Synthesis of 3-alkoxycarbonyl-1β-methylcarbapenem by using the palladium-catalyzed C-N bond-forming reaction between vinyl halide and β-lactam nitrogen

Article abstract of DOI:10.1021/jo020584i

3-Alkoxycarbonyl-1β-methylcarbapenem could be synthesized by using a palladium-catalyzed C-N bond-forming reaction between vinyl halide and β-lactam nitrogen. In this reaction, the use of Pd-(OAc)₂ and DPEphos gave a good result, and the generation of Pd(0) from Pd(OAc)₂ in the absence of a base is necessary to increase the yield.

Full text of DOI:10.1021/jo020584i

Syn th esis of 3-Alk oxyca r bon yl-1â-m eth ylca r ba p en em by Usin g th e
P a lla d iu m -Ca ta lyzed C-N Bon d -F or m in g Rea ction betw een Vin yl
Ha lid e a n d â-La cta m Nitr ogen
Yuji Kozawa and Miwako Mori*
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, J apan
mori@pharm.hokudai.ac.jp
Received September 4, 2002
3-Alkoxycarbonyl-1â-methylcarbapenem could be synthesized by using a palladium-catalyzed C-N
bond-forming reaction between vinyl halide and â-lactam nitrogen. In this reaction, the use of Pd-
(OAc)2 and DPEphos gave a good result, and the generation of Pd(0) from Pd(OAc)2 in the absence
of a base is necessary to increase the yield.
In tr od u ction
intramolecular nucleophilic attack of active methylene
to a π-allylpalladium complex, and he recently also
reported the synthesis of carbapenam derivatives using
metathesis reaction.6 We have investigated the possibility
of synthesizing a carbapenem skeleton using organo-
metallic reagents.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
extended to intramolecular reactions of aryl halides and
amides, carbamates, and sulfonamides, and it has been
utilized in many areas of organic synthesis.9
Extensive and succesive works have been performed
for the development of carbapenem antibiotics having
chemical and biological properties for clinical use since
the discovery by Merck’s group of thienamycin, the first
naturally occurring carbapenem antibiotic and one that
has strong antibiotic activity.1 The development of a new
method for forming a carbapenam skeleton is very
important in establishing a method for efficient synthesis
of new types of carbapenem antibiotics.2 In general, for
the construction of a carbapenam skeleton, a five-
membered ring is formed from four-membered â-lactam.
However, it is not so easy to construct a carbapenam
skeleton because of its highly strained structure. Orga-
nometallic 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 remarkable reports on the
construction of carbapenam skeletons with use of orga-
nometallic reagents.3 For example, as originally reported
by Merck’s group, intramolecular reaction of a rhodium-
carbene complex with the N-H bond of â-lactam is often
used for the synthesis of a wide range of carbapenem
derivatives.4 Trost reported the synthesis of carbapenam
derivatives using palladium-catalyzed cyclization.5 Genet
reported the synthesis of carbapenem derivatives by
Our plan for the construction of a carbapenem skeleton
involving the coupling of vinyl halide and amide in the
presence of a palladium catalyst is shown in Scheme 2,7c
although little is known about the reaction between vinyl
(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.
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K.; Takimoto, M. Org. Lett. 2000, 2, 3245. (b) Kozawa, Y.; Mori, M.
Tetrahedron Lett. 2001, 42, 4869. (c) Preliminary report of this
article: 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.;
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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,
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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,
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* Corresponding author.
(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.
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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.
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M.; Sciotti, R. J .; Wiedeman, P. E.; Djuric, S. W. Tetrahedron Lett.
2001, 42, 3681. (b) Cacchi, S.; Antonella Goggiamani, G. F.; Zappia,
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10.1021/jo020584i CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/15/2003
3064
J . Org. Chem. 2003, 68, 3064-3067

