Ar-H), 7.07 (dd, 1H,
J¼7.9, 1.5 Hz, Ar-H), 7.14 (d, 1H, J¼1.5 Hz, Ar-H), 7.34
(d, 1H, J¼15.8 Hz, CHCHCO), 7.86 (d, 1H, J¼8.7 Hz,
NH), 8.07 (d, 1H, J¼7.9 Hz, NH); IR (KBr, cmꢂ1): 3276.8,
2953.3, 1735.8, 1654.6, 1616.2, 1491.1, 1447.4, 1251.2,
1148.1, 1037.5, 981.1; FABMS: m/z¼471 (M+H)+; Anal.
Calcd for C20H26N2O9S: C (51.06%), H (5.57%), N
(5.95%). Found: C (51.14%), H (5.76%), N (5.86%).
5.7.3. N-{[(2S)-2-({2-[2-(Acetylamino)phenoxy]acetyl}-
amino)propyl]sulfonyl}-D-glutamic acid (23). White solid
(125 mg, 88%): Rf¼0.71 (CH3CN/MeOH/H2O¼3/1/1); mp
108–111 ꢀC; [a]2D3 +22.6 (c 0.248, MeOH); 1H NMR
(300 MHz, DMSO): d 1.22 (d, 3H, J¼6.8 Hz, CHCH3),
1.66–1.82 (m, 1H, CH2CH2CO), 1.90–2.04 (m, 1H,
CH2CH2CO), 2.11 (s, 3H, CH3CO), 2.25–2.37 (m, 2H,
CH2CH2CO), 3.10–3.29 (m, 2H, CH2SO2), 3.82–3.94 (m,
1H, CHCO), 4.24–4.39 (m, 1H, CHCH3), 4.51 (s, 2H,
OCH2CO), 6.89–7.12 (m, 4H, Ar-H), 7.85 (d, 1H, J¼7.5 Hz,
SO2NH), 8.45 (m, 1H, CONH), 9.45 (s, 1H, Ar-NHCO); IR
(KBr, cmꢂ1): 3386.0, 3224.1, 1717.1, 1652.0, 1536.9,
1263.4, 1158.9, 1050.2, 746.9; FABMS: m/z¼460 (M+H)+;
Anal. Calcd for C18H25N3O9S: C (47.05%), H (5.48%), N
(9.15%). Found: C (47.18%), H (5.59%), N (8.76%).
5.7.4. N-[((2S)-2-{[(E)-3-(1,3-Benzodioxol-5-yl)-2-prope-
noyl]amino}propyl)sulfonyl]-D-glutamic acid (24). White
solid (130 mg, 93%): Rf¼0.71 (CH3CN/MeOH/H2O¼3/1/
1); mp 115–118 ꢀC; [a]2D3 +51.6 (c 0.266, MeOH); 1H
NMR (300 MHz, DMSO): d 1.25 (d, 3H, J¼6.8 Hz,
CHCH3), 1.73–1.88 (m, 1H, CH2CH2CO), 1.92–2.05 (m,
1H, CH2CH2CO), 2.38–2.45 (m, 2H, CH2CH2CO), 3.09–
3.29 (m, 2H, CH2SO2), 3.96–4.06 (m, 1H, CHCO), 4.24–
4.36 (m, 1H, CHCH3), 6.07 (s, 2H, OCH2O), 6.41 (d, 1H,
J¼15.8 Hz, CHCHCO), 6.95 (d, 1H, J¼7.9 Hz, Ar-H),
7.07 (dd, 1H, J¼7.9, 1.5 Hz, Ar-H), 7.14 (d, 1H, J¼1.5 Hz,
Ar-H), 7.34 (d, 1H, J¼15.8 Hz), 7.86 (d, 1H, J¼8.7, NH),
8.07 (d, 1H, J¼7.9 Hz, NH); IR (KBr, cmꢂ1): 3314.7,
2965.9, 1717.1, 1653.6, 1525.9, 1448.1, 1338.5, 1252.6,
1123.9, 1038.2, 927.8; FABMS: m/z¼443 (M+H)+; Anal.
Calcd for C18H22N2O9S: C (48.86%), H (5.01%), N
(6.33%). Found: C (49.20%), H (5.41%), N (5.96%).
5.7. General procedure for the preparation of peptido-
sulfonamide inhibitors 21–24. Alkaline hydrolysis of
esters
To a stirred solution of dimethyl-protected peptidosulfon-
amide 17–20 (0.4 mmol) in dioxane (2 mL), 1 M NaOH
(2 mL) was added, and the reaction mixture was stirred over-
night at rt. After the solventwas removed under reduced pres-
sure, the oily residue was redissolved in H2O (20 mL) and
washed with EtOAc (2ꢃ20 mL). The aqueous phase was
acidified to pH 1–2 using an aqueous solution of 2 M HCl,
and extracted with EtOAc (3ꢃ15 mL). The combined
organic layers were washed with brine (1ꢃ20 mL), dried
over Na2SO4, filtered and evaporatedunder reduced pressure.
