1736 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 7
Kozikowski et al.
method D. [R]D +11.7° (c 0.33, MeOH); 1H NMR (D2O) δ 7.26-
7.15 (m, 10H), 4.32-4.28 (m, 2H), 2.98-2.75 (m, 6H), 2.20-
2.11 (m, 2H), 1.72-1.61 (m, 2H); 13C NMR (D2O) δ 178.49,
176.32, 160.30, 140.39, 130.30, 129.57, 127.60, 53.00, 45.41,
39.78, 35.75.
(2S,2′S,4S,4′S)-N,N′-Ca r b on yl-4,4′-d im et h yld iglu t a m -
ic Acid Tetr a ben zyl Ester (10c). 10c was synthesized from
9c according to method C. 1H NMR δ 7.36-7.26 (m, 20H),
5.14-4.98 (m, 10H), 4.55 (dt, 2H, J ) 4.8, 13.2 Hz), 2.65-
2.54 (m, 2H), 2.10-2.00 (m, 2H), 1.93-1.85 (m, 2H), 1.19 (d,
6H, J ) 6.9 Hz); 13C NMR δ 176.06, 172.75, 156.70, 135.89,
135.22, 128.56, 128.54, 128.37, 128.20, 128.11, 67.19, 66.42,
51.54, 36.32, 35.92, 17.11.
(s, 2H), 4.34 (m, 1H), 2.84-2.66 (m, 2H), 2.30 (m, 1H), 2.05
(m, 1H), 1.41 (s, 9H); 13C NMR δ 171.48, 154.00, 134.96, 133.10,
129.20, 128.92, 128.61, 128.56, 128.37, 127.48, 79.95, 67.40,
52.83, 50.67, 29.77, 28.20, 19.81.
(S,S)-4,4′-Bis(1-ben zyl-1H-tetr a zol-5-yl)-2,2′-u r eylen e-
d ibu tyr ic Acid Diben zyl Ester (19). 19 was synthesized
from 18 according to method C. 1H NMR δ 7.30-7.12 (m, 20H),
6.36 (d, 2H, J ) 8.4 Hz), 5.39, 5.33 (AB, 4H, J ) 15.6 Hz),
5.04 (s, 4H), 4.58-4.51 (m, 2H), 2.89-2.72 (m, 4H), 2.35-2.24
(m, 2H), 2.17-2.05 (m, 2H); 13C NMR δ 172.11, 157.45, 154.38,
135.09, 133.14, 129.05, 128.74, 128.47, 128.30, 128.02, 127.64,
67.06, 52.47, 50.55, 29.39, 19.79.
(S)-4-[(ter t-Bu toxycar bon yl)am in o]-4-[1-(2-cyan oeth yl)-
1H-tetr a zol-5-yl]bu tyr ic Acid Ben zyl Ester . This com-
pound was prepared from N-Boc-glutamic acid R-benzyl ester
and 3-aminopropionitrile fumarate according to methods A and
(2S,2′S,4S,4′S)-N,N′-Ca r b on yl-4,4′-d im et h yld iglu t a m -
ic Acid (5c). 5c was synthesized from 10c according to method
1
D. [R]D +8.0° (c 0.21, MeOH); H NMR (D2O) δ 4.27 (dd, 2H,
1
J ) 4.8, 9.6 Hz), 2.60 (dt, 2H, J ) 6.6, 21.0 Hz), 2.11-1.90 (m,
4H), 1.18 (d, 6H, J ) 6.6 Hz); 13C NMR (D2O) δ 181.17, 176.98,
159.39, 51.93, 36.69, 34.73, 16.40.
B. H NMR δ 7.35 (s, 5H), 5.71 (d, 1H, J ) 8.1 Hz), 5.19, 5.14
(AB, 1H, J ) 7.5 Hz), 5.11 (s, 2H), 4.80-4.64 (m, 2H), 3.06 (t,
2H, J ) 6.9 Hz), 2.70-2.43 (m, 2H), 2.37-2.30 (m, 2H); 13C
NMR δ 172.28, 155.61, 155.29, 135.37, 128.42, 128.18, 128.10,
115.91, 80.68, 66.47, 43.27, 42.45, 29.77, 28.31, 27.98, 18.21.
