Enantioselective synthesis of β-lactams via the IndaBox-Cu(II)-catalyzed Kinugasa reaction

Article abstract of DOI:10.1016/j.tetlet.2009.06.050

The enantioselective Kinugasa reaction of nitrones with terminal alkynes in the presence of 20 mol % of IndaBox-Cu(OTf)₂ and di-sec-butylamine (1.5 equiv) produced β-lactams with the highest level of enantiomeric excesses among the catalytic en

Full text of DOI:10.1016/j.tetlet.2009.06.050

Tetrahedron Letters 50 (2009) 4969–4972
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Enantioselective synthesis of b-lactams via the IndaBox–Cu(II)-catalyzed
Kinugasa reaction
*
*
Takao Saito , Tomohiro Kikuchi, Hiroaki Tanabe, Junichi Yahiro, Takashi Otani
Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective Kinugasa reaction of nitrones with terminal alkynes in the presence of 20 mol % of
IndaBox–Cu(OTf)2 and di-sec-butylamine (1.5 equiv) produced b-lactams with the highest level of enan-
tiomeric excesses among the catalytic enantioselective Kinugasa reactions reported so far.
Ó 2009 Published by Elsevier Ltd.
Received 20 April 2009
Revised 8 June 2009
Accepted 11 June 2009
Available online 13 June 2009
Keywords:
Kinugasa reaction
b-Lactam
Bis(oxazoline)
Enantioselective catalysis
Nitrone cycloaddition
b-Lactams1 are an important class of compounds because of
their utility as antibiotics such as penicillins, cephalosporins,
monobactams, and carbapenems. In addition, chiral b-lactams also
serve as versatile building blocks for stereocontrollable synthesis
of complex organic compounds. Among a number of synthetic ap-
proaches to chiral b-lactams,1,2 the chiral ligand–Cu(I or II)-cata-
lyzed cycloaddition of nitrones with terminal alkynes (known as
the enantioselective Kinugasa reaction) has recently received
much attention.3
In 1972, Kinugasa and Hashimoto first reported the reaction be-
tween copper(I) phenylacetylide and nitrones in dry pyridine to
produce b-lactams.4 In 1995, Miura et al. described the first cata-
lytic version of the Kinugasa reaction using bis-diph-
enylphosphinoalkane catalysts, and they also pioneered the
enantioselective Kinugasa reaction using 10–100 mol % of CuI–
bis(oxazoline) 1a–c catalysts in the reaction of phenylacetylene
(7a) with diphenylnitrone 8a to give cis-b-lactam (cis-9a) with
40–68% enantiomeric excesses (ees) and 30% diastereomeric ex-
cess (de) (Fig. 1).5 Fu and coauthors reported the C2-symmetric
bis(azaferrocene) 2–CuCl-catalyzed Kinugasa reaction, in which
they succeeded in achieving excellent cis:trans diastereoselectivity
(71:29 to >95:5 drs) and enantioselectivity (67–93% ees).6 Tang
and co-workers demonstrated the pseudo C3-symmetric tris(oxaz-
oline) 3–Cu(II)-catalyzed highly enantioselective (45–85% ees) and
diastereoselective (cis:trans = 97:3–67:33, 20:80–11:89) Kinugasa
reaction.7 They stated that the Cu(II) catalytic system is effective
even under air atmosphere and without rigorously dry reaction
conditions. Shintani and Fu described the first examples of an
intramolecular enantioselective Kinugasa reaction using a P,N-
mixed ligand 4–CuBr complex to attain 85–91% ees.8 Guiry et al.
also employed HETPHOX 5–Cu(I) as a P,N-mixed ligand complex
in the Kinugasa reaction; however, the enantioselectivities of the
predominant cis-b-lactams were only 4–48% ees with cis-selectiv-
ity (up to 88% de).9
L-Proline-mediated Kinugasa reaction for syn-
thesis of exomethylene b-lactams with up to 15% ee was
reported by Basak et al.10 Thus, only a very limited number of
the enantioselective Kinugasa reactions have appeared so far,11
and development of catalytic highly enantioselective Kinugasa
reactions is still a challenging task.
It is of value to find a potential ability of a simple and readily
available chiral ligand–metal complex inducing high enantioselec-
tivity in the Kinugasa reaction. In this context, IndaBox 6 would be
a candidate ligand for the chiral Lews acid-catalyzed Kinugasa
reaction.12 IndaBox 6 has received increasing attention among
C2-symmetric chiral bis(oxazoline) ligands.13 We have previously
found that the IndaBox 6a–Cu(II) complex catalyst effectively in-
duces high enantioselectivities in a hetero-Diels–Alder reaction
of 1-thiabutadienes14 and 1,3-dipolar cycloaddition of nitrones
with 3-alkenoyl-2-oxazolidinones.15 These findings suggested to
us that the IndaBox 6–Cu(II)-catalytic system would be applicable
to a Kinugasa reaction that must be carried out under Lewis base
conditions.12 We report here the catalytic, highly enantioselective
Kinugasa reaction using IndaBox 6 as the homochiral ligand.
In initial studies, we selected the reaction of phenylacetylene
(7a) with C,N-diphenylnitrone 8a as the model reaction using
* Corresponding authors. Fax: +81 03 5261 4631 (T.S.).
E-mail address: tsaito@rs.kagu.tus.ac.jp (T. Saito).
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.06.050

