Diastereoselective synthesis of carbapenams via Kinugasa reaction

Article abstract of DOI:10.1021/jo801212q

(Chemical Equation Presented) A facile approach to carbapenams via Kinugasa reaction between terminal copper acetylides and nonracemic cyclic nitrones derived from malic and tartaric acid is reported. The stereochemical preferences observed in these reactions are explained. The reaction provides an entry to the carbapenams basic skeleton.

Full text of DOI:10.1021/jo801212q

SCHEME 1
Diastereoselective Synthesis of Carbapenams via
Kinugasa Reaction
Sebastian Stecko, Adam Mames, Bartłomiej Furman, and
Marek Chmielewski*
Institute of Organic Chemistry of Polish Academy of
Sciences Kasprzaka 44/52, 01-224 Warsaw, Poland
rangement of the intermediate isoxazoline.5 Later on, Miura and
co-workers developed a first catalytic version of this reaction
with a substoichiometric amount of CuI.6 The same authors
reported also a first asymmetric version of the Kinugasa reaction
using chiral bisoxazoline ligands.6 In following years, the
extended asymmetric versions of the Kinugasa reaction have
been proposed by groups of Basak,7 Fu,8 Tang,9and Guiry.10
In previous attempts, mostly the acyclic nitrones have been
tested.5-10 Only a limited number of examples of the use of
cyclic 1,3-dipole have been reported to date. These tend to offer,
however, a poor yield of the bicyclic ꢀ-lactams.5 In connection
with our interest in the synthesis of ꢀ-lactams,11 as well as in
the 1,3-dipolar cycloadditions involving cyclic nitrones,12 we
decided to investigate, for the first time, a general and a highly
stereoselective approach to the construction of the carbapenams
basic skeleton, using Cu(I)-mediated cycloaddition of nonra-
cemic nitrones and simple acetylenes (Scheme 1).
chmiel@icho.edu.pl
ReceiVed June 5, 2008
A facile approach to carbapenams via Kinugasa reaction
between terminal copper acetylides and nonracemic cyclic
nitrones derived from malic and tartaric acid is reported. The
stereochemical preferences observed in these reactions are
explained. The reaction provides an entry to the carbapenams
basic skeleton.
In this Note, we report our preliminary studies on the
Kinugasa reaction involving cyclic nitrones 1-3 and simple,
terminal acetylenes 4a-f. Both nitrones 1 and 2 are readily
available from S-malic acid,13 whereas nitrone 3 is derived from
L-tartaric acid.13
The ꢀ-lactam antibiotics represent the most powerful tool
against the bacterial infections. Owing to their attractive
biological activity, the synthesis and properties of mono- and
polycyclic systems containing the ꢀ-lactam ring have been
extensively investigated.1 The history of ꢀ-lactams goes back
to 1907 when Staudinger discovered the imine-ketene cycload-
dition.2 To date, a number of methodologies for the ꢀ-lactam
ring construction in both diastereoselective and enantioselective
manner have been developed.3 Some of these methods have
also found application in syntheses of the non-ꢀ-lactam com-
pounds.3
In 1972 Kinugasa and Hashimoto reported a convergent route
to ꢀ-lactams through the reaction between copper phenyl
acetylides and nitrones.4 Four years later, Ding and Irwin
proposed the mechanism of the Kinugasa reaction, which
involved the 1,3-dipolar cycloaddition and subsequent rear-
(5) Ding, L. K.; Irwin, W. J. J. Chem. Soc., Perkin Trans.1 1976, 2382.
(6) (a) Okuro, K.; Enna, M.; Miura, M.; Nomura, M. J. Chem. Soc., Chem.
Commun. 1993, 1107. (b) Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org.
Chem. 1995, 60, 4999.
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Lett. 1997, 38, 643. (b) Basak, A.; Bahattacharya, G.; Bdour, H. M. Tetrahedron
1998, 54, 6529. (c) Basak, A.; Gosh, S. C.; Bhowmick, T.; Das, A. K.; Bertolasi,
V. Tetrahedron Lett. 2002, 43, 5499. (d) Basak, A.; Chandra, K.; Pal, R.; Ghosh,
S. C. Synlett 2007, 10, 1585. (e) Pal, R.; Ghosh, S.; Chandra, K.; Basak, A.
Synlett 2007, 15, 2321. (f) Ghosh, S.; Basak, A. Synlett 2004, 9, 1637.
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R.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 4082.
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2554. (b) Ye, M.-C.; Zhou, J.; Tang, Y. J. Org. Chem. 2006, 71, 3576.
