Soluble polymer-supported synthesis of trans β-lactams with high diastereoselectivity

Article abstract of DOI:10.1246/cl.2004.866

A general method for the liquid-phase synthesis of trans β-lactams with high diastereoselectivity is described. The mechanism can be explained by a chair-like transition state involving the imine and the (Z)-enolate.

Full text of DOI:10.1246/cl.2004.866

866
Chemistry Letters Vol.33, No.7 (2004)
Soluble Polymer-supported Synthesis of trans ꢀ-Lactams with High Diastereoselectivity
Shan-Zhong Jian and Yan-Guang Wangꢀ
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
(Received April 22, 2004; CL-040454)
A general method for the liquid-phase synthesis of trans ꢀ-
action conditions are mild enough not to alter the trans/cis ratio
of ꢀ-lactams. The results are summarized in Table 1.
lactams with high diastereoselectivity is described. The mecha-
nism can be explained by a chair-like transition state involving
the imine and the (Z)-enolate.
As shown in Table 1, when R1 was an aryl group (Entries
a–n), the reaction gave products 4 in high yields (85–96%), good
O
i
In recent years, the liquid-phase synthesis of small heterocy-
clic molecules has been a subject of intense research activity,1
since it represents one of the most promising ways to generate
small molecular libraries in the field of combinatorial chemis-
try.2 It profits from both the advantageous features of homogene-
ous solution chemistry (high reactivity, lack of diffusion phe-
nomena, and ease of analysis without following the cleavage-
and-check technique) and of solid-phase methods (use of excess
reagents and easy isolation and purification of products). Among
the various soluble polymers, polyethylene glycol (PEG) is the
most useful and promising.3 This polymer is soluble in many sol-
vents, e.g., THF, CH2Cl2, or H2O at room temperature, but can
be precipitated from a solution and thus purified by addition of
diethyl ether, hexane, or 2-propanol. Furthermore, each reaction
can be easily monitored by solution phase 1H NMR of a polymer
sample in CDCl3.
CHO
OH +
HOOC
CHO
O
O
1
O
O
iii
O
ii
1
1
R
N
R
N
6
2
3
2
R
O
O
O
O
O
MeOOC
iv
2
R
1
N
R
NH
N
Br
O
2
R
O
6
5
4
Scheme 1. i) 4 equiv. DCC, cat. DMAP, CH2Cl2, rt, overnight;
ii) 4 equiv. NH2R1, 4 equiv. HC(OCH3)3, CH2Cl2, rt, overnight;
iii) 4 equiv. 5, 4.8 equiv. zinc power, THF, reflux, 3 h; iv) Et3N/
MeOH (1/2, v/v), 60 ꢁC, 24 h.
ꢀ-Lactams are very important compounds existing widely in
various antibiotics and other natural products.4 Recent develop-
ments about the synthesis of ꢀ-lactams have mainly focused on
the catalytic asymmetric and the polymer supported synthesis.
Even though methods for the cis ꢀ-lactams preparation are well
studied in both liquid and solid phase,5 there are very limited
procedures available for the synthesis of the trans isomers.6 In
connection with our research on the PEG-supported liquid-phase
synthesis,7 we synthesized the trans ꢀ-lactams on PEG support
using an auxiliary. Herein we report the results of our work.
As shown in Scheme 1, the investigation began by coupling
4-formylbenzoic acid to PEG 4000 in the presence of 1,3-dicy-
clohexycarbodiimide (DCC) with a catalytic amount of DMAP
in anhydrous CH2Cl2 at room temperature for 24 h to give the
polymer-supported aldehyde 1.7 The representative imines 2
were prepared by treating 1 with aromatic amines in the presence
of trimethyl orthoformate in CH2Cl2 at room temperature. The
reaction gave the corresponding PEG-bound aldimines 2.7 In
general, the progress of both the esterification and imines forma-
tion steps was routinely monitored by 1H NMR spectroscopy.
After precipitated with ether and dried by vacuum, the poly-
mer-bound 2 reacted with 4 equivalents of the auxiliary carbox-
imide 58 and 4.8 equivalents of zinc power in THF to afford the
polymer supported trans ꢀ-lactams 3 with high diastereoselec-
Table 1. Liquid-phase synthesis of trans ꢀ-lactams using PEG
as support
Yield / Purity
/%a
Entry
R1
R2
trans/cisc
/%b
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
C6H5
C6H5
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