Synthesis of 3-Alkoxycarbonyl-1â-methylcarbapenem
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 e a n d
Am in es
SCHEME 3. Syn th esis of Vin yl Br om id es
SCHEME 2. Ou r P la n for th e Syn th esis of a
Ca r ba p en em Sk eleton
halide, instead of aryl halide, and amide in the presence
of a palladium catalyst.
If vinyl halide I is treated with Pd(0) in the presence
of a base, palladacycle II would be formed. Reductive
elimination from II would give carbapenem III having
the methoxycarbonyl group at the 3-position. Because it
is known that the presence of a 3-carboxyl group on the
five-membered ring in a carbapenem skeleton is very
important for antibiotic activity, III could be a potential
precursor for carbapenem having a carboxyl group at the
3-position. We report the synthesis of a carbapenem
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 ba p en em Ha vin g t h e Silyl-
oxym eth yl Gr ou p a t th e 3-P osition . At first, we
investigated the reaction of amide nitrogen in the â-lac-
tam ring with vinyl bromide having a silyloxymethyl
group in palladium-catalyzed amidation. Vinyl bromide
6 was synthesized from 2-azetidinone 1 (Scheme 3).10
Protection of the amide nitrogen of 1 with a silyl group
followed by ozonolysis gave aldehyde 3, which was
reacted with the Wittig reagent11 to give Z-vinyl bromide
4 in 78% yield along with E-vinyl bromide in 13% yield.
Reduction of 4 by DIBAL-H gave 5, which was converted
into 6 by the usual method.
Intramolecular coupling of 6 in the presence of a
palladium catalyst was examined. When a toluene solu-
tion of 6 was heated in the presence of 5 mol % of Pd2-
dba3‚CHCl3, 20 mol % of P(o-Tol)3, and 2 equiv of Cs2CO3
at 90 °C for 8.5 h, carbapenem 8 having a silyloxymethyl
group at the 3-position was obtained, although the yield
was low (Table 1, Run 1). In accordance with a recent
report by Buchwald,8k Pd(OAc)2-MOP and Pd(OAc)2-
BINAP were used as the catalyst systems, but good
results were not obtained (Runs 2 and 3). However,
surprisingly, when DPEphos was used as a ligand, the
TABLE 1. Rea ction of 6 w ith P a lla d iu m Ca ta lysts
yield (%)
temp time
run
Pd
ligand
(°C)
(h)
8.5 16
11
8
6
1a
2b
3b
4b
Pd2(dba)3CHCl3 P(o-Tol)3
90
80
80
80
75
65
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
(S)-MOP
BINAP
DPEphos
3
11
6
trace 76
96
-
a
5 mol % of Pd2(dba)3CHCl3 and 20 mol % of a ligand were
b
used. 10 mol % of Pd(OAc)2 and 15 mol % of a ligand were used.
participate well in a palladium-catalyzed C-N bond-
forming reaction.
Subsequently, the synthesis of 1â-methylcarbapenem
was investigated. In general, it is known that a carbap-
enem skeleton having a 1â-methyl group is both biologi-
cally and chemically more stable than is a nonsubstitu-
ented carbapenem skeleton and attention is currently
focused on its unique biological properties.1c,12
Consequently, the two diastereomers of 910 were sepa-
rated by column chromatography on silica gel, and isomer
9-â was ozonolyzed to give aldehyde 10, which was
converted into vinyl bromide 13a in a similar manner
as that for the synthesis of 613 (Scheme 4).
The coupling reaction of vinyl bromide 13a having a
silyloxymethyl group was examined. When a toluene
desired carbapenem 8 was obtained in 96% yield (Run
4). This result showed that a vinyl bromide could
(12) Shih, D. H.; Baker, F.; Cama, L.; Christensen, B. G. Heterocycles
1984, 21, 29.
(13) Wadsworth, W. S., J r.; Emmons, W. D. J . Am. Chem. Soc. 1961,
83, 1733.
(10) Imuta, M.; Itani, H.; Ona, H.; Hamada, Y.; Uyeo, S.; Yoshida,
T. Chem. Pharm. Bull. 1991, 39, 663.
(11) Ma¨rkl, G. Chem. Ber. 1962, 95, 3003.
J . Org. Chem, Vol. 68, No. 8, 2003 3065

Kozawa and Mori
SCHEME 6. Rea ction of 7 w ith a P a lla d iu m
SCHEME 4. Su bstr a tes for Syn th esis of
1â-Meth ylca r ba p en em
Ca ta lyst
TABLE 2. Rea ction of 14 w ith a P a lla d iu m Ca ta lyst
a
Method A: A toluene solution of 14, Pd(OAc)2, DPEphos, and
M2CO3 was heated at 100 °C. Method B: A toluene solution of
14, Pd(OAc)2, and DPEphos was heated at 100 °C for 2 min and
was added to a suspension of K2CO3 in toluene. Then the toluene
SCHEME 5. Rea ction of 13a w ith a P a lla d iu m
Ca ta lyst
b
solution was heated at 100 °C. The reaction mixture was stirred
until the starting material 14 had been completely consumed as
judged by TLC analysis.
ethoxycarbonyl group did not produce carbapenem 17
(Table 2, Run 1). However, when K2CO3 was used instead
of Cs2CO3, we were very pleased to find that 17 was
obtained in 59% yield (Run 2). The reaction rate of 14a
was much slower than that of 13a . Under the same
conditions, vinyl iodide 14b gave 17 in only 20% yield
(Run 3), although, in general, the reactivity of vinyl iodide
is higher than that of vinyl bromide in the oxidative
addition to Pd(0). To generate Pd(0) in a palladium-
catalyzed C-N bond-forming reaction, Buchwald has
carried out a special procedure. That is, a toluene solution
of the substrate, Pd(OAc)2, and the ligand was heated in
the absence of a base at 100 °C for 2 min to dissolve the
catalysts, and then the base was added at 0 °C. Then
the toluene solution was heated at an appropriate tem-
perature (method B).8k Our next trials were carried out
using this method (method B) reported by Buchwald.
When vinyl triflate 14c was used, 17 was obtained in only
low yield, although the starting material was consumed
(Run 4). However, surprisingly, the yield of 17 increased
to 90% when vinyl iodide 14b was reacted with Pd(OAc)2
and DPEphos, using method B (Run 5). Treatment of
vinyl bromide 14a by using method B also increased the
yield of 17 (Run 6). On the other hand, the use of Na2-
CO3 or Cs2CO3 as a base gave only a trace amount of 17
(Runs 7 and 8). When BINAP or DPPF or PPh3 as a
ligand was used, the yields were very low. These results
solution of 13a , Pd(OAc)2, DPEphos, and Cs2CO3 was
heated at 80 °C, carbapenem 15 was obtained in 97%
yield after only 1.5 h, at which time TLC analysis showed
complete consumption of starting material 13a (Scheme
5). The reaction of methyl-substituented 13a progressed
faster than that of nonsubstituented 6.
Con st r u ct ion of Ca r b a p en em H a vin g a Ca r -
ba lk oxy Gr ou p a t th e 3-P osition . Encouraged by the
excellent results obtained by using the substrates 6 and
13a having a silyloxymethyl group at the 3-position,
palladium-catalyzed coupling of vinyl bromide 7 having
a carbomethoxy group was attempted. Synthesis of 7 is
shown in Scheme 3. The reaction of 7 with Pd(OAc)2 and
DPEphos was carried out under the same reaction
conditions, but no cyclized product 16 was produced, and
the starting material 7 was recovered in 46% yield
(Scheme 6). The reaction was attempted under various
conditions, but the results were not satisfactory.
Next, with use of substrates 14a and 14b having
â-methyl and the carbethoxy groups at the 1- and
3-positions, synthesis of 3-ethoxycarbonyl-1â-methylcar-
bapenem was attempted. Synthesis of substrates 14a and
14b is shown in Scheme 4. Under the same reaction
conditions (method A), vinyl bromide 14a having an
3066 J . Org. Chem., Vol. 68, No. 8, 2003

