DiastereoselectivesSynthesis of trans β-lactams on soluble polymer support

Article abstract of DOI:10.1055/s-2006-942358

Liquid-phase synthesis of trans β-lactams was accomplished through both PEG-supported imine and PEG-bound auxiliary methodologies. The trans diastereoselectivity is explained by a chair-like transition state involving the imine and the Z-enolate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942358

PAPER
1829
Diastereoselective Synthesis of trans b-Lactams on Soluble Polymer Support
Synthesis of
bh
a
Soluble Po
n
lymer Suppo
-
rt Zhong Jian, Qing Yuan, Yan-Guang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax +86(571)87951512; E-mail: orgwyg@zju.edu.cn
Received 14 November 2005; revised 13 January 2006
promising non-antibiotic uses of b-lactams is in the inhi-
bition of other serine protease enzymes. Cytomegalovirus
Abstract: Liquid-phase synthesis of trans b-lactams was accom-
plished through both PEG-supported imine and PEG-bound auxil-
iary methodologies. The trans diastereoselectivity is explained by a
chair-like transition state involving the imine and the Z-enolate.
6
7
8
protease, prostate specific antigen, thrombin, and
9
elastase, are among the enzymes effectively inhibited by
b-lactam compounds. These applications have triggered a
renewed interest in the synthesis of new b-lactam systems.
Key words: lactam, PEG, Reformatsky reaction, resin-capture-re-
lease, Z-enolate
10
Based on our previous work, herein we give a full report
of our research on PEG supported synthesis of trans b-lac-
Although already widely used as a powerful tool in the tams. The synthesis of trans b-lactams on PEG-support
field of combinatorial chemistry, solid-phase synthetic with high diastereoselectivity was accomplished from
method suffers from some inherent disadvantages due to both PEG-bound imine (Scheme 1) and PEG-bound aux-
the heterogeneous reaction conditions, such as high de- iliary (Scheme 2).
mands on the compatibility of the individual components,
relatively low reactivity and selectivity, harsh reaction
conditions, as well as the difficulty for characterization of
As shown in Scheme 1, the investigation began by cou-
11
pling 4-formylbenzoic acid to PEG 4000 as reported.
The representative imines 2 were prepared by treating 1
with aromatic amines in the presence of trimethyl ortho-
formate in CH Cl at room temperature. The reaction went
1
the insoluble polymer-supported compounds. This stim-
ulated the development of various approaches for con-
struction of combinatorial libraries in solution, among
which liquid-phase synthesis using soluble polymers pro-
vides an attractive strategy by incorporating the positive
aspects of both classical solution and solid-phase chemis-
2
2
to completion over 24 hours and gave a high yield of the
corresponding PEG-bound aldimines 2. In general, the
progress of both the esterification and imine formation
1
steps was routinely monitored by H NMR spectroscopy.
After precipitation with diethyl ether and drying by vacu-
um, the resin 2 was mixed with 4 equivalents of the car-
2
try. It benefits from both the advantageous features of ho-
mogeneous solution chemistry (high reactivity, lack of
diffusion phenomena and ease of analysis without follow-
ing the cleavage-and-check technique) and of solid-phase
methods (use of excess reagents and easy isolation and
purification of products). With these advantages, this
strategy has recently caught the attention of the scientific
community as an effective technique for the construction
of combinatorial libraries of small organic molecules, es-
pecially heterocyclic compounds, of which many are im-
portant structural motifs of pharmaceuticals or
12
boximide 5 and 4.8 equivalents of zinc powder in THF.
The resulting mixture was refluxed for 15 minutes under
nitrogen, filtered through Celite, and washed three times
with THF. The filtrate was concentrated and diethyl ether
was added dropwise to afford the polymer supported trans
b-lactams 3 with high diastereoselectivity (Scheme 1).
1
Ratios of trans/cis were determined by H NMR, based on
the H-3/H-4 coupling constant values (J
13
= 1.5–2.5 Hz,
Jcis = 4.5–6.0 Hz). Substrate cleavage was accomplished
trans
3
biologically active compounds.
by treating 3 with Et N–MeOH (1:2) at 60 °C and moni-
3
The b-lactams are one of the best known and extensively tored for the disappearance of the polymeric b-lactams by
investigated heterocyclic ring systems as a result of both TLC. Normally, cleavage was complete after stirring for
4
their biological activity as antibiotics and their utility as 24 hours. The polymer was precipitated and discarded.
5
synthetic intermediates. Even though they have a long The resulting b-lactam was purified on a short column of
history of development starting from the discovery of pen- silica gel to remove the trace PEG and 6. The reaction
icillin in 1928, the quest for new synthetic methods and conditions are mild enough not to alter the trans/cis ratio
refinement of those already known remains appealing. of b-lactam. The results are summarized in Table 1.
And the research into the application of theses methods in
synthesizing novel biologically active azetidinone deriva-
tives still constitutes an active area in organic synthesis. In
addition, many scientists have begun to examine new ap-
plications of the b-lactam functionality. One of the most
1
As shown in Table 1, when R was an aryl group with an
electron-donating substituent (entries a–f and k–n), the
reaction gave products 4 in high yields (85–96%) with
good to excellent purities (81–93%) and high diastereose-
1
lectivity (trans/cis = >98:2). When R was an aryl group
with an electron-withdrawing substituent, the reaction
was incomplete and part of the imine was not transformed
into the b-lactam (Table 1, entries g–j). On the other hand,
SYNTHESIS 2006, No. 11, pp 1829–1835
x
x.
x
x
.
2
0
0
6
Advanced online publication: 05.05.2006
DOI: 10.1055/s-2006-942358; Art ID: F19805SS
Georg Thieme Verlag Stuttgart · New York
©

1
830
S.-Z. Jian et al.
