Asymmetric Synthesis of β-Lactams through Copper-Catalyzed Alkyne–Nitrone Coupling with a Prolinol–Phosphine Chiral Ligand

Article abstract of DOI:10.1002/chem.201702070

Prolinol–phosphine chiral ligands enabled highly enantioselective copper-catalyzed intermolecular alkyne–nitrone coupling (Kinugasa reaction) to produce 1,3,4-trisubstituted chiral β-lactams. A high level of enantiocontrol was achieved not only with aryl- or alkenylacetylenes but also with alkylacetylenes, which were important but unfavorable substrates in the previously reported protocols. Two-point hydrogen bonding between the chiral ligand and the nitrone oxyanion consisting of O?H???O and C(sp³)?H???O hydrogen bonds is proposed.

Full text of DOI:10.1002/chem.201702070

A Journal of
Accepted Article
Title: Asymmetric Synthesis of β-Lactams through Copper-Catalyzed
Alkyne-Nitrone Coupling with Prolinol-Phosphine Chiral Ligand
Authors: Yurie Takayama, Takaoki Ishii, Hirohisa Ohmiya, Tomohira
Iwai, Martin C. Schwarzer, Seiji Mori, Tohru Taniguchi, Kenji
Monde, and Masaya Sawamura
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of the final Version of Record (VoR). This work is currently citable by
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the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201702070
Link to VoR: http://dx.doi.org/10.1002/chem.201702070
Supported by

10.1002/chem.201702070
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b
Asymmetric Synthesis of -Lactams through Copper-Catalyzed
Alkyne–Nitrone Coupling with Prolinol-Phosphine Chiral Ligand
Yurie Takayama, Takaoki Ishii, Hirohisa Ohmiya, Tomohiro Iwai, Martin C. Schwarzer, Seiji Mori,
Tohru Taniguchi, Kenji Monde, and Masaya Sawamura*[a]
OH
Abstract: Prolinol-phosphine chiral ligands enabled highly
Ph
H
OH
O
O
O
Me
enantioselective copper-catalyzed intermolecular alkyne–nitrone
coupling (Kinugasa reaction) to produce 1,3,4-trisubstituted
chiral b-lactams. A high level of enantiocontrol was achieved not
only with aryl- or alkenylacetylenes but also with alkylacetylenes,
which were important but unfavorable substrates in the
previously reported protocols. Two-point hydrogen-bonding
between the chiral ligand and the nitrone oxyanion consisting of
O–H···O and C(sp3)–H···O hydrogen bonds is proposed.
H
N
N
N
F
CO2
N
Me
S
HO
F
MeO
OMe
Ezetimibe
(–)-SCH 48461
Biapenem
+
N
N
H
Figure 1. b-Lactam drug molecules.
Previously, we reported the copper-catalyzed asymmetric
direct alkynylation of aldehydes with terminal alkynes with
prolinol-phosphine chiral ligands (represented by L1) (Figure
2).[10] DFT calculations indicated directional catalyst–substrate
two-point hydrogen-bonding involving a non-classical C(sp3)–
H···O hydrogen bond in the enantioselectivity-determining
transition state.[11] In the present work, we examined the prolinol-
phosphine-copper system for its ability to solve problems in the
asymmetric Kinugasa reaction, expecting that similar two-point
hydrogen-bonding may also occur with the oxyanion of the
nitrone instead of the carbonyl oxygen of the aldehyde.
