L-Proline organocatalyzed Michael synthesis of monobactam and carbapenem β-lactam cores

Article abstract of DOI:10.1016/j.tetasy.2014.05.006

Herein, we report the development of mild, organocatalyzed routes to novel β-lactam carbapenem derivatives through Michael type CC bond forming reactions. The same methodology, followed by a retro-Dieckmann reaction, provides a pathway to novel and highly functionalized monobactam derivatives, another class of valuable β-lactam antibiotics.

Full text of DOI:10.1016/j.tetasy.2014.05.006

Tetrahedron: Asymmetry 25 (2014) 969–973
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
L-Proline organocatalyzed Michael synthesis of monobactam
and carbapenem b-lactam cores
Sibusiso Khanyase a, Tricia Naicker a, Glenn E. M. Maguire a, Hendrik G. Kruger a,
Per I. Arvidsson a,b, , Thavendran Govender a,
⇑
⇑
a Catalysis and Peptide Research Unit, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
b Science for Life Laboratory, Drug Discovery & Development Platform & Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and
Biophysics, Karolinska Institutet, Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 March 2014
Accepted 22 May 2014
Herein, we report the development of mild, organocatalyzed routes to novel b-lactam carbapenem
derivatives through Michael type CAC bond forming reactions. The same methodology, followed by a
retro-Dieckmann reaction, provides
a pathway to novel and highly functionalized monobactam
derivatives, another class of valuable b-lactam antibiotics.
Ó 2014 Elsevier Ltd. All rights reserved.
NH2
S
1. Introduction
N
The efficient generation of new CAC bonds may be seen as the
essence of synthetic organic chemistry, as it allows the preparation
of valuable natural and unnatural compounds.1,2 The Michael addi-
tion reaction is well known as one of the most widely used CAC
bond-forming reactions in organic synthesis.1,2 Similarly, the inter-
est in optically active molecules has promoted a considerable
interest in the development of more efficient catalytic stereoselec-
tive methods.3,4 Asymmetric organocatalysis has emerged as a new
powerful methodology for the catalytic production of enantiomeri-
cally pure organic compounds, and is subsequently one of the most
rapidly growing research areas in synthetic organic chemistry.3,5,6
Organocatalysis through enamine activation7 is essentially the
use of primary and secondary amines to facilitate electrophilic sub-
H
N
N
O
S
O
O
HN
CH3
N
O
O
OH
N
OH
H
O
O
SO3H
aztreonam
penicillin
OH
NH
H
NH
S
N
O
O
HO
imipenem
stitution reactions, typically at the
a-position of carbonyl com-
pounds via HOMO-rising strategies.8–12 We recently reported our
introductory results on the first amino catalyzed stereospecific
CAC bond forming reactions on a b-lactam core through aldol,
Mannich,13 and Michael-type reactions.14 b-Lactams of the penicil-
lin class (Fig. 1) were among the first antimicrobial agents devel-
oped for the treatment of infectious diseases.15,16 Various other
b-lactam containing drugs have since been developed as powerful
antibiotics, for example, monobactams such as aztreonam and
carbapenems such as imipenem (Fig. 1). The carbapenem subgroup
possesses the broadest range of activity and the greatest potency
against Gram-positive and negative bacteria.
Figure 1. Representative b-lactam antibiotics; archetypical penicillin, monobactam
aztreonam, and the carbapenem imipenem.
As a result, this class is often used as antibiotics for critically ill
patients.15,17–19 The recent emergence of multidrug-resistance
(MDR) pathogens has seriously constrained the efficiency of these
agents.19,20 As result, the global threat of antimicrobial drug resis-
tance has prompted the search and development of new antibacte-
rial agents based on this pharmaceutically relevant skeleton.
Herein we report an expansion of the scope of mild organocatalytic
asymmetric Michael addition transformations onto the carbape-
⇑
Corresponding authors. Tel.: +27 31 2601845; fax: +27 31 2603091 (T.G.).