PAPER
O
O
O
O
CHO
i
ii
OH + HOOC
CHO
N
R1
1
2
O
O
O
O
MeOOC
O
R2
iii
iv
R1
O
N
NH
O
N
R1
Br
O
N
6
R2
3
R2
4
5
O
6
1
Scheme 1 Reagents and conditions: i) DCC (4 equiv), cat. DMAP, CH Cl , r.t., overnight; ii) R NH (4 equiv), HC(OMe) , CH Cl , r.t., over-
2
2
2
3
2
2
night; iii) 5 (4 equiv), zinc powder (4.8 equiv), THF, reflux, 3 h; iv) Et N–MeOH (1:2), 60 °C, 24 h.
3
Table 1 Liquid-Phase Synthesis of trans b-Lactams 4 Using PEG-
Supported Imines
mide 11 in the presence of pyridine. The Reformatsky re-
action occurred between 12 and imine 13 in THF, and it
not only chemically produced b-lactams but also pro-
voked release of the product from the resin back into the
solution. Precipitated with diethyl ether, the polymer was
removed by filtration. After work-up and purification by
chromatography over silica gel, the resulting b-lactams 7
was successfully isolated. The trans/cis ratios were also
1
2
c
Entry
R
R
Yield
a
Purity
b
(%)
trans/cis
(
%)
a
b
c
d
e
f
Ph
Ph
Me
Et
91
89
92
87
89
90
85
88
89
89
95
90
87
90
85
81
90
86
93
92
89
87
83
89
90
85
85
83
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
1
4-MeOC H4
6
Me
Et
determined by H NMR analysis. As shown in Table 2,
imines derived from anilines and aromatic or a,b-unsatur-
ated aldehydes gave good to satisfactory yields (83–91%).
4-MeOC H4
6
4-MeC H4
6
Me
Et
Table 2 Traceless Synthesis of trans b-Lactams 14 through a ‘Res-
in-Capture-Release’ Methodology
4-MeC H4
6
d
d
d
d
1
2
3
b
g
h
i
4-FC H4
6
Me
Et
Entry
R
R
R
Yield trans/cis
a
(
%)
4-FC H4
6
a
b
c
d
e
f
Me
Me
Me
Me
Et
Ph
Ph
Ph
Ph
85
83
87
88
84
90
91
89
98:2
98:2
98:2
98:2
98:2
98:2
98:2
98:2
4-ClC H4
6
Me
Et
4-ClC H
6
4
j
4-ClC H4
6
4-MeOC H
6
4
k
l
2-MeC H4
6
Me
Et
4-MeOC H
6
Ph
Ph
Ph
4
4
2-MeC H4
6
Ph
m
3,4-Me C H
2
Me
Et
6
3
3
Et
4-MeOC H
6
n
3,4-Me C H
2 6
g
Me
Et
Ph
Ph
trans-styryl
trans-styryl
a
Yields refer to products cleaved from the resin.
Purity determined by HPLC analysis of crude products.
1
Determined by H NMR from 3 and 4.
Two times of loading are needed to insure the yield.
b
c
d
h
a
Yields refer to imine 13.
1
Determined by H NMR spectroscopy.
b
1
when R was benzyl or phenylethyl, the cycloaddition re- The formation of the trans b-lactams could be explained
1
5
action did not occur.
by the chair-like transition state involving the imine and
the Z-enolate (Scheme 3). The transition state I gave the
intermediate II, which cyclized to produce the trans b-lac-
tam, and at the same time to release the auxiliary. The for-
mation of the Z-enolate involving in the transition state I
may be due to the steric repulsion of the six-membered
ring.
In Scheme 2, the ‘resin-capture-release’ methodology
1
was adopted to synthesize b-lactams. In order to attach
auxiliary 9 to a polymer, PEG was initially activated by
mesylation in the presence of Et N. The reaction of mesy-
lated PEG with Na salt of 9 (2 equiv) afforded PEG-bound
auxiliary 10. This was transformed into the Reformatsky
reagent precursor 12 by treating with a-bromoacetyl bro-
4
3
Synthesis 2006, No. 11, 1829–1835 © Thieme Stuttgart · New York

PAPER
Synthesis of b-Lactams on Soluble Polymer Support
1831
O
O
O
R1
NH
N
iii
i
ii
OH
Br
OMs
O
O
O
O
dihydroxyl-PEG
MW = 4000
8
10
12
O
O
O
R2
R2
O
NH
R3
N
R1
iv
N
Br
HO
R3
Br
11
R1
1
4
13
9
Scheme 2 Reagents and conditions: i) MsCl (4 equiv), Et N (4 equiv), CH Cl , r.t.; ii) 9 (4 equiv), NaOMe (4 equiv), DMF; iii) 11 (2 equiv),
3
2
2
pyridine, CH Cl ; iv) 13 (0.8 equiv), zinc powder (1.6 equiv), THF, reflux, 15 min.
2
2
R
O
BrZn
O
R2
O
O
O
O
N
R1
O
R3
R2
O
R3
NH
N
+
N
R3
R1
N
R
ZnBr
R
O
N
R1
R2
I
II
Scheme 3
In summary, we successfully synthesized the trans b-lac- Methyl trans-4-(3-Methyl-4-oxo-1-phenylazetidin-2-yl)ben-
zoate (4a)
Colorless oil.
tams using both PEG-supported imine and ‘resin-capture-
release’ methodologies. The diastereoselectivity of the
–
1
present liquid-phase reaction on soluble polymer support IR (film): 1753, 1723 cm .
1
is almost as good as that of the conventional solution-
1
H NMR (500 MHz, CDCl ): d = 1.51 (d, J = 7.4 Hz, 3 H), 3.13 (dq,
3
6
phase reaction. The protocols are general and efficient. J = 2.3, 7.4 Hz, 1 H, H-3), 3.91 (s, 3 H), 4.64 (d, J = 2.3 Hz, 1 H, H-
4), 7.05 (m, 1 H), 7.25 (m, 4 H), 7.42 (d, J = 8.3 Hz, 2 H), 8.04 (d,
J = 8.3 Hz, 2 H).