(10) Coyne, A.; Mu¨ller-Bunz, H.; Guiry, P. J. Tetrahedron: Asymmetry 2007,
18, 199.
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Commun. 1996, 2689. (b) Furman, B.; Borsuk, K.; Kałuz˙a, Z.; Łysek, R.;
Chmielewski, M. Curr. Org. Chem. 2004, 8, 463. (c) Łysek, R.; Borsuk, K.;
Furman, B.; Kałuz˙a, Z.; Kazimierski, A.; Chmielewski, M. Curr. Med. Chem.
2004, 11, 1813. (d) Cierpucha, M.; Panfil, I.; Danh, T. T.; Chmielewski, M.;
Kurztkowski, W.; Rajnisz, A.; Solecka, J. J. Antibiot. 2007, 60, 622. (e)
Furman,B.; Kałuz˙a, Z.; Stencel, A.; Grzeszczyk, B.; Chmielewski, M. In Topics
in Heterocyclic Chemistry; El Ashry, S., Ed.; Springer-Verlag: New York, 2007;
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(12) (a) Jurczak, M.; Rabiczko, J.; Socha, D.; Chmielewski, M.; Cardona,
F.; Goti, A.; Brandi, A. Tetrahedron: Asymmetry 2000, 11, 2015. (b) Socha, D.;
Jurczak, M.; Frelek, J.; Klimek, A.; Rabiczko, J.; Urban´czyk-Lipkowska, Z.;
Suwin´ska, K.; Chmielewski, M.; Cardona, F.; Goti, A.; Brandi, A. Tetrahedron:
Asymmetry 2001, 12, 3163. (c) Pas´niczek, K.; Socha, D.; Jurczak, M.; Frelek,
J.; Suszczyn´ska, A.; Urban´czyk-Lipkowska, Z.; Chmielewski, M. J. Carbohydr.
Chem. 2003, 22, 613. (d) Stecko, S.; Pas´niczek, K.; Jurczak, M.; Urban´czyk-
Lipkowska, Z.; Chmielewski, M. Tetrahedron: Asymmetry 2006, 17, 68. (e)
Stecko, S.; Pas´niczek, K.; Jurczak, M.; Urban´czyk-Lipkowska, Z.; Chmielewski,
M. Tetrahedron: Asymmetry 2007, 18, 1085.
(1) (a) ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E.F., Eds.; Pergamon: New York, 1996; Chapter 1.18-1.20.
(b) Ojima, I.; Delaloge, F. Chem. ReV. Soc. 1997, 26, 377. (c) Ojima, I. Acc.
Chem. Res. 1995, 28, 383. (d) Magriotis, P. A. Angew. Chem., Int. Ed. 2001,
40, 4377. (e) Synthesis of ꢀ-Lactam Antibiotics, Chemistry, Biocatalysis and
Process Integration; Bruggink, A., Ed.; Kluwer: Dordrecht, The Netherlands,
2001. (f) Chemistry and Biology of ꢀ-Lactam Antibiotics; Morin, M. B. M.,
Gorman, M.B., Eds.; Academic Press: New York, 1982. (g) The Organic
Chemistry of ꢀ-Lactams; Georg, G.I., Ed.;Wiley-VCH: New York, 1993.
(2) Staudinger, H. Ann. Chem. 1907, 356, 51.
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Chem. 2004, 11, 1837. (b) Deshmukh, A.R.A.S.; Bhwal, B. M.; Krishnaswamy,
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Alcaide, B.; Almendros, P.; Argoncillo, C. Chem. ReV. 2007, 107, 4437.
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7402 J. Org. Chem. 2008, 73, 7402–7404
10.1021/jo801212q CCC: $40.75 2008 American Chemical Society
Published on Web 08/08/2008

The reaction of nitrone 1 with phenylacetylene gave two
bicyclic products 5a and 6a in a ratio of about 85:15,
respectively. The configuration of both compounds was assigned
by the NMR spectra and NOE experiments. For 5a, the
configuration assignment was confirmed by the X-ray crystal
structure analysis.14 Our initial experiments were carried out in
degassed MeCN using 1 equiv of Et3N and 1 equiv of CuI.
Unfortunately, the yield of the reaction did not exceed 56%
even after 20 h. Further extension of the reaction time led to
the increase of the amount of the 5,6-trans product 6b only
(Table 1, entry 2). The replacement of the triethylamine by a
bulky amine (Table 1, entries 3 and 4) resulted in an increase
of the diasteroselectivity up to 96% but simultaneously de-
creased the overall reaction yield. The use of other amines such
as pyridine or N,N,N′,N′-tetramethylethylenediamine did not
improve the reaction outcome (Table 1, entries 5 and 6).