E-mail address: govenderthav@ukzn.ac.za (T. Govender).
nem core 1. L-Proline was used as the catalyst with different
http://dx.doi.org/10.1016/j.tetasy.2014.05.006
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

970
S. Khanyase et al. / Tetrahedron: Asymmetry 25 (2014) 969–973
Table 1
Table 2
a
Substrate scope for the catalytic Michael addition with electron deficient olefin
Substrate scope for the catalytic Michael addition reaction with
ketones and various b,
a
,b-unsaturated
a
c
-unsaturated
a
-ketoesters
O
OH
O
OH
OH
OH
NH
OH
H
H
H
H
OH
NH
R1
H
H
H
H
(20 mol%)
O
O
OH
(20 mol%)
+
N
N
*
O
**
O
R2
N
R1
O
O
DMSO, rt
*
N
O
**
R2
O
2
r.t.
PNBO
3a-c
Product Yieldb (%)
PNBO
O
O
PNBO
PNBO
O
O
1
R1
Entry
R2
Time (h)
drc
4
5a-f
1
O
1
2
3
4
5
NO2
NO2
NO2
CN
4-MeOC6H4
24
20
17
72
72
3a
3b
3c
Trace
Trace
41
42
46
88:12
60:40
87:13
C6H5
4-ClC6H4
H
H
Entry Substrate
Time
(h)
Product Yieldb (%)
drc
(CN)2
O
a
The reaction was carried out with carbapenem 1 (0.574 mmol) and 2 (2 equiv) in
DMSO (0.5 mL).
1
24 5a
67
63
90:10
90:10
b
c
Yield of isolated product.
O
Diastereomeric ratio determined by 1H NMR.
2
24 5b
electrophilic substrates, such as chalcones, which are the precur-
sors of flavonoids and isoflavonoids that possess a wide variety
of biological activities.21 Similarly, cyclic enones, known to be part
of a variety of bioactive compounds, were also employed.22–25
Herein a new transformation of the optically active Michael prod-
uct into a monocyclic b-lactam structure is reported. Such mono-
bactams represent another important subclass of antibacterial
agents.
O
3
40 NR
40 NR
O
4
O
O
5
6
40 NR
40 NR
2. Results and discussion
O
Based on our initial report, for the reaction between carbape-
nem core 1 and trans-4-methoxy-b-nitrostyrene,14 we examined
the substrate scope of the asymmetric Michael addition with other
electrophilic olefins (Table 1). As previously reported, trans-4-
methoxy-b-nitrostyrene proceeded smoothly to afford product 3a
in modest yield (41%) and good dr (88:12) (Table 1, entry 1). For
nitrostyrene, yielding 3b, relatively poor dr (60:40) was obtained
although the yield (42%) was similar as compared with 3a (Table 1,
entries 1 and 2, respectively). It was found that changing to a more
electron-withdrawing substituent on the aromatic ring did not
affect the selectivity as product 3c was produced in similar yield
(45%) and dr (87:13) as compared with 3a. To further explore the
substrate scope, benchmark organonitriles were examined. Unfor-
tunately only trace amounts were observed via LC–MS analysis of
the crude reaction mixture (Table 1, entries 4 and 5, respectively).
Having explored electron deficient olefins, we next evaluated
O
O
O
7
8
9
15 5c
55 NR
31 5d
63
91:9
O
O
O
60
62
90:10
88:12
the asymmetric Michael additions of various
ketones and b, -unsaturated -ketoesters on the carbapenem core
1 by using 20 mol % of -proline as a catalyst (Table 2). The reac-
tions were complete within 15–35 h and gave products in moder-
ate yields (55–67%) and with good dr (88:12–92:8). Reactions were
general for both 5 and 6-membered a,b-unsaturated cyclic enones
with products 5a and 5b (67% and 63%) being obtained in good
yields and dr (90:10) (Table 2, entries 1 and 2, respectively). Olefins
a,b-unsaturated
O
c
a
O
L
10
11
24 5e
O
F
O
O
substituted at the
a- or b-positions did not give any conversion
35 5f
55
92:8
O
after 40 h (Table 2, entries 3 and 4). Methylvinylketone and a viny-
lester also proved to be inefficient Michael acceptors (Table 2,
O
O
entries 5 and 6) for the carbapenem donor 1. Acyclic
rated ketones furnished product 5c in good yields (63%) and dr
(91:9) (Table 2, entry 6), while the ,b-unsaturated ester analogue
was unreactive (Table 2, entry 7). b, -Unsaturated -ketoesters
bearing either electron-withdrawing or electron-donating
a,b-unsatu-
a
The reaction was carried out with carbapenem 1 (0.574 mmol) and 4 (2 equiv) in
DMSO (0.5 mL).
a
b
c
Yield of isolated product.
c
a
Diastereomeric ratio determined by 1H NMR.