(S,S)-4,4′-Bis[1-(2-cyanoethyl)-1H-tetrazol-5-yl]-4,4′-ureyl-
en ed ibu tyr ic Acid Diben zyl Ester . This compound was
prepared from the preceding intermediate according to method
C. 1H NMR δ 7.40-7.25 (m, 10H), 6.52 (d, 2H, J ) 8.1 Hz),
5.29-5.21 (m, 2H), 5.08, 5.03 (AB, 4H, J ) 12.3 Hz), 4.76-
(S,S)-N,N′-Car bon yl-2,2′-dim eth yldiglu tam ic Acid Tetr a-
ben zyl Ester (10d ). 10d was synthesized from 9d according
to method C. 1H NMR δ 7.32-7.30 (m, 20H), 5.33 (s, 2H),
5.13-5.06 (m, 8H), 2.46-2.16 (m, 8H), 1.53 (s, 6H); 13C NMR
δ 174.28, 172.96, 155.24, 135.75, 135.50, 128.48, 128.45,
128.20, 128.16, 128.12, 128.08, 67.24, 66.30, 59.00, 32.11,
29.21, 23.53.
(S,S)-N,N′-Ca r bon yl-2,2′-d im eth yld iglu ta m ic Acid (5d ).
5d was synthesized from 10d according to method D. [R]D
+5.2° (c 0.57, MeOH); 1H NMR (D2O) δ 2.43-2.20 (m, 6H),
2.12-2.02 (m, 2H), 1.41 (s, 6H); 13C NMR (D2O) δ 178.57,
178.03, 157.56, 58.06, 31.46, 28.81, 22.70.
4.60 (m, 4H), 3.02 (t, 4H, J ) 6.9 Hz), 2.25-2.20 (m, 8H); 13
C
NMR δ 172.48, 156.70, 156.17, 135.51, 128.68, 128.49, 128.36,
116.01, 66.75, 42.90, 42.73, 30.01, 28.76, 18.41.
(S,S)-4,4′-Bis[1-(2-cyanoethyl)-1H-tetrazol-5-yl]-4,4′-ureyl-
en ed ibu tyr ic Acid (6a ). 6a was prepared from the preceding
intermediate according to method D. [R]D -31.2° (c 0.67,
(2S,2′S,4R)-4-Ben zyl-N,N′-ca r b on yld iglu t a m ic Acid
Tetr a ben zyl Ester (10e). 10e was synthesized from 5b and
1
MeOH); H NMR (D2O) δ 5.22 (t, 2H, J ) 7.2 Hz), 4.82-4.77
1
(m, 4H), 3.25 (t, 4H, J ) 6.6 Hz), 2.49 (t, 4H, J ) 6.9 Hz),
2.31-2.24 (m, 4H); 13C NMR (D2O) δ 177.19, 158.04, 156.75,
118.10, 43.63, 43.16, 30.02, 27.71, 18.00.
isocyanate 11. H NMR δ 7.36-6.99 (m, 25H), 5.16-4.98 (m,
10H), 4.63-4.49 (m, 2H), 2.93 (m, 1H), 2.84-2.67 (m, 2H),
2.47-2.10 (m, 4H), 1.93 (m, 1H), 1.77 (m, 1H); 13C NMR δ
174.43, 172.71, 172.59, 172.49, 156.42, 138.22, 135.73, 135.19,
128.95, 128.55, 128.53, 128.49, 128.42, 128.40, 128.36, 128.30,
128.16, 128.04, 126.47, 67.16, 67.09, 66.40, 66.38, 52.40, 51.70,
43.62, 38.33, 33.98, 30.16, 27.97.
