Novel synthesis of carbapenam by intramolecular attack of lactam nitrogen toward η1-allenyl and η3-propargylpalladium complex

Article abstract of DOI:10.1021/jo030123c

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

Full text of DOI:10.1021/jo030123c

Novel Syn th esis of Ca r ba p en a m by In tr a m olecu la r Atta ck of
La cta m Nitr ogen tow a r d η1-Allen yl a n d η3-P r op a r gylp a lla d iu m
Com p lex
Yuji Kozawa and Miwako Mori*
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, J apan
mori@pharm.hokudai.ac.jp
Received April 10, 2003
When a THF solution of â-lactam having propargyl phosphate was warmed in the presence of 5
mol % of Pd2(dba)3‚CHCl3, 20 mol % of a 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 carbon of a η3-propargylpalladium complex, which was formed from propargyl phosphate
and Pd(0).
SCHEME 1. P a lla d iu m -Ca ta lyzed C-N
Bon d -F or m in g Rea ction betw een Ar yl Ha lid es a n d
Am in es
In tr od u ction
Many works have been carried out to develop carba-
penem antibiotics having chemical and biological proper-
ties for clinical use since the discovery by Merck’s group
of thienamycin, the first naturally occurring carbapenem
antibiotic.1 The establishment of a new method for
forming a carbapenem skeleton is very important to
develop new types of carbapenem antibiotics that have
strong antibiotic activity.2 Generally, a five-membered
ring is formed from four-membered 2-azetidinone having
proper residual groups at the 1- and/or 4-position for the
construction of a carbapenam skeleton. However, it is not
so easy to construct a carbapenam or carbapenem skel-
eton because carbapenam or carbapenem having a 4-5
fused ring system has a highly strained structure com-
pared with the structures of other â-lactam antibiotics
such as penam and penem, and there have been few
reports on a simple method for constructing a carba-
penam skeleton.
Organometallic reagents have been extensively studied
over the past few decades by many organic chemists, and
they now play very important roles in synthetic organic
chemistry.
There are several notable reports on the construction
of carbapenam skeletons with organometallic reagents.3
As originally reported by Merck’s group, intramolecular
reaction of a rhodium-carbene complex with the N-H
bond of â-lactam has often been used for the synthesis
of a wide range of carbapenem derivatives.4 Trost re-
ported the synthesis of carbapenam derivatives using
palladium-catalyzed cyclization.5 Genet reported the
synthesis of carbapenem derivatives by intramolecular
nucleophilic attack of active methylene to a π-allylpal-
ladium complex, and he recently also reported the
synthesis of carbapenam derivatives using a metathesis
reaction.6 Recently, we have investigated potential meth-
ods for synthesizing a carbapenam and carbapenem
skeleton by reductive elimination from a six-membered
metalacycle.7
Palladium-catalyzed C-N bond-forming reactions be-
tween aryl halides and amines have been extensively
investigated over the past few years by Buchwald,
Hartwig, and others (Scheme 1).8 This reaction has been
(4) (a) Ratcliffe, R. W.; Salzmann, T. N.; Christensen, B. G.
Tetrahedron Lett. 1980, 21, 31. (b) Salzmann, T. N.; Ratcliffe, R. W.;
Christensen, B. G.; Bouffard, F. A. J . Am. Chem. Soc. 1980, 102, 6161.
(c) Williams, M. A.; Hsiao, C.-N.; Miller, M. J . J . Org. Chem. 1991, 56,
2688. (d) Kume, M.; Kubota, T.; Iso, Y. Tetrahedron Lett. 1995, 36,
8043.
(5) Trost, B. M.; Chen, S.-F. J . Am. Chem. Soc. 1986, 108, 6053.
(6) (a) Roland, S.; Durand, J . O.; Savignac, M.; Geneˆt, J . P.
Tetrahedron Lett. 1995, 36, 3007. (b) Galland, J .-C.; Roland, S.;
Malpart, J .; Savignac, M.; Genet, J .-P. Eur. J . Org. Chem. 1999, 621.
(c) Duboc, R.; He´naut, C.; Savignac, M.; Genet, J .-P.; Bhatnagar, N.
Tetrahedron Lett. 2001, 42, 2461.
(7) (a) Mori, M.; Kozawa, Y.; Nishida, M.; Kanamaru, M.; Onozuka,
K.; Takimoto, M. Org. Lett. 2000, 2, 3245. (b) Preliminary report of
this article: Kozawa, Y.; Mori, M. Tetrahedron Lett. 2001, 42, 4869.