4970
T. Saito et al. / Tetrahedron Letters 50 (2009) 4969–4972
Me
Me
Me
Me
Ph
O
Ph
Ph
Ph
O
Ph
Ph
Y mol % Cu(I) or Cu(II)
Ph
O
H
Me
Me
N
1.1Y mol % 6
Ph
+
+
Me
O
O
N
N
Fe
N
N
N
Ph
Z equiv amine
N
O
O
N
N
N
Me
Me
Me
Fe
R
R
Me
7a
8a
cis-9a
trans-9a
Me
Me
Me
O
1a R = iPr
Scheme 1.
1b R = tBu
3
2
ent-1c R = Ph
R
R
Table 2
Me
Me
PPh2
O
N
O
O
Catalytic enantioselective Kinugasa reaction: variation of the nitrone N-aryl
substituent R
P
Ph
N
N
Fe
N
Me
Me
Me
R
S
R
Entry
8
R
Time (h)
Adduct
Yielda (%)
Cis:transb
Cis eec (%)
Me
O
Me
1
2
3
4
5
8a
8b
8c
8d
8e
H
38
136
135
106
138
9a
9b
9c
9d
9e
47
41
40
49
72
85:15
81:19
79:21
86:14
83:17
90
89
93
79
81
Me
MeO
Cl
6a: R = H
6b: R = Me
6c: R-R = CH2-CH2
5a R = iPr
4a R = iPr
4b R = tBu
5b R = tBu
5c R = Ph
EtO2C
a
Figure 1. Chiral ligands used in the Kinugasa reaction.
Total yield of cis- and trans-isomers.
Determined by 1H NMR.
Determined by chiral HPLC.
b
c
6–Cu(I or II) chiral catalyst (Y mol %) and an amine (Z equiv) under
the conditions (solvent, temperature, and time) listed in Table 1
(Scheme 1). First, in order to evaluate the IndaBox ligands 6a–c,
the model reaction between 7a and 8a was carried out in the pres-
ence of 20 mol % 6a–c–Cu(ClO4)2Á6H2O and 1.0 equiv dicyclohexyl-
amine (Cy2NH) in dichloromethane at room temperature (20 °C)
(entries 1–3).7 b-Lactam 9a was obtained (42%, 49%, and 51%
yields) in cis:trans ratios of 85:15–86:14 with 78%, 67%, and 69%
ees of the cis-isomer, respectively. Thus, IndaBox 6a gave the best
enantioselectivity. We next examined 6a–Cu(I) salt complexes in
the Kinugasa reaction (entries 4–7) because Fu et al. achieved high
enantioselectivity (77% ee for 9a) using the CuCl–2 complex.6 Cop-
per(I) halides gave high cis-selectivities (95:5–86:14) but moder-
ate enantioselectivities (53–23% ees) (entries 4–6), with no b-
lactam (9a) being formed with CuOTf (entry 7). The Cu(OTf)2–6a
catalyst was found to be the best choice among the copper salts
examined, giving 84:16 cis:trans selectivity and 82% ee (entry 8).
Next, screening of amines as a base was performed. Primary
amines RNH2 (R = n-Pr, Cy), secondary amines R2NH (R = Et, i-Pr,
n-Bu, n-Oct, piperidine, and morpholine), and triethylamine
showed low to moderate enantioselectivities (15–71% ees) and
cis:trans selectivities (86–61:14–39). Gratifyingly, di-sec-butyl-
amine (s-Bu2NH) gave high enantio- and diastereoselectivities
(82% ee and cis:trans 84:16, entry 9), which are comparable with
the results (Cy2NH) in entry 8. When the reaction using 1.5 equiv
amounts of s-Bu2NH was carried out, a high level of enantioselec-
tivity (85% ee) and diastereoselectivity (cis:trans 84:16) was ob-
tained (entry 10), but the use of an excess amount (2.0 equiv) of
the amine resulted in reduction of both yield and enantioselectiv-
ity (21%, 69% ee).
Optimization of the solvents (entries 10–14) led us to find
somewhat higher enantioselectivity (87% ee) with good diastere-
oselectivity (cis:trans 84:16) when using isopropyl acetate (entry
14). The reaction at a higher temperature (40 °C) shortened the
reaction time (to 1 h) with slight reduction of both the stereoselec-
tivities (83% ee, cis:trans 83:17) (entry 15). Finally, when the reac-
tion at 5 °C in i-PrOAc was performed using a 20 mol % Cu(OTf)2–6a
catalyst and 1.5 equiv s-Bu2NH, the highest enantioselectivity (90%
ee) of cis-isomer 9a was attained in a cis:trans ratio of 85:15 (entry
16). The amounts of the catalyst could be reduced to 15 mol % or
10 mol % while maintaining a good enantiomeric excess of 88%
ee (entry 17) or 85% ee (entry 18), respectively.
Under the optimized reaction conditions (Table 1, entry 16), the
reaction of phenylacetylene (7a) with nitrones 8 with variation of
Table 1
Screening of the copper catalysts and amines and optimization of the reaction conditions
Entry
Ligand
Cu(I) or Cu(II)
Y (mol %)
Amine
Z (Equiv)
Solvent
Temp (°C)
Time (h)
Yielda (%)
Cis:transb
Cis eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
6a
6b
6c
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
Cu(ClO4)2Á6H2O
Cu(ClO4)2Á6H2O
Cu(ClO4)2Á6H2O
CuCl
CuBr
CuI
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
15
10
Cy2NH
Cy2NH
Cy2NH
Cy2NH
Cy2NH
Cy2NH
Cy2NH
Cy2NH
s-Bu2NH
s-Bu2NH
s-Bu2NH
s-Bu2NH
s-Bu2NH
s-Bu2NH
s-Bu2NH
s-Bu2NH
s-Bu2NH
s-Bu2NH
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
20
20
20
20
20
20
20
20
20
20
20
20
20
20
40
5
14
21
22
17
6
42
49
51
58
55
50
0
32
40
32
40
60
61
39
30
47
47
41
85:15
85:15
86:14
95:5
92:8
86:14
—
84:16
84:16
84:16
77:23
78:22
91:9
84:16
83:17
85:15
82:18
84:16
78
67
69
53
35
23
—
82
82
85
68
75
18
87
83
90
88
85
8
8
CuOTf
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
15
21
14
28
16
5
14
1
38
46
65
THF
MeCN
iPrOAc
i-PrOAc
i-PrOAc
i-PrOAc
i-PrOAc
5
5
a
Total yield of cis- and trans-isomers.
Determined by 1H NMR.
Determined by chiral HPLC.
b
c

