Diastereoselective Synthesis of syn-β-Lactams Using Rh-Catalyzed Reductive Mannich-Type Reaction of α,β-Unsaturated Esters

Article abstract of DOI:10.1021/acs.joc.5b01233

The combination of Et₂Zn and RhCl(PPh₃)₃ led to the facile generation of a rhodium-hydride complex (Rh-H) that catalyzed the 1,4-reduction of α,β-unsaturated esters. The resulting rhodium enolate performed as a Reformatsky-type reagent and reacted with various imines to give syn-β-lactams in good to excellent yields with high diastereoselectivity.

Full text of DOI:10.1021/acs.joc.5b01233

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Diastereoselective Synthesis of synꢀβꢀLactams Using Rh Catalyzed
Reductive MannichꢀType Reaction of α,βꢀUnsaturated Esters
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Motoyuki Isoda, Kazuyuki Sato, Masato Funakoshi, Keiko Omura, Atsushi Tarui,
Masaaki Omote, and Akira Ando*
Faculty of Pharmaceutical Sciences, Setsunan University, 45ꢀ1 Nagaotogeꢀcho, Hirakata, Osaka
573ꢀ0101, Japan
Eꢀmail: aando@pharm.setsunan.ac.jp
Abstract
R'''
R"
RhCl(PPh3)3
O
R'''
H
O
N
N
+
Et2Zn
R'
RO
R'
R"
DMF, 0°C → rt
23 examples
(up to 93%, dr = 97: 3 )
The combination of Et2Zn and RhCl(PPh3)3 led to the facile generation of a
rhodiumꢀhydride complex (Rh–H) that catalyzed the 1,4ꢀreduction of α,βꢀunsaturated
esters. The resulting rhodium enolate performed as a Reformatskyꢀtype reagent, and
reacted with various imines to give synꢀβꢀlactams in good to excellent yields with high
diastereoselectivity.
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βꢀLactam (azetidinꢀ2ꢀone) skeletons can be found in a wide range of bioactive natural
products and pharmaceutical compounds, such as antibiotics1 and therapeutic agents
for the treatment of dyslipidemia.2 Following on from Sir Alexander Fleming’s discovery
of penicillin in 1928,3 there have been numerous studies directed towards evaluating
the biological properties of βꢀlactams. Furthermore, a wide variety of different
approaches have been developed for the preparation of βꢀlactams.4 For example, the
intramolecular cyclization of βꢀamino acid derivatives and the Staudinger ketene
cycloaddition reaction are both classical methods for the construction of βꢀlactams.5
Several other methods have also been developed, including the metalꢀcatalyzed
carbonylation for aziridines,6 the intramolecular C–H insertion reactions using diazo
compounds7 and the Kinugasa reaction, which involves the reaction of a nitrone with a
terminal alkyne.8
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A wide variety of Mannichꢀtype reaction have been reported to give βꢀamino esters
and/or βꢀlactams via the reaction of a metal enolate with a copper,9 cobalt10 or rhodium
catalyst.11 In contrast, there have been very few reports pertaining to the development
of reductive Mannichꢀtype reactions to give βꢀamino esters and/or βꢀlactams using R3Si–
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H, Li(Et3BH) or hydrogen as a reductant.10b,11a,12 We recently reported a reductive
Reformatsky–Honda reaction with various electrophiles (e.g., acid derivatives,
aldehydes and ketones) to give the corresponding products in good to excellent yields.13
Imines also reacted smoothly under these conditions to give the corresponding
βꢀlactams as the major products, together with a small amount of the βꢀamino esters. It
is noteworthy that this reaction afforded synꢀβꢀlactams with good diastereoselectivity.
In general, the formation of synꢀβꢀlactams is particularly rare,14 and there are no report
for synthesizing synꢀβꢀlactams using reductive Mannich reaction. Herein, we would like
to report the syn selective synthesis of βꢀlactams via the reductive Mannichꢀtype
reaction of α,βꢀunsaturated esters with various imines.
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In our previous paper,13a we reported that the reaction of methyl acrylate (1a) with
imine 2Aa gave the corresponding βꢀlactam 3Aa in 70% yield and the βꢀamino ester 4Aa
in 12% yield with good syn selectivities (Scheme 1). Each diastereomers of 3Aa could
separate by column chromatography and its stereochemistry was determined by NOE
between the CH3 and C6H5 groups on azetidinꢀ2ꢀone ring and the coupling constant of
protons on the C3 and C4 (syn form:
J = 5.0–6.0 Hz, anti form: J = 2.0–3.0 Hz). In
addition, 4Aa was transformed into 3Aa and the stereochemistry was determined by
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same manner. However, it was very difficult to separate the desired βꢀlactam 3Aa and
the corresponding amino ester 4Aa from reaction mixture because of using the excess
amount of imine 2Aa. This transformation was therefore selected as a model reaction by
reducing the amount of imine 2Aa from 2 equiv. to 1.2 equiv., and the reaction
conditions were optimized. The results are summarized in Table 1. It seemed that the
amino ester 4Aa transformed to the βꢀlactam 3Aa over time, and reached the similar
yield of previous result by 72h as shown in entries 2–4. However we thought the
reaction time in entry 4 was too long to obtain 3Aa, and we examined the solvents while
fixing time for 24h to improve the yield (Table 1, entry 6–10). Finally, we decided entry 3
with optimal condition.
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Scheme 1. Previous result
Bn
Ph
Bn
+
O
Bn
O
O
HN
RhCl(PPh3)3 (2 mol%)
N
N
+
Et2Zn (1.5 equiv.)
0°C
MeO
MeO
Ph
H
Ph
4Aa
1a
2Aa
3Aa
(2 equiv.)
70 %
syn: anti = 81 : 19
12 %
syn only
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Table 1. Optimization of the reaction conditions
Bn
Bn
O
Bn
O
O
HN
RhCl(PPh3)3
N
N
+
+
Et2Zn (1.5 equiv.)
MeO
MeO
Ph
Ph
H
9
Ph
10
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1a
2Aa
(1.2 equiv.)
3Aa
4Aa
yield (%)a
b
entry RhCl(PPh3)3
solv.
THF
time (h)
5
temp. (ºC)
3Aa [syn
:anti
]
4Aac,d
0
1
2
none
0
0
0
0
rt
0
0
0
0
0
0
2mol%
2mol%
2mol%
2mol%
2mol%
2mol%
2mol%
2mol%
2mol%
THF
3
40 [77:23]
64 [83:17]
71 [83:17]
58 [78:22]
0
45
22
17
26
30
32
39
43
33
3
THF
24
4
THF
72
5
THF
24
6
Hexane
Toluene
CH2Cl2
Et2O
24
7
24
12 [75:25]
17 [100:0]
0
8
24
9
24
10
DME
24
34 [74:26]
a
b
: Isolated yield.
: Diastereomeric ratio (syn:anti) after purification.
c
: Only syn isomer was obtained.
d
: The stereochemistry was determined by 1H NMR after transforming into 3Aa.
With the optimum conditions in hand (Table 1, entry 3), we proceeded to examine the
scope of the reaction by varying the nature of the substituent on the nitrogen of the
imine, and the results are summarized in Table 2. Benzyl, phenyl and pꢀmethoxyphenyl
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(PMP) groups gave the corresponding βꢀlactams in moderate to good yields with high
diastereoselectivities (Table 2, entries 1–3). In contrast, the use of alkyl and phosphonic
groups failed to provide any of the desired products, although the phosphonic amide
gave the synꢀβꢀamino ester 4Fa in low yield (Table 2, entries 4–6).