(c) Kozawa, Y.; Mori, M. Tetrahedron Lett. 2002, 43, 111.
(8) (a) Hartwig, J . F. Angew. Chem., Int. Ed. 1998, 37, 2046. (b)
Wolfe, J . P.; Wagaw, S.; Marcoux, J .-F.; Buchwald, S. L. Acc. Chem.
Res. 1998, 31, 805. (c) Ali, M. H.; Buchwald, S. L. J . Org. Chem. 2001,
66, 2560. (d) Stauffer, S. R.; Lee, S.; Stambuli, J . P.; Hauck, S. I.;
Hartwig, J . F. Org. Lett. 2000, 2, 1423. (e) Roy, A. H.; Hartwig, J . F.
J . Am. Chem. Soc. 2001, 123, 1232. (f) Nishiyama, M.; Yamamoto, T.;
Koie, Y. Tetrahedron Lett. 1998, 39, 617. (g) Yamamoto, T.; Nishiyama,
M.; Koie, Y. Tetrahedron Lett. 1998, 39, 2367. (h) Wolfe, J . P.;
Buchwald, S. L. J . Org. Chem. 1997, 62, 1264. (i) Huang, J .; Grasa,
G.; Nolan, S. P. Org. Lett. 1999, 1, 1307. (j) Wolfe, J . P.; Rennels, R.
A.; Buchwald, S. L. Tetrahedron 1996, 52, 7525. (k) Yang, B. H.;
Buchwald, S. L. Org. Lett. 1999, 1, 35. (l) Yin, J .; Buchwald, S. L. Org.
Lett. 2000, 2, 1101. (m) Shakespeare, W. C. Tetrahedron Lett. 1999,
40, 2035.
(1) (a) Kahan, J . S.; Kahan, F. M.; Goegelman, R.; Currie, S. A.;
J ackson, M.; Stapley, E. O.; Miller, T. W.; Miller, A. K.; Hendlin, D.;
Mochales, S.; Hernandez, S.; Woodruff, H. B.; Birnbaum, J . J . Antibiot.
1979, 32, 1. (b) Albers-Scho¨nberg, G.; Arison, B. H.; Hensens, O. D.;
Hirshfield, J .; Hoogsteen, K.; Kaczka, E. A.; Rhodes, R. E.; Kahan, J .
S.; Kahan, F. M.; Ratcliffe, R. W.; Walton, E.; Ruswinkle, L. J .; Morin,
R. B.; Christensen, B. G. J . Am. Chem. Soc. 1978, 100, 6491. (c)
Sunagawa, M.; Sasaki, A. Heterocycles 2001, 54, 497.
(2) Berks, A. H. Tetrahedron 1996, 52, 331.
(3) Barrett, A. G. M.; Sturgess, M. A. Tetrahedron 1988, 44, 5615.
10.1021/jo030123c CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/19/2003
8068
J . Org. Chem. 2003, 68, 8068-8074

Novel Synthesis of Carbapenam
SCHEME 2. P a lla d iu m -Ca ta lyzed C-N
Bon d -F or m in g Rea ction betw een a P r op a r gyl
Gr ou p a n d â-La cta m Nitr ogen
SCHEME 4. Syn th esis of â-La cta m s Ha vin g th e
P r op a r gyl Moeity on th e Sid e Ch a in a
SCHEME 3. P a lla d iu m -Ca ta lyzed Am id e
Cycliza tion of Bisca r ba m a tes
extended to intramolecular reactions of aryl halides and
amides, carbamates, and sulfonamides, and these pro-
cedures have been utilized in many areas of organic
synthesis.9
Our new plan for the construction of a carbapenam
skeleton involving the coupling of a propargyl group is
shown in Scheme 2.7b If the reaction of â-lactam I having
a propargyl alcohol moiety and Pd(0) affords σ-allenylpal-
ladium complex II,10 the lactam nitrogen in II would
react with the σ-allenylpalladium complex to give palla-
dacycle III. Reductive elimination from III would give
carbapenam IV having the ethenylidene group at the
3-position.
a
Reaction conditions: For 9a , ClCOOMe, pyridine, CH2Cl2,
97%. For 9b, Ac2O, Pyridine, CH2Cl2, 97%. For 9c, PhCOCl,
pyridine, CH2Cl2, 91%. For 9d , 4-MeOC6H4COCl, pyridine, CH2Cl2,
93%. For 9e, (EtO)2P(O)Cl, pyridine, DMAP, CH2Cl2, 85%. For 9f,
PhOH, PPh3, DEAD, THF, 84%.