The trans b-lactams exclusively obtained can be ex-
plained by a chair-like transition state involving the imine
and the Z-enolate.
1
3
C NMR (125 MHz, CDCl ): d = 13.40, 52.48, 55.62, 62.46,
3
1
1
17.10, 124.24, 126.05, 129.38, 130.60, 130.73, 137.81, 143.31,
66.77, 168.11.
All chemicals were obtained from commercial suppliers and used
without further purification. Melting points are uncorrected. Flash
column chromatography was carried out on 300–500 mesh silica
gel. IR spectra were recorded on a PerkinElmer 983 FT-IR spec-
trometer. H NMR and C NMR spectra were recorded on a Bruker
Avance DMX 500 instrument. ESI-MS data were obtained on a
Bruker Esquire 3000 plus instrument. HRMS data were obtained on
a Bruker FT-ICR-MS Apex III apparatus (ESI).
+
HRMS (ESI): m/z calcd for C H NO + Na [M + Na] : 318.1101;
found: 318.1104.
1
8
17
3
1
13
Methyl trans-4-(3-Ethyl-4-oxo-1-phenylazetidin-2-yl)benzoate
4b)
Colorless oil.
(
–
1
IR (film): 1748, 1721 cm .
1
H NMR (500 MHz, CDCl ): d = 1.12 (t, J = 7.4 Hz, 3 H), 1.90 (m,
3
trans-Lactams 4; General Procedure
1
H), 2.02 (m, 1 H), 3.03 (m, 1 H, H-3), 3.91 (s, 3 H), 4.73 (d, J = 2.2
A mixture of polymer-supported imine 2 (2 g), carboximide 5 (4
mmol), and zinc powder (4.8 mmol) in anhyd THF (8 mL) was heat-
ed to reflux under N for 15 min. After filtering through Celite and
Hz, 1 H, H-4), 7.05 (m, 1 H), 7.25 (m, 4 H), 7.42 (d, J = 8.3 Hz, 2
H), 8.04 (d, J = 8.3 Hz, 2 H).
2
1
3
C NMR (125 MHz, CDCl ): d = 11.46, 21.99, 52.20, 60.30, 62.06,
3
16.84, 123.94, 125.81, 129.10, 130.29, 130.51, 137.52, 143.40,
66.53, 167.31.
washing with THF (3 × 2.5 mL), the filtrate was concentrated to the
original volume. Cold Et O (30 mL) was added to precipitate the
1
1
2
PEG-bound trans b-lactam. The precipitate was then collected on a
sintered glass funnel and thoroughly washed with Et O (3 × 10 mL).
The resulting PEG-bound trans b-lactam was cleaved by Et N (3
3
+
HRMS (ESI): m/z calcd for C H NO + Na [M + Na] : 332.1257;
found: 332.1261.
2
19 19
3
mL) in MeOH (6 mL) at 60 °C for 24 h. Cold Et O (30 mL) was
2
added to precipitate the detached PEG-OH. The polymer was fil-
tered and the combined filtrate was flash passed through a short col-
umn of silica gel to remove trace amount of PEG and 6. The solvent
was removed to give the corresponding crude products.
Methyl trans-4-[1-(4-Methoxyphenyl)-3-methyl-4-oxoazetidin-
2-yl]benzoate (4c)
Colorless oil.
–
IR (film): 1746, 1723 cm .
1
Synthesis 2006, No. 11, 1829–1835 © Thieme Stuttgart · New York

1
832
S.-Z. Jian et al.
PAPER
1
13
H NMR (500 MHz, CDCl ): d = 1.51 (d, J = 7.4 Hz, 3 H), 3.12 (dq,
3
C NMR (100 MHz, CDCl ): d = 13.08, 52.25, 55.56, 62.37,
3
J = 2.1, 7.4 Hz, 1 H, H-3), 3.74 (s, 3 H), 3.91 (s, 3 H), 4.60 (d,
J = 2.1 Hz, 1 H, H-4), 6.78 (d, J = 9.0 Hz, 2 H), 7.19 (d, J = 9.0 Hz,
115.90 (JC,F = 22.5 Hz), 118.22 (JC,F = 8.6 Hz), 125.78, 130.46,
130.50, 133.75 (JC,F = 2.7 Hz), 133.77, 142.67, 159.00
(JC,F = 241.9 Hz), 166.45, 167.56.
2
H), 7.42 (d, J = 8.3 Hz, 2 H), 8.04 (d, J = 8.3 Hz, 2 H).
1
3
+
HRMS (ESI): m/z calcd for C H FNO + Na [M + Na] : 336.1006;
found: 336.1011.
C NMR (125 MHz, CDCl ): d = 13.15, 52.22, 55.32, 55.41, 62.25,
3
18 16
3
1
1
14.31, 118.12, 125.81, 130.26, 130.42, 131.09, 143.13, 156.01,
66.52, 167.27.
+
HRMS (ESI): m/z calcd for C H NO + Na [M + Na] : 348.1214;
found: 348.1206.
Methyl trans-4-[3-Ethyl-1-(4-fluorophenyl)-4-oxoazetidin-2-
yl]benzoate (4h)
Colorless oil.
1
9
19
4
–
1
IR (film): 1750, 1723 cm .
Methyl trans-4-[3-Ethyl-1-(4-methoxyphenyl)-4-oxoazetidin-2-
yl]benzoate (4d)
Colorless oil.
1
H NMR (500 MHz, CDCl ): d = 1.11 (t, J = 7.4 Hz, 3 H), 1.93 (m,
3
1
H), 2.01 (m, 1 H), 3.04 (m, 1 H, H-3), 3.91 (s, 3 H), 4.64 (d, J = 2.3
Hz, 1 H, H-4), 6.94 (m, 2 H), 7.22 (m, 2 H), 7.41 (d, J = 8.3 Hz, 2
H), 8.04 (d, J = 8.3 Hz, 2 H).
–
IR (film): 1746, 1723 cm .