Chiral b-lactams constitute an important heterocycle family
due to their biological activity and utility as building blocks in
organic synthesis.[1,2] Among various approaches to b-lactams,
copper-catalyzed coupling between terminal alkynes and
nitrones (Kinugasa reaction) is the most straightforward.[3] The
first catalytic asymmetric version was reported by Miura in
1995.[4] The reaction between phenylacetylene and C,N-
diphenylnitrone with a copper(I)/bisoxazoline chiral catalyst
afforded a cis/trans mixture of 1,3,4-triphenyl-b-lactam with
moderate diastereo- and enantioselectivities. Since this work,
significant progress in enantioselectivity of the asymmetric
Kinugasa reaction of aryl- or alkenylacetylenes has been made
owing to the development of new chiral ligands on copper.[5–7]
However, the substrate scope is still limited. In particular, the
intermolecular asymmetric Kinugasa reaction of alkylacetylenes
producing chiral b-lactams having an alkyl side chain at the
carbonyl a-position (C3) remains underdeveloped[6d–f]. This is an
important issue because most b-lactam drug molecules have an
alkyl pendant at this position (Figure 1).[8,9] Enabling to install
alkyl groups at this position would also be important in using the
b-lactams as chiral building blocks for asymmetric synthesis of
acyclic compounds.[2]
O
HO
H
Previous work
cat. Cu(I)/L1
R2
tBuOH
R1
H
+
R2
H
R1
tBu
PPh2
Ph
O–H···O
R2
O
O
H
P
OH
Ph
H
N
H
Cu
H
N
H
L1
C(sp3)–H···O
R1
TS by DFT calculations
Figure 2. Copper-catalyzed asymmetric direct alkynylation of aldehydes with
terminal alkynes with prolinol-phosphine chiral ligand L1.
Preliminary screening of reaction conditions was conducted
using L1 with
a
well-studied substrate combination of
phenylacetylene (1a) and C-cyclohexyl-N-phenylnitrone (2a).
Product yield, cis/trans selectivity, and enantioselectivity were
sensitive to reaction parameters such as copper sources, bases
(typically used in
a stoichiometric amount), solvents, and
reaction temperature (see Supporting Information for details). To
our delight, the reaction occurred under significant
enantiocontrol in some cases, and the most efficient reaction
(1a/2a 1:1, 0.2 mmol) occurred in the presence of Cu(OTf)2/L1
(1:1 10 mol%) and Et2NH (1 equiv) in toluene (1 mL) at –40 °C
over 24 h, giving the b-lactam 3aa in 81% yield with a moderate
diastereoselectivity (87:13) in favor of the cis isomer (Table 1,
entry 1). The cis isomer was enantioenriched at 84% ee for
(3R,4S)-3aa, while the trans isomer was enriched for (3S,4S)-
3aa with 20% ee. The reaction also occurred even in the
absence of a ligand under otherwise identical conditions to
afford racemic 3aa in 56% yield with a low cis/trans selectivity
(Table 1, entry 2).
[a]
Y. Takayama, Dr. T. Ishii, Prof. Dr. H. Ohmiya, Prof. Dr. T. Iwai,
Prof. Dr. M. Sawamura
Department of Chemistry, Faculty of Science
Hokkaido University
Sapporo 060-0810, Japan
E-mail: sawamura@sci.hokudai.ac.jp
Homepage:
http://wwwchem.sci.hokudai.ac.jp/~orgmet/index.php?id=25
Dr. M. C. Schwarzer, Prof. Dr. Seiji Mori
Institute of Quantum Beam Science, Ibaraki University
Prof. Dr. T. Taniguchi, Prof. Dr. K. Monde
Frontier Research Center for Advanced Material and Life Science,
Faculty of Advanced Life Science, Hokkaido University
Among the other observations in the condition screening, it
should be noted that alcohol solvents gave nearly racemic
Supporting information for this article is given via a link at the end of
the document.
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[a] Conditions: 1a (0.2 mmol), 2a (0.2 mmol), Cu(OTf)2/ligand (10 mol%),
Et2NH (0.2 mmol), toluene (1.0 mL) at –40 ˚C for 24 h. [b] Yield of isolated
product as isomeric mixture. [c] Determined by 1H NMR spectroscopy. [d] The
ee values were determined by HPLC analysis. Absolute configurations of cis-
and trans-3aa were separately determined by their optical rotations (c.f. ref.
6c).
products. This is in sharp contrast to the mandatory use of an
alcohol solvent in the asymmetric copper-catalyzed aldehyde
alkynylation with L1. Another important observation is that bases
had a strong impact on the enantioselectivity. This suggests
participation of the base in an enantioselectivity-determining
step.