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Table 2. Substituent effect of imines
RhCl(PPh3)3
(2 mol%)
R
R
O
R
O
O
HN
N
N
+
+
Et2Zn (1.5 equiv.)
MeO
MeO
Ph
Ph
H
Ph
THF, 0°C
24h
1a
2
3
4
yield (%)a
βꢀamino ester (4)c
entry
imine
βꢀlactam (3)
64 [83:17]
1
Bn
Ph
2Aa
2Ba
2Ca
2Da
2Ea
2Fa
3Aa
3Ba
3Ca
3Da
3Ea
3Fa
22
41
21
nd
nd
26
4Aa
4Ba
4Ca
4Da
4Ea
4Fa
2
53 [100:0]
3
PMP
Me
62 [100:0]
4
nd
nd
nd
5
tertꢀBu
P(O)Ph2
6
a
b
: Isolated yield.
: The individual diastereomers were isolated by column chromatography.
c
: Only the syn isomer was obtain.
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Table 3. Synthesis for
Nꢀbenzyl substituted βꢀlactams
Bn
O
Bn
8
9
RhCl(PPh3)3
(2 mol%)
N
O
N
+
Et2Zn (1.5 equiv.)
THF, 0°C
24h
MeO
H
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R
R
1a
2A
3A
Bn
O
O
Bn
O
Bn
N
N
N
OMe
3Aa
64%a
3Ab
3Ac
[72:28]c
69%a
CF3
[80:20]b
[83:17]b
83%a
O
O
Bn
N
O
Bn
O
Bn
N
N
3Ae
3Af
3Ad
73%a [82:18]b
Cl
OMe
[72:28]c
[75:25]c
60%a
56%a
O
Bn
O
Bn
N
O
Bn
N
N
Cl
Cl
3Ai
69%a
3Ag
[80:20]c
3Ah
69%a
[72:28]c
[65:35]c
81%a
a
b
: Isolated yield.
: The individual diastereomers were isolated by column chromatography.
anti) was determined by 1H NMR.
c
: The diastereomeric ratio (syn
:
Various
Nꢀbenzyl substituted imines 2A were also investigated to further evaluate the
scope of the reaction (Table 3). The presence of an electron withdrawing or electron
donating group on the benzene ring did not give a significant influence in the yield and
selectivity and the desired products were obtained in good yields in all cases, together
with small amounts of the corresponding synꢀβꢀamino esters.
We found that the use of
NꢀPMP imines 2C in the Rh catalyzed reaction in DMF
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resulted in the significant improvement of the synꢀstereoselectivity. Unfortunately,
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some of
NꢀPMP imines did not react under the optimized reaction condition because
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they were insoluble to THF. For this reason, several alternative solvents were examined,
and it was found that changing the solvent to DMF led to significant improvements in
the yield and selectivity of the reaction (Table 4). Having identified as suitable solvent
for the
NꢀPMP imines, we proceeded to evaluate the scope of the reaction. The presence
of an electron withdrawing group on the benzene ring led to a slight decrease in the
yield, although the products were isolated with high syn selectivity. Imines bearing an
electron donating group on their benzene ring gave the corresponding products in
excellent yields with high syn selectivity, even when the substituent was positioned at
the metaꢀ or orthoꢀposition. Notably, the imines derived from an aliphatic aldehyde and
a ketone were also well tolerated and gave the corresponding βꢀlactams in moderate
yields. The most interesting of these examples was the spiroꢀβꢀlactam 3Cj, which was
obtained in a oneꢀpot reaction using ketimine.
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Table 4. Synthesis for
N
ꢀ
p
ꢀmethoxyphenyl substituted βꢀlactams
RhCl(PPh3)3
(2 mol%)
PMP
PMP
O
O
N
N
+
R'
MeO
Et2Zn (1.5 equiv.)
DMF, 0°C → rt
24h
R
R'
2C
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R
1a
3C
PMP
O
PMP
O
PMP
N
O
N
N
OMe
3Ca
88%a [96: 4]b
3Cb
64%a [89:11]b
3Cc
66%a [92: 8]b
CF3
O
PMP
O
PMP
O
PMP
O
N
N
N
3Cd
69%a [94: 6]b
3Ce
3Cf
Cl
OMe
N
81%a [95: 5]b
86%a [97: 3]b
O
PMP
O
PMP
O
PMP
O
PMP
N
N
N
Cl
Cl
3Cg
84%a [93: 7]b
3Ch
93%a [100:0]b
3Ci
61%a [62:38]b
3Cj
48%a
a
b
: Isolated yield.
: Diastereomeric ratio (syn:anti) after purification.
It was envisaged that a rhodiumꢀhydride complex (Rh–H) was involved in this reaction.
We therefore considered a nucleophilic attack by rhodium enolate into imines at first.15
However, an additional role of Zn species affects for a several stages in this reaction and
the active species was zinc enolate in this reaction, because most of reductive Mannich
reactions without zinc species did not give the βꢀlactams but the βꢀamino esters. With
this in mind, we proposed a plausible mechanism for this reaction, which is shown in
Figure 1.13 The Rh catalyst would react with Et2Zn to give the Rh–H species 6 via the
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elimination of ethylene from the ethyl rhodium complex 5. The 1,4ꢀreduction of
α,βꢀunsaturated ester 1 with 6 would give rhodium enolate 7, which would undergo a
transmetalation reaction with zinc species 8 to give the Reformatskyꢀtype reagent Int A.
Int A would then react with the imine substrate to give the corresponding βꢀlactam 3
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and/or βꢀamino ester 4. It seems reasonable to suggest that the
Nꢀzinc βꢀamino ester
intermediate Int B would cyclize to give the synꢀβꢀlactam via an intramolecular
nucleophilic substitution reaction.
Figure 1. Plausible reaction mechanism
Et2Zn
R'
Rh
X
N
R
H
ZnEt
OR"
EtZn
O
R'
R
N
O
R"O
XZn Et
Int B
Int A
8
O
Rh
H
Rh Et
OR"
7
5
R'
R
O
R'
O
HN
N
O
R"O
R
Rh H
1
CH2 CH2
OR"
6
To develop a deeper understanding of the mechanism responsible for the high
diastereoselectivity of the reaction, we investigated the reaction of tertꢀbutyl acrylate
(1b) with imine 2Ca under the same conditions that gave the synꢀβꢀamino ester 9 in 86%
as the sole product. Several attempts were made to trap the Int A species formed during
this reaction from tertꢀbutyl acrylate with TMS–Cl, and it is noteworthy that this
trapping procedure only resulted in the detection of the
Eꢀsilyl enolate. Given that the
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configuration of the Int A species was identified as that of the
Eꢀenolate, it was
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speculate that the reaction was proceeding via a linear transition state (Figures 2 and
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3).
Figure 2. Reaction of 1b and 2Ca and the configuration of Int A
1) RhCl(PPh3)3 (2 mol%)
Et2Zn (1.2 equiv.)
THF, 0°C, 5min
TMS
O
O
t-Bu
t-BuO
O
2) TMSCl (1.2 equive.)