SCHEME 5. Rea ction of 9a w ith a P a lla d iu m
Ca ta lyst
Little is known about the reaction between propargyl
alcohol derivatives and amide in the presence of a
palladium catalyst. Tamaru reported the synthesis of
4-ethenylidene-2-oxazolidinones in high yields by pal-
ladium-catalyzed aminocyclization of 2-butyn-1,4-diol
biscarbamates (Scheme 3).11
We report the synthesis of a carbapenam skeleton
using a palladium-catalyzed intramolecular C-N bond-
forming reaction.
Resu lts a n d Discu ssion
Con st r u ct ion of Ca r b a p en a m H a vin g a n E t h -
ozonolysis gave aldehyde 5, which was reacted with
triphenylphosphine and carbon tetrabromide to give
dibromoalkene 6. The resultant 6 was treated with BuLi
and then paraformaldehyde to give propargyl alcohol 7,
which was converted into 8 by deprotection. The reaction
of 8 with methyl chloroformate afforded 9a .
Intramolecular coupling of 9a in the presence of a
palladium catalyst was examined. When a toluene solu-
tion of 9a was heated in the presence of 5 mol % of Pd2-
(dba)3‚CHCl3, 20 mol % of P(o-tol)3, and 2 equiv of Cs2CO3
at 50 °C for 12 h, carbapenam 10 having an ethenylidene
group at the 3-position was obtained, although the yield
was only 5% (Scheme 5). The starting material 9a was
not recovered because of its unstability under the reaction
conditions.
en ylid en e Gr ou p a t t h e 3-P osit ion via
a σ-Al-
len ylp a lla d iu m Com p lex. At first, we investigated the
reaction of â-lactam having a methyl carbonate in a
tether as a leaving group in palladium-catalyzed cycliza-
tion. Propargyl carbonate 9a was synthesized from
4-acetoxy-2-azetidinone 1 (Scheme 4). 4-Acetoxy azetidi-
none 1 was converted into sulfone 2, to which the
substitution by Grignard reagent produced 3. Protection
of the amide nitrogen of 3 with a silyl group followed by
(9) (a) Madar, D. J .; Kopecka, H.; Pireh, D.; Pease, J .; Pliushchev,
M.; Sciotti, R. J .; Wiedeman, P. E.; Djuric, S. W. Tetrahedron Lett.
2001, 42, 3681. (b) Cacchi, S.; Antonella Goggiamani, G. F.; Zappia,
G. Org. Lett. 2001, 3, 2539. (c) He, F.; Foxman, B. M.; Snider, B. B. J .
Am. Chem. Soc. 1998, 120, 6417. (d) Peat, A. J .; Buchwald, S. L. J .
Am. Chem. Soc. 1996, 118, 1028. (e) Wagaw, S.; Rennnels, R. A.;
Buchwald, S. L. J . Am. Chem. Soc. 1997, 119, 8451.
(10) Tsuji, J .; Mandai, T. Angew. Chem., Int. Ed. 1995, 34, 2589.
(11) Kimura, M.; Wakamiya, Y.; Horino, Y.; Tamaru, Y. Tetrahedron
Lett. 1997, 38, 3963.
Presumably, the reaction of 9a with Pd(0) gives σ-al-
lenylpalladium complex V via decarboxylation, and it
reacts with the lactam nitrogen in the presence of a base
J . Org. Chem, Vol. 68, No. 21, 2003 8069

Kozawa and Mori
SCHEME 6. Syn th esis of th e P r ecu r sor for
TABLE 1. Effects of Lea vin g Gr ou p s
1â-Meth ylca r ba p en a m
yield (%)
compd
no.
temp
(°C)
time
(h)
run
X
10
11
1
2
3
4
5
6
7
OCOMe
OCOPh
OCOPh
OCOPh
OCO-p-MeOC6H4
OP(O)(OEt)2
OPh
9b
9c
9c
9c
9d
9e
9f
70
70
55
40
70
70
70
4
5
9
48
8
6
44
2
57b
32b
29
7
4
44
3a
a
The solution was warmed at 70 °C for 3 h and then at 90 °C
b
for 2 h. The starting material was recovered in 17% (run 3) or
45% yield (run 4).
to give palladacyclohexane VI. Reductive elimination
from VI affords 10.
