Enantioselective synthesis of β-lactams using a chiral auxiliary

Article abstract of DOI:10.1055/s-2006-939082

An efficient and enantioselective synthesis of trans-β-lactams from carboximide 1 and imines 2 using a chiral auxiliary under the classical Reformatsky reaction conditions is described. An enolate-imine mechanism has been proposed for this reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939082

LETTER
1113
Enantioselective Synthesis of b-Lactams Using a Chiral Auxiliary
Enantioselective
S
i
ynthesi
n
s
of
b
-Lacta
g
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax +86(571)87951512; E-mail: orgwyg@zju.edu.cn
Received 18 December 2005
Abstract: An efficient and enantioselective synthesis of trans-b-
lactams from carboximide 1 and imines 2 using a chiral auxiliary
under the classical Reformatsky reaction conditions is described.
An enolate–imine mechanism has been proposed for this reaction.
Key words: b-lactams, imines, Reformatsky reaction, enantio-
selectivity
Since Gilman1 and Speeter reported the Reformatsky ad-
dition reaction to imines in 1943, it has been employed to
synthesize b-lactams, b-amino acids and their deriva-
tives.2 The b-lactams are one of the best known and exten-
sively investigated heterocyclic ring systems as a result of
both their biological activity as antibiotics3 and their util-
ity as synthetic intermediates,4 which spurred the stereo-
Figure 1 ORTEP view of 3b (ellipsoids draw at 50% probability).
controlled synthesis of this important building block. The
Gilman–Speeter reaction gave almost always a mixture of
cis and trans b-lactams with the cis isomer predominat-
ing.5 The economic importance of enantiomerically pure
compounds has stimulated considerable research efforts
toward the enantioselective synthesis of b-lactams.6
Previously, we developed an efficient method for the syn-
thesis of trans b-lactams with high diastereoselectivity by
the Refomatsky addition reaction of imines using an aux-
iliary.7 To extend the applications of this methodology,
we investigated the possibility for enantioselective forma-
tion of trans b-lactamic ring through a chiral auxiliary
method (Scheme 1). We herein disclose the results of this
effort.
proceeded in THF under reflux conditions, and was com-
pleted within 10–20 minutes to give the corresponding b-
lactam 3 with a recycle of chiral auxiliary 4.9 The products
3 were exclusively trans isomers. The trans configura-
1
tions of 3 were assigned from the H NMR spectra
through the coupling constant JH–H of the two protons on
C3 and C4 (Jtrans = 1.5–2.5 Hz, Jcis = 4.5–6.0 Hz).10 The ee
value turned out to be in the range of 75–86% determined
by HPLC using a chiral column. Recrystallization from n-
hexane–EtOAc gave optically pure 3b. X-ray crystal
1
structure analysis of 3b confirmed the H NMR assign-
ment and showed that the absolute configuration of new
chiral centers is 3S and 4R (Figure 1).11
Carboximides 1 were obtained by treating the correspond-
ing carbonyl bromides with chiral auxiliary 4, which can
be prepared easily from inexpensive salicylamide accord-
ing to the established procedure.7,8 The Reformatsky reac-
tion of 1 with imines 2 in the presence of zinc dust
As shown in Table 1, imines derived from anilines and
aromatic or a,b-unsaturated aldehydes gave good to satis-
factory yields (63–81%). Unfortunately, N-benzylimine
did not react. When there was no b-amino carbonyl, a
R2
ZnBr
R3
O
O
O
O
O
O
O
N
R1
R2
O
R2
N
NH
cyclization
Zn
N
N
N
+
+
Br
R1
THF, reflux
O
R3
R1
R3
1
2
3
4
Scheme 1
SYNLETT 2006, No. 7, pp 1113–1115
0
3.
0
5.
2
0
0
6
Advanced online publication: 24.04.2006
DOI: 10.1055/s-2006-939082; Art ID: W11205ST
© Georg Thieme Verlag Stuttgart · New York

