Journal of Medicinal Chemistry
Article
Carbapenem 6b. Following the general procedure for Cu(I)-
catalyzed 1,3 cycloaddition (Conditions A), carbapenem 6b was
obtained (43 mg, 43%) starting from compound 4 (60 mg, 0.14
152.5, 160.5, 172.5, 172.9. HRMS: calcd for C H N O SNa [M +
Na] : 731.2112; found: 731.2107.
33
36
6
10
+
Carbapenem 6g. Following the general procedure for Cu(I)-
catalyzed 1,3 cycloaddition (Conditions B), carbapenem 6g was
obtained (17 mg, 37%) starting from compound 4 (30 mg, 0.07
1
mmol) and azide 5b (50 mg, 0.17 mmol). H NMR (500 MHz,
CDCl ): δ = 1.25 (d, J = 6.9 Hz, 3 H), 1.34 (d, J = 6.2 Hz, 3 H), 3.15−
3
1
3
3
.16 (m, 2 H), 3.19−3.24 (m, 1 H), 3.27 (dd, J = 6.7, 1.9 Hz, 1 H),
.30−3.34 (m, 1 H), 3.43−3.49 (m, 1 H), 4.19−4.24 (m, 2 H), 5.17
mmol) and azide 5g (17 mg, 0.07 mmol). H NMR (500 MHz,
CDCl ): δ = 1.12 (d, J = 7.4 Hz, 3 H), 1.32 (d, J = 6.1 Hz, 3 H), 2.18
3
(
d, J = 14.1 Hz, 1 H), 5.24 (s, 2 H), 5.46 (d, J = 14.1 Hz, 1 H), 7.19 (t,
(s, 3 H), 2.98−3.04 (m, 1 H), 3.06−3.13 (m, 2 H), 3.17−3.21 (m, 2
H), 3.24−3.31 (m, 1 H), 399 (dd, J = 8.9, 2.6 Hz, 1 H), 4.20−4.23 (m,
1 H), 5.25 (d, J = 13.5 Hz, 1 H), 5.48 (d, J = 13.5 Hz, 1 H), 7.64 (d, J
= 8.2 Hz, 2 H), 7.72 (d, J = 8.9 Hz, 2 H), 7.95−7.97 (m, 2 H), 8.02 (s,
J = 7.4 Hz, 1 H), 7.29 (d, J = 7.4 HZ, 1 H), 7.45 (t, J = 7.7 Hz, 1 H),
.52 (d, J = 8.1 Hz, 2 H), 7.62 (d, J = 8.8 Hz, 2 H), 8.16−8.20 (m, 4
7
13
H). C NMR (125 MHz, CDCl ): δ = 16.9, 21.9, 26.3, 30.7, 43.3,
3
5
1
6.1, 59.9, 65.3, 65.8, 65.9, 123.2, 123.8, 123.9, 124.2, 124.3, 128.2,
28.5, 130.1, 143.0, 143.2, 147.7, 147.8, 151.7, 153.1, 160.5, 172.9.
Carbapenem 6c. Following the general procedure for Cu(I)-
1 H), 8.20 (d, J = 8.7 Hz, 2 H). 13C NMR (125 MHz, CDCl ): δ =
3
16.6, 21.8, 24.7, 26.3, 30.3, 43.0, 55.6, 59.7, 65.3, 65.7, 119.7, 121.8,
123.7, 123.8, 128.2, 129.5, 130.1, 142.9, 144.5, 144.9, 147.6, 151.4,
+
catalyzed 1,3 cycloaddition (Conditions A), carbapenem 6c was
obtained (56 mg, 60%) starting from compound 4 (55 mg, 0.13
160.3, 169.1, 172.7. HRMS: calcd for C H N O S [M + H] :
29
31
6
9 2
671.1594; found: 671.1583.