1
1
H NMR (500 MHz, CDCl ): d = 1.11 (t, J = 7.4 Hz, 3 H), 1.89 (m,
3
1
3
1
4
H), 1.98 (m, 1 H), 3.03 (m, 1 H, H-3), 3.74 (s, 3 H), 3.91 (s, 3 H),
.68 (d, J = 2.2 Hz, 1 H, H-4), 6.78 (d, J = 9.0 Hz, 2 H), 7.19 (d,
C NMR (100 MHz, CDCl ): d = 11.45, 21.86, 52.28, 60.16, 62.03,
3
115.85 (JC,F = 22.7 Hz), 118.26 (JC,F = 8.6 Hz), 125.68, 130.48,
130.52, 133.71 (JC,F = 2.8 Hz), 133.75, 142.64, 159.06
(JC,F = 242.1 Hz), 166.39, 167.54.
J = 9.0 Hz, 2 H), 7.41 (d, J = 8.3 Hz, 2 H), 8.04 (d, J = 8.3 Hz, 2 H).
1
3
C NMR (125 MHz, CDCl ): d = 11.47, 21.90, 52.23, 60.23, 62.00,
3
+
HRMS (ESI): m/z calcd for C H FNO + Na [M + Na] : 350.1163;
found: 350.1168.
1
1
14.35, 118.16, 125.79, 130.27, 130.38, 131.05, 143.15, 156.05,
66.56, 167.26.
1
9
18
3
+
HRMS (ESI): m/z calcd for C H NO + Na [M + Na] : 362.1363;
found: 362.1370.
2
0
21
4
Methyl trans-4-[1-(4-Chlorophenyl)-3-methyl-4-oxoazetidin-2-
yl]benzoate (4i)
Colorless oil.
Methyl trans-4-[3-Methyl-1-(4-methylphenyl)-4-oxoazetidin-2-
yl]benzoate (4e)
Colorless oil.
–
1
IR (film): 1749, 1723 cm .
1
H NMR (500 MHz, CDCl ): d = 1.51 (d, J = 7.4 Hz, 3 H), 3.15 (dq,
3
–
IR (film): 1750, 1723 cm .
1
J = 2.3, 7.4 Hz, 1 H, H-3), 3.91 (s, 3 H), 4.62 (d, J = 2.3 Hz, 1 H, H-
4), 6.19 (m, 4 H), 7.40 (d, J = 8.3 Hz, 2 H), 8.05 (d, J = 8.3 Hz, 2 H).
1
H NMR (500 MHz, CDCl ): d = 1.50 (d, J = 7.4 Hz, 3 H), 2.26 (s,
3
1
3
3 H), 3.11 (dq, J = 2.2, 7.4 Hz, 1 H, H-3), 3.91 (s, 3 H), 4.61 (d,
J = 2.2 Hz, 1 H, H-4), 7.04 (d, J = 8.3 Hz, 2 H), 7.14 (d, J = 9.0 Hz,
C NMR (125 MHz, CDCl ): d = 13.43, 52.47, 55.53, 62.41,
3
117.10, 121.24, 126.05, 129.38, 130.60, 132.73, 137.23, 143.56,
166.80, 167.93.
2
H), 7.41 (d, J = 8.3 Hz, 2 H), 8.04 (d, J = 8.3 Hz, 2 H).
1
3
+
HRMS (ESI): m/z calcd for C H ClNO + Na [M + Na] :
352.0711; found: 352.0718.
C NMR (125 MHz, CDCl ): d = 13.13, 20.83, 52.19, 55.27, 62.11,
3
18 16
3
1
1
16.75, 125.77, 129.57, 130.23, 130.40, 133.58, 135.07, 143.15,
66.52, 167.58.
+
HRMS (ESI): m/z calcd for C H NO + Na [M + Na] : 332.1257;
found: 332.1266.
Methyl trans-4-[1-(4-Chlorophenyl)-3-ethyl-4-oxoazetidin-2-
yl]benzoate (4j)
Colorless oil.
1
9
19
3
–
IR (film): 1750, 1723 cm .
1
Methyl trans-4-[3-Ethyl-1-(4-methylphenyl)-4-oxoazetidin-2-
yl]benzoate (4f)
Colorless oil.
1
H NMR (500 MHz, CDCl ): d = 1.11 (t, J = 7.4 Hz, 3 H), 1.92 (m,
3
1
H), 2.03 (m, 1 H), 3.02 (m, 1 H, H-3), 3.91 (s, 3 H), 4.68 (d, J = 2.3
–
IR (film): 1750, 1723 cm .
1
Hz, 1 H, H-4), 6.19 (m, 4 H), 7.41 (d, J = 8.3 Hz, 2 H), 8.05 (d,
J = 8.3 Hz, 2 H).
1
H NMR (500 MHz, CDCl ): d = 1.11 (t, J = 7.4 Hz, 3 H), 1.89 (m,
3
1
3
1
4
H), 1.99 (m, 1 H), 2.26 (s, 3 H), 3.04 (m, 1 H, H-3), 3.91 (s, 3 H),
.69 (d, J = 1.7 Hz, 1 H, H-4), 7.04 (d, J = 8.3 Hz, 2 H), 7.14 (d,
C NMR (125 MHz, CDCl ): d = 11.40, 21.88, 52.21, 60.23, 62.00,
3
117.11, 121.36, 125.98, 129.32, 130.65, 132.75, 137.18, 143.49,
166.67, 167.88.
J = 9.0 Hz, 2 H), 7.41 (d, J = 8.3 Hz, 2 H), 8.04 (d, J = 8.3 Hz, 2 H).
1
3
+
HRMS (ESI): m/z calcd for C H ClNO + Na [M + Na] :
366.0867; found: 366.0871.
C NMR (125 MHz, CDCl ): d = 11.48, 20.85, 21.98, 52.21, 60.17,
3
19 18
3
6
1
1.95, 116.72, 125.79, 129.57, 130.14, 130.45, 133.55, 135.02,
43.48, 166.53, 167.04.