S. Khanyase et al. / Tetrahedron: Asymmetry 25 (2014) 969–973
971
O
E
OH
H
O
H
N
O
N
OH
H
O
OH
O
H
E
O
H
H
OPNB
N
N
+H2O
O
N
O
O
O
E
O
PNBO
OPNB
HO
-H+
H
N
O
O
OH
H
O
H
N
-H2O
N
O
O
OH
H
PNBO
H
O
O
O
PNBO
Scheme 1. Catalytic cycle for the proline-catalyzed Michael reaction of carbapenem core 1.
substituents, worked well and gave the desired products 5d–5f in
moderate yields (55–60%) and with good dr (88:12–92:8).
We propose that this reaction occurred via enamine catalysis, as
shown in Scheme 1.
The formation of the new CAC bond in product 3a was con-
firmed by observing the shift of C8 from 64.0 ppm for 1 to
76.4 ppm for 3a in the 13C NMR spectrum and the disappearance
of H8 as a singlet at 4.76 ppm for 1 in the 1H NMR spectrum
(Fig. 2). In addition H17 showed an HMBC correlation with C8.
Next we found that treatment of the Michael products, for
example, 5a, with potassium carbonate in aqueous THF (Scheme 2)
led to ring-opening of the five-membered ketone ring through a
retro-Dieckmann condensation.26 The monocyclic b-lactam 6 thus
obtained represents another important class of antibacterial
agents—a monobactam.
6
OH
O
4H
OH
6
OH
1
H
9
1
4
5
7
H
H
7
10
10
9
5
2
N3
6
OH
6
OH
H
17
O
2
N3
1
4
8
O
21
20
1
4
H
8
21
20
19
17
7
H
H
H
7
*
O
10
9
O
5
10
9
O
5
11
O
THF : H2O
r.t., 20h
**
11
O
+ K2CO3
O
18
O
O
2
N3
18
2
N3
19
O
8
8
17
12
12
NO2
O
O
14
13
11
13
11
14
15
O
O
18
15
16
19
O
O
12
12
13
14
20
16
13
14
NO2
21
O2N
16
NO2
O
15
22
16
5a
6
15
O2N
yield 91%
3a
1
Scheme 2. Synthesis of product 6.
Figure 2. Numbering used for the NMR assignment of carbapenem intermediate 1
and Michael product 3a.
From the 13C NMR spectrum we observed the shift of C9 at
208.0 ppm for 5a to 173.3 ppm for 6 (indicative of an acid group)
and C8 at 76.6 ppm for 5a to 59.9 ppm for 6. In addition, C9 showed
the same HMBC correlation with the H10 protons as in 5a. In the 1H
NMR spectrum, a new H8 signal appeared at 4.09 ppm for 6 which
showed HMBC correlations with C17 and C11. From the NOESY
spectra, we observed a correlation between H8 and H4, thus con-
firming the configuration of the newly attached H8 proton. It
should be noted that the stereochemistry at C17 was not confirmed.
There are several methods for the synthesis of monocyclic
b-lactams including the classical Staudinger,27 Reformatsky,28 and
Kinugasa reactions.29 More recently, organocatalysts have been
employed in an effort to make the Staudinger reaction more
efficient.30 However, to the best of our knowledge this is the first
From the elucidation of the 2D NMR spectra, we established a
NOESY correlation between H4 and H19, which confirmed the
exo-configuration of the newly attached group in 3a. This is in
agreement with our previous report which showed that the stereo-
chemical outcome of the reaction was dictated by the chiral ketone
1 rather than the catalyst (similar results were obtained with D-
proline and pyrrolidine/acetic acid), as might be expected when
considering the bent conformation of the cyclobutanone ring at
the bicyclic core. The newly formed stereogenic centers at C8 and
C17 in compound 3a were determined to be created with a diaste-
reomeric ratio of 88:12. The configuration of C17 could not be
unambiguously confirmed from the 2D NMR spectra.

972
S. Khanyase et al. / Tetrahedron: Asymmetry 25 (2014) 969–973
report whereby the sequential use of an organocatalytic Michael
reaction followed by a retro-Dieckmann reaction transforms a bicy-
clic-b-lactam, that is, carbapenem, into a monocyclic-b-lactam, that
is, monobactam, with the addition of two new stereogenic centers.