1
mmol) and azide 6c (41 mg, 0.15 mmol). H NMR (500 MHz,
Carbapenem 6h. Following the general procedure for Cu(I)-
catalyzed 1,3 cycloaddition (Conditions A), carbapenem 6h was
obtained (60 mg, 71%) starting from compound 4 (60 mg, 0.14
CDCl ):δ = 1.23 (d, J = 6.9 Hz, 3 H), 1.33 (d, J = 6.1 Hz, 3 H), 3.11−
3
3
3
5
7
.21 (m, 3 H), 3.26 (dd, J = 7.1, 1.9 Hz, 1 H), 3.29−3.36 (m, 1 H),
.45−3.48 (m, 1 H), 4.19−4.25 (m, 2 H), 5.15 (d, J = 13.8 Hz, 1 H),
.44 (d, J = 13.8 Hz, 1 H), 5.47 (s, 2 H), 7.57−7.63 (m, 5 H), 7.96−
.97 (m, 1 H), 8.11 (d, J = 7.9 Hz, 1 H), 8.14 (d, J = 8.7 Hz, 2 H), 8.23
1
mmol) and azide 5h (31 mg, 0.17 mmol). H NMR (500 MHz,
CDCl ): δ = 1.11 (d, J = 6.9 Hz, 3 H), 1.27 (d, J = 3 H), 2.84−2.88
3
(m, 2 H), 2.99−3.04 (m, 1 H), 3.08−3.12 (m, 1 H), 3.17−3.22 (m, 3
H), 3.30−3.3 (m, 1 H), 4.10 (d, J = 8.2 Hz, 1 H), 4.15 (quint, J = 6.5
Hz, 1 H), 4.46−4.52 (m, 2 H), 5.10 (d, J = 13.8 Hz, 1 H), 5.37 (d, J =
13.8 Hz, 1 H), 6.85 (s, 1 H), 7.01 (t, J = 7.5 Hz, 1 H), 7.08 (d, J = 7.5
13
(
d, J = 8.7 Hz, 2 H), 8.35 (s, 1 H). C NMR (125 MHz, CDCl ): δ =
3
1
1
1
6.9, 21.9, 26.4, 30.8, 43.2, 56.0, 59.8, 65.2, 65.8, 65.9, 121.4, 123.7,
24.0, 125.1, 128.1, 128.7, 129.8, 130.3, 131.4, 137.3, 142.7, 143.1,
47.6, 147.9, 152.0, 160.5, 164.9, 172.9. HRMS: calcd for
Hz, 1 H), 7.25 (d, J = 8.3 Hz, 1 H), 7.40 (d, J = 7.7 Hz, 1 H), 7.50 (d, J
+
13
C H N O S [M + H] : 729.1979; found: 729.1967.
= 8.2 Hz, 2 H), 8.04 (s, 1 H). C NMR (125 MHz, CDCl ): δ = 16.9,
3
5
33
6
6
3
Carbapenem 6d. Following the general procedure for Cu(I)-
21.9, 26.0, 26.6, 30.9, 43.3, 50.9, 56.2, 59.7, 65.3, 65.9, 110.5, 111.6,
118.1, 119.5, 122.1, 123.2, 123.3, 123.7, 126.7, 128.1, 136.3, 143.0,
147.8, 153.5, 160.8, 173.0.
General Procedure for the Deprotection of para-Nitro-
benzyl (PNB) Group by Hydrogenation. A pressure reactor was
charged with para-nitrobenzyl protected carbapenem (1 equiv), 10 wt
% Pd/C (3 equiv), and a 1/1 mixture of THF/triethylammonium
bicarbonate buffer (pH 8.5). The reactor was pressurized with 3.5 bar
catalyzed 1,3 cycloaddition (Conditions A), carbapenem 6d was
obtained (28 mg, 56%) starting from compound 4 (30 mg, 0.07
1
mmol) and azide 5d (25 mg, 0.08 mmol). H NMR (500 MHz,
CDCl ): δ = 1.24 (d, J = 6.9 Hz, 3 H), 1.34 (d, J = 6.4 Hz, 3 H), 3.13−
3
3
3
.16 (m, 2 H), 3.18−3.24 (m, 1 H), 3.27 (dd, J = 6.5, 1.9 Hz, 1 H),
.29−3.38 (m, 1 H), 3.43−3.50 (m, 1 H), 4.2 (dd, J = 8.7, 2.0 Hz, 1
H), 4.21−4.26 (m, 1 H), 5.17 (d, J = 13.2 Hz, 1 H), 5.45 (d, J = 13.2
Hz, 1 H), 5.47 (s, 1 H), 7.61 (t, J = 9.2 Hz, 4 H), 7.82 (d, J = 8.1 Hz, 2
H), 7.91 (s, 1 H), 8.16 (d, J = 8.1 Hz, 2 H), 8.21 (d, J = 8.1 Hz, 2 H),
H , and the closed system was stirred for 2 h. Palladium was removed
2
by filtration through Celite, and the filtrate concentrated. The residue
was purified by HPLC. The appropriate fractions were collected and
lyophilized, to give triethylammonium salt.