1b
E-enolate only
ZnEt
O
t-Bu
O
Int A
RhCl(PPh3)3
(2 mol%)
PMP
HN
PMP
O
O
Syn only
N
+
Et2Zn (1.5 equiv.)
t-BuO
t-BuO
Ph
Yield 86%
Ph
H
THF, 0°C
24h
1b
2Ca
9
Figure 3. Tentative transition–state model
PMP
N
M
PMP
PMP
N
O
O
N
Me
MeO
Ph
Ph
H
MeO
Ph
OM
favored
syn-Int B
syn-3Ca
PMP
O
N
+
MeO
Ph
H
PMP
M
PMP
Ph
PMP
O
N
1a
2Ca
O
N
N
Me
MeO
Ph
MeO
H
Ph
antiꢀ3Ca
OM
disfavored
anti-Int B
To conclude this study, we also investigated the application of the optimized conditions
to a series of α,βꢀunsaturated esters (Table 5). The presence of a substituent at the
βꢀposition of the α,βꢀunsaturated ester was found to have very little impact on the
outcome of the reaction. Methyl crotonate (1c) gave the βꢀlactam 10 in low yield with
reasonably high syn selectivity, whereas methyl cinnamate (1d) failed to provide any of
the desired products. Notably, the α,βꢀunsaturated γꢀ and δꢀlactones reacted smoothly to
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give the desired products (12 and 13), although the stereochemistry of these products
was determined to be the antiꢀconfiguration. It currently remains unclear as to why the
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α,βꢀunsaturated lactone substrates gave the corresponding antiꢀβꢀlactams exclusively.
Table 5. Steric effect for βꢀsubstituted α,βꢀunsaturated ester or lactone
RhCl(PPh3)3
(2 mol%)
PMP
PMP
O
O
N
N
+
Et2Zn (1.5 equiv.)
DMF, 0°C → rt
24h
RO
R'
Ph
H
R'
Ph
2Ca
1
product
yield (%)
entry
1
1
O
PMP
N
O
34%a
[100:0]b
1c
10
MeO
O
O
PMP
N
2
3
4
1d
1e
1f
11
12
13
nd
MeO
O
PMP
N
O
O
28%a
[0:100]b
O
O
HO
O
PMP
N
11%a
[0:100]b
HO
a
b
: Isolated yield.
: Diastereomeric ratio (syn:anti) after purification.
In conclusion, we have developed a highly diastereoselective reductive Mannichꢀtype
reaction using a Rh catalyst with Et2Zn. This reaction provided rapid access to
βꢀlactams in good to excellent yields with excellent synꢀselectivity.
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Experimental Section
General Information:
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NMR spectra were obtained from a solution in CDCl3 using 400 MHz for 1H, 100 MHz
1
for 13C and 90 MHz for 19F. Chemical shifts of H NMR and 13C NMR are reported in
ppm from tetramethylsilane (TMS) as an internal standard. Chemical shifts of 19F NMR
are reported in ppm from ethyl trifluoroacetate (ETFA) as an internal standard. All data
are reported as follows: chemical shifts, relative integration value, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, qd = quartet doublet, br = broad, m =
multiplet), coupling constants (Hz). Highꢀresolution mass spectroscopy (HRMS)
experiments were measured on a doubleꢀfocusing mass spectrometer with an ionization
mode of EI or positive FAB as indicated for each compound. Infrared (IR) spectra were
recorded in KBr tablets or thin films on either KBr disks. Melting points were measured
uncorrected.
Materials
Tetrahydrofuran (THF) was purchased from Kanto Chemical Co. Inc. as “Dehydrated”.
All imines were prepared from corresponding aldehydes and amines. Methyl acrylate
and tertꢀbutyl acrylate were distilled just before use. Other commercially available
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reagents were used without further purification. All experiments were carried out
under an argon atmosphere in flameꢀdried glassware using standard inert techniques
for introducing reagents and solvents unless otherwise noted.
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Method 1: Typical procedure for synthesis of
Nꢀbenzyl or Nꢀphenylꢀazetidinꢀ2ꢀone
Methyl acrylate (1a, 1 mmol) and (E)ꢀNꢀbenzylidene(phenyl)methanamine (2Aa, 1.2
mmol) were added to a solution of RhCl(PPh3)3 (2 mol %) in THF (2.5 mL) at 0 °C.
Then, 1.0 M Et2Zn in hexane (1.5 mmol, 1.5 mL) was gradually added to the mixture at
0 °C, and the mixture was stirred at same temperature for 24h. The mixture was
quenched with sat. NaHCO3 and extracted with AcOEt. The AcOEt layer was washed
with sat. NaCl and dried over MgSO4. The solvent was removed in vacuo, and the
residue was purified by column chromatography (AcOEt:hexane = 2:8) and each
diastereomers were obtained in 53% (132.7 mg; synꢀ3Aa) and 11% yield (26.9 mg;
antiꢀ3Aa), respectively. The stereochemistry of products were determined by NOE
between the CH3 and C6H5 groups on azetidinꢀ2ꢀone ring and coupling constant between
each protons of C3 and C4 (syn form:
J = 5.0–6.0 Hz, anti form: J = 2.0–3.0 Hz).
Method 2: Typical procedure for synthesis of
Nꢀ(pꢀmethoxyphenyl)ꢀazetidinꢀ2ꢀone
Methyl acrylate (1a, 1 mmol) and (E)ꢀNꢀbenzylideneꢀ4ꢀmethoxybenzenamine (2Ca, 1.2
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mmol) were added to a solution of RhCl(PPh3)3 (2 mol %) in DMF (2.5 mL) at 0 °C.
Then, 1.0 M Et2Zn in hexane (1.5 mmol, 1.5 mL) was gradually added to the mixture at
0 °C, and the mixture was stirred at room temperature for 24h. The mixture was
quenched with sat. NH4Cl and extracted with AcOEt. The AcOEt layer was washed
with sat. NaCl and dried over MgSO4. The solvent was removed in vacuo, and the
residue was purified by column chromatography (AcOEt:hexane = 2:8) and each
diastereomers were obtained in 84% (225.9 mg; synꢀ3Ca) and 4% yield (9.9 mg;
antiꢀ3Ca), respectively. The stereochemistry of products were determined by NOE
between the CH3 and C6H5 groups on azetidinꢀ2ꢀone ring and coupling constant between
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each protons of C3 and C4 (syn form:
J = 5.0–6.0 Hz, anti form: J = 2.0–3.0 Hz).
1ꢀBenzylꢀ3ꢀmethylꢀ4ꢀphenylazetidinꢀ2ꢀone (3Aa). The title product (3Aa) was purified
by column chromatography (AcOEt:hexane = 2:8) and each diastereomers were obtained
in 53% (132.7 mg; syn form) and 11% yield (26.9 mg; anti form), respectively.
synꢀ3Aa; A colorless oil; 1H NMR (400 MHz, CDCl3) δ: 0.83 (3H, d,
J = 7.2 Hz), 3.50 (1H,
m), 3.90 (1H, d,
J = 14.8 Hz), 4.59 (1H, d, J = 5.2 Hz), 4.90 (1H, d, J = 14.8 Hz), 7.14–7.18
(4H, m), 7.24–7.42 (6H, m); 13C NMR (100 MHz, CDCl3) δ: 9.743, 44.37, 49.99, 57.95,
127.2, 127.6, 128.0, 128.4, 128.5, 128.7, 135.3, 135.6, 171.0; MS m/z: 251 (M+); HRMS
Calcd. for C17H17NO: 251.131 (M+), Found: 251.132; IR (neat) cmꢀ1: 3484, 1748.
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antiꢀ3Aa; A colorless oil; 1H NMR (400 MHz, CDCl3) δ: 1.35 (3H, d,
J = 7.2 Hz), 3.07 (1H,
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m), 3.75 (1H, d,
J = 15.0 Hz), 3.96 (1H, d, J = 1.6 Hz), 4.83 (1H, d, J = 15.0 Hz), 7.13–7.15
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(2H, m), 7.23–7.39 (8H, m); 13C NMR (100 MHz, CDCl3) δ: 12.91, 55.25, 62.03, 126.4,
127.5, 128.3, 128.3, 128.7, 128.8, 135.6, 137.6, 170.8; MS m/z: 251 (M+); HRMS Calcd.
for C17H17NO: 251.131 (M+), Found: 251.130; IR (neat) cmꢀ1: 3486, 1746.