+
HRMS (ESI): m/z calcd for C H NO + Na [M + Na] : 346.1414;
found: 346.1421.
Methyl trans-4-[3-Methyl-1-(2-methylphenyl)-4-oxoazetidin-2-
yl]benzoate (4k)
Colorless oil.
2
0
21
3
–
IR (film): 1753, 1723 cm .
1
Methyl trans-4-[1-(4-Fluorophenyl)-3-methyl-4-oxoazetidin-2-
yl]benzoate (4g)
Colorless oil.
1
H NMR (500 MHz, CDCl ): d = 1.53 (d, J = 7.3 Hz, 3 H), 2.42 (s,
3
3
H), 3.21 (dq, J = 2.3, 7.4 Hz, 1 H, H-3), 3.89 (s, 3 H), 4.82 (d,
–
1
IR (film): 1751, 1723 cm .
J = 2.3 Hz, 1 H, H-4), 7.07–7.17 (m, 4 H), 7.38 (d, J = 8.2 Hz, 2 H),
8.00 (d, J = 8.2 Hz, 2 H).
1
H NMR (500 MHz, CDCl ): d = 1.51 (d, J = 7.4 Hz, 3 H), 3.15 (dq,
3
1
3
J = 2.2, 7.4 Hz, 1 H, H-3), 3.92 (s, 3 H), 4.62 (d, J = 2.2 Hz, 1 H, H-
C NMR (125 MHz, CDCl ): d = 13.54, 19.78, 52.46, 54.58, 64.16,
3
4), 6.94 (m, 2 H), 7.22 (m, 2 H), 7.41 (d, J = 8.3 Hz, 2 H), 8.05 (d,
J = 8.3 Hz, 2 H).
122.56, 126.46, 126.68, 126.75, 130.53, 131.82, 132.40, 135.05,
143.66, 166.76, 168.50.
Synthesis 2006, No. 11, 1829–1835 © Thieme Stuttgart · New York

PAPER
HRMS (ESI): m/z calcd for C H NO + Na [M + Na] : 332.1257;
found: 332.1264.
Synthesis of b-Lactams on Soluble Polymer Support
1833
+
Polymer-Bound Amide 10
1
9
19
3
A mixture of NaOMe (0.21 g, 3.8 mmol) and 9 (0.88 g, 3.8 mmol)
in DMF (5 mL) was added to a solution of 8 (3 g) in DMF (20 mL).
The mixture was stirred for 18 h at 50 °C, and then distilled to re-
move DMF until the residue became slightly viscous. The residue
Methyl trans-4-[3-Ethyl-1-(2-methylphenyl)-4-oxoazetidin-2-
yl]benzoate (4l)
–
IR (film): 1753, 1724 cm .
1
was dissolved in H O and further neutralized with dilute aq HCl un-
2
1
til pH 7. Then the whole mixture was extracted with CH
C1 . The
2 2
H NMR (500 MHz, CDCl ): d = 1.13 (t, J = 7.4 Hz, 3 H), 1.92 (m,
3
organic phase was washed with H O, dried (Na SO ), filtered and
2
2
4
1
4
H), 2.01 (m, 1 H), 2.42 (s, 3 H), 3.02 (m, 1 H, H-3), 3.91 (s, 3 H),
.89 (d, J = 2.2 Hz, 1 H, H-4), 7.07–7.17 (m, 4 H), 7.38 (d, J = 8.2
concentrated under vacuum until the residue became slightly vis-
cous. Purification by precipitation in cold Et O gave 10; yield: 2.3
g (77%).
2
Hz, 2 H), 8.00 (d, J = 8.2 Hz, 2 H).
1
3
C NMR (125 MHz, CDCl ): d = 11.45, 20.89, 21.88, 52.29, 60.09,
3
1
H NMR (500 MHz, CDCl ): d = 1.20–1.70 (m, 10 H), 3.50–3.86
3
6
1
2.86 122.57, 126.39, 126.69, 126.78, 130.56, 131.79, 132.43,
35.00, 143.62, 166.67, 168.52.
(
PEGOCH CH OPh), 6.29 (br s, 1 H), 6.45 (m, 1 H), 6.61 (m, 1 H),
m, PEG backbone, OCH CH O), 4.14 (t, J = 5 Hz, 2 H,
2 2
2
2
+
HRMS (ESI): m/z calcd for C H NO + Na [M + Na] : 346.1414;
found: 346.1421.
2
0
21
3
7.80 (m, 1 H).
Polymer-Bound Imides 12; General Procedure
Methyl trans-4-[3-Methyl-1-(3,4-dimethylphenyl)-4-oxoazeti-
din-2-yl]benzoate (4m)
Colorless oil.
To a mixture of 10 (2 g), pyridine (0.4 g, 5 mol) and toluene (20 mL)
was added 11 (5 mmol) at 5–15 °C. This mixture was stirred at the
same temperature for 30 min and then overnight at r.t. The precipi-
tated salt was removed by filtration, and the filtrate was concentrat-
ed under vacuum until the residue became slightly viscous.
–
IR (film): 1751, 1724 cm .
1
1
H NMR (500 MHz, CDCl ): d = 1.49 (d, J = 7.4 Hz, 3 H), 2.17 (s,
3
Purification by precipitation with cold Et O gave 12.
2
3
4
1
H), 2.18 (s, 3 H) 3.15 (dq, J = 2.3, 7.4 Hz, 1 H, H-3), 3.91 (s, 3 H),
.60 (d, J = 2.3 Hz, 1 H, H-4), 6.83 (m, 1 H), 6.97 (m, 1 H), 7.19 (m,
H), 7.41 (d, J = 8.2 Hz, 2 H), 8.03 (d, J = 8.2 Hz, 2 H).
1
2a (R = Me)
1
Yield: 1.9 g (95%).