13
8
2
1
1
7
.26 (d, J = 8.8 Hz, 2 H). C NMR (125 MHz, CDCl ): δ = 16.9, 21.9,
3
6.4, 30.8, 43.2, 56.1, 59.8, 65.3, 65.7, 65.9, 120.0, 123.8, 124.0, 127.1,
28.2, 128.6, 129.7, 131.6, 140.4, 143.0, 146.0, 147.7, 148.0, 151.9,
Carbapenem 7a. Following the general procedure for deprotection
+
60.5, 164.9, 172.8. HRMS: calcd for C H N O S [M + H] :
of PNB by hydrogenation, carbapenem 7a was obtained (8.5 mg, 27%)
35
33
6
10
1
29.1979; found: 729.1968.
Carbapenem 6e. Following the general procedure for Cu(I)-
starting from compound 6a (42 mg, 0.076 mmol). H NMR (250
MHz, D O): δ = 1.05 (d, J = 6.8 Hz, 3 H), 1.17 (d, J = 6.8 Hz, 3 H),
2
catalyzed 1,3 cycloaddition (Conditions A), carbapenem 6e was
obtained (69 mg, 56%) starting from compound 4 (70 mg, 0.16
mmol) and azide 5e (80 mg, 0.24 mmol). H NMR (500 MHz,
1.24 (t, J = 7.4 Hz, 9 H), 3.00−3.09 (m, 3 H), 3.16 (q, J = 7.6 Hz, 6
H), 3.24−3.28 (m, 1 H), 3.69−3.73 (m, 1 H), 4.01−4.11 (m, 1 H),
1
7.51−7.61 (m, 3 H), 7.66−7.69 (m, 2 H), 8.21 (s, 1 H). HRMS: calcd
+
CDCl ): δ = 1.18 (d, J = 6.9 Hz, 3 H), 1.29−1.32 (m, 3 H), 1,95 (t, J =
for C20
H
N
23
4
O
4
S [M + H] : 415.1440; found: 415.1444.
3
6
2
5
5
.2 Hz, 3 H), 2.96−3.03 (m, 2 H), 3.07−3.11 (m, 1 H), 3.20−3.24 (m,
H), 3.39−3.42 (m, 1 H), 4.08−4.13 (m, 1 H), 4.18−4.22 (m, 1 H),
.17 (d, J = 14.0 Hz, 1 H), 5.41 (s, 1 H), 5.45 (d, J = 14.0 Hz, 1 H),
.80 (quint, J = 6.3 Hz, 1 H), 7.27−7.29 (m, 2 H), 7.34 (s, 1 H), 7.56
Carbapenem 7b. Following the general procedure for deprotection
of PNB by hydrogenation, carbapenem 7b was obtained (4.3 mg,
1
13%) starting from compound 6b (43 mg, 0.059 mmol). H NMR
(250 MHz, D O): δ = 1.16 (d, J = 7.1 Hz, 3 H), 1.24−1.33 (m, 12 H),
2
(
d, J = 7.9 Hz, 2 H), 7.61 (d, J = 8.5 Hz, 2 H), 8.03 (d, J = 7.8 Hz, 2
3.08−3.31 (m, 10 H), 3.35−3.38 (m, 2 H), 3.91−3.95 (m, 1 H), 4.17−
4.22 (m, 1 H), 6.98−7.11 (m, 2 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.43 (t, J
= 8.0 Hz, 1 H), 8.07 (s, 1 H). HRMS: calcd for C H N O S [M −
13
H), 8.14 (d, J = 8.7 Hz, 2 H), 8.20 (d, J = 8.7 Hz, 2 H). C NMR (125
MHz, CDCl ): δ = 16.6, 21.2, 21.8, 26.5, 30.8, 43.2, 56.0, 59.7, 59.9,
3
21 21
4
6
+
6
1
5.2, 65.4, 65.8, 120.9, 123.7, 123.9, 126.6, 128.2, 128.4, 129.7, 130.5,
H] : 457.1182; found: 457.1195.