Methyl 3ꢀ(benzylamino)ꢀ2ꢀmethylꢀ3ꢀphenylpropanoate (4Aa). The title product (4Aa)
was purified by column chromatography (AcOEt:hexane = 1:9) and was obtained in 22%
yield (62.9 mg).
synꢀ4Aa; A colorless oil; 1H NMR (400 MHz, CDCl3) δ: 1.18 (3H, d,
J = 6.8 Hz), 1.84 (1H,
br), 2.71–2.78 (1H, m), 3.48 (1H, d,
J = 13.2 Hz), 3.51 (3H, s), 3.70 (1H, d, J = 13.2 Hz),
3.94 (1H, d,
J
= 6.0 Hz), 7.23–7.36 (10H, m); 13C NMR (100 MHz, CDCl3) δ: 12.54, 46.64,
51.27, 51.44, 63.51, 126.8, 127.2, 127.5, 128.0, 128.18, 128.22, 140.3, 141.2, 175.2; MS
(FAB+) m/z: 284 (M+H)+; HRMS Calcd. for C18H22NO2 (C18H21NO2+H): 284.165, Found:
284.165; IR (neat) cmꢀ1: 3337, 1735.
3ꢀMethylꢀ1,4ꢀdiphenylazetidinꢀ2ꢀone (3Ba). The title product (3Ba) was purified by
column chromatography (AcOEt:hexane = 2:8) and only the syn diastereomer was
obtained in 53% yield (126.0 mg).
synꢀ3Ba; A colorless solid; M.p. 95–96 °C; 1H NMR (400MHz, CDCl3) δ: 0.89 (3H, d,
J =
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8.0 Hz), 3.69 (1H, qd,
J = 8.0, 5.6 Hz), 5.20 (1H, d, J = 5.6 Hz), 7.03–7.07 (1H, m), 7.23–
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7.28 (4H, m), 7.31–7.39 (5H, m); 13C NMR (100 MHz, CDCl3) δ: 9.777, 49.38, 58.47, 117.3,
123.9, 127.1, 128.3, 128.9, 129.2, 135.2, 137.9, 168.7; MS m/z: 237 (M+); HRMS Calcd.
for C16H15NO: 237.115 (M+), Found: 237.116; IR (KBr) cmꢀ1: 1743.
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Methyl 2ꢀmethylꢀ3ꢀphenylꢀ3ꢀ(phenylamino)propanoate (4Ba). The title product (4Ba)
was purified by column chromatography (AcOEt:hexane = 2:8) and only the syn
diastereomer was obtained in 41% yield (110.7 mg).
synꢀ4Ba; A colorless solid; M.p. 97.5–98.5 °C; 1H NMR (400 MHz, CDCl3) δ: 1.16 (3H, d,
J
= 7.2 Hz), 2.96 (1H, qd, J = 7.2, 4.8 Hz), 3.62 (3H, s), 4.50 (1H, br), 4.72 (1H, br), 6.51–
6.53 (2H, m), 6.62–6.66 (1H, m), 7.06–7.07 (2H, m), 7.21–7.36 (5H, m); 13C NMR (100
MHz, CDCl3) δ: 11.90, 46.15, 51.96, 59.72, 113.8, 117.8, 127.0, 127.5, 128.7, 129.2, 140.8,
147.2, 174.8; MS m/z: 269 (M+); HRMS Calcd. for C17H19NO2: 269.142 (M+), Found:
269.142; IR (KBr) cmꢀ1: 3418, 1743.
1ꢀ(pꢀMethoxyphenyl)ꢀ3ꢀmethylꢀ4ꢀphenylazetidinꢀ2ꢀone (3Ca). The title product (3Ca)
was purified by column chromatography (AcOEt:hexane = 2:8) and each diastereomers
were obtained in 84% (225.9 mg; syn form) and 4% yield (9.9 mg; anti form),
respectively.
synꢀ3Ca; A colorless solid; M.p. 125.6–126.5 °C; 1H NMR (400 MHz, CDCl3) δ: 0.88 (3H,
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d,
J = 7.2 Hz), 3.67 (1H, qd, J = 7.2, 5.6 Hz), 3.75 (3H, s), 5.16 (1H, d, J = 5.6 Hz), 6.80
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(2H, m), 7.22–7.38 (7H, m); 13C NMR (100 MHz, CDCl3) δ: 9.772, 55.41, 49.28, 58.43,
114.2, 118.2, 126.9, 127.9, 128.5, 131.3, 135.0, 155.8, 167.7; MS m/z: 267 (M+); HRMS
Calcd. for C17H17NO2: 267.126 (M+), Found: 267.126; IR (KBr) cmꢀ1: 1730.
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antiꢀ3Ca; A colorless solid; M.p. 42.0–43.0 °C; 1H NMR (400 MHz, CDCl3) δ: 1.48 (3H, d,
J
= 7.2 Hz), 3.11 (1H, qd,
J = 7.2, 2.0 Hz), 3.74 (3H, s), 4.54 (1H, d, J = 2.0 Hz), 6.76–6.80
(2H, m), 7.21–7.25 (2H, m), 7.30–7.39 (5H, m); 13C NMR (100 MHz, CDCl3) δ: 13.07,
55.26, 55.37, 62.71, 114.1, 118.1, 125.7, 128.2, 128.9, 131.3, 137.9, 155.7, 167.5; MS m/z
:
267 (M+); HRMS Calcd. for C17H17NO2: 267.126 (M+), Found: 267.126; IR (KBr) cmꢀ1:
1736.
Methyl 3ꢀ(pꢀmethoxyphenylamino)ꢀ2ꢀmethylꢀ3ꢀphenylpropanoate (4Ca)
.
The title
product (4Ca) was purified by column chromatography (AcOEt:hexane = 2:8) and only
the syn diastereomer was obtained in 6% yield (18.9 mg).
synꢀ4Ca; A colorless solid; M.p. 138.0–138.5 °C; 1H NMR (400 MHz, CDCl3) δ: 1.15 (3H,
d,
J
= 7.6 Hz), 1.59 (1H, br), 2.94 (1H, qd,
J = 7.6, 4.8 Hz), 3.61 (3H, s), 3.68 (3H, s), 4.65
(1H, d,
J
= 4.8 Hz), 6.45–6.49 (2H, m), 6.65–6.69 (2H, m), 7.20–7.31 (5H, m); 13C NMR
(100 MHz, CDCl3) δ: 11.89, 46.11, 51.75, 55.66, 60.49, 114.6, 114.9, 126.8, 127.1, 128.3,
140.8, 141.1, 152.0, 174.5; MS m/z: 299 (M+); HRMS Calcd. for C18H21NO3: 299.152 (M+),
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Found: 299.152; IR (KBr) cmꢀ1: 3382, 1712.