1
3
C NMR (125 MHz, CDCl ): d = 13.46, 19.46, 20.15, 52.48, 55.50,
3
1
H NMR (500 MHz, CDCl ): d = 1.20–2.50 (m, 10 H), 1.90 (d,
3
6
1
2.40, 114.30, 118.58, 126.03, 130.25, 130.50, 130.69, 132.67,
35.71, 137.87, 143.61, 166.84, 167.88.
J = 6.6 Hz, 3 H), 3.50–3.86 (m, PEG backbone, OCH CH O), 4.18
2
2
(m, 2 H, PEGOCH CH OPh), 5.13 (q, J = 6.6 Hz, 1 H), 6.50 (s, 1
H), 6.67 (d, J = 9.0 Hz, 1 H), 7.82 (d, J = 9.0 Hz, 1 H).
2 2
+
HRMS (ESI): m/z calcd for C H NO + Na [M + Na] : 346.1414;
found: 346.1416.
2
0
21
3
1
2b (R = Et)
1
Yield : 1.8 g (90%).
Methyl trans-4-[3-Ethyl-1-(3,4-dimethylphenyl)-4-oxoazetidin-
-yl]benzoate (4n)
1
2
IR (film): 1752, 1724 cm .
H NMR (500 MHz, CDCl ): d = 1.13 (t, J = 7.4 Hz, 3 H), 1.29 (m,
3
–
1
1 H), 1.45 (m, 1 H), 1.53–2.41 (m, 10 H), 3.50–3.86 (m, PEG back-
1
bone, OCH
J = 5.2, 8.9 Hz, 1 H), 6.50 (s, 1 H), 6.67 (d, J = 9.0 Hz, 1 H), 7.82
d, J = 9.0 Hz, 1 H).
2
CH O), 4.18 (m, 2 H, PEG OCH CH OPh), 4.98 (dd,
2
2
2
H NMR (500 MHz, CDCl ): d = 1.11 (t, J = 7.4 Hz, 3 H), 1.89 (m,
3
1
3
1
H), 1.99 (m, 1 H), 2.17 (s, 3 H), 2.18 (s, 3 H) 3.02 (m, 1 H, H-3),
.91 (s, 3 H), 4.69 (d, J = 2.2 Hz, 1 H, H-4), 6.84 (m, 1 H), 6.97 (m,
H), 7.18 (m, 1 H), 7.41 (d, J = 8.2 Hz, 2 H), 8.03 (d, J = 8.2 Hz, 2
(
trans-b-Lactams 14; General Procedure
H).
A mixture of 12 (1 mmol), imine 13 (0.8 mmol) and zinc dust (3
mmol) in THF (5 mL) was refluxed for 10–20 min, and then con-
centrated under vacuum until the residue became slightly viscous.
1
3
C NMR (125 MHz, CDCl ): d = 11.71, 19.44, 20.13, 22.24, 52.48,
3
6
1
0.40, 62.17, 114.25, 118.54, 126.04, 129.76, 130.22, 130.70,
32.61, 135.65, 137.85, 143.93, 166.83, 167.31.
After the addition of Et O (10 mL), PEG was precipitated and re-
2
+
HRMS (ESI): m/z calcd for C H NO + Na [M + Na] : 360.1570;
found: 360.1579.
moved by filtration. The filtrate was washed with brine, dried
(Na SO ), and evaporated in vacuo. The residue was purified by
flash column chromatography on silica gel (eluent: hexane–EtOAc)
2
1
23
3
2 4
to give 14.
7-Hydroxyspiro[2H-1,3-benzoxazine-2,1¢-cyclohexan]-4(3H)-
one (9)
trans-3-Methyl-1,4-diphenylazetidin-2-one (14a)
Colorless oil.
A mixture of 2,4-dihydroxybenzamide (13.2 g, 86 mmol), cyclo-
hexanone (10.7 g, 110 mmol), and TsOH·H O (1.4 g, 7.3 mmol) in
2
toluene (100 mL) was refluxed under conditions of removal of wa-
ter using a Dean–Stark apparatus for 12 h. After gradual cooling
down to 10 °C, the mixture was stirred for 1 h at the same tempera-
ture. The resulting crystals were collected, washed successively
with toluene (10 mL) and i-PrOH (10 mL), and dried at 50 °C to af-
ford 10.2 g (51%) of 9 as colorless crystals; mp 204–208 °C.
1
–1
IR (film): 1744 cm .
1
H NMR (500 MHz, CDCl ): d = 1.52 (d, J = 7.4 Hz, 3 H), 3.17 (dq,
3
J = 2.4, 7.4 Hz, 1 H, H-3), 4.60 (d, J = 2.4 Hz, 1 H, H-4), 7.07 (m,
1
H) 7.26–7.43 (m, 9 H).
1
3
C NMR (125 MHz, CDCl ): d = 13.35, 55.56, 62.97, 117.21,
3
123.99, 126.07, 128.69, 129.28, 129.38, 138.08, 138.20, 168.63.
H NMR (500 MHz, DMSO-d ): d = 1.22–1.24 (m, 1 H), 1.55 (m,
6
+
ESI-MS: m/z = 238 [M + H] .
7
8
H), 1.94–1.96 (m, 2 H), 6.29 (s, 1 H), 6.46 (m, 1 H), 7.54 (d, J =
.4 Hz, 2 H), 8.28 (s, 1 H), 10.2 (br s, 1 H).
1
3
trans-4-(4-Chlorophenyl)-3-methyl-1-phenylazetidin-2-one
(14b)
Colorless oil.
C NMR (500 MHz, DMSO-d ): d = 21.99, 24.78, 35.92, 88.17,
6
1
03.17, 110.06, 110.23, 129.17, 157.24, 161.88, 163.38.
+
HRMS (ESI): m/z calcd for C H NO + Na [M + Na] : 256.0944;
found: 256.0951.
1
3
15
3
–1
IR (film): 1748 cm .
Synthesis 2006, No. 11, 1829–1835 © Thieme Stuttgart · New York

1
834
S.-Z. Jian et al.