(400 MHz, CDCl3): d 8.24 (d, J = 8.60 Hz, 2H), 7.48 (d, J = 8.60 Hz,
2H), 7.21 (d, J = 8.68 Hz, 2H), 6.82 (d, J = 8.72 Hz, 2H), 5.32 (m,
2H), 5.00 (dd, J = 13.17, 11.17 Hz, 2H), 4.36 (dd, J = 11.11, 4.10 Hz,
1H), 4.10 (m, 1H), 3.56 (m, 1H), 3.12 (dd, J = 5.20, 2.56 Hz, 1H),
2.43 (dd, J = 8.80, 8.72 Hz, 1H), 2.27 (dd, J = 6.88, 6.96 Hz, 1 Hz)
1.29 (d, J = 6.28 Hz, 3H) ppm. 13C NMR (100 MHz CDCl3): d 207.3,
171.5, 164.9, 160.9, 141.7, 131.7, 129.1, 124.1, 114.5, 94.5, 74.3,
67.3, 67.1, 55.4, 55.0, 51.1, 44.1, 40.5, 21.2 ppm. HRMS (ESI+) m/z
calcd for C25H25N3O10: 527.1539; found [M+H] 528.3154.
3. Conclusion
In conclusion, we have demonstrated that it is possible to
synthesize novel b-lactam derivatives by utilizing organocatalyzed
Michael addition reactions on the carbapenem intermediate 1 with
various electrophilic olefins, that is,
b, -unsaturated -ketoesters. Good yields and some excellent
diastereoselectivities were obtained with -proline as the organocata-
lyst. The Michael products obtained could be smoothly interconverted
into monobactams through a retro-Dieckmann reaction, thereby
leading to another highly valued class of b-lactam antibiotics.
a,b-unsaturated ketones and
4.5. (2S,5R,6S)-4-Nitrobenzyl 6-((R)-1-hydroxyethyl)-2-((R)-2-ni
tro-1-phenylethyl)-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-car
boxylate 3b
c
a
L
The crude product was purified by column chromatography
(EtOAc/hexane, 50:50; Rf = 0.2) to afford the product (120 mg,
42%) as
a semi-solid [a]
20 = +90.6 (c 0.1, CHCl3) 1H NMR
D
4. Experimental
4.1. General
(400 MHz, CDCl3): d 8.12 (d, J = 8.28 Hz, 2H), 7.41 (d, J = 8.08 Hz,
2H), 7.20 (m, 5H), 5.10 (m, 3H), 4.91 (dd, J = 13.91, 6.22 Hz, 2H)
4.35 (m, 1H), 4.03 (m, 1H), 3.35 (m, 1H), 2.99 (m, 1H), 2.34 (dd,
J = 9.12, 8.60, 1H), 2.17 (dd, J = 7.63, 6.78 Hz, 1H), 1.21 (d,
J = 5.96 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): d 207.1, 172.0,
165.0, 141.7, 135.4, 132.7, 129.9, 129.0, 128.9, 128.8, 124.0, 76.2,
74.8, 67.6, 67.4, 64.4, 50.9, 44.2, 40.2, 21.9 ppm. HRMS (ESI+) m/z
calcd for C24H23N3O9: 497.1434; found [M+H] 498.1483.
Reagents and solvents were purchased from Sigma Aldrich and
Merck. All NMR spectra were recorded on Bruker AVANCE III
400 MHz or 600 MHz instruments at room temperature. Chemical
shifts are expressed in ppm downfield from TMS as an internal
standard, and coupling constants are reported in Hz. Thin layer
chromatography (TLC) was performed using Merck Kieselgel 60
F254. Crude compounds were purified with column chromatogra-
phy using silica gel (60–200 mesh unless otherwise stated). All sol-
vents were dried using standard procedures. Optical rotations were
recorded on a Perkin–Elmer Polarimeter (Model 341). High-resolu-
tion mass spectrometric data were obtained using a Bruker micrO
TOF-Q II instrument operating at ambient temperatures and a sam-
ple concentration of approximately 1 ppm.