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1ꢀBenzylꢀ3ꢀmethylꢀ4ꢀ(pꢀ(trifluoromethyl)phenyl)azetidinꢀ2ꢀone (3Ab). The title product
(3Ab) was purified by column chromatography (AcOEt:hexane = 2:8) and each
diastereomers were obtained in 66% (211.1 mg; syn form) and 17% yield (54.3 mg; anti
form), respectively.
synꢀ3Ab; A colorless oil; 1H NMR (400 MHz, CDCl3) δ: 0.83 (3H, d,
J = 7.2 Hz), 3.55 (1H,
q,
J = 7.2, 6.0 Hz), 3.92 (1H, d, J = 14.8 Hz), 4.63 (1H, d, J = 6.0 Hz), 4.90 (1H, d, J = 14.8
Hz), 7.15–7.17 (2H, m), 7.26–7.31 (4H, m); 13C NMR (100 MHz, CDCl3) δ: 9.739, 44.81,
50.30, 57.68, 124.1 (q,
J = 271.6 Hz), 125.7 (q, J = 3.4 Hz), 127.7, 128.0, 128.7, 129.0,
130.6 (q,
J
= 32.4 Hz), 135.5, 140.1, 170.8; 19F NMR (90 MHz, CDCl3) δ: 12.69 (3F, s); MS
m/z: 319 (M+); HRMS Calcd. for C18H16F3NO: 319.118 (M+), Found: 319.118; IR (neat)
cmꢀ1: 1755, 1325.
antiꢀ3Ab; A colorless oil; 1H NMR (400 MHz, CDCl3) δ: 1.37 (3H, d,
J = 8.0 Hz), 3.07 (1H,
qd,
J = 8.0, 2.0 Hz), 3.81 (1H, d, J = 14.4 Hz), 4.01 (1H, d, J = 2.0 Hz), 4.84 (1H, d, J =
14.4 Hz), 7.11–7.14 (2H, m), 7.27–7.35 (8H, m); 13C NMR (100 MHz, CDCl3) δ: 12.94,
44.88, 55.77, 61.789, 124.2 (q,
J = 271.1 Hz), 126.2 (q, J = 4.0 Hz), 127.0, 128.1, 128.7,
129.1, 131.0 (q,
J
= 32.5 Hz), 135.6, 142.4, 170.7; 19F NMR (90 MHz, CDCl3) δ: 12.62 (3F,
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s); MS m/z: 319 (M+); HRMS Calcd. for C18H16F3NO: 319.118 (M+), Found: 319.119; IR
(neat) cmꢀ1: 1756, 1327.
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Methyl 4ꢀ(1ꢀbenzylꢀ3ꢀmethylꢀ4ꢀoxoazetidinꢀ2ꢀyl)benzoate (3Ac). The title product (3Ac)
was purified by column chromatography (AcOEt:hexane = 2:8) and each diastereomers
were obtained in 50% (154.7 mg; syn form) and 19% yield (58.8mg; anti form),
respectively.
synꢀ3Ac; A colorless oil; 1H NMR (400 MHz, CDCl3) δ: 0.82 (3H, d,
J = 8.0 Hz), 3.54 (1H,
qd,
J
= 8.0, 5.2 Hz), 3.93 (1H, d,
J = 15.2 Hz), 3.93 (3H, s), 4.63 (1H, d, J = 5.2 Hz), 4.90
(1H, d,
J
= 15.2 Hz), 7.14–7.17 (2H, m), 7.23–7.33 (6H, m); 13C NMR (100 MHz, CDCl3)
δ: 9.779, 44.90, 50.38, 52.24, 57.95, 127.5, 128.0, 128.8, 129.0, 130.1, 130.3, 135.6, 141.2,
166.9, 171.0; MS m/z: 309 (M+); HRMS Calcd. for C19H19NO3: 309.136 (M+), Found:
309.136; IR (KBr) cmꢀ1: 1741, 1714.
antiꢀ3Ac; A colorless oil; 1H NMR (400 MHz, CDCl3) δ: 1.36 (3H, d,
J = 7.2 Hz), 3.06 (1H,
m), 3.79 (1H, d,
J = 15.2 Hz), 3.93 (3H, s), 4.00 (1H, d, J = 1.6 Hz), 4.83 (1H, d, J = 15.2
Hz), 7.11–7.13 (2H, m), 7.25–7.32 (6H, m), 8.02–8.04 (2H, m); 13C NMR (100 MHz,
CDCl3) δ: 12.94, 44.79, 52.25, 55.62, 61.92, 126.6, 128.0, 128.7, 129.0, 130.4, 130.5,
135.6, 143.3, 166.8, 170.8; MS m/z: 309 (M+); HRMS Calcd. for C19H19NO3: 309.136 (M+),
Found: 309.136; IR (neat) cmꢀ1: 1754, 1724.
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1ꢀBenzylꢀ4ꢀ(pꢀchlorophenyl)ꢀ3ꢀmethylazetidinꢀ2ꢀone (3Ad). The title product (3Ad) was
purified by column chromatography (AcOEt:hexane = 2:8) and each diastereomers were
obtained in 60% (142.9 mg; syn form) and 13% yield (37.1 mg; anti form), respectively.
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synꢀ3Ad; A colorless oil; 1H NMR (400 MHz, CDCl3) δ: 0.82 (3H, d,
J = 8.0 Hz), 3.49 (1H,
qd,
J = 8.0, 5.6 Hz), 3.89 (1H, d, J = 14.8 Hz), 4.55 (1H, d, J = 5.6 Hz), 4.86 (1H, d, J =
14.8 Hz), 7.09–7.16 (4H, m), 7.25–7.36 (4H, m); 13C NMR (100 MHz, CDCl3) δ: 9.787,
44.69, 50.21, 57.65, 128.0, 128.7, 128.8, 129.0, 129.1, 134.2, 134.3, 135.7, 171.1; MS m/z
:
285 (M+); HRMS Calcd. for C17H16ClNO: 285.092 (M+), Found: 285.091; IR (neat) cmꢀ1:
1753.
antiꢀ3Ad; A colorless oil; 1H NMR (400 MHz, CDCl3) δ: 1.34 (3H, d,
J = 7.2 Hz), 3.02 (1H,
qd,
J = 7.2, 2.4 Hz), 3.76 (1H, d, J = 15.2 Hz), 3.92 (1H, d, J = 2.4 Hz), 4.80 (1H, d, J =
15.2 Hz), 7.11–7.17 (4H, m), 7.26–7.34 (4H, m); 13C NMR (100 MHz, CDCl3) δ: 12.89,
44.61, 55.53, 61.67, 127.9, 128.0, 128.6, 129.0, 129.3, 134.4, 135.7, 136.6, 170.9; MS m/z
:
285 (M+); HRMS Calcd. for C17H16ClNO: 285.092 (M+), Found: 285.092; IR (neat) cmꢀ1:
1754.
1ꢀBenzylꢀ4ꢀ(pꢀmethoxyphenyl)ꢀ3ꢀmethylazetidinꢀ2ꢀone (3Ae). The title product (3Ae)
was purified by column chromatography (AcOEt:hexane = 2:8) and was obtained in 56%
yield (syn:anti = 72:28) as a diastereomeric mixture.
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diastereomeric mixtureꢀ3Ae; H NMR (400 MHz, CDCl3) δ: 0.84 (2.4H, d,
J = 7.6 Hz),
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3.72 (0.2H, d,
J
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= 7.6 Hz), 3.06 (0.2H, qd, J = 7.6, 2.0 Hz), 3.45 (0.8H, qd, J = 7.6, 5.6 Hz),
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= 15.6 Hz), 3.14–3.82 (3H, m), 3.87 (0.8H, d,
J
= 15.6 Hz), 3.91 (0.2H, d,
J
= 2.0 Hz), 4.54 (0.8H, d,
J
= 5.6 Hz), 4.79 (0.2H, d,
J
= 15.6 Hz), 4.86 (0.8H, d,
J
= 15.6
Hz), 6.88–6.92 (2H, m), 7.07–7.17 (4H, m), 7.24–7.32 (3H, m); 13C NMR (100 MHz,
CDCl3) δ: 9.60, 12.73, 44.30, 44.34, 44.40, 49.99, 55.10, 55.23, 57.68, 61.76, 159.6, 159.9,
127.3, 127.7, 127.8, 128.47, 128.55, 128.58, 128.7, 129.6, 114.1, 114.4, 135.9, 136.0, 171.0,
171.3; MS m/z: 251 (M+); HRMS Calcd. for C17H17NO: 251.131 (M+), Found: 251.132.