The careful analysis of the reaction revealed that the cyclic
nitrone readily undergoes the Cu(I)-mediated deoxygenation.
This process is well-known in literature.15 The rate of the side
reaction is similar to that of the cycloaddition, which explains
the poor yield of the ꢀ-lactam. Moreover, the fast decomposition
of the nitrone and simultaneous deactivation of copper elimi-
nated the possibility to carry out the catalytic version of the
reaction. In an experiment with 10 mol % of CuI, only a trace
of products was detected. It was found that the addition of
hydrazine monohydrate (20 mol %) to the reaction mixture
stopped the deoxygenation process and allowed a significant
increase of the yield.16 At the same time we observed, however,
a decrease of the stereoselectivity (Table 1, entries 7 and 8).
The replacement of triethylamine by hydrazine resulted in
decrease of both the yield and the diastereoselectivity.
FIGURE 1
TABLE 1. Effect of Base and Additives on the Kinugasa Reaction
entry
aminea
Et3N
time [h]
yield [%]
cis:transb
1
2
3
4
5
6
7
8
9
20
48
20
21
22
20
24
48
21
56
58
38
50
10
85:15
52:48
98:2
Et3N
i-Pr2NEt
(c-C6H11)2NMe
pyridine
TMEDA
Et3N
Et3N
NH2NH2 ·H2O
95:5
54:46
55:45
74:26
60:40
70:30
26
80c
70c
58
a Standard condition: nitrone (2 equiv), acetylene (1 equiv), base (1
equiv), CuI (1 equiv) in MeCN. b According to HPLC. c With 20 mol %
of NH2NH2 ·H2O.
TABLE 2. Reaction of Nitrone 1 with Acetylenes 4a-fa
Having optimized the reaction conditions, we attempted to
test the scope of this reaction (Table 2). The use of other
acetylenes 4b-f provided products with a high diastereoselec-
tivity but rather a poor yield (Table 2). In all cases, the anti-
approach to the t-BuO was observed and the 5,6-cis penams
5a-f were obtained as a major component. For acetylenes 4b,
4c, and 4e only a trace amount of 5,6-trans products was
observed in the NMR spectra and HPLC but they were not
isolated. The ethyl propiolate 4d gave only the trans-product
6d, which underwent a rapid decomposition, probably by the
ꢀ-elimination process.17
In case of acetylenes having silyl (4b-c) or Cbz (4e)
protections, addition of hydrazine monohydrate to the reaction
mixture decreased the reaction yield. For compounds 4b, 4c,
and 4e a hydrazine-mediated deprotection of hydroxyl or amine
group was also observed. Similar results were also observed
when the anhydrous hydrazine was used.
entry
R
time [h]
5:6 ratio
yield [%]
1
Ph
Ph
4a
4a
4b
4b
4c
4c
4c
4d
4e
4e
4f
20
24
20
22
23
23
23
24
23
22
22
23
85:15
74:26
56
80
33
15
32
10
15
10d
36
13
72
44
2b
3
CH2OTBDPS
CH2OTBDPS
CH2CH2OTBDPS
CH2CH2OTBDPS
CH2CH2OTBDPS
COOEt
CH2NHCbz
CH2NHCbz
CH(OEt)2
CH(OEt)2
>95:<5
>95: <5
>95: <5
>95:<5
>95:<5
0:100
>95:<5
>95:<5
85:15
4b
5
6b
7c
8
9
10b
11
12b
4f
83:17
a Standard condition: nitrone (1.3 mmol), acetylene (1 mmol), Et3N (1
mmol), CuI (1 mmol), MeCN (3 mL). b In the presence of 20 mol %
NH2NH2 ·H2O. c In the presence of 20 mol % anhydrous NH2NH2 and 1
equiv anhydrous K2CO3. d Product undergoes fast decomposition.
It should be pointed out that the stereochemical outcome of
the Kinugasa reaction is controlled by the initial cycloaddition
step leading to the isoxazoline intermediate. The cycloaddition
step determines the configuration at the bridgehead carbon atom.
Two possible approaches of acetylide to the nitrone are depicted
in Figure 1. The approach of acetylide to the si side of the
nitrone (syn to t-BuO) is disfavored due to the steric interactions.
The lack of steric hindrance for the nitrone re side makes the
(14) Complete crystallographic data for the structural analysis of 5a have
been deposited with Cambridge Data Center, CCDC 686539.