To increase the yield of the desired compound 10, the
reaction was carried out with substrates having various
leaving groups. The results are shown in Table 1.
Propargyl acetate 9b afforded 10 in only 6% yield (run
1). However, surprisingly, the reaction of propargyl
benzoate 9c gave carbapenam 10 in 44% yield along with
carbapenam 11, produced by isomerization of allene to
diene, in 2% yield (run 2). Presumably, in oxidative
addition to Pd(0), the reactivity of benzoate 9c is gener-
ally low but the stability of 9c toward the base is higher
than that of 9a . A reduction in the reaction temperature
resulted in an increase in the yield of 10 to 57% (run 3),
but the reaction rate was much slower and the yield
decreased when the reaction temperature was lowered
far (run 4).
SCHEME 7. Rea ction of 21 w ith a P a lla d iu m
Ca ta lyst
The electron-donating group on the aromatic ring of
benzoate decreased the yield of 10 (run 5). Noticeably,
propargyl phosphate 9e also gave a good result as well
as propargyl benzoate 9c (run 6). Propargyl phenyl ether
9f did not give carbapenam 10 (run 7).
Con str u ction of Ca r ba p en a m Ha vin g a â-Meth yl
Gr ou p a t th e 1-P osition . Next, we examined the
construction of carbapenam having a â-methyl group at
the 1-position. It is known that a carbapenam skeleton
having a 1â-methyl group is both metabolically and
chemically more stable than a nonsubstituented carba-
penem skeleton, and attention has therefore been re-
cently focused on its unique biological properties. A
mixture of two diastereomers 1312 (ratio of 1 to 1) was
ozonolyzed to aldehyde 14, and this was followed by
reaction with lithium acetylide to give propargyl alcohol
15. Three isomers were separated by column chromatog-
raphy on silica gel, and isomer 15-1â having a â-methyl
group was silylated to give 16. Two silyl groups of 16 were
deprotected, and the amide nitrogen was silylated again.
The resultant 18 was treated with BuLi and then
paraformaldehyde to give propargyl alcohol 19, which
was converted into 21 (Scheme 6).
When a toluene solution of 21, Pd2dba3‚CHCl3, P(o-tol)3,
and Cs2CO3 was heated at 55 °C for 22 h, carbapenam
22 was obtained in only 29% yield along with the starting
material 21 in 60% yield. When the reaction temperature
was raised to 80 °C, the yield of carbapenam 22 increased
to 55% along with 23 in 8% yield (Scheme 7). The
mechanism of the formation of 23 is not clear. The reason
for the good yield even at a higher temperature was
thought to be the superior stability of carbapenam or the
substrate having a 1â-methyl group. From the coupling
constant between the proton at the 1-position and the
proton at the 2-position of 22, it is clear that the
stereochemistry of the methyl group at the 1-position and
the silyloxy group at the 2-position is trans.13
The cyclization reaction of propargyl benzoate 21
having a â-methyl group at the 1-position was examined.
Effects of Liga n d s. Subsequently, the effects of
ligands were examined. The results are shown in Table
(12) Imuta, M.; Itani, H.; Ona, H.; Hamada, Y.; Uyeo, S.; Yoshida,
T. Chem. Pharm. Bull. 1991, 39, 663.
8070 J . Org. Chem., Vol. 68, No. 21, 2003

Novel Synthesis of Carbapenam
TABLE 2. Effects of Liga n d s on th e Rea ction of 9c w ith
a P a lla d iu m Ca ta lyst
SCHEME 8. P ossible Rea ction Cou r se
SCHEME 9. Alter n a tive P la n for th e Syn th esis of
Ca r ba p en em
2. No ligand gave a better yield than that obtained by
the use of P(o-tol)3. However, interestingly, the use of
monodentate ligands such as P(2-furyl)3 and P(cyclo-
hexyl)3 gave carbapenam 10 in moderate yields (runs 2
and 3), but the use of bidentate ligands such as DPPF,
BINAP, and DPPB gave carbacepham 24 instead of
carbapanam 10 (runs 4-7).