The scope of the Kinugasa reaction of aryl- or
alkenylacetylenes was explored under the optimized conditions
[1a-g/2a-h (0.2 mmol), Cu(OTf)2/L8 (10 mol%), Et2NH (1 equiv),
toluene, –40 °C, 24 h] (Table 2). Yields of b-lactams (3) and cis
selectivities were moderate or good in most cases. As another
general trend, the cis isomers had higher enantiomeric purities
than the trans isomers. As listed in Table 2, entries 1–4, various
N-substituents (R3) were compatible. Thus, the nitrones with
electron-donating (2b: p-MeO) or -withdrawing (2c: p-CF3)
substituents underwent the reaction with 1a under a high level of
enantiocontrol (entries 1 and 2). More sterically demanding N-
substituents such as o-tolyl (2d) and 1-naphthyl (2e) groups
were compatible (entries 3–4). Remarkably, the reaction of the
C-cyclohexyl-N-naphthylnitrone (2e) occurred with high yield
(91%) with almost complete enantioselectivity (99% ee) for the
cis isomer, and the trans isomer also had a high enantiomeric
purity (90% ee).
Next, effects of C-substituents of the nitrone were investigated
with the N-substituent fixed to Ph (Table 2, entries 5–7).
Nitrones with a-branched C-alkyl groups such as isopropyl (2f)
or N-Boc-4-piperidyl (2g) groups underwent the reaction with 1a
to give the corresponding cis-b-lactams (3af and 3ag) with 91%
ee and 92% ee, respectively (entries 5 and 6). The reaction
between 1a and the nitrone 2h with an unbranched C-alkyl
group gave cis-3ah with 82% ee (entry 7). Thus, various alkyl
groups were tolerated as the C-substituent of the nitrone.
Unfortunately, however, nitrones with aryl C-substituents were
not suitable for the reaction with phenylacetylene (1a). Under the
reaction conditions, decomposition of the C-arylnitrones was
dominant, resulting in the formation of deoxygenated imines and
other unidentified compounds accompanied by oxidative
Effects of ligand modification are listed in Table 1, entries 3–
10. Overall, cis/trans ratios were low or moderate, and higher
yields obtained using better ligands were accompanied by better
cis/trans selectivities and enantioselectivities. Changing the
hydroxy group of L1 into a methoxy group (L1-OMe) resulted in
almost total loss of enantioselectivity (entry 3). The yield was
lower than that in the no-ligand reaction. These results support
our assumption that the hydroxy group of L1 works as a
hydrogen-bonding donor site toward the oxyanion of the nitrone
for enantioface discrimination.
Next, effects of the substituent (R1) at the position a to the
hydroxyl group were investigated. By replacing the neopentyl
group of L1 with
a
Me3SiCH2 group (L2), significant
improvements in yield (95%) and enantioselectivities for both
diastereomers (cis-3aa, 87% ee; trans-3aa, 31% ee) were
achieved (Table 1, entry 4). Elongation of alkyl chains in the
R3Si group into ethyl (L3) or n-propyl (L4) groups caused a slight
increase in enantioselectivity (entries 5 and 6).
Next, P-substituents (R2) were explored. Introduction of
electron-donating MeO groups at the para position of the P-
aromatic rings of the neopentyl-armed ligand (L5) induced slight
increases in yield (84%), cis/trans ratio (90:10), and
enantiomeric excess of cis-3aa (86% ee) (Table 1, entry 7). On
the other hand, an F atom at the same position (L6) was
unfavorable (entry 8). The reactions with L7[10] bearing a
dicyclohexylphosphino
group
gave
low
yield
and
stereoselectivities, while the higher enantiomeric excess of
trans-3aa over that of the cis isomer was noticeable (entry 9).
Next, we tried to find the best mix. In fact, the ligand L8 having a
nPr3SiCH2 group at the alcohol moiety and the 4-MeO-C6H4 P-
substituent produced the most efficient catalyst system,
affording 3aa in 97% yield with 90% cis/trans selectivity and
92% ee for cis-(3R,4S)-3aa (entry 10).
coupling
between
1a
and
Et2NH
to
form
N,N-
diethylphenylacetamide.[12] Even when b-lactams were obtained
in low yield, enantioselectivities (≤73% ee) were lower than
those in the reaction of the C-alkylnitrones.