T. Saito et al. / Tetrahedron Letters 50 (2009) 4969–4972
4971
20 mol % Cu(OTf)2
20 mol % Cu(OTf)2
Ph
O
H
R
O
Ph
Ph
R
O
Ph
Ph
Ph
O
H
22 mol % 6a
22 mol % 6a
Ph
+
R
+
+
N
1.5 equiv s-Bu2NH
N
N
N
1.5 equiv s-Bu2NH
i-PrOAc
Ph
i-PrOAc
R
5 ºC
5 ºC
8
7a
7
8a
cis-9
trans-9
Ph
Ph
Ph
Ph
Scheme 4.
+
N
N
O
O
R
R
cis-9
Scheme 2.
trans-9
tron-donating p-MeOC6H4 substituent showed the highest 93% ee
(entry 3). Because the reaction of 7a with nitrones 8 bearing an al-
kyl substituent such as methyl or benzyl group failed, an N-aryl
substituent seems to be necessary for the reaction, which is com-
patible with Fu’s and Tang’s results.6,7
The nitrone C-aryl substituent effects were also examined
(Scheme 3, Table 3). In these cases, the strongly electron-with-
drawing substituents (R = CF3, NO2) showed the highest level of
enantioselectivity (entries 5 and 6, 92% ee and 94% ee), in contrast
to slight lowering by the p-MeO group (87% ee, entry 3). The p-bro-
mo group was as low as 81% ee.
Finally, the scope with respect to the alkyne component 7 was
probed (Scheme 4, Table 4). The electron-donating p-tolyl and p-
MeOC6H4 substituents showed the highest level of enantioselectiv-
ity (93% and 94% ees, entries 2 and 3). Although, in the case of the
p-BrC6H4 and p-CF3C6H4 substituents, the cis-isomer was the major
product (76:24 and 72:28, entries 4 and 5), the much more elec-
tron-withdrawing substituent (R = p-NO2C6H4) clearly affects the
cis:trans diastereoselectivity (18:82, entry 6). In contrast, trans-
isomer was formed as the major b-lactam while maintaining a high
level of enantioselectivity. Because of the fact that separated cis-9o
with 86% ee was completely transformed into trans-9o maintain-
ing 86% ee after addition of an amine (s-Bu2NH) or left under the
same reaction conditions, it is likely that the initially formed cis-
isomer bearing an electron-withdrawing substituent (R) epimeriz-
Table 3
Catalytic enantioselective Kinugasa reaction: variation of the nitrone C-aryl
substituent R
Entry
8
R
Time (h)
Adduct
Yielda (%)
Cis:transb
Cis eec (%)
1
2
3
4
5
6
8a
8f
8g
8h
8i
H
38
48
40
48
48
37
9a
9f
9g
9h
9i
47
50
64
45
41
47
85:15
80:20
84:16
87:13
84:16
84:16
90
92
87
81
92
94
Me
MeO
Br
CF3
NO2
8j
9j
a
Total yield of cis- and trans-isomers.
Determined by 1H NMR.
Determined by chiral HPLC.
b
c
R
20 mol % Cu(OTf)2
22 mol % 6a
1.5 equiv s-Bu2NH
i-PrOAc
5 ºC
H
Ph
+
N
O
Ph
7a
8
R
R
es highly selectively at the acidic 3-CH,
a to the lactam carbonyl
Ph
Ph
group, to the thermodynamically more stable trans-isomer while
maintaining high enantioselectivity.5,16 Similarly, the reaction of
ethyl propiolate (7g) produced trans-isomer 9p only (54%) but, in
this case, with low enantioselectivity (32% ee, entry 7). The reac-
tion of aliphatic acetylene, 1-cyclohexenylacetylene (7h), gave 9q
(31%) in a cis:trans ratio of 83:17 with high enantioselectivity
(83% ee, entry 8).
+
N
N
O
O
Ph
Ph
cis-9
Scheme 3.
trans-9
Although in the present reaction chemical yields and diastere-
oselectivities were not improved, the highest level of enantioselec-
tivities were attained using the Cu(OTf)2 complex with the simple
and readily available C2-symmetric IndaBox ligand (6a) (commer-
cially and cheaply available) and the optimal amine under the
optimized reaction conditions.
N-aryl substituents R was examined (Scheme 2). The results are
shown in Table 2. The electron-withdrawing N-aryl substituent
(R = Cl, EtO2C) lowered the enantioselectivity to 79% and 81% ee
(entries 4 and 5) compared with the phenyl and p-tolyl groups
(R = H, Me entry 1 and 2, 90% and 89% ees), whereas the elec-
Table 4
Catalytic enantioselective Kinugasa reaction: variation of the alkyne substituent R
Entry
7
R
Time (h)
Adduct
Yielda (%)
Cis:transb
Cis eec (%)
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
Ph
38
21
90
336
25
64
0.1
36
9a
9k
9l
9m
9n
9o
9p
9q
47
38
40
38
55
51
54
31
85:15
63:37
83:17
76:24
72:28
18:82
Trans only
83:17
90
p-MeC6H4
p-MeOC6H4
p-BrC6H4
p-CF3C6H4
p-NO2C6H4
EtO2C
93
94
88
91
86d
32d
83
7g
7h
1-Cyclohexenyl
a
Total yield of cis- and trans-isomers.
Determined by 1H NMR.
Determined by chiral HPLC.
ee for trans-isomer.
b
c
d

