Construction of a carbapenam skeleton using palladium-catalyzed cyclization

Article abstract of DOI:10.1016/S0040-4039(01)00870-X

When a THF solution of β-lactam having propargyl phosphate was warmed in the presence of 5 mol% of Pd₂(dba)₃·CHCl₃, 20 mol% of bidentate ligand and sodium acetate (1.5 equiv.) at 40°C for 22 h, carbapenam was produced in h

Full text of DOI:10.1016/S0040-4039(01)00870-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4869–4873
Construction of a carbapenam skeleton using palladium-catalyzed
cyclization
Yuji Kozawa and Miwako Mori*
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Received 27 April 2001; revised 17 May 2001; accepted 18 May 2001
Abstract—When a THF solution of b-lactam having propargyl phosphate was warmed in the presence of 5 mol% of
Pd2(dba)3·CHCl3, 20 mol% of bidentate ligand and sodium acetate (1.5 equiv.) at 40°C for 22 h, carbapenam was produced in
high yield. In this reaction, the lactam nitrogen attacked the central sp carbon of a s-allenylpalladium complex, which was formed
from propargyl phosphate and Pd(0). © 2001 Elsevier Science Ltd. All rights reserved.
Carbapenem has an important antibiotic activity and
the development of a novel method for synthesizing
carbapenam is needed in order to find new b-lactam
antibiotics. In general, for the construction of a car-
bapenam skeleton, a five-membered ring is formed
from four-membered b-lactam. However, it is not so
easy to construct carbapenam skeleton because of the
highly strained structure. Organometallic reagents are
very attractive tools for the construction of these
skeletons.1 Recently, we reported a novel method for
synthesizing a carbapenam skeleton using ruthenium-
catalyzed cyclization.2 Our concept for the formation
of carbapenam skeleton II using transition metals was
to construct the five-membered rings by reductive
elimination from six-membered metalacycle I fused by
a four-membered b-lactam. Although the previous
method for the construction of a carbapenam skele-
ton involved forming
C1ꢀC2 bond,2 the new
a
method involves formation of a C3ꢀN bond from
palladacyclohexane Ia. For that purpose, we consid-
ered how to make palladacyclohexane having an
NꢀPdꢀC bond. It has been shown that the reaction of
propargyl carbonate with Pd(0) affords a s-allenylpal-
ladium complex or a s-propargylpalladium complex.3
Recent works by Buchwald and Hartwig have indi-
cated that the reaction of amine or amide with s-
arylpalladium halide affords amide, imide, or lactam
in the presence of a base via the processes of an
NꢀPdꢀC bond formation and reductive elimination
from it.4 These results prompted us to try to con-
struct carbapenam IIa from propargyl carbonate III.
Our plan is shown in Scheme 1.
1
2
M
N
N
O
O
3
O
M
II
I
Pd(0)
NH
NH
XPd
N
N
O
·
Pd
·
O
O
·
IV
Ia
IIa
III
X
Scheme 1. Our plan for the synthesis of the carbapenam skeleton.
Keywords: b-lactam; carbapenam; cyclization; palladium catalysts; s-allenylpalladium complex.
* Corresponding author. Fax: 81-11-706-4982; e-mail: mori@pharm.hokudai.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00870-X

4870
Y. Kozawa, M. Mori / Tetrahedron Letters 42 (2001) 4869–4873
To increase the yield of the desired compound 2, the
reaction was carried out under various conditions, and
the results are shown in Table 1. As a base, Cs2CO3 was
used, and acetate 1b afforded 2 in 6% yield (run 2).
However, the reaction of benzoate 1c with a palladium
catalyst gave 2 in 44% yield (run 3). The electron-
donating group on the aromatic ring of benzoate
decreased the yield of 2 (run 4), and a lower reaction
temperature increased the yield of 2 (run 8). Propargyl
phosphate 1e also gave moderate yield of 2 (runs 5 and
9).
The reaction of propargyl carbonate and Pd(0) would
afford a s-allenylpalladium complex IV, and the reac-
tion of lactam nitrogen with the s-allenylpalladium
complex would give palladacycle Ia, and then reductive
elimination from Ia would produce IIa. When a toluene
solution of methyl carbonate 1a was warmed in the
presence of 5 mol% of Pd2(dba)3·CHCl3, 20 mol% of
P(o-tolyl)3, and K2CO3 (2 equiv.) at 50°C for 12 h, a
small amount of carbapenam 2 was obtained (Scheme
2).
Presumably, the reaction of 1a with Pd(0) gives s-
propargylpalladium complex, which converts into s-
allenylpalladium complex 3 via decarboxylation, and it
reacts with lactam nitrogen in 3 in the presence of a
base to give palladacyclohexane 4. Reductive elimina-
tion from 4 affords 2.
Subsequently, the effects of the ligands were examined,
and the results are shown in Table 2. Use of monoden-
tate ligands such as P(o-tolyl)3, P(2-furyl)3 and P(cyclo-
hexyl)3 gave carbapenam 2 in moderate yields (runs
1–4). Surprisingly, the use of a bidentate ligand, such as
5 mol%
SiO
SiO
Pd2(dba)3·CHCl3
20 mol%
P(o-tolyl)3
H H
NH
H H
N
toluene, K2CO3(2 equiv.)
50 °C, 12 h
O
O
·
5%
OCO2Me
Si=TBDMS
2
1a
SiO
SiO
H H
N
H H
Pd(0)
-CO2
1a
2
NH
Pd
Pd
·
·
O
O
OMe
4
3
Scheme 2. Reaction of 1a with palladium catalyst.
Table 1. Reaction of 1 with Pd2(dba)3·CHCl3 under various conditionsa
SiO
SiO
H H
SiO
H H
Pd2(dba)3
H H
N
P(o-tolyl)3
NH
+
N
O
Cs2CO3
toluene
O
O
·
X
1
2
5
Si=TBDMS
Run
X
Temp. (°C)
Time (h)
Yield (%)
2
5
1
2
3
4
5
6
7
8
9
OCO2Me
OCOMe
OCOPh
OCO-p-MeOC6H4
OPO(OEt)2
OPh
OCOPh
OCOPh
OPO(OEt)2
1a
1b
1c
1d
1e
1f
1c
1c
1e
50
70
70
70
70
70b
40
55
55
12
4
5
8
4
3
48
9
6
6
–
–
2
7
–
–
–
–
–
44
29
44
–
32c
57c
38
9
a All reactions were carried out using Pd2(dba)3·CHCl3 (5 mol%), P(o-tolyl)3 (20 mol%), and Cs2CO3 (2 equiv.) in toluene.
b After the solution was warmed at 70°C for 3 h and then at 90°C for 2 h.
c The starting material was recovered in 45% (run 7) or 14% yield (run 8), respectively.