Table 1. Ligand effects in the reaction between 1a and 2a[a]
Phenylacetylene derivatives (1b, 1c, 1d, and 1e) with MeO, F,
Br, or CO2Me para-substituents also participated in the reaction
with C-cyclohexyl-N-phenylnitrone (2a) (Table 2, entries 8–11).
The reaction between thiophene-substituted acetylene 1f and 2a
occurred under a very high level of enantiocontrol for both cis
and trans isomers (3fa, 99 and 98% ees) (entry 12). As shown in
entry 13, conjugated enyne 1g was also a suitable substrate; the
reaction with 2a gave a 3-alkenylated cis-b-lactam (3ga) with
98% ee (entry 13).
–O
Ph
H
+
N
Ph
O
Ph
O
Cu(OTf)2 (10 mol%)
ligand (10 mol%)
+
+
Ph
H
N
N
Et2NH (1.0 eq)
toluene
–40 °C, 24 h
Ph
Ph
1a
(0.2 mmol)
2a
(0.2 mmol)
cis-(3R,4S)-3aa trans-(3S,4S)-3aa
L1: R1 = tBu, R2 = Ph
L2: R1 = Me3Si, R2 = Ph
L3: R1 = Et3Si, R2 = Ph
L4: R1 = nPr3Si, R2 = Ph
L5: R1 = tBu, R2 = 4-MeO-C6H4
L6: R1 = tBu, R2 = 4-F-C6H4
L7: R1 = tBu, R2 = Cy
PR2
PPh2
OMe
2
OH
H
H
N
R1
N
L1-OMe
L8: R1 = nPr3Si, R2 = 4-MeO-C6H4
Table 2. Asymmetric Kinugasa reaction of aryl- and alkenylacetylenes.[a]
entry
ligand
yield
cis/trans[c]
ee (%) [d]
MeO
(%)[b]
R1
R2
cis trans
R1
R2
R1
R2
Cu(OTf)2 (10 mol%)
L8 (10 mol%)
O
O
–O
R2
R3
H
+
N
1
L1
tBu
Ph
n.a.
Ph
81
56
27
95
90
89
84
67
43
97
87:13
56:44
69:31
86:14
87:13
88:12
90:10
86:14
69:31
90:10
84
20
R1
(0.2 mmol)
H
+
+
OMe
N
N
2
no ligand n.a.
n.a. n.a.
Et2NH (1.0 eq)
toluene
–40 °C, 24 h
P
N
R3
R3
1
2
3
L1-OMe tBu
6
87
89
89
86
71
29
92
10
31
47
49
8
cis-3
trans-3
OH
(0.2 mmol)
H
SinPr3
4
L2
L3
L4
L5
L6
L7
L8
SiMe3 Ph
R1: aryl or alkenyl
L8
5
SiEt3
Ph
6
SinPr3 Ph
entry alkyne
R1
nitrone
R2
yield cis/trans[c] ee (%)[d]
7
tBu
tBu
tBu
4-MeO-C6H4
(%)[b]
R3
cis trans
80 37
8
4-F-C6H4
Cy
31
52
51
1
Ph (1a)
Cy
4-MeO-C6H4
54
87:13
80:20
9
(2b)
(3ab)
10
SinPr3 4-MeO-C6H4
2
Ph (1a)
Cy
4-F-C6H4 (2c) 61
90 54
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(3ac)
31
Table 3. Asymmetric Kinugasa reaction of alkylacetylenes.[a]
3
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Cy
Cy
iPr
2-Me-C6H4
92:8
92 80
99 90
91 54
92 46
(2d)
(3ad)
R1
R2
R1
–O
R2
R3
H
+
N
Cu(OTf)2 (10 mol%)
L8 (10 mol%)
O
O
4
1-naphthyl (2e) 91
(3ae)
79
90:10
89:11
75:25
77:23
96:4
R1
H
+
+
N
N
Et2NH (1.0 eq)
toluene
–40 °C, 24 h
R3
R3
R2
1 (0.2 mmol)
2
(0.2 mmol)
cis-3
trans-3
5
Ph (2f)
Ph (2g)
Ph (2h)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
R1: alkyl
(3af)
71
entr alkyne