4972
T. Saito et al. / Tetrahedron Letters 50 (2009) 4969–4972
dipolarophile reacting with a nitrone to finally give a b-lactam together with
the reformed chiral Lewis acid catalyst after stereo-controlled protonation.
Supplementary data
Supplementary data (experimental procedure, full entries data
of Table 1, 1H and 13C NMR spectral data, compounds characteriza-
tion data, and chiral HLPC copies of compounds 9) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.06.050.
β-Lactam
(TfO)2Cu(II)
+
+
6a
(ligand)
-
NH
TfO
Nitrone
(TfO)2Cu(II)-6a [chiral LA catalyst]
References and notes
-
+
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(b)Synthesis of b-Lactam Antibiotics, Chemistry, Biocatalysis and Process
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+
N
-
R
Cu(I) OTf
6a
+
(X)
NH OTf
Catalytic cycle
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12. A referee pointed out that the reaction would proceed through Cu(I) acetylides
as a key intermediate, rather than a Lewis acid-catalyzed reaction in the
presence of a Lewis base. However, we believe that the following catalytic
cycle is involved in this Kinugasa reaction. Cu(II) triflate and chiral ligand 6a
produce (TfO)2Cu(II)–6a complex. This complex actually works as the chiral
Lewis acid in the catalytic cycle to give the copper acetylide–6a-complex (X) by
the reaction with acetylide formed by the action of an amine (base) as shown
in the scheme. The complex
X is indeed the key species as the chiral