1ꢀBenzylꢀ3ꢀmethylꢀ4ꢀpꢀtolylazetidinꢀ2ꢀone (3Af). The title product (3Af) was purified by
column chromatography (AcOEt:hexane = 2:8) and was obtained in 60% yield (syn:anti
= 75:25) as a diastereomeric mixture.
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diastereomeric mixtureꢀ3Af; H NMR (400 MHz, CDCl3) δ: 0.83 (2.4H, d,
J = 7.6 Hz),
1.33 (0.6H, d,
J
= 7.6), 2.37(3H, s), 3.04 (0.2H, qd,
J
J
= 7.6, 4.0 Hz), 3.62 (0.8H, qd, J = 7.6,
5.2 Hz), 3.72 (0.2H, d,
J
= 14.8 Hz), 3.88 (0.8H, d,
= 14.8 Hz), 3.93 (0.2H, d, J = 4.0 Hz),
4.56 (0.8H, d,
J = 5.2 Hz), 4.83 (0.2H, d, J = 14.8 Hz), 4.89 (0.8H, d, J = 14.8 Hz), 7.05–
7.40 (9H, m); 13C NMR (100 MHz, CDCl3) δ: 9.74, 12.90, 21.16, 44.33, 44.43, 50.09, 55.33,
58.02, 62.08, 126.6, 127.5, 127.77, 127.80, 128.6, 126.7, 128.9, 129.5, 129.8, 132.5, 134.9,
136.0, 138.0, 138.4, 171.2, 171.4 ; MS m/z: 265 (M+); HRMS Calcd. for C18H19NO:
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265.147 (M+), Found: 265.146.
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1ꢀBenzylꢀ4ꢀ(mꢀchlorophenyl)ꢀ3ꢀmethylazetidinꢀ2ꢀone (3Ag). The title product (3Ag) was
purified by column chromatography (AcOEt:hexane = 2:8) and was obtained in 81%
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yield (syn
:anti = 80:20) as a diastereomeric mixture.
diastereomeric mixtureꢀ3Ag; 1H NMR (400 MHz, CDCl3) δ: 0.84 (2.55H, d,
J
= 7.2 Hz),
1.34 (0.45H, d,
J
= 7.2 Hz), 3.03 (0.15H, qd,
J
= 7.2, 2.0 Hz), 3.51 (0.85H, qd,
J
= 7.2, 6.0
Hz), 3.80 (0.15H, d,
J = 14.4 Hz), 3.92 (0.85, d, J = 14.4 Hz), 3.92 (0.15H, d, J = 2.0 Hz),
4.55 (0.85H, d,
J = 6.0 Hz), 4.80 (0.15H, d, J = 14.4 Hz), 4.86 (0.85H, d, J = 14.4 Hz)
7.05–7.20 (4H, m), 7.30–7.33 (5H, m); 13C NMR (100 MHz, CDCl3) δ: 9.757, 12.86, 44.69,
44.77, 50.30, 55.58, 57.68, 61.72, 124.7, 125.5, 126.8, 127.54, 127.9, 128.0, 128.5, 128.6,
128.7, 129.0, 130.1, 130.4, 135.0, 135.2, 135.6, 135.7, 138.1, 140.3, 170.8, 171.0; MS m/z
285 (M+); HRMS Calcd. for C17H16ClNO: 285.092 (M+), Found: 285.093.
:
1ꢀBenzylꢀ4ꢀ(oꢀchlorophenyl)ꢀ3ꢀmethylazetidinꢀ2ꢀone (3Ah). The title product (3Ah) was
purified by column chromatography (AcOEt:hexane = 2:8) and was obtained in 69%
yield (syn
:anti = 65:35) as a diastereomeric mixture.
diastereomeric mixtureꢀ3Ah; 1H NMR (400 MHz, CDCl3) δ: 0.83 (1H, d,
J
J
= 7.6 Hz), 1.43
= 7.6, 5.2 Hz),
(2H, d,
J = 7.6 Hz), 3.00 (0.67H, qd, J = 7.6, 2.0 Hz), 3.62 (0.33H, qd,
3.90 (0.67H, d,
J = 14.8), 4.02 (0.33H, d, J = 14.8 Hz), 4.50 (0.67H, d, J = 2.0 Hz), 4.88–
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4.96 (1.43H, m), 7.12–7.40 (9H, m); 13C NMR (100 MHz, CDCl3) δ: 9.555, 13.38, 45.19,
45.36, 49.88, 55.20, 55.66, 58.66, 126.6, 127.0, 127.5, 127.9, 127.97, 128.03, 128.6, 128.7,
129.02, 129.05, 129.1, 129.2, 130.0, 130.1, 133.3, 133.4, 134.1, 135.7, 135.8, 136.2, 171.3,
171.6; MS m/z: 285 (M+); HRMS Calcd. for C17H16ClNO: 285.092 (M+), Found: 285.092.
1ꢀBenzylꢀ3ꢀmethylꢀ4ꢀ(naphthalenꢀ2ꢀyl)azetidinꢀ2ꢀone (3Ai). The title product (3Ai) was
purified by column chromatography (AcOEt:hexane = 2:8) and was obtained in 69%
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(
syn
:
anti = 72.28) as a diastereomeric mixture.
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diastereomeric mixtureꢀ3Ai; H NMR (400 MHz, CDCl3) δ: 0.85 (2.4H, d,
J = 7.2 Hz),
1.39 (0.6H , d,
3.80 (0.2H, d,
J
J
= 7.2 Hz), 3.15 (0.2H, qd, J = 7.2, 2.4 Hz), 3.57 (0.8H, qd, J = 7.2, 5.6 Hz),
= 14.8 Hz), 4.00 (0.8H, d,
J = 14.8 Hz), 4.13 (0.2H, d, J = 2.4 Hz), 4.75
(0.8H, d,
J = 5.6 Hz), 4.87 (0.2H, d, J = 14.8 Hz), 4.94 (0.8H, d, J = 14.8 Hz), 7.13–7.19
(2H, m), 7.25–7.36 (4H, m), 7.48–7.54 (2H, m), 7.63–7.67 (1H, m), 7.79–7.87 (3H, m); 13
C
NMR (100 MHz, CDCl3) δ: 9.825, 12.99, 44.57, 44.73, 50.33, 55.39, 58.37, 62.43, 123.7,
125.1, 126.2, 126.4, 126.5, 126.64, 126.67, 126.73, 127.84, 127.90, 127.94, 127.97, 128.02,
128.57, 128.63, 128.7, 128.93, 128.94, 129.16, 133.29, 133.34, 133.41, 133.5, 135.4, 135.9,
136.0, 171.2, 171.4; MS m/z: 301 (M+); HRMS Calcd. for C21H19NO: 301.147 (M+), Found:
301.147.
1ꢀ(pꢀMethoxyphenyl)ꢀ3ꢀmethylꢀ4ꢀ(pꢀ(trifluoromethyl)phenyl)azetidinꢀ2ꢀone (3Cb). The
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title product (3Cb) was purified by column chromatography (AcOEt:hexane = 2:8) and
each diastereomers were obtained in 57% (191.0 mg; syn form) and 7% yield (23.6 mg;
anti form), respectively.