nitrone
R2
yield
(%)[b]
cis/tran ee (%) [d]
s[c]
6
Boc-N
R3
cis trans
98 97
y
R1
(3ag)
72
nBu (1h)
nBu (1h)
nBu (1h)
nBu (1h)
nBu (1h)
nBu (1h)
nBu (1h)
Cy
Ph (2a)
1
55
80:20
7
nPent
Cy
82
7
(3ha)
44
(3ah)
95
Cy
Cy
Cy
Cy
iPr
4-MeO-C6H4(2b)
4-F-C6H4 (2c)
2-Me-C6H4 (2d)
1-naphthyl (2e)
Ph (2f)
2
88:12
79:21
71:29
68:32
79:21
72:28
78:22
67:33
78:22
71:29
84:16
80:20
>99 99
8
4-MeO-C6H4
(1b)
92 36
91 44
92 41
83 78
99 98
(3hb)
30
(3ba)
55
3
98
97
9
4-F-C6H4 (1c)
Cy
88:12
83:17
62:38
83:17
(3hc)
92
(3ca)
67
4
>99 98
10
11
12
4-Br-C6H4 (1d)
Cy
(3hd)
>99
(3he)
38
(3da)
82
5
99
99
98
97
99
97
99
98
97
98
98
96
91
98
92
99
97
94
4-MeO2C-C6H4 Cy
(1e)
Me
(3ea)
71
6
S
Cy
(3hf)
50
(3fa)
1f
nPent Ph (2h)
7
13
Cy
Ph (2a)
73
78:22
98 73
(3hh)
50
1g
(3ga)
Ph
8
Cy
Cy
Ph (2a)
Ph (2a)
[a] Conditions: 1 (0.2 mmol), 2 (0.2 mmol), Cu(OTf)2/L8 (10 mol%), Et2NH (0.2
mmol), toluene (1.0 mL) at –40 ˚C for 24 h. [b] Yield of isolated product as
isomeric mixture. [c] Determined by 1H NMR spectroscopy. [d] The ee values
were determined by HPLC analysis. See Supporting Information for
determination of absolute configurations.
1i
(3ia)
52
iBu (1j)
Cy (1k)
9
(3ja)
48
10
11
Cy
Cy
Cy
Cy
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
As mentioned above, enantiocontrolled installation of an alkyl
chain at the C3 position of b-lactams is an important task in the
development of the asymmetric Kinugasa reaction. As shown in
Table 3, alkylacetylenes were suitable substrates for the present 12
asymmetric Kinugasa reaction protocol with L8. Although yields
and cis selectivities were moderate in most cases, both cis and
trans isomers of b-lactams had high enantiomeric purities (91–
99% ees).[13] The absolute configurations of the cis and trans
isomers were identical at the C4 position and inverted at the C3
position (vide infra for C3-epimerization). Simple unbranched
(3ka)
48
PivO
3
1l
(3la)
53
TBDMSO
3
1m
(3ma)
66
O
13
O
(3na)
1n
Cl
Cl
14
15
16
17
18
19
20
Cy
Cy
Ph (2a)
49
82:18
75:25
88:12
89:11
68:32
54:46
87:13
98
99
99
94
99
96
98
95
98
98
78
97
97
95
1o
(3oa)
>99
(3oe)
58
1-naphthyl (2e)
Ph (2g)
alkylacetylene
1-hexyne
(1h)
underwent
a
highly
1o
1o
enantioselective reaction with various C-cyclohexylnitrones (2a–
e) with different N-aryl groups (entries 1–5). The alkyne 1h also
reacted with C-isopropyl- or -n-pentyl-N-phenylnitrones (2f,h)
with high enantioselectivities (entries 6 and 7).