5.7.1. N-({(2S)-2-[(2-Naphthylsulfonyl)amino]propyl}-
sulfonyl)-D-glutamic acid (21). White solid (160 mg,
92%): Rf¼0.72 (CH3CN/MeOH/H2O¼3/1/1); mp 246–
248 ꢀC; [a]2D3 ꢂ44.5 (c 0.297, MeOH); 1H NMR
(300 MHz, DMSO): d 1.06 (d, 3H, J¼6.4 Hz, CHCH3),
1.62–1.77 (m, 1H, CH2CH2CO), 1.82–1.99 (m, 1H,
CH2CH2CO), 2.26 (t, 2H, J¼7.4 Hz, CH2CH2CO), 3.07
(dd, 1H, J¼13.9, 9.0 Hz, CH2SO2), 3.20 (dd, 1H, J¼13.9,
4.0 Hz, CH2SO2), 3.58–3.73 (m, 1H, CHCH3), 3.80–3.91
(m, 1H, CHCO), 7.63–8.22 (m, 8H, Naph-H+2ꢃNH), 8.47
(s, 1H, Naph-H), 12.55 (br s, 2H, 2ꢃCOOH); IR (KBr,
cmꢂ1): 3288.9, 1706.1, 1420.5, 1314.5, 1216.7, 1156.2,
987.9, 821.0, 666.1; FABMS: m/z¼457 (MꢂH)ꢂ; Anal.
Calcd for C18H22N2O8S2: C (47.15%), H (4.84%), N
(6.11%). Found: C (47.05%), H (4.94%), N (6.22%).
5.8. General procedure for the preparation of peptido-
sulfonamide inhibitors 14, 15
BBTO cleavage: to a stirred solution of BBTO (3.0 mmol) in
toluene (20 mL), dimethyl-protected peptidosulfonamide 12,
13 (1.0 mmol) was added. The mixture was refluxed for 48 h
and the solvent evaporated under reduced pressure. The
resulting oil was dissolved in EtOAc (30 mL) and washed
with 5% aqueous NaHCO3 (3ꢃ20 mL). The aqueous phase
was acidified to pH 2–3 using an aqueous solution of 2 M
HCl, and extracted with EtOAc (3ꢃ15 mL). The combined
organic layers were washed with brine (1ꢃ20 mL), dried
over Na2SO4, filtered and evaporated under reduced pressure.
5.7.2. N-({(2S)-2-[([1,10-Biphenyl]-4-yl-sulfonyl)amino]-
propyl}sulfonyl)-D-glutamic acid (22). White solid
(170 mg, 92%): Rf¼0.76 (CH3CN/MeOH/H2O¼3/1/1);
5.8.1. N-{[(2S)-2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-
2-yl)propyl]sulfonyl}-D-glutamic acid (14). Colourless oil
(380 mg, 82%): Rf¼0.60 (CH3CN/MeOH/H2O¼3/1/1);
[a]2D3 +34.5 (c 0.330, MeOH); 1H NMR (300 MHz,
DMSO): d 1.46 (d, 3H, J¼6.8 Hz, CH3), 1.65–1.79 (m, 1H,
CH2CH2CO), 1.92–2.05 (m, 1H, CH2CH2CO), 2.25–2.37
(m, 2H, CH2CH2CO), 3.46 (dd, 1H, J¼14.3, 4.7 Hz,
CH2SO2), 3.80 (dd, 1H, J¼14.3, 9.0 Hz, CH2SO2), 3.85–
3.93 (m, 1H, CHCO), 4.66–4.80 (m, 1H, CHCH3), 7.75 (d,
1
mp 201–203 ꢀC; [a]D23 ꢂ50.1 (c 0.316, MeOH); H NMR
(300 MHz, DMSO): d 1.11 (d, 3H, J¼6.8 Hz, CHCH3),
1.63–1.81 (m, 1H, CH2CH2CO), 1.86–2.02 (m, 1H,
CH2CH2CO), 2.23–2.33 (m, 2H, CH2CH2CO), 3.07 (dd,
1H, J¼13.9, 9.4 Hz, CH2SO2), 3.23 (dd, 1H, J¼13.9,
3.8 Hz, CH2SO2), 3.58–3.71 (m, 1H, CHCH3), 3.79–3.89