Successive copper(I)-catalyzed cross-couplings in one pot: A novel and efficient starting point for synthesis of carbapenems

Article abstract of DOI:10.1021/ol800845r

(Chemical Equation Presented) An efficient approach for synthesizing a series of 2-sulfide carbapenems has been developed using two successive Cu(I)-catalyzed crosscouplings in a single pot. The method involves highly selective intramolecular coupling of lactam and dihaloalkene using 2,2′-bipyridine as a ligand, followed by intermolecular C-S formation in the presence of another ligand (1,10-phenanthroline, PPh₃) and mercaptan.

Full text of DOI:10.1021/ol800845r

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2737-2740
Successive Copper(I)-Catalyzed
Cross-Couplings in One Pot: A Novel
and Efficient Starting Point for
Synthesis of Carbapenems
Biao Jiang,* Hua Tian, Zuo-Gang Huang, and Min Xu
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, PRC
jiangb@mail.sioc.ac.cn
Received April 14, 2008
ABSTRACT
An efficient approach for synthesizing a series of 2-sulfide carbapenems has been developed using two successive Cu(I)-catalyzed cross-
couplings in a single pot. The method involves highly selective intramolecular coupling of lactam and dihaloalkene using 2,2′-bipyridine as
a ligand, followed by intermolecular C-S formation in the presence of another ligand (1,10-phenanthroline, PPh3) and mercaptan.
As the latest members of the ꢀ-lactam family, carbapenem
antibiotics occupy a central role in fighting bacterial infection
due to their broad-spectrum activity and excellent resistance
to ꢀ-lactamase.1 Carbapenems are characterized by a five-
membered enamine ring fused to the ꢀ-lactam ring. However,
thienamycin 1, the first carbapenem isolated from Strepto-
myces cattleya,2 could not be marketed due to its chemical
and biological instabilities. Thus, extensive efforts over the
past decades have sought to synthesize more promising
compounds based on this leading structure.
been described.3 Developing an efficient methodology for
constructing the carbapenem skeleton still remains challeng-
ing for organic synthesis because of its highly strained
four-five fused ring system. A great deal of synthetic efforts
have been devoted to the synthesis of the bicyclic nucleus,
involving Rh-mediated carbenoid N-H insertion,4 intramo-
lecular Wittig-type reaction,5 radical cyclization,6 Dieckmann
condensation,7 and cyclizations catalyzed by Pd8 or other
(3) Coulthurst, S. J.; Barnard, A. M. L.; Salmond, G. P. C. Nat. ReV.
Microbiol. 2005, 3, 295.
Currently, a number of carbapenems are in clinical use,
such as imipenem, panipenem, ertapenem, biapenem, Mero-
penem, and doripenem. Unlike penicillins and cephalospor-
ins, whose precursors are produced by industrial fermenta-
tion, carbapenems can be made only through total synthesis,
since no effective enzymatic process for their production has
(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.;
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(1) (a) Sunagawa, M.; Sasaki, A. Heterocycles 2001, 54, 497. (b) Georg,
G. I. The Organic Chemistry of ꢀ-Lactams; VCH Publishers: New York,
1993.
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10.1021/ol800845r CCC: $40.75
Published on Web 05/30/2008
2008 American Chemical Society