1114
Q. Yuan et al.
LETTER
Table 1 Enantioselective Synthesis of b-Lactams
25
Entry
R1
R2
R3
Producta
3a
ee (%)b
85
Yield (%)c
[α]D
1
2
Me
Me
Me
Me
Me
Et
Ph
Ph
65
73
81
75
66
72
63
69
79
70
+67.2 (c 1.0, CHCl3)
+38.5 (c 0.7, CHCl3)
+50.1 (c 1.0, CHCl3)
+38.9 (c 0.8, CHCl3)
–31.3° (c 1.0, CHCl3)
+43.6 (c 0.8, CHCl3)
+42.1 (c 0.7, CHCl3)
+72.3 (c 0.9, CHCl3)
+45.5 (c 1.0, CHCl3)
+53.2 (c 1.0, CHCl3)
Ph
4-ClC6H4
Ph
3b
80
3
4-MeOC6H4
4-ClC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4
Ph
3c
77
4
3,4-(OCH2O)C6H3
4-MeOC6H4
3,4-(OCH2O)C6H3
Ph
3d
83
5
3e
82
6
3f
85
7
Et
3g
86
8
Et
Ph
3h
83
9
Me
Et
trans-Styryl
trans-Styryl
3i
75
10
Ph
3j
78
a Determined by 1H NMR to be 100% trans.
b Determined by HPLC with a chiral column (Chiralpak AD-H 0.46 × 15 cm, Daicel Chemical Ind. Ltd).
c Isolated yield based on carboximide.
non-cyclized product formed as the by-product in these ly hindered environment. The zinc enolate then favors the
reactions, which is usually a big problem in the reported less hindered re-face attack on the imine, preferably
Reformatsky-type reactions.5 This may be due to the good leading to major isomer.
leaving ability of the chiral auxiliary 4, which facilitates
the cyclization of the intermediate.
In summary, we successfully synthesized b-lactams with
good enantioselectivity via a chiral auxiliary induced
The first step of the Reformatsky reaction should involve Reformatsky reaction. The chiral auxiliary 4 could be re-
the reduction of the a-bromocarbonyl group of 1 to give cycled in the reaction. An enolate–imine mechanism was
the Z-imide enolate, which nucleophilically attacks the proposed for this reaction.
imine as shown in Scheme 2. The formation of the Z-eno-
late involved in the transition state may be due to the steric
repulsion of the menthyl moiety. The stereochemistry of
Acknowledgment
We thank the National Natural Science Foundation of China (No.
20272051) as well as the Teaching and Research Award Program
for Outstanding Young Teachers in Higher Education Institutions
of MOE, P. R. of China.
the reaction could be explained by the chair-like transition
state involving the imine and the Z-enolate. In the chelated
transition state, zinc enolate disfavors a si-face attack on
imine because the isopropyl group is oriented in a sterical-
R2
ZnBr
R3
O
O
O
N
O
R2
R3
N
N
O
O
N
cyclization
R1
re attack
N
R1
R3
O
ZnBr
major
R1
favored
R2
R2
ZnBr
R3
O
R2
R3
O
O
O
N
N
cyclization
si attack
O
N
O
N
R1
N
R1
R3
BrZn
minor
O
R2
R1
disfavored
Scheme 2
Synlett 2006, No. 7, 1113–1115 © Thieme Stuttgart · New York

LETTER
Enantioselective Synthesis of b-Lactams
1115
(9) Typical Procedure for the Synthesis of b-Lactams 3.
A mixture of carboximide 1 (1.0 mmol), imine 2 (1.2 mmol)
and zinc dust (3 mmol) in THF (5 mL) was refluxed for 10–
20 min, cooled to r.t., poured into H2O (5 mL), and then
extracted with CH2Cl2 (3 × 5 mL). The combined extracts
were washed with brine, dried over anhyd Na2SO4, and
evaporated in vacuo. The residue was chromatographed
through a silica gel column with hexane–EtOAc to give pure
b-lactams 3 and chiral auxiliary 4.
References and Notes
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and Biology of b-Lactam Antibiotics, Vol. 1–3; Morin, R. B.;
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1997, 47.
(3S,4R)-4-(4-Chlorophenyl)-3-methyl-1-phenylazetidin-
2-one (3a): 1H NMR (500 MHz, CDCl3): d = 1.51 (d, J = 7.4
Hz, 3 H), 3.16 (dq, J = 2.4, 7.4 Hz, 1 H, H-3), 4.61 (d, J = 2.4
Hz, 1 H, H-4), 7.06 (m, 1 H) 7.26–7.43 (m, 9 H). 13C NMR
(125 MHz, CDCl3): d = 13.35, 55.56, 62.97, 117.21, 123.99,
126.07, 128.69, 129.28, 129.38, 138.08, 138.20, 168.63.
ESI-MS: m/z = 238 [M + H]+.
(3S,4S,E)-3-Ethyl-1-phenyl-4-styrylazetidin-2-one (3j):
1H NMR (500 MHz, CDCl3): d = 1.09 (t, J = 7.4 Hz, 3 H),
1.83 (m, 1 H), 1.94 (m, 1 H), 3.06 (m, 1 H, H-3), 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). 13C NMR
(125 MHz, CDCl3): d = 11.63, 21.85, 59.21, 60.04, 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 = 278 [M + H]+, 300
[M + Na]+, 577 [2 M + Na]+.
(10) Cainelli, G.; Panunzio, M.; Bandini, E.; Martelli, G.; Spunta,
G. Tetrahedron 1996, 52, 1685.
(11) CCDC 273640 contains the supplementary crystallographic
data (excluding structure factors) for compound 3b. These
data can be obtained free of charge via http://www.ccdc.
cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge
CB2 1EZ, UK; fax: +44(1223)336033; or
deposit@ccdc.cam.ac.uk].
Synlett 2006, No. 7, 1113–1115 © Thieme Stuttgart · New York