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synꢀ3Cb; A colorless solid; M.p. 108.0–109.0 °C; 1H NMR (400 MHz, CDCl3) δ: 0.87 (3H,
d,
J
= 7.6 Hz), 3.73 (1H, qd,
J
= 7.6, 6.0 Hz), 3.76 (3H, s), 5.21 (1H, d,
J
= 6.0 Hz), 6.80–
6.83 (2H, m), 7.21–7.25 (2H, m), 7.36 (2H, d,
J = 8.4 Hz), 7.63 (2H, d, J
= 8.4 Hz); 13C
NMR (100 MHz, CDCl3) δ: 9.867, 49.35, 55.40, 57.88, 114.3, 118.1, 123.8 (q,
J = 270.2
Hz), 125.6 (q,
J = 3.5 Hz), 127.2, 127.8, 130.3 (q, J = 32.4 Hz), 130.9, 139.4, 156.0, 167.1;
19F NMR (90 MHz, CDCl3) δ: 12.67 (3F, s); MS m/z: 335 (M+); HRMS Calcd. for
C18H16F3NO2: 335.113 (M+), Found: 335.114; IR (KBr) cmꢀ1: 1737, 1328.
antiꢀ3Cb; A colorless oil; 1H NMR (400 MHz, CDCl3) δ: 1.50 (3H, d,
J = 7.2 Hz), 3.10 (1H,
qd,
J
= 7.2, 2.0 Hz), 3.75 (3H, s), 4.61 (1H, d,
J
= 2.0 Hz), 6.78–6.82 (2H, m), 7.18–7.22
(2H, m), 7.46 (2H, d,
J = 8.4 Hz), 7.64 (2H, d, J
= 8.4 Hz); 13C NMR (100 MHz, CDCl3) δ:
13.172, 55.55, 55.58, 62.23, 114.6, 118.4, 124.1 (q,
J = 270.3 Hz), 126.4 (q, J = 4.1 Hz),
126.4, 130.9 (q,
J
= 32.8 Hz), 131.3, 142.4, 156.4, 167.4; 19F NMR (90 MHz, CDCl3) δ:
12.62 (3F, s); MS m/z: 335 (M+); HRMS Calcd. for C18H16F3NO2: 335.113 (M+), Found:
335.114; IR (neat) cmꢀ1: 1769, 1331.
Methyl 4ꢀ(1ꢀ(pꢀmethoxyphenyl)ꢀ3ꢀmethylꢀ4ꢀoxoazetidinꢀ2ꢀyl)benzoate (3Cc). The title
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product (3Cc) was purified by column chromatography (AcOEt:hexane = 2:8) and each
diastereomers were obtained in 61% (197.6 mg; syn form) and 5% yield (16.3 mg; anti
form), respectively.
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synꢀ3Cc; A colorless solid; M.p. 124.0–125.0 °C; 1H NMR (400 MHz, CDCl3) δ: 0.87 (3H,
d,
J
= 7.2 Hz), 3.72 (1H, qd,
J
= 7.2, 6.0 Hz), 3.75 (3H, s), 3.92 (3H, s), 5.21 (1H, d,
J
J
= 6.0
= 8.0
Hz), 6.78–6.82 (2H, m), 7.21–7.25 (2H, m), 7.31 (2H, d,
J = 8.0 Hz), 8.04 (2H, d,
Hz); 13C NMR (100 MHz, CDCl3) δ: 9.801, 49.30, 52.14, 55.38, 58.02, 114.2, 118.1, 126.9,
129.8, 129.9, 130.9, 140.3, 155.8, 166.4, 167.2; MS m/z: 325 (M+); HRMS Calcd. for
C19H19NO4: 325.131 (M+), Found: 325.131; IR (KBr) cmꢀ1: 1756, 1725.
antiꢀ3Cc; A colorless oil; 1H NMR (400 MHz, CDCl3) δ: 1.50 (3H, d,
J = 7.2 Hz), 3.11 (1H,
qd,
J = 7.2, 2.4 Hz), 3.74 (3H, s), 3.91 (3H, s), 4.60 (1H, d, J = 2.4 Hz), 6.76–6.80 (2H, m),
7.18–7.21 (2H, m), 7.40–7.43 (2H, m), 8.03–8.06 (2H, m); 13C NMR (100 MHz, CDCl3) δ:
13.19, 52.27, 55.49, 55.54, 62.46, 114.5, 118.3, 126.0, 130.56, 130.63, 131.4, 143.4, 156.3,
166.7, 167.5; MS m/z: 325 (M+); HRMS Calcd. for C19H19NO4: 325.131 (M+), Found:
325.132; IR (neat) cmꢀ1: 1731.
4ꢀ(pꢀChlorophenyl)ꢀ1ꢀ(pꢀmethoxyphenyl)ꢀ3ꢀmethylazetidinꢀ2ꢀone (3Cd)
.
The title
product (3Cd) was purified by column chromatography (AcOEt:hexane = 2:8) and each
diastereomers were obtained in 65% (195.7 mg; syn form) and 4% yield (12.5 mg; anti
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form), respectively.
synꢀ3Cd; A colorless solid; M.p. 123.0–124.0 °C; 1H NMR (400 MHz, CDCl3) δ: 0.88 (3H,
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d,
J = 8.0 Hz), 3.68 (1H, qd, J = 8.0, 5.2 Hz), 3.75 (3H, s), 5.13 (1H, d, J = 5.2 Hz), 6.78–
6.82 (2H, m), 7.15–7.18 (2H, m), 7.21–7.25 (2H, m), 7.33–7.35 (2H, m); 13C NMR (100
MHz, CDCl3) δ: 9.807, 49.27, 55.41, 57.83, 114.3, 118.2, 128.2, 128.8, 131.0, 133,7, 133.9,
155.9, 167.3; MS m/z: 301 (M+); HRMS Calcd. for C17H16ClNO2: 301.087 (M+), Found:
301.086; IR (neat) cmꢀ1: 1735.
antiꢀ3Cd; A colorless oil; 1H NMR (400 MHz, CDCl3) δ: 1.47 (3H, d,
J = 7.2 Hz), 3.08 (1H,
qd,
J = 7.2, 2.0 Hz), 3.74 (3H, s), 4.52 (1H, d, J = 2.0 Hz), 6.77–6.81 (2H, m), 7.18–7.21
(2H, m), 7.26–7.29 (2H, m), 7.33–7.36 (2H, m); 13C NMR (100 MHz, CDCl3) δ: 13.10,
55.49, 55.53, 62.23, 114.5, 118.4, 127.4, 129.5, 131.4, 134.4, 136.8, 156.3, 167.7; MS m/z
:
301 (M+); HRMS Calcd. for C17H16ClNO2: 301.087 (M+), Found: 301.086; IR (neat) cmꢀ1:
1732.
1,4ꢀBis(pꢀmethoxyphenyl)ꢀ3ꢀmethylazetidinꢀ2ꢀone (3Ce). The title product (3Ce) was
purified by column chromatography (AcOEt:hexane = 2:8) and each diastereomers were
obtained in 77% (228.8 mg; syn form) and 4% yield (12.0 mg; anti form), respectively.
synꢀ3Ce; A colorless solid; M.p. 123.0–124.0 °C; 1H NMR (400 MHz, CDCl3) δ: 0.89 (3H,
d,
J = 7.6 Hz), 3.63 (1H, qd, J = 7.6, 5.2 Hz), 3.75 (3H, s), 3.80 (3H, s), 5.11 (1H, d, J = 5.2
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Hz), 6.77–6.81 (2H, m), 6.87–6.91 (2H, m), 7.13–7.16 (2H, m), 7.24–7.28 (2H, m); 13C
NMR (100 MHz, CDCl3) δ: 9.771, 49.26, 55.18, 55.36, 57.98, 1139, 114.1, 118.2, 126.7,
128.0, 131.2, 155.6, 159.2, 167.9; MS m/z: 297 (M+); HRMS Calcd. for C18H19NO3:
297.136 (M+), Found: 297.136; IR (KBr) cmꢀ1: 1730.