(S,S)-4,4′-Di-(1H -t et r a zol-5-yl)-4,4′-u r eylen ed ib u t yr ic
Acid (6b). 6b was synthesized from 6a according to method
E. [R]D -26.0° (c 0.10, MeOH); 1H NMR (D2O) δ 5.16 (dd, 2H,
J ) 6.0, 9.0 Hz), 2.52 (t, 4H, J ) 6.9 Hz), 2.38-2.29 (m, 4H);
13C NMR (D2O) δ 177.10, 158.58, 158.37, 45.22, 29.94, 27.97.
(S)-2-[3-[(S)-3-(Ben zyloxycar bon yl)-1-[1-(2-cyan oeth yl)-
1H-tetr azol-5-yl]pr opyl]u r eido]pen tan edioic Acid Diben -
zyl Ester . This compound was prepared from (S)-4-[(tert-
butoxycarbonyl)amino]-4-[1-(2-cyanoethyl)-1H-tetrazol-5-
yl]butyric acid benzyl ester and isocyanate 11. 1H NMR δ
7.37-7.26 (m, 15H), 6.35 (d, 1H, J ) 9.0 Hz), 5.98 (d, 1H, J )
7.8 Hz), 5.36, 5.31 (AB, 1H, J ) 8.1 Hz), 5.18-5.08 (m, 4H),
5.00 (s, 2H), 4.80-4.58 (m, 2H), 4.45 (m, 1H), 2.95 (t, 2H, J )
6.6 Hz), 2.61-1.90 (m, 8H); 13C NMR δ 172.61, 172.53, 172.29,
156.79, 156.38, 135.69, 135.52, 135.20, 128.57, 128.55, 128.53,
128.39, 128.33, 128.28, 128.24, 128.13, 115.97, 67.18, 66.71,
66.36, 52.69, 42.70, 42.55, 30.13, 29.99, 28.92, 27.31, 18.34.
(S)-2-[3-[(S)-3-Ca r boxy-1-[1-(2-cya n oeth yl)-1H-tetr a zol-
5-yl]p r op yl]u r eid o]p en ta n ed ioic Acid (7a ). 7a was pre-
pared from the preceding intermediate according to method
D. [R]D +10.4° (c 0.25, MeOH); 1H NMR (D2O) δ 5.25 (dd, 1H,
J ) 6.6, 8.1 Hz), 4.82-4.77 (m, 2H), 4.16 (dd, 1H, J ) 5.1, 9.3
Hz), 3.24 (t, 2H, J ) 6.6 Hz), 2.62-2.49 (m, 6H), 2.14 (m, 1H),
1.92 (m, 1H); 13C NMR (D2O) δ 177.94, 177.52, 177.50, 158.82,
156.97, 118.23, 53.77, 43.72, 43.29, 30.64, 30.25, 27.95, 26.92,
18.14.
(S )-2-[3-[(S )-3-Ca r b oxy-1-(1H -t e t r a zol-5-yl)p r op yl]-
u r eid o]p en ta n ed ioic Acid (7b). 7b was synthesized from
7a according to method E. [R]D -18.8° (c 0.46, MeOH); 1H NMR
(D2O) δ 5.18 (dd, 1H, J ) 5.4, 9.0 Hz), 4.22 (dd, 1H, J ) 5.1,
9.0 Hz), 2.57-2.46 (m, 4H), 2.39-2.11 (m, 3H), 1.98 (m, 1H);
13C NMR (D2O) δ 177.69, 177.29, 176.66, 159.15, 158.65, 53.06,
45.33, 30.43, 30.09, 28.19, 26.46.