Y. Kozawa, M. Mori / Tetrahedron Letters 42 (2001) 4869–4873
4871
Table 2. Effects of ligandsa
SiO
SiO
Pd2(dba)3
Ligand
H H
N
H H
N
1c
Cs2CO3
toluene
+
O
O
·
Si=TBDMS
2
6
Run
Ligand
Temp. (°C)
Time (h)
Yield (%)
2
6
1c
1
2
3
4
5
6
7
8
9
P(o-tolyl)3
P(2-furyl)3
P(cyclohexyl)3
P(cyclohexyl)3
DPPF
(+)-BINAP
(−)-BINAP
DPPB
55
70
70
55
70
70
70
70
55
9
8
8
21
5
10
8
57
19
39
33
–
–
–
–
50
–
–
–
–
14
35
32
40
–
26
10
3
56b
8
24
26
–
5
21
–
23
a All reactions were carried out using Pd2(dba)3·CHCl3 (5 mol%), ligand (20 mol%) and Cs2CO3 (2 equiv.) in toluene.
b 7 was obtained in 9% yield along with 6 in 56% yield.
SiO
PPh2
PPh2
PPh2
H H
3
P
PPh2
PPh2
O
Fe
N
PPh2
X
O
7
P(2-furyl)3
DPPF
BINAP
DPPB
X=OCOPh
DPPF, BINAP and DPPB, produced carbacepham 6
instead of carbapenam 2 (runs 5–8). In the absence of a
ligand, the desired carbapenam 2 was produced in good
yield (run 9).
dium complex 10, which is in a state of equilibrium
with p-allylpalladium complex 10%. Reductive elimina-
tion from 10 affords 7 and b-hydride elimination from
10 gives 6. It means that when the palladium complex
has bidentate ligand, the lactam nitrogen reacts with
the central sp carbon of the s-allenylpalladium com-
plex, not the palladium metal.
The possible reaction course was shown in Scheme 3.
The lactam nitrogen of s-allenylpalladium complex 8
reacts with palladium metal to give palladacyclohexane
4, which converts into carbapenam 2. On the other
hand, the lactam nitrogen of 8 attacks the central sp
carbon of the allenyl group to give palladium carbene
complex 9.3,5 Reaction of 9 with HX gives s-allylpalla-
Although the reasons why a monodentate ligand accel-
erates the formation of palladacycle 4 and a bidentate
ligand accelerates the formation of palladium carbene
complex 9 are not clear, the results are very interesting.
SiO
SiO
SiO
H H
H H
H H
N
HX
N
H
N
Pd-X
·
Pd
X
O
Pd
O
O
8
10
9
Si=TBDMS
HX=PhCO2H
4
SiO
Pd(0)
HPdX
H H
6
7
2
N
O
PdX
10'
Scheme 3. Possible reaction mechanism for the formation of 6 and 7.