(15) Singh, S. K.; Reddy, M. S.; Mangle, M.; Ganesh, K. R. Tetrahedron
2007, 63, 126.
(16) It has been found that addition of hydrazine significantly improved yields
of cyclopropane formation from styrenes and ethyl diazoacetate in the presence
of Cu(I) triflate and an imidazole N-oxide derivative used as chiral catalyst.
Mucha, P., Ph.D. Thesis, University of Ło´dz´, in preparation.
(17) Chmielewski, M.; Grodner, J.; Fudong, W.; Urban´czyk-Lipkowska, Z.
Tetrahedron 1992, 48, 2935.
J. Org. Chem. Vol. 73, No. 18, 2008 7403

SCHEME 2
approach of acetylide with respect to the 3-t-BuO group in the
nitrone is more favorable than the syn-approach (Scheme 2).
We have presented the stereoselective synthesis of carbap-
enams via Kinugasa reaction involving readily available cyclic
nitrones. As it has been shown, the diastereoselectivity of the
reaction, which is controlled by the 3-tert-butoxy group of
nitrone, is high, and the 5,6-cis carbapenam is a major product.
The 5,6-cis/trans ratio depends on the structure of acetylene as
well as the type of amine used. Due to the nitrones’ deoxygen-
ation process mediated by Cu(I), the products were obtained in
a poor yield. It was found, however, that in some cases the
addition of hydrazine to the reaction mixture stopped this side
reaction and consequently allowed increase of the reaction yield.
Owing to the presence of the tert-butyl-protected hydroxyl group
in the five-membered ring and a variety of substituents at C-6
of the penam skeleton, further transformations of adducts or
introduction of new substituents is possible.
approach from that direction more favorable. Owing to that,
the cycloaddition step proceeded with a high diastereoselectivity,
and only products with a cis arrangement of the t-BuO group
and the bridgehead proton were obtained. According to the
mechanism proposed by Fu,8 subsequently the rearrangement
of the enolate A to ꢀ-lactams 5/6 occurs (Figure 2). The
protonation of the less shielded side (convex) of the double bond
leads to the 5,6-cis ꢀ-lactams, whereas the protonation of the
more shielded concave side gives thermodynamically more
stable 5,6-trans products. This explains very well a high
diastereoselectivity of the reaction with acetylenes bearing a
bulky group, or when the reaction is carried out in the presence
of hindered amines. The basic conditions of the reaction cause
epimerization at the C-6 carbon atom upon extension of the
reaction time, which resulted in marked decrease of the 5,6-
cis/trans selectivity (5:6 ratio).
The introduction of a second t-BuO group to the nitrone (3)
did not affect the stereochemical outcome of the cycloaddition
step, and the 5,6-cis penam (7) was formed as a major product.
The shift of the t-BuO group from C-3 to C-4 of the nitrone
moiety (2), however, did change the observed diastereoselec-
tivity significantly (Scheme 2).
Due to the lack of steric interactions, both nitrone faces are
accessible, and the approach of acetylide to the nitrone 2 may
occur from both sides. The decreased facial selectivity led to
the formation of two 5,6-cis products 9 and 10 in ratio of 1:3,
respectively. The increased content of 10 indicates that the anti-
Experimental Section
Reaction of Nitrones with Acetylenes. General Method. To a
suspension of CuI (1 mmol) in dry, degassed acetonitile (3 mL)
were added triethylamine (1 mmol) and hydrazine monohydrate
(0.2 mmol) under nitrogen. After cooling to 0 °C acetylene 4 was
added (1 mmol). The mixture was stirred for 10 min, and then a
solution of nitrone (2 mmol) in acetonitrile was added slowly at 0
°C. After next 30 min the mixture was warmed up and stirred at
room temperature under nitrogen. The progress of the reaction was
monitored by TLC. At the end, buffer solution (pH 7) and ethyl
acetate were added. The aqueous layer was washed with ethyl
acetate, and the combined organic layers were dried over anhydrous
sodium sulfate. After removal of solvent, the residue was purified
by column chromatography.
Acknowledgment. Authors are grateful to Prof. Grzegorz
Mloston´ (University of Ło´dz´, Poland) for fruitful discussion and
advices. Financial support for this work was provided through
the Polish Ministry of Science and Higher Education, grant PBZ-
KBN-126/T09/08/2004.
Supporting Information Available: Experimental proce-
dures, characterization data of compounds 5a-c, 5e, f, 6a, f, 7,
9 and 10 and crystallographic information file of 5a in CIF
format. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO801212Q
7404 J. Org. Chem. Vol. 73, No. 18, 2008