Cl
Boc-N
1o
(3og)
41
Cl
Ph
4-EtO2C-C6H4
(2i)
(3oi)
42
The protocol was effective for the reactions of terminal
alkynes with varied steric effects such as 5-phenyl-1-pentyne
(1i), isobutylacetylene (1j), or cyclohexylacetylene (1k) (Table 3,
entries 8–10). Functionalized alkylacetylenes with a pivalate
ester (1l), silyl ether (1m), acetal (1n), or alkyl chloride (1o) at
the chain terminus participated in the reaction with 2a (entries
11–17). Among these functionalized alkynes, 6-chlorohexyne
(1o) was also used for the reactions with C-cyclohexyl-N-1-
naphthylnitrone (2e), C-(N-Boc-4-piperidyl)-N-phenylnitrone (2g),
and C-phenyl-N-4-ethoxycarbonylphenylnitrone (2i) (entries 15–
17). It should be noted that even the C-arylnitrone 2i, which was
not suitable for the reaction with phenylacetylene (1a), reacted
with an acceptable yield under efficient enantiocontrol (entry 17).
Propargyl N,N-dibenzylamine (1p) and methoxymethyl propargyl
ether (1q) were also suitable substrates (entries 18 and 19).
Interestingly, non-protected propargyl alcohol (1r) reacted with
2a in good yield to furnish 3-hydroxymethyl-substituted b-lactam
3ra (entry 20).
Bn2N
Cy
Cy
Cy
Ph (2a)
1p
(3pa)
69
MOMO
Ph (2a)
Ph (2a)
1q
(3qa)
76
HO
1r
(3ra)
[a] Conditions: 1 (0.2 mmol), 2 (0.2 mmol), Cu(OTf)2/L8 (10 mol%), Et2NH (0.2
mmol), toluene (1.0 mL) at –40 ˚C for 24 h. [b] Yield of isolated product as
isomeric mixture. [c] Determined by 1H NMR spectroscopy. [d] The ee values
were determined by HPLC analysis. See Supporting Information for
determination of absolute configurations.
Feasibility of epimerization[4,6f] at the alkylated C3 position to
allow cis-to-trans isomerization was examined with KOtBu as a
base for representative 3-alkyl-b-lactams in a cis/trans mixture
(eq 1). These reactions gave diastereomerically pure trans-b-
lactams with high enantiomeric purities, confirming the
stereochemical course leading to the trans isomers (Tables S5–
7).
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R1
R1
R1
O
synthesis of a variety of 3-alkyl-b-lactams. Further elaboration of
the chiral catalyst system is underway in our laboratory.
O
O
KOtBu (15 mol%)
(1)
+
N
N
N
THF
Ph
Ph
Cy
Ph
Cy
Cy
cis-(3R,4S)-3 trans-(3S,4S)-3
trans-(3S,4S)-3
Acknowledgements
3ha: R1 = nBu, 93% yield, 97% ee (r.t., 1 h)
3ka: R1 = Cy; 96% yield, 96% ee (50 °C, 6 h)
3na: R1 = 2-(1,3-dioxane-2-yl)ethyl, 93% yield, 97% ee (r.t., 1 h)
This work was supported by CREST and ACT-C
(JPMJCR12YN), JST to M.S. Y.T. thanks JSPS for scholarship
support.
Our scenario for the catalytic asymmetric Kinugasa reaction is
illustrated in Figure 3. We propose that Cu(OTf)2 is first reduced
to a Cu(I) species in the reaction mixture containing potential
reducing agents such as the terminal alkyne and Et2NH. A
Keywords: asymmetric catalysis · cooperative catalysis ·
copper · nitrone · b-lactam
P,N,O-bound copper(I)–alkyne complex forms
a hydrogen-
bonded complex (A) with Et2NH. Proton relay through Et2NH in
A leads to C(sp)–H activation of terminal alkyne 1 to form
copper acetylide B with a Cu-bound OH group. Nitrone 2 is
[1]
For books on the biological activity of b-lactams, see: a) The Chemistry
of b-Lactams (Ed.: M. I. Page), Blackie Academic & Professional, New
York, 1992; b) Chemistry and Biology of b-Lactam Antibiotics, Vol. 1–3
(Eds.: R. B. Morin, M. Gorman), Academic Press, New York, 1982.