43.1, 143.2, 144.9, 145.4, 145.5, 147.6, 147.8, 152.4, 165.4, 172.9.
Carbapenem 7c. Following the general procedure for deprotection
+
HRMS: calcd for C H N O S [M + H] : 757.2292; found:
of PNB by hydrogenation, carbapenem 7c was obtained starting from
37
37
6
10
1
7
57.2277.
Carbapenem 6f. Following the general procedure for Cu(I)-
compound 6c (56 mg, 0.076 mmol). H NMR (250 MHz, D O): δ =
2
1.14 (d, J = 7.3 Hz, 3 H), 1.23−1.32 (m, 21 H), 3.17−3.25 (m, 15 H),
3.33−3.36 (m, 2 H), 3.53−3.61 (m, 1 H), 3.85−3.98 (m, 1 H), 4.13−
4.17 (m, 1 H), 7.69 (t, J = 7.8 Hz, 1 H), 7.88 (d, J = 8.7 Hz, 1 H), 8.03
(d, J = 8.7 Hz, 1 H), 8.21 (s, 1 H), 8.34 (s, 1 H). HRMS: calcd for
catalyzed 1,3 cycloaddition (Conditions A), carbapenem 6f was
obtained (20 mg, 41%) starting from compound 4 (30 mg, 0.07
1
mmol) and azide 5f (23 mg, 0.08 mmol). H NMR (500 MHz,
+
CDCl ): δ = 1.21 (d, J = 7.0 Hz, 3 H), 1.34 (d, J = 6.1 Hz, 3 H), 1.63−
C H N O S [M + H] : 459.1338; found: 459.1336.
3
21 23
4
6
1
.69 (m, 2 H), 1.90−1.96 (m, 2 H), 2.42−2.45 (m, 2 H), 3.01−3.06
Carbapenem 7d. Following the general procedure for deprotection
(
m, 2 H), 3.10−3.14 (m, 1 H), 3.24−3.25 (m, 2 H), 3.42−3.45 (m, 1
of PNB by hydrogenation, carbapenem 7d was obtained (2.4 mg,
1
H), 4.16 (dd, J = 9.2, 1.6 Hz, 1 H), 4.23 (quint, J = 4.6 Hz, 1 H),
21%) starting from compound 6d (13 mg, 0.017 mmol). H NMR
4
=
=
.30−4.33 (m, 2 H), 5.18 (s, 1 H), 7.49 (d, J = 8.5 Hz, 2 H), 7.65 (d, J
(250 MHz, D O): δ = 1.08 (d, J = 6.6 Hz, 3 H), 1.19 (d, J = 6.6 Hz, 3
2
13
8.5 Hz, 2 H), 8.19−8.21 (m, 4 H). C NMR (125 MHz, CDCl ): δ
H), 1.28 (t, J = 7.0 Hz, 18 H), 3.04−3.23 (m, 4 H), 3.25−3.33 (m, 2
H), 3.43 (q, J = 6.6 Hz, 12 H), 3.77−3.79 (m, 1 H), 4.07−4.13 (m, 1
H), 7.78 (d, J = 8.2 Hz, 2 H), 8.03 (d, J = 8.2 Hz, 2 H), 8.31 (s, 1 H).
3
16.9, 21.8, 21.9, 26.5, 29.6, 31.0, 33.2, 43.3, 50.0, 56.1, 59.8, 65.0,
5.3, 65.9, 122.0, 123.8, 123.9, 128.3, 128.5, 143.1, 144.8, 147.7, 147.8,
6
I
J. Med. Chem. XXXX, XXX, XXX−XXX