4.6. (2S,5R,6S)-4-Nitrobenzyl 2-((R)-1-(4-chlorophenyl)-2-nitro
ethyl)-6-((R)-1-hydroxyethyl)-3,7-dioxo-1-azabicyclo[3.2.0]hep
tane-2-carboxylate 3c
The crude product was purified by column chromatography
(EtOAc/hexane, 50:50; Rf = 0.2) to afford the product (140 mg,
46%) as a semi-solid [a]
20 = +101.0 (c 0.1, CHCl3) 1H NMR
D
(400 MHz, CDCl3): d 8.18 (d, J = 8.18 Hz, 2H), 7.41 (d, J = 8.64 Hz,
2H), 7.21 (m, 4H), 5.25 (m, 2H), 4.84 (dd, J = 13.50, 11.19 Hz, 2H),
4.33 (dd, J = 11.11, 3.98 Hz, 1H), 4.20 (m, 1H), 3.41 (m, 1H), 3.06
(dd, J = 4.78, 2.50, 1H), 2.38 (dd, J = 8.92, 8.96 Hz, 1H), 2.23 (dd,
J = 6.84, 6.88 Hz, 1H), 1.21 (d, J = 6.32 Hz, 3H) ppm. 13C NMR
(100 MHz CDCl3): d 206.2, 171.6, 164.3, 140.6, 135.1, 131.3,
131.1, 129.2, 129.1, 124.1, 76.0, 74.2, 67.7, 67.5, 64.3, 50.6, 43.8,
4.2. Representative procedure for the Michael addition reaction
of olefins,
a,b-unsaturated ketones, and b,c-unsaturated a-keto-
ester with carbapenem
To a stirred solution of compound 1 (0.574 mmol) and catalyst
(0.115 mmol) in DMSO (0.5 mL) at room temperature, was added a
Michael acceptor (2.0 equiv). The mixture was stirred at ambient
temperature for 24 h while being monitored by TLC. The reaction
mixture was then quenched by adding water (5 mL) and the aque-
ous layer was extracted three times with DCM (30 mL). The com-
bined organic layers were dried over MgSO4, which was
subsequently removed by filtration. The concentrated extract was
subjected to silica gel for purification to afford the desired product.
40.2, 21.7 ppm. HRMS (ESI+) m/z calcd for
C24H22N3O9Cl:
531.1044; found [M+H] 532.1073.
4.7. (2S,5R,6S)-4-Nitrobenzyl 6-((R)-1-hydroxyethyl)-3,7-dioxo-
2-((R)-3-oxocyclopentyl)-1-azabicyclo[3.2.0]heptane-2-carbox
ylate 5a
The crude product was purified by column chromatography
(EtOAc/hexane, 50:50; Rf = 0.2) to afford the product (165 mg, 67%)
4.3. Representative procedure for the synthesis of product 6
as a semi-solid. [a]
20 = +215.0 (c 0.1, CHCl3) 1H NMR (400 MHz,
D
CDCl3): d 8.22 (d, J = 7.16 Hz, 2H), 7.45 (d, J = 8.56 Hz, 2H), 5.27 (s,
2H), 4.25 (s, 1H), 4.03 (s, 1H), 3.29 (t, 1H), 3.17 (d, 1H), 2.97–2.95
(d, J = 11.05 Hz, 1H), 2.55–2.39 (dd, J = 17.91, 8.58 Hz, 2H), 2.19 (d,
J = 9.49 Hz, 2H), 2.04 (d, J = 7.08 Hz, 1H), 1.80 (d, J = 19.61 Hz, 1H),
1.34 (d, J = 4.80 Hz, 3H) ppm. 13C NMR (100 MHz CDCl3): d 215.3,
208.0, 164.9, 161.0, 140.8, 128.7, 124.5, 76.6, 66.5, 66.2, 64.9, 50.2,
42.1, 40.9, 38.4, 38.0, 23.6, 21.9 ppm. HRMS (ESIÀ) m/z calcd for
To a stirred solution of compound 5a (500 mg) at room tempera-
ture was added K2CO3 (20 mg) in 2:1 THF and H2O, respectively.
The mixture was stirred at ambient temperature for 12 h while being
monitored by TLC. The reaction mixture was then quenched by add-
ing 30% acetic acid and the aqueous layer was extracted five times
with ethyl acetate (30 mL). The combined organic layers were dried
over MgSO4, which was subsequently removed by filtration. The con-
centrated extract was dried in vacuo to afford the desired product.