For books on the synthetic chemistry of b-lactams, see: a) Synthesis of
b-Lactam Antibiotics: Chemistry, Biocatalysis and Process Integration
(Ed.: A. Bruggink), Kluwer, Dordrecht, Netherlands, 2001; b)
Enantioselective Synthesis of b-Amino Acids (Ed.: E. Juaristi), VCH,
New York, 1997; c) The Organic Chemistry of b-Lactams (Ed.: G. I.
Georg), VCH, New York, 1993. For a review, see: d) C. Ro. Pitts, T.
Lecka, Chem. Rev. 2014, 114, 7930–7953.
captured by
B
through O–H···O/C(sp3)–H···O two-point-
hydrogen-bonding to form complex C.[10,11] Subsequent C–C
bond formation may occur in a stepwise manner rather than a
[3+2] cycloaddition manner because the oxyanion is hydrogen-
bonded.[14, 15] In the transition state [TS (C-D)] for bond formation
between the alkyne carbon b to Cu and the nitrone imino carbon,
the steric repulsion between the substituent of the alkyne (R)
and the N-aryl group (Ar’) should be minimized. We propose this
stereochemical model based on the observation that more
sterically demanding N-substituents such as o-tolyl and 1-
naphthyl groups gave better enantioselectivities (Table 2, entries
3 and 4; Table 3, entries 4 and 5). Next, C–C-bonded product D
undergoes a second bond formation between the oxyanion and
the acetylide carbon a to Cu to give a five-membered N,O-
heterocyclic organocopper intermediate (E). Rearrangement of
E accompanied by diastereoselective protodemetalation and re-
coordination of the alkyne 1 produces b-lactam 3 and A. The
major diastereomer with the cis-configuration should result from
protonation from the less hindered diastereotopic face. This
rearrangement/protodemetalation may demand an additional
Et2NH molecule.
[2]
[3]
[4]
[5]
M. Kinugasa, S. Hashimoto, J. Chem. Soc., Chem. Commun. 1972,
466–467.
M. Miura, M. Enna, K. Okuro, M. Nomura, J. Org. Chem. 1995, 60,
4999–5004.
For reviews on the asymmetric Kinugasa reaction, see: a) S. R.
Chemler, P. H. Fuller, Chem. Soc. Rev. 2007, 36, 1153–1160; b) R. Pal,
S. C. Ghosh, K. Chandra, A. Basak, Synlett 2007, 2321–2330; c) L. M.
Stanley, M. P. Sibi, Chem. Rev. 2008, 108, 2887–2902; d) S. Stecko, B.
Furman, M. Chmielewski, Tetrahedron, 2014, 70, 7817–7844.
a) M. M.-C. Lo, G. C. Fu, J. Am. Chem. Soc. 2002, 124, 4572–4573; b)
R. Shintani, G. C. Fu, Angew. Chem. Int. Ed. 2003, 42, 4082–4085; c)
M..-C. Ye, J. Zhou, Z.-Z. Huang, Y. Tang, Chem. Commun. 2003, 2554–
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Org. Chem. 2006, 71, 3576–3582. f) Z. Chen, L. Lin, M. Wang, X. Liu,
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Tanabe, J. Yahiro, T. Otani, Tetrahedron Lett. 2009, 50, 4969–4972; h)
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18, 199–207; i) B. Baeza, L. Casarrubios, M. A. Sierra, Chem. Eur. J.
2013, 19, 11536–11540.
[6]
The significant difference in enantiomeric purities between the
cis- and trans-b-lactams observed in the reactions of aryl- or
alkenylacetylenes (Tables 1 and 2) is curious. This suggests
reversibility of the C–C bond formation step or the existence of
different reaction pathways.
[7]
[8]
[9]
For diastereoselective Kinugasa reactions, see: a) M. Maciejeko, S.
Stecko, O. Staszewska-Krajewska, M. Jurczak, B. Furman, M.
Chemielewski, Synthesis 2012, 44, 2825–2839; b) X. Zhang, R. P.
Hsung, H. Li, Y. Zhang, W. L. Johnson, R. Figueroa, Org. Lett. 2008,
10, 3477–3479.