PAPER
1
H NMR (500 MHz, CDCl ): d = 1.47 (d, J = 7.4 Hz, 3 H), 3.09 (dq,
3
(dd, J = 8.4, 15.9 Hz, 1 H), 6.80 (d, J = 15.9 Hz, 1 H), 7.05–7.45 (m,
10 H).
J = 2.3, 7.4 Hz, 1 H, H-3), 4.55 (d, J = 2.3 Hz, 1 H, H-4), 7.04 (m,
1
H), 7.23–7.40 (m, 8 H).
13
C NMR (125 MHz, CDCl ): d = 12.89, 52.03, 61.71, 116.83,
3
1
3
C NMR (125 MHz, CDCl ): d = 13.33, 55.65, 62.23, 117.12,
3
123.68, 126.51, 126.76, 128.01, 128.70, 128.93, 133.99, 135.54,
138.18, 168.13.
1
24.18, 127.43, 129.35, 129.63, 134.49, 136.71, 137.81, 168.27.
+
ESI-MS: m/z = 272 [M + H] .
+
ESI-MS: m/z = 264 [M + H] , 549 [2 × M + Na] .
+
trans-4-(4-Methoxyphenyl)-3-methyl-1-phenylazetidin -2-one
(14c)
Yellow solid; mp 76–77 °C.
trans-3-Ethyl-1-phenyl-4-[(E)-2-phenylethenyl]azetidin-2-one
(14h)
Colorless oil.
–
IR (KBr): 1745 cm .
1
–1
IR (film): 1754 cm .
1
1
H NMR (500 MHz, CDCl ): d = 1.48 (d, 3 H, J = 7.4 Hz), 3.11 (dq,
3
H NMR (500 MHz, CDCl ): d = 1.09 (t, J = 7.4 Hz, 3 H), 1.83 (m,
3
J = 2.2, 7.4 Hz, 1 H, H-3), 3.73 (s, 3 H), 4.56 (d, J = 2.2 Hz, 1 H, H-
4
1 H), 1.94 (m, 1 H), 3.06 (m, H-3, 1 H), 4.33 (dd, J = 1.9, 8.4 Hz, 1
H, H-4), 6.30 (dd, J = 8.4, 15.9 Hz, 1 H), 6.78 (d, J = 15.9 Hz, 1 H),
7.03–7.50 (m, 10 H).
), 6.76–7.38 (m, 9 H).
1
3
C NMR (125 MHz, CDCl ): d = 13.23, 55.50 (CCH and OCH
3
3
3
1
3
overlap), 62.68, 114.68, 117.15, 123.86, 127.33, 129.16, 130.77,
38.04, 159.87, 168.73.
C NMR (125 MHz, CDCl ): d = 11.63, 21.85, 59.21, 60.04,
3
1
117.03, 123.93, 126.83, 127.67, 128.53, 128.95, 129.28, 133.84,
136.02, 138.56, 167.61.
+
ESI-MS: m/z = 268 [M + H] .
+
ESI-MS: m/z = 278 [M + H] , 577 [2 × M + Na] .
+
trans-1-(4-Methoxyphenyl)-3-methyl-4-phenylazetidin-2-one
(14d)
Colorless oil.
Acknowledgment
–
1
IR (film): 1749 cm .
We thank the National Natural Science Foundation of China (No.
29972037) as well as the Teaching and Research Award Program
for Outstanding Young Teachers in Higher Education Institutions
of MOE, P.R. of China.
1
H NMR (500 MHz, CDCl ): d = 1.46 (d, J = 7.4 Hz, 3 H), 3.10 (dq,
3
J = 2.2, 7.4 Hz, 1 H, H-3), 3.80 (s, 3H), 4.53 (d, J = 2.2 Hz, 1 H, H-
4
), 6.89–7.29 (m, 9 H).
1
3
C NMR (125 MHz, CDCl ): d = 13.51, 55.03, 55.09, 62.63,
3
1
1
14.01, 118.03, 125.58, 128.21, 128.92, 131.11, 137.67, 155.73, References
67.60
(1) (a) Lam, K. S. M.; Lebl, M.; Krchnak, V. Chem. Rev. 1997,
+
ESI-MS: m/z = 268 [M + H] .
97, 411. (b) Krchnak, V.; Holladay, M. W. Chem. Rev. 2002,
102, 61. (c) Blaney, P.; Grigg, R.; Sridharan, V. Chem. Rev.
2002, 102, 2607. (d) Balkenhohl, F.; von dem Bussche-
trans-3-Ethyl-1,4-diphenylazetidin-2-one (14e)
Colorless oil.
Hunnefeld, C. V. D.; Lansky, A.; Zechel, C. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2288.
–1
IR (film): 1757 cm .
(
2) (a) Oikawa, M.; Tanaka, T.; Kusomoto, S.; Sasaki, M.
Tetrahedron Lett. 2004, 45, 787. (b) Swamy, K. M. K.; Yeh,
W. B.; Lin, M. J.; Sun, C. M. Curr. Med. Chem. 2003, 10,
1
H NMR (500 MHz, CDCl ): d = 1.09 (t, J = 7.4 Hz, 3 H), 1.85 (m,
3
H), 1.95 (m, 1 H), 3.06 (m, 1 H, H-3), 4.67 (d, J = 2.2 Hz, 1 H),
.02–7.46 (m, 10 H).
1
7
2403. (c) Sun, C. M.; Swamy, K. M. K.; Lin, M. J.; Yeh, W.
1
3
C NMR (125 MHz, CDCl ): d = 11.71, 22.25, 61.00, 62.23,
3
B.; Chen, F. Y.; Tseng, W. H. Comb. Chem. High
Throughput Screening 2003, 6, 133. (d) Gravert, D. J.;
Janda, K. D. Chem. Rev. 1997, 97, 489. (e) Toy, P. H.;
Janda, K. D. Acc. Chem. Res. 2000, 33, 546.
1
1
17.19, 123.92, 126.06, 128.56, 129.26, 129.39, 138.04, 138.50,
68.04.