C21H22N2O8: 430.1376; found [MÀH] 429.1440.
4.4. (2S,5R,6S)-4-Nitrobenzyl 6-((R)-1-hydroxyethyl)-2-((S)-1-(4-
methoxyphenyl)-2-nitroethyl)-3,7-dioxo-1-azabicyclo[3.2.0] hept
ane-2-carboxylate 3a
4.8. (2S,5R,6S)-4-Nitrobenzyl 6-((R)-1-hydroxyethyl)-3,7-dioxo-
2-((R)-3-oxocyclohexyl)-1-azabicyclo[3.2.0]heptane-2-carboxyl
ate 5b
The crude product was purified by column chromatography
The crude product was purified by column chromatography
(EtOAc/hexane, 50:50; Rf = 0.2) to afford the product (124 mg,
(EtOAc/hexane, 50:50; Rf = 0.2) to afford the product (161 mg, 63%)
41%) as a semi-solid. [a]
20 = +156.7 (c 0.1, CHCl3) 1H NMR
D
as a semi-solid. [a]
20 = +43.2 (c 0.1, CHCl3) 1H NMR (400 MHz,
D

S. Khanyase et al. / Tetrahedron: Asymmetry 25 (2014) 969–973
973
CDCl3): d 8.22 (d, J = 8.64 Hz, 2H), 7.45 (d, J = 8.46 Hz, 2H), 5.24 (d,
J = 11.34 Hz, 2H), 4.33 (m, 1H), 3.96 (m, 1H), 3.27 (m, 1H), 2.89 (m,
1H), 2.76 (m, 2H), 2.68 (m, 2H), 2.40 (m, 2H), 2.25 (m, 2H), 2.04 (m,
2H), 1.29 (d, J = 5.10 Hz, 3H) ppm. 13C NMR (100 MHz CDCl3): d
209.2, 208.6, 170.8, 164.1, 147.9, 141.8, 128.4, 124.0, 67.6, 67.0,
64.6, 50.7, 42.9, 41.4, 41.0, 40.9, 25.7, 24.3, 21.7 ppm. HRMS (ESI+)
m/z calcd for C22H24N2O8: 444.1532; found [M+Na] 467.1432.
55%) as
a
semi-solid
[
a
]
20 = +97.3 (c = 0.1, CHCl3) 1H NMR
D
(400 MHz, CDCl3): d 8.15 (d, J = 8.52 Hz, 2H), 7.40 (d, J = 8.56 Hz,
2H), 6.64 (m, 3H), 5.84 (d, J = 7.08, 2H), 5.10 (dd, J = 12.88,
12.84 Hz, 2H), 4.22 (m, 1H), 4.05 (dd, J = 4.64, 4.32 Hz, 1H), 3.71
(s, 3H), 3.46 (m, 2H), 3.05 (dd, J = 2.24, 2.36 Hz, 1H), 2.35 (dd,
J = 8.88, 8.88 Hz, 1H), 2.16 (dd, J = 6.88, 6.88 Hz), 1.22 (d,
J = 6.28 Hz, 3H) ppm. 13C NMR (100 MHz CDCl3): d 208.4, 191.2,
171.5, 165.2, 161.3, 148.0, 147.2, 141.2, 129.8, 128.9, 123.9,
123.3, 110.3, 108.3, 101.2, 76.4, 67.1, 64.8, 53.0, 50.9, 41.9, 40.9,
4.9. (2S,5R,6S)-4-Nitrobenzyl 6-((R)-1-hydroxyethyl)-3,7-dioxo-
2-((S)-3-oxo-1-phenylbutyl)-1-azabicyclo[3.2.0]heptane-2-carb
oxylate 5c
40.6, 21.5 ppm. HRMS (ESI+) m/z calcd For
582.1485; found [M+H] 583.1534.