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antiꢀ3Ce; A colorless oil; 1H NMR (400 MHz, CDCl3) δ: 1.45 (3H, d,
J = 7.2 Hz), 3.09 (1H,
qd,
J = 7.2, 2.4 Hz), 3.73 (3H, s), 3.80 (3H, s), 4.49 (1H, d, J = 2.4 Hz), 6.75–6.79 (2H, m),
6.88–6.91 (2H, m), 7.21–7.29 (4H, m); 13C NMR (100 MHz, CDCl3) δ: 13.08, 55.39, 55.52,
62.61, 114.3, 114.7, 118.4, 127.4, 130.1, 131.7, 156.1, 159.9, 168.1; MS m/z: 297 (M+);
HRMS Calcd. for C18H19NO3: 297.136 (M+), Found: 297.137; IR (neat) cmꢀ1: 1738.
1ꢀ(pꢀMethoxyphenyl)ꢀ3ꢀmethylꢀ4ꢀpꢀtolylazetidinꢀ2ꢀone (3Cf). The title product (3Cf) was
purified by column chromatography (AcOEt:hexane = 2:8) and each diastereomers were
obtained in 83% (234.7 mg; syn form) and 3% yield (7.3 mg; anti form), respectively.
synꢀ3Cf; A colorless solid; M.p. 115.0–119.0 °C; 1H NMR (400 MHz, CDCl3) δ: 0.88 (3H, d,
J
= 7.6 Hz), 2.34 (3H, s), 3.64 (1H, qd, J = 7.6, 5.6 Hz), 3.75 (3H, s), 5.12 (1H, d, J = 5.6
Hz), 6.77–6.81 (2H, m), 7.10 (2H, d,
J = 7.6 Hz), 7.16 (2H, d, J = 7.6 Hz), 7.24–7.28 (2H,
m); 13C NMR (100 MHz, CDCl3) δ: 9.80, 21.19, 49.32, 55.53, 58.42, 114.5, 118.5, 127.14,
129.5, 131.6, 132.2, 138.0, 156.1, 168.2; MS m/z: 281 (M+); HRMS Calcd. for C18H19NO2:
281.142 (M+), Found: 281.142; IR (KBr) cmꢀ1: 1732.
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antiꢀ3Cf; A colorless oil; 1H NMR (400 MHz, CDCl3) δ: 1.46 (3H, d,
J = 7.2 Hz), 2.34 (3H,
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9
s), 3.09 (1H, qd,
J = 7.2, 2.4 Hz), 3.73 (3H, s), 4.50 (1H, d, J = 2.4 Hz), 6.75–6.19 (2H, m),
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7.18–7.26 (6H, m); 13C NMR (100 MHz, CDCl3) δ: 13.25, 21.34, 55.56, 55.66, 62.97, 114.6,
118.6, 126.2, 130.1, 131.9, 135.4, 138.6, 156.3, 168.3; MS m/z: 281 (M+); HRMS Calcd. for
C18H19NO2: 281.142 (M+), Found: 281.141; IR (neat) cmꢀ1: 1738.
4ꢀ(mꢀChlorophenyl)ꢀ1ꢀ(pꢀmethoxyphenyl)ꢀ3ꢀmethylazetidinꢀ2ꢀone (3Cg)
.
The title
product (3Cg) was purified by column chromatography (AcOEt:hexane = 2:8) and each
diastereomers were obtained in 78% (235.7 mg; syn form) and 6% yield (17.7 mg; anti
form), respectively.
synꢀ3Cg; A colorless solid; M.p. 123.0–124.0 °C; 1H NMR (400 MHz, CDCl3) δ: 0.90 (3H,
d,
J = 7.2 Hz), 3.68 (1H, qd, J = 7.2, 6.0 Hz), 3.76 (3H, s), 5.11 (1H, d, J = 6.0 Hz), 6.79–
6.83 (2H, m), 7.09–7.12 (1H, m), 7.22–7.32 (5H, m); 13C NMR (100 MHz, CDCl3) δ: 9.701,
49.20, 55.29, 57.69, 114.2, 118.0, 124.9, 126.8, 128.1, 129.8, 130.8, 134.6, 137.2, 155.7,
167.2; MS m/z: 251 (M+); HRMS Calcd. for C17H17NO: 251.131 (M+), Found: 251.132; IR
(KBr) cmꢀ1: 1736.
antiꢀ3Cg; A colorless oil; 1H NMR (400 MHz, CDCl3) δ: 1.48 (3H, d,
J = 7.2 Hz), 3.10 (1H,
qd,
J = 7.2, 2.0 Hz), 3.75 (3H, s), 4.51 (1H, d, J = 2.0 Hz), 6.78–6.82 (2H, m), 7.20–7.34
(6H, m); 13C NMR (100 MHz, CDCl3) δ: 13.12, 55.51, 55.54, 62.23, 114.6, 118.4, 124.1,
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for C17H17NO: 251.131 (M+), Found: 251.132; IR (neat) cmꢀ1: 1732.
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4ꢀ(oꢀChlorophenyl)ꢀ1ꢀ(pꢀmethoxyphenyl)ꢀ3ꢀmethylazetidinꢀ2ꢀone (3Ch)
.
The title
product (3Ch) was purified by column chromatography (AcOEt:hexane = 2:8) and only
the syn diastereomer was obtained in 93% yield (280.6 mg).
1
synꢀ3Ch; A colorless solid; H NMR (400 MHz, CDCl3) δ: 0.90 (3H, d,
J = 7.6 Hz), 3.68
(1H, qd,
J = 7.6, 5.6 Hz), 3.76 (3H, s), 5.12 (1H, d, J = 5.6 Hz), 6.79–6.83 (2H, m), 7.10–
7.13 (1H, m), 7.22–7.31 (5H, m); 13C NMR (100 MHz, CDCl3) δ: 9.84, 49.45, 55.53, 57.97,
114.6, 118.4, 125.3, 127.3, 128.6, 130.2, 131.3, 135.0, 137.7, 156.3, 167.7; MS m/z: 251
(M+); HRMS Calcd. for C17H17NO: 251.131 (M+), Found: 251.132; IR (neat) cmꢀ1: 1749.
1ꢀ(pꢀMethoxyphenyl)ꢀ3ꢀmethylꢀ4ꢀstyrylazetidinꢀ2ꢀone (3Ci). The title product (3Ci) was
purified by column chromatography (AcOEt:hexane = 2:8) and each diastereomers were
obtained in 38% (110.9 mg; syn form) and 23% yield (68.0 mg; anti form), respectively.
synꢀ3Ci; A yellow oil; 1H NMR (400 MHz, CDCl3) δ: 1.27 (3H, d,
J = 8.0 Hz), 3.54–3.61
(1H, m), 3.76 (3H, s), 4.70–4.73 (1H, m), 6.24 (1H, dd,
J = 16.0, 8.4 Hz), 6.75 (1H, d, J =
16 Hz), 6.81–6.85 (2H, m), 7.26–7.41 (7H, m); 13C NMR (100 MHz, CDCl3) δ: 9.878, 49.18,
55.60, 57.49, 114.6, 118.4, 125.0, 126.8, 128.5, 128.9, 132.2, 135.5, 136.2, 156.3, 168.0;
MS m/z: 293 (M+); HRMS Calcd. for C19H19NO2: 293.142 (M+), Found: 293.142; IR (neat)
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