SinPr3
SinPr3
SinPr3
Et
NHEt2
H
H
H
H
NHEt2
Ar2
P
H
Ar2
P
H
N
Ar2
P
H
Et
H
O
H
–
O
O
O
Ar'
+
N
H
Cu
Cu
Cu
H
H
N
–O
R2
Ar'
H
N
+
R2
N
R1
N
R1
R1
R1
R2
For selected reports on the synthesis of b-lactam cholesterol absorption
inhibitors and their biological activities: a) D. A. Burnett, Tetrahedron
Lett. 1994, 35, 7339–7342; b) G. Wu, Y. Wong, X. Chen, Z. Ding, J.
Org. Chem. 1999, 64, 3714–3718; c) J. W. Clader, J. Med. Chem.
2004, 47, 1–9.
A
B
C
O
2
N
R1
SinPr3
H
Ar'
3
1
SinPr3
NHEt2
SinPr3
NHEt2
H
H
H
NHEt2
Ar2
P
Ar2
P
Ar2
P
O
H
O
H
O
H
–
–
O
The first synthesis of biapenem: Y. Nagao, Y. Nagase, T. Kumagai, H.
Matsunaga, T. Abe, O. Shimada, T. Hayashi, Y. Inoue, J. Org. Chem.
1992, 57, 4243–4249.
δ
+
H
O
H
H
Ar'
Cu
O
Cu
Cu
N
N
Ar'
H
H
Ar'
N
R2
R2
N
N
N
+
δ
+
H
H
H
R1
R2
[10] (a) T. Ishii, R. Watanabe, T. Moriya, H. Ohmiya, S. Mori, M. Sawamura,
Chem. Eur. J. 2013, 19, 13547–13553. (b) Y. Asano, K. Hara, H. Ito, M.
Sawamura, Org. Lett. 2007, 9, 3901–3904. (c) Y. Asano, H. Ito, K. Hara,
M. Sawamura, Organometallics 2008, 27, 5984–5996.
R1
TS (C-D)
E
R1
D
Figure 3. A scenario for the catalytic enantiocontrolled Kinugasa reaction.
In summary, prolinol-phosphine chiral ligands served as
efficient catalysts for the asymmetric Kinugasa reaction. While
limited applicability toward C-arylnitrones remains an issue, high
enantioselectivities were attained in the reaction of C-
alkylnitrones not only with aryl- or alkenylacetylenes but also
with alkylacetylenes. This new protocol for the Kinugasa reaction
with alkylacetylenes enabled straightforward asymmetric
[11] (a) R. C.Johnston, P. H.-Y. Cheong, Org. Biomol. Chem. 2013, 11,
5057–5064. (b) Y. Gu, T. Kar, S. Scheiner, J. Am. Chem. Soc. 1999,
121, 9411–9422. (c) P. Chakrabarti, S. Chakrabarti, J. Mol. Biol. 1998,
284, 867–873. (d) Z. S. Derewenda, L. Lee, U. Derewenda, J. Mol. Biol.
1995, 252, 248–262.
[12] J. Kim, S. S. Stahl, J. Org. Chem. 2015, 80, 2448–2454.
[13] Vibrational circular dichroism was used to determine absolute
configurations of 4-alkyl-b-lactams: He, Y.; Wang, B.; Dukor, R. K.;
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[14] A theoretical suggestion of stepwise bonds formation: S. Santoro, R.-Z.
Liao, T. Marcelli, P. Hammar, F. Himo, J. Org. Chem. 2015, 80, 2649–
2660.
[15] The difficulty in the previously described asymmetric Kinugasa
reactions of alkylacetylenes may have been due to existence of
stepwise heterocycle formation pathways. Without a hydrogen-bonding
site in the catalyst, enantiodiscrimination for acyclic C–C-bond-forming
transition states should be more difficult than that for concerted [3+2]
cycloaddition transition states.
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Yurie Takayama, Takaoki Ishii, Hirohisa
Ohmiya, Tomohiro Iwai, Martin C.
Schwarzer, Seiji Mori, Tohru Taniguchi,
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Asymmetric Synthesis of -Lactams
b
through Copper-Catalyzed Alkyne–
Nitrone Coupling with Prolinol-
Phosphine Chiral Ligand
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