transition metals.9Only the Rh-carbene process has proven
to be practical for synthesizing a series of carbapenems. This
method involves four reaction sequences: diazetization of
ꢀ-ketoester, Rh-catalyzed carbene insertion to the N-H bond,
activation of the ketoester with phosphoryl chloride or triflic
anhydride, and last, incorporation of a C-2 side chain. Despite
its successful industrial application, this procedure suffers
several drawbacks, such as the use of an expensive catalyst,
harsh reaction conditions, and long reaction steps. Therefore,
there is still great interest in an economical protocol that
can rapidly lead to varieties of carbapenems to meet clinical
demands and that can uncover new types of carbapenems
with enhanced performance.
cessive coupling strategy. In our procedure, the C-S side
chains are incorporated in an intermolecular manner, and the
bicyclic nucleus is made by an intramolecular regioselective
coupling14 of ꢀ-lactam with an endo-orientated vinyl iodide.
Previously, we reported a convenient method for the
preparation of 4-propargyl-2-azetidinone 2 from 4-acetoxy-
2-azetidinone and propargyl bromides via a zinc-mediated
Barbier-type reaction.15 Subsequently, we investigated the
stereoselective diiodination of the alkyne 2 to give the (E)-
1,2-diiodoalkene 3, using a modified method (Scheme 2),
Scheme 2. Synthesis of the (E)-1,2-Dihaloalkene Intermediate
In view of the fact that carbapenems possess both vinyl
sulfide and enamide groups, we speculated that a series of
carbapenems could be synthesized through two successive
cross-coupling reactions as shown in Scheme 1. Metal-
Scheme 1. Structure of Thienamycin and Synthetic Strategy
in which the ꢀ-lactam nitrogen was first selectively iodinated
by NIS, the triple bond was diiodinated by ICl/NaI, and
finally the iodide substituted on the nitrogen was removed
by NaHSO3, giving an overall yield of 79%.16 The triple
bond could also be diiodinated directly and selectively by
treating with iodine in the presence of a source of iodide
ion.
Starting from (E)-R,ꢀ-diiodoacrylic acid ester 3, we set
out to study Cu(I)-catalyzed intramolecular C-N coupling.
Initial ligand screening was performed using CuI with
Cs2CO3 or K3PO4 as the base. To our delight, among the
seven ligands examined, N,N′-dimethylethylenediamine (L1),
N,N-dimethylglycine (L2), and 2,2′-bipyridine (bpy) (L6)
gave good results. L6, in particular, produced the desired
enamide at 87% yield (Table 1, entries 2, 3, and 7). When
using 1,10-phenanthroline (L3) or N,N,N′,N′-tetramethyleth-
ylenediamine (L4) as ligand, deiodination occurred to give
the precursor 2 in 40-50% yield (entries 4 and 5). We also
tested other copper(I) systems like copper thiophene-2-
carboxylate (CuTC) and [Cu(phen)(PPh3)2]NO3, which have
shown excellent reactivities for synthesis of enamides12b and
vinylsulfide.13 No product was formed using CuTC (entry
11), while [Cu(phen)(PPh3)2]NO3 gave only unproductive
results similar to those obtained with L3 and L4 (entry 10).
Notably, under Mori’s conditions17 with Pd(OAc)2/DPEphos,
deiodination occurred and gave more than 50% alkyne side
product, along with a trace of cyclization product (entry 12).
On the basis of the good performance of bpy, several other
solvents and bases were screened. Toluene was the best
solvent, while polar solvents such as DMF, NMP, THF, and
ethanol gave much lower yields. Cs2CO3 or K2CO3 gave
catalyzed carbon-heteroatom bond formation has attracted
much attention in organic synthesis, such as copper-catalyzed
cross-coupling reactions10 for the synthesis of enol ethers,11
vinylsulfide, and enamides. N-Vinylation reactions catalyzed
by copper(I), particularly in combination with bidentate
amine ligands, is a mild and efficient protocol for stereo-
controlled coupling of vinyl halides with amides.12 In
addition, synthesis of vinyl sulfides via copper(I)-catalyzed
stereospecific cross-coupling of vinyl iodides and thiols has
recently been developed.13 In this paper, we report an
efficient synthesis of carbapenems based on this two suc-
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1443. (b) Shen, R.; Porco, J. A., Jr Org. Lett. 2000, 2, 1333. (c) Jiang, L.;
Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667. (d) Pan,
X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809. (e) Coleman, R. S.; Liu,
P.-H. Org. Lett. 2004, 6, 577. (f) Han, C.; Shen, R.; Su, S.; Porco, J. A., Jr
Org. Lett. 2004, 6, 27. (g) Trost, B. M.; Stiles, D. T. Org. Lett. 2005, 7,
2117.
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46, 572.
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(16) (a) Hollins, R. A.; Campos, M. P. A. J. Org. Chem. 1979, 44, 3931.
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2738
Org. Lett., Vol. 10, No. 13, 2008

Table 1. Copper(I)-Catalyzed Intramolecular N-Vinylation
Reaction
Table 2. CuI/bpy-Catalyzed Intramolecular Cross-Coupling for
Synthesis of 2-Iodocarbapenema
entry
catalysta
T (°C) base t (h) yieldb,c (%)
1
2
3
4
5
6
7
9
8
None
40 K3PO4
40 Cs2CO3 17
rt Cs2CO3
40 K3PO4
40 K3PO4
40
24
72
71
5(50)
6(44)
32
CuI/L1
CuI/L2
CuI/L3
CuI/L4
CuI/L5
CuI/L6
CuI/L6
CuI/L7
3
25
25
40 Cs2CO3 48
40 K3PO4
40 K3PO4
40 K3PO4
40 K3PO4
70 Cs2CO3 30
100 K2CO3
50
21
20
15
87
94d
18
10e [Cu(phen)(PPh3)2]NO3
11e Cu(TC)
8(42)
0
<3(51)
12f Pd(OAc)2/DPEphos
1
a Unless otherwise indicated, reactions were performed using 20 mol
% of CuI, 40 mol % of ligand, and 2.0 equiv of base. b Isolated yield.
c The alkyne compound 2 is given in parentheses. d 1 equiv of H2O as
additive. e 20 mol % of catalyst was used. f 10 mol % of Pd(OAc)2 and 15
mol % of DPEphos were used.
yields ∼2-5% lower than K3PO4. We found that by using
K3PO4 in combination with 1 equiv of H2O the coupling
could be completed within 21 h to give the desired product
in 94% yield (entry 9). The product 2-iodocarbapenem 4a
was stable in solid form for months at room temperature in
the dark. Moreover, its structure was confirmed unambigu-
ously by X-ray crystallography.18
Next, the range of possible substrates was investigated
under the following conditions: CuI/2,2′-bipyridine as cata-
lyst, K3PO4 as base with 1 equiv of H2O as additive, and
toluene as solvent (Table 2). For all substrates tested,
intramolecular coupling took place in excellent yields. The
important 1ꢀ- or 1R-methyl 2-iodocarbapenem intermediates
for synthesis of 1-methyl carbapenem were formed smoothly
in good yield without epimerization of the allylic carbon
(entries 4 and 5). In particular, the substrate p-nitrobenzyl
ester gave a reaction that produced 4f (entry 6) in 94% yield,
and this can be readily transformed into important car-
bapenems now on the market. Diiodoalkenes without an
electron-withdrawing ester group were also found to be
excellent substrates for cyclization (entries 2 and 3). The
allyllic compounds 3g and 3h gave desired products that offer
the potential to functionalize the acetoxy methylene or
benzyloxy methylene groups in the final carbapenems (entries
a The reaction was performed in the presence of 20 mol % of CuI and
40 mol % of bpy in 0.04 M toluene solution at 40 °C. b Isolated yield. c No
H2O was added.
7 and 8). The R-iodo, ꢀ-chloro, or bromo-acrylic acid esters,
which were prepared by dihalogenating the N-iodonation
product of 2 using IX/NaX (X ) Cl or Br) instead of I2/
NaI, could also undergo rapid cyclization to yield the
corresponding 2-chlorocarbapenem or 2-bromicarbapenem
(entries 9 and 10), while these substrates show low reactivity
and only moderate selectivity in the intermolecular ver-
sions.19 In all cases, no intermolecular coupling was ob-
(18) CCDC-671461 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Org. Lett., Vol. 10, No. 13, 2008
2739