Notably, when DPPF was used as a ligand, carba-
cephams 24 and 25 were obtained in 56% and 9% yields,
respectively (run 4). These results suggested that a five-
membered carbapenam should be obtained by using a
monodentate ligand, while a six-membered carbacepham
should be obtained by using a bidentate ligand from the
same substrate. It is known that a σ-allenylpalladium
complex is in a state of equilibrium with a η3-propar-
gylpalladium complex and that the latter is formed in a
more stable manner in the presence of a bidentate ligand
than in the presence of a monodentate ligand.14 It has
also been reported that the central carbon of the η3-
propargylpalladium complex is attacked by a nucleophile
to give a π-allylpalladium complex, which is further
attacked by a second nucleophile.15
into carbapenam 10. On the other hand, when a biden-
tate ligand is used, the lactam nitrogen attacks the
central carbon of the η3-propargylpalladium complex VII,
which is formed in a more stable manner, to give
π-allylpalladium complex VIII. â-Hydride elimination
from VIII gives 24, and the reaction of VIII with the
benzoate anion gives 25.
Con str u ction of Ca r ba p en a m via a η3-P r op a r -
gylp a lla d iu m Com p lex. Encouraged by the interesting
finding that six-membered carbacephams 24 and 25 were
formed from 9c in the presence of a bidentate ligand,
DPPF, in good yields, we tried to construct a carbapenam
skeleton by an alternative plan (Scheme 9). If â-lactam
IX, in which one carbon of the side chain is shortened, is
used in palladium-catalyzed cyclization in the presence
of a bidentate ligand, allenylpalladium complex X, which
would be in a state of equilibrium with η3-propargylpal-
ladium complex XI, would be formed. The lactam nitro-
gen attacks the central carbon of η3-propargylpalladium
complex XI to form π-allylpalladium complex XII. From
XII, carbapenam XIII would be formed.
The possible reaction courses for the formation of
carbapenam and carbacepham are shown in Scheme 8.
When a monodentate ligand is used, the lactam nitrogen
of σ-allenylpalladium complex V reacts with palladium
metal to give palladacyclohexane VI, which is converted
To examine this reaction, â-lactams 32a and 32b, of
which one carbon was shortened compared with that of
9, were synthesized from 4-allyl-2-azetidinone 2612
(Scheme 10). Protection of the amide nitrogen of 26 with
a silyl group followed by ozonolysis gave aldehyde 28,
which was reacted with triphenylphosphine and carbon
(13) The coupling constant J between 1- and 2-positions of 41-2r
having the 2R-benzoyloxy group is 0 Hz. On the other hand, the
coupling constant J between the 1- and 2-positions of 41-2â having
the 2â-benzoyloxy group is 5.9 Hz. The fact that the coupling constant
J between the 1- and 2-position of 22 was 0 Hz indicates that the
silyloxy group was placed at the R-position.
(14) (a) Tsutsumi, K.; Ogoshi, S.; Nishiguchi, S.; Kurosawa, H. J .
Am. Chem. Soc. 1998, 120, 1938. (b) Tsutsumi, K.; Kawase, T.;
Kakiuchi, K.; Ogoshi, S.; Okada, Y.; Kurosawa, H. Bull. Chem. Soc.
J pn. 1999, 72, 2687.
(15) (a) Minami, I.; Yuhara, M.; Tsuji, J . Tetrahedron Lett. 1987,
28, 629. (b) Fournier-Nguefack, C.; Lhoste, P.; Sinou, D. Synlett 1996,
553. (c) Labrosse, J .-R.; Lhoste, P.; Sinou, D. Tetrahedron Lett. 1999,
40, 9025. (d) Labrosse, J .-R.; Lhoste, P.; Sinou, D. Org. Lett. 2000, 2,
527. (e) Yoshida, M.; Ihara, M. Angew. Chem., Int. Ed. 2001, 40, 616.
(f) Yoshida, M.; Fujita, M.; Ishii, T.; Ihara, M. J . Am. Chem. Soc. 2003,
125, 4874.
J . Org. Chem, Vol. 68, No. 21, 2003 8071

Kozawa and Mori
SCHEME 10. Syn th esis of P r ecu r sor s
F IGURE 1.
SCHEME 11. Syn th esis of P r ecu r sor s for
1â-Meth ylca r ba p en a m
TABLE 3. Syn th esis of Ca r ba p en em Un d er Va r iou s
Rea ction Con d ition s
the use of sodium benzoate as a base resulted in a better
yield, since sodium benzoate worked as not only a base
but also a nucleophile, and the formation of carbapenam
34 from π-allylpalladium complex XII would progress
easily (Table 3, run 2). The use of THF instead of toluene
as a solvent gave a good result, the total yield of
carbapenam being 55% (run 3).