91
89
92
87
89
90
85d
88d
89d
89d
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
—
p-MeOC6H4
p-MeOC6H4
p-MeC6H4
p-MeC6H4
p-FC6H4
p-FC6H4
p-ClC6H4
p-ClC6H4
o-MeC6H4
o-MeC6H4
3, 4-Me2C6H3 Me
3, 4-Me2C6H3 Et
C6H5CH2
C6H5CHMe
Me
Me
1
tivity. The trans/cis ratio was determined by H NMR, based
—
on the H-3/H-4 coupling constant values (Jtrans ¼ 1:5–2.5 Hz,
Jcis ¼ 4:5–6.0 Hz). Substrate cleavage was accomplished by
treating 3 with Et3N/MeOH (1/2, v/v) at 60 ꢁC and monitored
for the disappearance of the polymeric ꢀ-lactams by TLC.9 Nor-
mally, cleavage was completed after stirring for 24 h.10 The re-
aYields refer to products cleaved from the resin.
bPurity determined by HPLC analysis of crude products. All
products show satisfactory H NMR and MS (ESI) data.
1
cDetermined by 1H NMR from 3 and 4.
dTwo times of loading are needed to insure the yield.
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.7 (2004)
867
to excellent purities (81–93%) and high diastereoselectivity
(trans/cis > 98:2). However, when R1 was benzyl (Entry o) or
phenylethyl (Entry p), the cycloaddition reaction did not take
place.
The production of the trans ꢀ-lactams could be explained by
the chair-like transition state 7 involving the imine and the (Z)-
enolate (Scheme 2). The transition state gave the intermediate 8,
which cyclized to produce the trans ꢀ-lactam 3. The formation
of the (Z)-enolate involving in the transition state may be due
to the steric repulsion of the six-membered ring.
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BrZn
R1
O
O
N
6
7
V. Molteni, R. Annuniziata, M. Cinquini, F. Cozzi, and
M. Benaglia, Tetrahedron Lett., 39, 1257 (1998).
N
R
O
O
N
3
R2
N
O
a) Y. J. Shang and Y. G. Wang, Tetrahedron Lett., 43, 2247
(2002). b) M. Xia and Y. G. Wang, Tetrahedron Lett., 43,
7703 (2002). c) X. F. Lin, J. Zhan, and Y. G. Wang,
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R
ZnBr
O
8
R2
R1
7
OOC
R=
8
9
Scheme 2. Plausible mechanism for the formation of ꢀ-
lactams.
In summary, we have developed a general method for the
liquid-phase synthesis of trans ꢀ-lactams on PEG-support. The
protocol gave the trans products in high diastereoselectivity
and yields with good purity.
The polymeric ꢀ-lactams exhibited fluorescence on TLC, so
the disappearance of fluorescence of the polymer point on
TLC could indicate the completion of cleavage reactions.
10 Typical procedure for synthesis of trnas ꢀ-lactams: The
mixture of polymer-supported imine (1 mmol), carboximide
(4 mmol), and zinc powder (4.8 mmol) in anhydrous THF
(8 mL) was refluxed under N2 for 15 min. After filtering
through celite and washing with THF (3 ꢂ 2:5 mL), the fil-
trate was concentrated to the original volume. The cold Et2O
(30 mL) was added to precipitate the PEG-bound trans ꢀ-
lactam. The precipitate was then collected on a sintered glass
funnel and thoroughly washed with Et2O (10 mL ꢂ 3). The
resulting PEG-bound trans ꢀ-lactam was cleaved by 3-mL
Et3N in 6-mL MeOH at 60 ꢁC for 24 h. Cold Et2O (30 mL)
was added to precipitate the detached PEG-OH. The polymer
was filtered and the combined filtrate was flash passed
through a short column to remove trace amount of PEG
and 6. The solvent was removed to give the corresponding
crude product. Compound 3m 1H NMR (500 MHz, CDCl3):
ꢁ ¼ 8:05 (d, 1 H), 7.41 (d, 1 H), 7.17 (s, 1 H), 6.94 (d, 1 H),
6.85(m, 1 H), 4.61 (d, 1 H, J ¼ 1:9 Hz), 4.47 (t, 2 H, J ¼
4:6 Hz, PEGOCH2CH2OCO), 3.13 (dq, 1 H, J1 ¼ 7:4 Hz,
J2 ¼ 1:9 Hz), 2.18 (s, 3 H, J ¼ 7:4 Hz), 2.17 (s, 3 H), 1.49
(d, 3H, J ¼ 7:4 Hz). Compound 4m 1H NMR (500 MHz,
CDCl3): ꢁ ¼ 8:05 (d, 1 H), 7.41 (d, 1 H), 7.17 (s, 1 H),
6.94 (d, 1 H), 6.85(m, 1 H), 4.60 (d, 1 H, J ¼ 1:9 Hz), 3.91
(s, 3 H,), 3.13 (dq, 1 H, J1 ¼ 7:4 Hz, J2 ¼ 1:9 Hz), 2.18 (s,
3 H), 2.17 (s, 3 H), 1.49 (d, 3H, J ¼ 7:4 Hz) ESI-MS m=z
346 ([M + Na]þ) IR (film) 1751.2, 1724.1, 1278.2.
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. C.
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4
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Published on the web (Advance View) June 14, 2004; DOI 10.1246/cl.2004.866