+
ESI-MS: m/z = 274 [M + Na] .
(3) (a) Lin, X. F.; Zhang, J.; Wang, Y. G. Tetrahedron Lett.
2
003, 44, 4113. (b) Lin, X. F.; Zhang, J.; Cui, S. L.; Wang,
trans-3-Ethyl-1-(4-methoxyphenyl)-4-phenylazetidin-2-one
(14f)
Colorless oil.
Y. G. Synthesis 2003, 1569. (c) Shang, Y. J.; Wang, Y. G.
Tetrahedron Lett. 2002, 43, 2247. (d) Shang, Y. J.; Wang,
Y. G. Chin. J. Chem. 2003, 21, 7. (e) Xia, M.; Wang, Y. G.
Tetrahedron Lett. 2002, 43, 7703. (f) Chen, C. P.; Chen, Y.
J. Tetrahedron Lett. 2004, 45, 113. (g) Cheng, M. F.; Fang,
J. M. J. Comb. Chem. 2004, 6, 99. (h) Tung, C. L.; Sun, C.
M. Tetrahedron Lett. 2004, 45, 1159.
–1
IR (film): 1727 cm .
1
H NMR (500 MHz, CDCl ): d = 1.10 (t, J = 7.5 Hz, 3 H), 1.86 (m,
3
1
1
H), 1.96 (m, 1 H), 3.05 (m, 1 H), 3.76 (s, 3 H), 4.62 (d, J = 2.5 Hz,
H), 6.66–7.89 (9 H, m).
1
3
(4) (a) Magriotis, P. A. Angew. Chem. Int. Ed. 2001, 40, 4377.
b) Ojima, I. Acc. Chem. Res. 1995, 28, 283. (c) Ojima, I.;
C NMR (125 MHz, CDCl ): d = 11.51, 22.03, 55.38, 60.81, 61.88,
3
(
1
1
14.33, 118.22, 125.76, 128.39, 128.30, 131.42, 138.30, 155.89,
67.23.
Delaloge, F. Chem. Soc. Rev. 1997, 26, 377.
5) Synthesis of beta-Lactam Antibiotics: Chemistry,
Biocatalysis and Process Integration; Bruggink, A., Ed.;
Kluwer: Dordrecht, 2001.
(
(
+
ESI-MS: m/z = 304 [M + Na] .
trans-3-Methyl-1-phenyl-4-[(E)-2-phenylethenyl]azetidin-2-one
(14g)
Colorless oil.
6) Bonneau, P. R.; Hasani, F.; Plouffe, C.; Malenfant, E.;
LaPlante, S. R.; Guse, I.; Ogilvie, W. W.; Plante, R.;
Davidson, W. C.; Hopkins, J. L.; Morelock, M. M.;
Cordingley, M. G.; Deziel, R. J. Am. Chem. Soc. 1999, 121,
–1
IR (film): 1748 cm .
2965.
1
H NMR (500 MHz, CDCl ): d = 1.44 (d, J = 7.4 Hz, 3 H), 3.13 (dq,
3
J = 1.7, 7.4 Hz, 1 H, H-3), 4.24 (dd, J = 1.1, 8.1 Hz, 1 H, H-4), 6.28
Synthesis 2006, No. 11, 1829–1835 © Thieme Stuttgart · New York

PAPER
Synthesis of b-Lactams on Soluble Polymer Support
1835
(
(
7) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi Puglisi,
F. A. Bioorg. Med. Chem. 2002, 10, 1813.
8) Han, W. T.; Trehan, A. K.; Wright, J. J. K.; Federici, M. E.;
Seiler, S. M.; Meanwell, N. A. Bioorg. Med. Chem. 1995, 3,
(14) Kirschning, A.; Monenschein, H.; Wittenberg, R. Chem.
Eur. J. 2000, 6, 4445.
(15) (a) Nagao, Y.; Kumagai, T.; Tamai, S.; Abe, T.; Kuramoto,
Y.; Taga, T.; Aoyagi, S.; Nagase, Y.; Ochiai, M.; Inoue, Y.;
Fujita, E. J. Am. Chem. Soc. 1986, 108, 4673. (b) Fuentes,
L. M.; Shinkai, I.; Saltsmann, T. N. J. Am. Chem. Soc. 1986,
108, 4675. (c) Ito, Y.; Sasaki, A.; Tamoto, K.; Sunagawa,
M.; Terashima, S. Tetrahedron 1991, 47, 2801. (d) Nagao,
Y.; Nagase, Y.; Kumagai, T.; Matsunaga, H.; Abe, T.;
Shimada, O.; Hayashi, T.; Inoue, Y. J. Org. Chem. 1992, 57,
4243. (e) Fukuzawa, S.; Matsuzawa, H.; Yoshimitsu, S. J.
Org. Chem. 2000, 65, 1702.
1123.
(
9) Firestone, R. A.; Barker, P. L.; Pisano, J. M.; Ashe, B. M.;
Dahlgren, M. E. Tetrahedron 1990, 46, 2255.
(
(
(
10) Jian, S. Z.; Wang, Y. G. Chem. Lett. 2004, 33, 866.
11) Shang, Y. J.; Shou, W. G.; Wang, Y. G. Synlett 2003, 1064.
12) Auxiliary 5 was prepared by the method described by:
Kondo, K.; Seki, M.; Kuroda, T.; Yamanaka, T.; Iwasaki, T.
J. Org. Chem. 1997, 62, 2877.
(
13) See for example: (a) Townes, J. A.; Evans, M. A.;
Queffelec, J.; Taylor, S. J.; Morken, J. P. Org. Lett. 2002, 4,
(16) Jian, S. Z.; Ma, C.; Wang, Y. G. Synthesis 2005, 725.
2537. (b) Chen, L.; Zhao, G.; Ding, Y. Tetrahedron Lett.
2003, 44, 2611.
Synthesis 2006, No. 11, 1829–1835 © Thieme Stuttgart · New York