Next, the leaving group was changed from a benzoate
group to a phosphate group (runs 4 and 5). When 4 equiv
of sodium benzoate was used, the total yield of carbap-
enams was 62%, and the carbapenams were obtained
along with undesired product 35 in 26% yield (run 4).
The latter compound 35 would be obtained by attack of
2 mol of benzoate anions to η3-propargyl complex XI. To
avoid the production of 35, when only 1.5 equiv of sodium
benzoate was used, the total yield of carbapenams
slightly increased (66%, run 5).
Con str u ction of Ca r ba p en a m Ha vin g a â-Meth yl
Gr ou p a t th e 1-P osition . Subsequently, we tried to
synthesize 1â-methylcarbapenam. For the synthesis of
1â-methylcarbapanam, substrate 39 was synthesized in
a similar manner as that for the synthesis of non-
substituented 32b (Scheme 11).
When phosphate 39 was treated under the best condi-
tions for the synthesis of carbapenams 33 and 34, the
desired carbapenams 40 and 41 were obtained in 5% and
71% yields, respectively (Scheme 12). The latter com-
pound 41 consists of two diastereomers at the 2-position
and the ratio of â to R is 5.5 to 1. The stereochemistry
was determined by an NOE experiment on 41-2â to be
41-2â and 41-2r.
tetrabromide to give dibromoalkene 29. The resultant 29
was treated with BuLi and then paraformaldehyde to
give propargyl alcohol 30, which was converted into
â-lactams 32a and 32b by the usual methods.
When a toluene solution of propargyl benzoate 32a was
heated in the presence of 5 mol % of Pd2dba3‚CHCl3, 20
mol % of DPPF, and 2 equiv of Cs2CO3 at 50 °C for 12 h,
the desired carbapenams 33 and 34 were obtained,
although the yields were only 9% and 2%, respectively
(Table 3, run 1). Compound 34 consists of two isomers
in a ratio of 1 to 1, and the stereochemistry at the
2-position of 34 was determined by NOE experiments to
be 34-â and 34-R (Figure 1).
Various reaction conditions were used to try to increase
the yield of carbapenams 33 and 34. It was found that
To examine the effect on the stereochemistry of the
methyl group at the â-position on the formation of 1â-
8072 J . Org. Chem., Vol. 68, No. 21, 2003

Novel Synthesis of Carbapenam
SCHEME 12. Syn th esis of 1â-Meth yl- a n d
1r-Meth ylca r ba p en a m s
F IGURE 2.
F IGURE 3.
attacks the central carbon of η3-propargylpalladium
complex XIV to give π-allylpalladium complex XV or XV′.
The benzoate anion attacks from the backside of the
palladium metal on π-allylpalladium complex XV and
XV′ to give 41-2â and 41-2r, respectively.
SCHEME 13. P ossible Rea ction Cou r se
The reason for the difference between the ratio of 41-
2â to 41-2r (5.5 to 1) and that of 34-2â and 34-2r (1 to
1) is thought to be the steric hindrance between the
palladium metal on the π-allylpalladium complex and the
1â-methyl group. Formation of π-allylpalladium complex
XV should be easier than that of XV′ because of the steric
hindrance of the â-methyl group on the five-membered
ring of carbapenam. Since the nucleophile attacks from
the backside of XV and XV′, the yield of 41-2â is higher
than that of 41-2r (Figure 2).
However, in the case of the reaction of 32, R- and â-π-
allylpalladium complexes XVII and XVII′ should be
formed in the same ratios, and the nucleophile attacks
from each opposite side to give 34-2â and 34-2r in a ratio
of 1 to 1 (Figure 3).
On the other hand, in the case of 42, the ratio of 43-2â
to 43-2r is 1 to 4. Presumably, the structures of π-al-
lylpalladium complexes would be XVI and XVI′. The
benzoate anion would attack from the backside of the
palladium metal. In these cases, formation of 43-2r is
easier than that of 43-2â because of the steric hindrance
between the R-methyl group and the palladium metal on
XVI. Finally, we found that when sodium acetate was
used instead of sodium benzoate as a base under the
condition of a lower reaction temperature (40 °C), only
1â-methylcarbapenam 44 was obtained in 78% yield
(Scheme 14).