served, and no 4-exo cyclization products were detectable,
even though this reaction mode has been applied in the
synthesis of azetidine20 and 2-methyleneoxetane.21 Starting
from 2-iodocarbapenem, we turned our attention to the
copper(I)-promoted intermolecular C-S bond formation at
the C-2 position. Initially, we applied the Venkataraman
coupling with protected 2-amino-ethanethiol, which leads to
thienamcyin (entry 6). Considering that both successive
couplings were catalyzed by copper(I) species, we reasoned
that it might be possible to perform the requisite intramo-
lecular N-vinylation and intermolecular S-vinylation in one
pot without the need to isolate the monoiodocarbapenem
intermediate or to add more CuI. Indeed, as shown in method
B, one-pot synthesis of carbapenems could be performed by
adding 1,10-phenanthroline (L3), PPh3, and the correspond-
ing thiol to the N-vinylation coupling mixture once the
diiodoalkene was consumed completely. Comparison of the
yields obtained by the one-pot and stepwise methods suggests
that the catalytic activities of the CuI and phenanthroline
were maintained even in the presence of bipyridine.
In conclusion, an efficient approach using two successive
copper(I)-catalyzed couplings has been developed for the
synthesis of carbapenems with a series of sulfide side chains
at the C-2 position. The remarkable transformation in our
sequence is the regioselective CuI/bpy-catalyzed intramo-
lecular cross-coupling of the trans-diiodoalkene side chain
with the ꢀ-lactam nitrogen to yield the key intermediate
2-iodocarbapenem, which further undergoes copper(I)/1,10-
phenanthroline-mediated intermolecular coupling with dif-
ferent thiols to provide a series of carbapenems. In addition,
the two successive couplings can be performed in one pot
simply by adding a 1,10-phenanthroline ligand and thiol
substrate to the completed N-vinylation coupling reaction;
isolation of intermediates or addition of more copper(I) is
unnecessary. The advantages of this novel synthetic meth-
odology include the use of readily available starting materials
and inexpensive catalyst, fewer synthetic steps, and mild
reaction conditions. Notably, this protocol not only provides
rapid access to the classical carbapenems but also allows
for combinatorial diversification at the C-2 and C-3 positions.
This creates the potential for exploring new types of
carbapenem antibiotics with enhanced chemotherapeutic
activities.
protocol13 by using 20 mol
%
of soluble
[Cu(phen)(PPh3)2]NO3. This catalyst system was compatible
with the sensitive structures, as indicated in Table 3. The
Table 3. Synthesis of Carbapenems Substituted with Sulfur at
the C-2 Position
Acknowledgment. This work was financially supported
by the Science & Technology Commission of Shanghai
Municipality and the National Natural Science Foundation
of China.
a The reaction was performed with 20 mol % of catalyst in toluene at
60 °C. b 20 mol % of phenanthroline, 40 mol % of PPh3, and 1.2 equiv of
RSH were added after cyclization. c Isolated yield. d 100 mol % of catalyst
was used. e 80 mol % of CuI, 1.0 equiv of phenanthroline, and 2.0 equiv of
PPh3 were added after the cyclization.
Supporting Information Available: General experimental
metheods, X-ray crystallographic data for compound 4a, and
spectroscopic data for all new compounds are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
2-iodocabarpenems reacted with benzyl, aryl, alkyl, and
heteroaryl thiol to give high yields of coupling products under
milder conditions than ordinary alkene iodides, probably due
at least in part to activation by a ꢀ-ester group (method A).22
A stoichiometric amount of catalyst was required when
OL800845R
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2740
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