Synthesis of 3-Alkoxycarbonyl-1â-methylcarbapenem
SCHEME 7. P ossible Rea ction Cou r se
SCHEME 8. Su bstr a te for Syn th esis of
1r-Meth ylca r ba p en em
suggest that K2CO3 as a base and DPEphos as a ligand
would be the best combination in intramolecular pal-
ladium-catalyzed coupling of 14a .
The difference between methods A and B in this
reaction is the presence or absence of a base in the
generation of Pd(0). In this reaction, Pd(0) would be
generated from Pd(OAc)2 and DPEphos.14 In the case of
method B, when the solution is heated for 2 min in the
absence of a base, Pd(OAc)2 is dissolved by the coordina-
tion of the ligand and then Pd(0) would be formed. In
the absence of a base, only DPEphos would completely
coordinate to the palladium metal. Then the base is
added and the nitrogen anion is produced to form
palladacycle V (Scheme 7).
SCHEME 9. Syn th esis of 1r-Meth ylca r ba p en em
However, in the case of method A, since the generation
of the nitrogen anion by the base and the generation Pd-
(0) from Pd(OAc)2 occur simultaneously upon heating at
100 °C, various palladium species involving the coordina-
tion of the nitrogen anion on palladium metal would be
produced under the reaction conditions, because the
palladium catalyst should not form an eight-membered
ring by coordination of DPEphos. As result, the yields of
17 would be decreased.
Next, to compare the reactivity of vinyl bromide having
a 1â-methyl group with that of vinyl bromide having a
1R-methyl group in the palladium-catalyzed C-N bond-
forming reaction, 3-ethoxycarbonyl-1R-methylcarbapen-
em 21 was synthesized from vinyl bromide 20. Vinyl
bromide 20 was also synthesized in a similar manner
with 14a (Scheme 8).
When 20 was treated following method B under similar
reaction conditions, 21 was obtained in 56% yield (Scheme
9). However, when 7, which has no substituent at the
1-position, was treated in a similar manner, no cyclized
product 16 was produced. This means that the substitu-
ent at the 1-position is important for this cyclization.
In conclusion, 3-alkoxycarbonyl-1â-methylcarbapenem
and 3-alkoxycarbonyl-1R-methylcarbapenem could be
synthesized by using a palladium-catalyzed C-N bond-
forming coupling of vinyl halide and â-lactam nitrogen.
In this reaction, the use of Pd(OAc)2-DPEphos as a
catalyst system and the use of K2CO3 as a base are
suitable, and the generation of Pd(0) in the absence of a
base is necessary to increase the yield. Although only aryl
halide has been used for C-N bond-forming reactions,
our results also indicated that vinyl bromide or vinyl
iodide can be used for a palladium-catalyzed C-N bond-
forming reaction. This new efficient method for the
construction of a carbapenem skeleton with a palladium
catalyst is expected to be a powerful tool for research on
next-generation carbapenem antibiotics.
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 2-8, 11a ,
11b, 12, 13a , 14a , 14b, 15, 17, 19, 20, and 21. This material
is available free of charge via the Internet at http://pubs.acs.org.
(14) Ozawa, F.; Kubo, A.; Hayashi, T. Chem. Lett. 1992, 2177.
J O020584I
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