In conclusion, we have developed a novel method for
synthesizing carbapenam via a η3-propargylpalladium
complex. It is interesting that different ring-sized het-
erocycles, carbapenam and carbacepham, can be conve-
niently synthesized from the same â-lactam having a
propargyl alcohol moiety, using Pd(0) with a monodentate
methylcarbapenam, 1R-methylcarbapenam was synthe-
sized. For that purpose, 42 was synthesized from 36-1r.
When phosphate 42 was treated under the same reaction
conditions, the desired carbapenams 40 and 43 were
obtained in 17% and 50% yields, respectively, and the
ratio of 43-2â to 43-2r was 1 to 4.
The possible reaction course is shown in Scheme 13.
Oxidative addition of propargyl phosphate 39 to Pd(0)
in the presence of a bidentate ligand gives a σ-allenylpal-
ladium complex, which is in a state of equilibrium with
η3-propargylpalladium complex XIV. The lactam nitrogen
J . Org. Chem, Vol. 68, No. 21, 2003 8073

Kozawa and Mori
in THF (1 mL) was added a solution of 39 (49.2 mg, 0.110
mmol) in THF (2 mL) at 0 °C followed by degassing, then the
mixture was stirred at room temperature for 5 min, then at
40 °C for 22 h. After removal of the solvent, the residue was
purified by silica gel column chromatography (hexane/Et2O 5/1)
to afford 44 (30.3 mg, 0.0857 mmol, 78%) as a colorless oil. 1H
NMR (270 MHz, CDCl3) δ 0.07 (s, 6 H), 0.80 (d, J ) 7.3 Hz, 3
H), 0.87 (s, 9 H), 1.22 (d, J ) 6.5 Hz, 3 H), 2.16 (s, 3 H), 2.80
(qdd, J ) 7.3, 5.9, 5.9 Hz, 1 H), 3.15 (dd, J ) 5.9, 2.7 Hz, 1 H),
3.87 (dd, J ) 5.9, 2.7 Hz, 1 H), 4.22 (qd, J ) 6.5, 5.9 Hz, 1 H),
4.47 (dd, J ) 2.2, 2.2 Hz, 1 H), 4.96 (dd, J ) 2.2, 2.2 Hz, 1 H),
5.69 (ddd, J ) 5.9, 2.2, 2.2 Hz, 1 H). 13C NMR (100 MHz,
CDCl3) δ -4.91 (CH3), -4.18 (CH3), 8.55 (CH3), 17.97 (C), 20.80
(CH3), 22.60 (CH3), 25.71 (CH3), 36.37 (CH), 53.93 (CH), 60.77
(CH), 65.62 (CH), 77.26 (CH), 92.14 (CH2), 140.90 (C), 169.84
(C), 170.19 (C). IR (neat) 2955, 2930, 2885, 2857, 1777, 1751,
SCHEME 14. Syn th esis of 1â-Meth ylca r ba p en a m
ligand or a bidentate ligand. In this reaction, the type of
ligand plays an important role in determination of the
ring size of the cyclized compound, and two types of 1â-
methylcarbapenams, which are expected to have poten-
tially unique biological properties, can be synthesized
from â-lactams having a propargyl group on the side
chain by palladium-catalyzed cyclization by two different
methods.
t
1658 cm-1. LRMS (EI, m/z) 338 (M - Me)+, 296 (M - Bu)+.
HRMS (EI) calcd for C14H22NO4Si 296.1318 (M - tBu)+, found
296.1314.
Exp er im en ta l Section
Su p p or t in g In for m a t ion Ava ila b le: Information on
experimental procedures, spectral data for substrate 2-9, 15-
21, 27-32, and 36-39 and for carbapenams and carba-
cephams 10, 11, 22-25, 33-35, 40, 41, and 43. This material
is available free of charge via the Internet at http://pubs.acs.org.
Typ ica l P r oced u r e for th e Syn th esis of Ca r ba p en a m :
(1R,2R,5R,6S)-2-Acetoxy-6-[(R)-1-ter t-bu tyld im eth ylsily-
loxyeth yl]-1-m eth yl-3-m eth ylid en e-ca r ba p en a m (44). To
a suspension of Pd2(dba)3CHCl3 (5.7 mg, 0.00551 mmol), DPPF
(12.2 mg, 0.0220 mmol), and MeCOONa (13.5 mg , 0.165 mmol)
J O030123C
8074 J . Org. Chem., Vol. 68, No. 21, 2003