(S)-2-[3-[(S)-1-Ca r boxy-3-[1-(2-cya n oeth yl)-1H-tetr a zol-
5-yl]p r op yl]u r eid o]p en ta n ed ioic Acid (7c). 7c was syn-
thesized from 16 according to method D. [R]D +3.7° (c 0.21,
MeOH); 1H NMR (D2O) δ 4.72 (t, 2H, J ) 6.3 Hz), 4.31 (m,
1H), 4.24 (m, 1H), 3.19 (t, 2H, J ) 6.3 Hz), 3.10 (t, 2H, J ) 7.5
(2S,2′S,4R)-4-Ben zyl-N,N′-car bon yldiglu tam ic Acid (5e).
5e was synthesized from 10e according to method D. [R]D -3.2°
(c 0.22, MeOH); 1H NMR (D2O) δ 7.39-7.26 (m, 5H), 4.25-
4.18 (m, 2H), 3.00-2.87 (m, 3H), 2.49 (t, 2H, J ) 7.2 Hz), 2.27-
2.10 (m, 2H), 2.01-1.83 (m, 2H); 13C NMR (D2O) δ 179.26,
177.64, 176.80, 176.67, 159.22, 138.74, 129.20, 128.83, 126.96,
52.96, 52.09, 44.52, 38.25, 33.07, 30.29, 26.64.
(2S,2′S,4S)-N,N′-Ca r b on yl-4-m et h yld iglu t a m ic Acid
Tetr a ben zyl Ester (10f). 10f was synthesized from 5c and
1
isocyanate 11. H NMR δ 7.33-7.31 (m, 20H), 5.18-4.96 (m,
10H), 4.59-4.50 (m, 2H), 2.60 (m, 1H), 2.49-2.31 (m, 2H),
2.24-1.85 (m, 4H), 1.20 (d, 3H, J ) 6.9 Hz); 13C NMR δ 176.08,
172.79, 172.73, 172.39, 156.59, 135.87, 135.75, 135.20, 135.17,
128.57, 128.54, 128.42, 128.39, 128.21, 128.09, 67.24, 67.22,
66.44, 66.43, 52.53, 51.62, 36.38, 35.92, 30.20, 27.88, 17.14.
(2S,2′S,4S)-N,N′-Car bon yl-4-m eth yldiglu tam ic Acid (5f).
5f was synthesized from 10f according to method D. [R]D
1
+18.0° (c 0.16, MeOH); H NMR (D2O) δ 4.17-4.09 (m, 2H),
2.48 (m, 1H), 2.37 (t, 2H, J ) 7.5 Hz), 2.10-1.78 (m, 4H), 1.06
(d, 3H, J ) 7.2 Hz); 13C NMR (D2O) δ 181.13, 177.57, 176.91,
176.67, 159.34, 52.90, 51.89, 36.71, 34.64, 30.26, 26.50, 16.42.
(S )-4-(Be n zylca r b a m oyl)-2-[(t er t -b u t oxyca r b on yl)-
a m in o]bu tyr ic Acid Ben zyl Ester (17). 17 was synthesized
1
from 12 and benzylamine according to method A. H NMR δ
7.29-7.17 (m, 10H), 6.97 (br, 1H), 5.68 (d, 1H, J ) 8.1 Hz),
5.11, 5.04 (ABq, 2H, J ) 12.3 Hz), 4.30 (d, 2H, J ) 5.4 Hz),
4.25 (m, 1H), 2.32 (t, 2H, J ) 7.2 Hz), 2.11 (m, 1H), 1.94 (m,
1H), 1.39 (s, 9H); 13C NMR δ 172.09, 171.92, 155.60, 137.90,
135.04, 128.27, 128.10, 127.94, 127.33, 127.27, 127.02, 79.64,
66.74, 53.02, 43.19, 31.94, 27.98.
(S)-4-(1-Ben zyl-1H-tetr a zol-5-yl)-2-[(ter t-bu toxyca r bon -
yl)a m in o]bu tyr ic Acid Ben zyl Ester (18). 18 was synthe-
sized from 17 according to method B. 1H NMR δ 7.37-7.12
(m, 10H), 5.44, 5.38 (ABq, 2H, J ) 15.6 Hz), 5.21 (m, 1H), 5.11