C28H26N2O12:
The crude product was purified by column chromatography
4.13. 2-((2R,3S)-3-(1-Hydroxyethyl)-1-(2-(4-nitrobenzyloxy)-2-o
(EtOAc/hexane, 60:40; Rf = 0.2) to afford the product (179 mg,
xo-1-(3-oxocyclopentyl)ethyl)-4-oxoazetidin-2-yl)acetic acid 6
63%) as
a semi-solid [a]
20 = +80 (c 0.1, CHCl3) 1H NMR
D
(400 MHz, CDCl3): d 8.23 (d, J = 8.64 Hz, 2H), 7.48 (d, J = 8.64 Hz,
2H), 7.22 (m, 5H), 5.32 (dd, J = 12.96, 12.93 Hz, 2H), 4.19 (m, 1H),
4.14 (dd, J = 5.44, 5.48 Hz, 2H), 3.39 (m, 1H), 3.18 (m, 2H), 3.12
(dd, J = 2.48, 2.52 Hz, 1H), 2.38 (dd, J = 8.84, 8.80 Hz, 1H), 2.17
(dd, J = 6.88, 6.88 Hz, 1H), 2.05 (s, 3H), 1.30 (d, J = 6.32 Hz, 3H)
ppm. 13C NMR (100 MHz CDCl3): d 208.3, 205.6, 171.4, 165.1,
148.0, 141.4, 136.8, 129.9, 128.8, 128.6, 127.8, 123.9, 76.8, 67.2,
67.0, 64.8, 50.9, 45.4, 41.7, 40.5, 30.4, 21.6 ppm. HRMS (ESI+) m/z
calcd for C26H26N2O8: 494.1689; found [M+H] 495.1797.
Product was afforded as a semi-solid, yield (474 mg, 91%),
[a
]
20 = À17.4 (c 0.1,CHCl3) 1H NMR (400 MHz, CDCl3): d 8.16 (d,
D
J = 8.60 Hz, 2H), 7.48 (d, J = 8.32 Hz, 2H), 5.16 (d, J = 5.24 Hz, 2H),
4.09 (m, 1H), 3.98 (m, 1H), 3.88 (m, 1H), 2.87 (m, 1H), 2.81 (m,
1H), 2.76 (m, 2H), 2.58 (m, 2H), 2.17 (m, 2H) 1.99 (m, 2H), 1.21
(d, J = 6.36 Hz, 3H) ppm. 13C NMR (100 MHz CDCl3): d 217.1,
173.3, 168.5, 167.4, 147.9, 141.7, 128.9, 123.8, 66.1, 65.8, 63.0,
59.9, 53.5, 52.1, 42.7, 38.3, 37.9, 37.2, 36.6, 27.2, 21.0 ppm. HRMS
(ESIÀ) m/z calcd for
C21H24N2O9: 448.1510; found [MÀH]
447.1477.
4.10. (2S,5R,6S)-4-Nitrobenzyl 6-((R)-1-hydroxyethyl)-2-((S)-4-
methoxy-3,4-dioxo-1-phenylbutyl)-3,7-dioxo-1-azabicyclo [3.
2.0]heptane-2-carboxylate 5d
References
1. Schinzer, D. Conjugate Addition Reactions in Organic Syntheses; Wiley-VCH,
1993. Vol. 105.
2. Tokoroyama, T. Discovery of the Michael Reaction; Wiley-VCH, 2010.
3. Gaunt, M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug Discovery Today
2007, 12, 8.
The crude product was purified by column chromatography
(EtOAc/hexane, 60:40; Rf = 0.2) to afford the product (189 mg,
60%) as
a semi-solid [a]
20 = +40.1 (c 0.1, CHCl3) 1H NMR
D
4. MacMillan, D. W. C. Nature 2008, 455, 304.
(400 MHz, CDCl3): d 8.23 (d, J = 8.36 Hz, 2H), 7.48 (d, J = 8.40 Hz,
2H), 7.23 (m, 5H), 5.17 (dd, J = 12.88, 12.88 Hz, 2H), 4.29 (M, 1H),
4.20 (dd, J = 4.01, 4.01 Hz, 1H), 3.78 (s, 3H), 3.61 (m, 2H), 3.40
(m, 1H), 3.12 (dd, J = 2.51, 2.50 Hz, 1H), 2.42 (dd, J = 8.79, 8.76 Hz,
1H), 2.21 (dd, J = 6.82, 6.79 Hz, 1H), 1.30 (d, J = 6.12 Hz, 3H) ppm.
13C NMR (100 MHz CDCl3): d 208.4, 191.5, 171.2, 165.6, 161.0,
148.4, 141.7, 136.4, 130.0, 128.9, 128.6, 128.0, 123.9, 76.4, 67.4,
67.1, 64.7, 53.0, 50.7, 41.5, 40.6, 21.6 ppm. HRMS (ESI+) m/z calcd
for C27H26N2O10: 538.1587; found [M+H] 539.1694.
5. Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
6. Almasi, D.; Alonso, D. A.; Najera, C. Tetrahedron: Asymmetry 2007, 18, 299.
7. Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
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Res. 2012, 45, 248.
9. Jiang, H.; Albrecht, L.; Jorgensen, K. A. Chem. Sci. 2013, 4, 2287.
10. Yang, C.; Chen, W.; Yang, W.; Zhu, B.; Yan, L.; Tan, C.-H.; Jiang, Z. Chem. Asian J.
2013, 8, 2960.
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1704.
13. Cele, Z. E. D.; Pawar, S. A.; Naicker, T.; Maguire, G. E. M.; Arvidsson, P. I.; Kruger,
H. G.; Govender, T. Eur. J. Org. Chem. 2014, 2253.
14. Pawar, S. A.; Alapour, S.; Khanyase, S.; Cele, Z. E. D.; Chitti, S.; Kruger, H. G.;
Govender, T.; Arvidsson, P. I. Org. Biomol. Chem. 2013, 11, 8294.
15. Rodloff, A. C.; Goldstein, E. J. C.; Torres, A. J. Antimicrob. Chemother. 2006, 916.
16. Elander, R. P. Appl. Microbiol. Biotechnol. 2003, 385.
17. Bradley, J. S.; Garau, J.; Lode, H.; Rolston, K. V. I.; Wilson, S. E.; Quinn, J. P. Int. J.
Antimicrob. Agents 1999, 11, 93.
18. Paterson, D. L. Clin. Microbiol. Infect. 2000, 6, 460.
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833.
4.11. (2S,5R,6S)-4-Nitrobenzyl 2-((S)-1-(4-fluorophenyl)-4-met
hoxy-3,4-dioxobutyl)-6-((R)-1-hydroxyethyl)-3,7-dioxo-1-azab
icyclo[3.2.0]heptane-2-carboxylate 5e
The crude product was purified by column chromatography
(EtOAc/hexane, 60:40; Rf = 0.2) to afford the product (198 mg,
62%) as
a semi-solid [a]
20 = +50.2 (c 0.1, CHCl3) 1H NMR
D
(400 MHz, CDCl3): d 8.15 (d, J = 8.60 Hz, 2H), 7.40 (d, J = 8.60 Hz,
2H), 7.21 (d, J = 5.68 Hz, 2H), 6.88 (d, J = 8.50 Hz, 2H), 5.09 (dd,
J = 12.88, 12.88 Hz, 2H), 4.21 (m, 1H), 4.13 (dd, J = 5.04, 5.04 Hz,
1H), 3.71 (s, 3H), 3.50 (m, 2H), 3.31 (m, 1H), 3.06 (dd, J = 2.36,
2.34 Hz, 1H), 2.35 (dd, J = 8.88, 8.79 Hz, 1H), 2.18 (dd, J = 6.86,
6.69 Hz, 1H), 1.22 (d, J = 6.28 Hz, 3H) ppm. 13C NMR (100 MHz
CDCl3): d 208.4, 191.3, 172.2, 165.2, 163.5, 161.0, 148.0, 141.2,
132.0, 131.6, 128.9, 123.9, 115.4, 76.3, 67.4, 67.1, 64.5, 53.0,
50.7, 41.7, 40.6, 40.5, 21.6 ppm. HRMS (ESI+) m/z calcd for
20. Fish, D. N. Ther. Clin. Risk Manag. 2006, 2, 401.
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4969.
C27H25N2O10F: 556.1493; found [M+H] 557.1553.
30. Sereda, O.; Blanrue, A.; Wilhelm, R. Chem. Commun. 2009, 1040.
4.12. (2S,5R,6S)-4-Nitrobenzyl 2-((S)-1-(benzo[d][1,3]dioxol-5-
yl)-4-methoxy-3,4-dioxobutyl)-6-((R)-1-hydroxyethyl)-3,7-dio
xo-1-azabicyclo[3.2.0]heptane-2-carboxylate 5f
The crude product was purified by column chromatography
(EtOAc/hexane, 60:40; Rf = 0.2) to afford the product (184 mg,