4872
Y. Kozawa, M. Mori / Tetrahedron Letters 42 (2001) 4869–4873
ous conditions, and the results are shown in Table 3.
When the reaction was carried out using sodium ben-
zoate as a base, the yield of carbapenams increased (run
2).
On the basis of these results, if one carbon of the side
chain of b-lactam is shortened, s-allenylpalladium com-
plex VI would be formed. In this reaction, if bidentate
ligand is used, the lactam nitrogen of s-allenylpalla-
dium complex VI attacks the central sp carbon of the
allenyl group to form palladium carbene complex VII,
which would react with HX to give s-palladium com-
plex VIII or p-allylpalladium complex VIII%. From VIII
or VIII%, carbapenam would be produced (Scheme 4).
As a solvent, THF gave a good result and the total
yield of carbapenam was 55% (run 3). Phosphate can be
used as a leaving group (runs 4–7), but the lower
temperature decreased the yield of 12 (run 5). When the
amount of the base decreased, the yields of 12 and 13a
increased to 66% (run 6). The use of sodium acetate as
a base gave 12 and 13c in 59% yield (run 7).6
Pd-X
Pd(0)L
Pd
NH
·
NH
N
Finally, we tried to synthesize 1-b-methylcarbapenam.
The starting material 14a was synthesized from 17,
whose stereochemistry has been already determined.7
O
O
O
X
VI
VII
V
HX
L: Bidentate Ligand
When phosphate 14a was treated with Pd2(dba)3·CHCl3
and DPPF in THF at 40°C for 22 h, the desired
1-b-methylcarbapenams 15a and 16 were obtained in 78
and 8% yields, respectively (Scheme 5). The result of an
NOE experiment indicates that the stereochemistry of
the methyl and acetoxy groups on the five-membered
ring is cis. This means that the nucleophile attacks from
the backside of the p-allylpalladium complex 188 and it
attacks the carbon on the five-membered ring of p-allyl-
palladium complex.
Pd-X
N
N
O
O
PdX
VIII
VIII'
Scheme 4. Plan for the synthesis of the carbapenam skeleton.
When a toluene solution of propargyl benzoate 11a was
warmed in the presence of 5 mol% of Pd2(dba)3·CHCl3,
20 mol% of DPPF and Cs2CO3 (2 equiv.) at 50°C for
12 h, desired carbapenams 12 and 13a were obtained in
9 and 2% yields, respectively (Table 3, run 1). Although
the yield was not good, the lactam nitrogen attacked
the central sp carbon of s-allenylpalladium complex VI
to form palladium carbene complex VII, which gave
carbapenam. The reaction was carried out under vari-
It was quite interesting that 1-b-methylcarbapenam
could be synthesized from b-lactam 14a having a
propargyl derivative on the side chain by palladium-
catalyzed cyclization in high yield.
Further studies are in progress.
Table 3. Cyclization of 11 under various conditions
5 mol %
Pd2(dba)3·CHCl3
20 mol % DPPF
SiO
SiO
SiO
H H
NH
H H
N
H H
N
X
+
PhCO2Na
O
O
O
X
12
11a X=OCOPh
11b X=OPO(OEt)2
11c X=OCOMe
13a X=OCOPh
13c X=OCOMe
Si=TBDMS
Run
X
PhCO2Na (equiv.)
Solvent
Temp. (°C)
Time (h)
Yield (%)
12
13
11
1
2
3
4
5
6
7
OCOPha
OCOPh
OCOPh
OPO(OEt)2
OPO(OEt)2
OPO(OEt)2
OPO(OEt)2
2
2
4
4
4
1.5
1.5
Toluene
Toluene
THF
THF
THF
50
70
55
55
40
55
55
12
8.5
17
5
6
5
9
4
23
27
7
2
31
32
35
24
44
33e
–
33
16
–
71b
13b
7c
THF
THF
22
26
d
5
a Cs2CO3 was used instead of PhCO2Na.
b 11a.
c 11c.
d MeCOONa was used instead of PhCO2Na.
e 13c was obtained.

Y. Kozawa, M. Mori / Tetrahedron Letters 42 (2001) 4869–4873
4873
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5 mol %
Pd2(dba)3·CHCl3
20 mol % DPPF
SiO
H H
MeCO2Na (1.5 equiv.)
THF, 40 °C, 22 h
NH
14a
O
OPO(OEt)2
Si=TBDMS
NOE
+
2. Mori, M.; Kozawa, Y.; Nishida, M.; Kanamaru, M.;
Onozuka, K.; Takimoto, M. Org. Lett. 2000, 2, 3245.
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SiO
SiO
H H
N
H H
N
H
OR
O
O
OR
15a
16
8%
78%
R=COMe
PdX
SiO
SiO
H H
H H
NH
N
5. (a) Fournier-Nguefack, C.; Lhoste, P.; Sinou, D. Synlett
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O
O
17
18
Scheme 5. Formation of the carbapenam skeleton from 14.
6. The ratio of a to b of the acetoxy or benzoyloxy group at
the 2-position in 13a or 13c is 1:1.
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(1.5 equiv.) in THF at 55°C for 5 h, 15b (1b-Me, 2b-
OCOPh) was obtained in 60% yield along with 15c (1b-
Me, 2a-OCOPh) in 11% yield. On the other hand, under
similar conditions, 14b (1a-Me) afforded 15d (1a-Me, 2a-
OCOPh) in 40% yield along with 15e (1a-Me, 2b-OCOPh)
in 10% yield.
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