Stereospecific preparation of γ-lactam derivatives via ring expansion of cis and trans β-lactam derivatives: α-Substituent effect of β-lactam derivatives

Full text of DOI:10.1002/bkcs.10697

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DOI: 10.1002/bkcs.10697
BULLETIN OF THE
M.-J. Lee and C. Ahn
KOREAN CHEMICAL SOCIETY
Stereospecific Preparation of γ-Lactam Derivatives via Ring Expansion
of cis and trans β-Lactam Derivatives: α-Substituent Effect
of β-Lactam Derivatives
*
Mi-Ji Lee and Chuljin Ahn
Department of Chemistry, Changwon National University, Changwon 641-773, Korea.
*E-mail: cjahn@cwnu.ac.kr
Received March 26, 2015, Accepted December 3, 2015, Published online March 18, 2016
Keywords: β-Lactam derivatives, Ring expansion, γ-Lactam derivatives
The stereochemistry in γ-lactam has been a great impor-
The configurations of trans β-lactam 7a and cis β-lactam
1
tance in medicinal and synthetic chemistry due to a wide
variety of biological activities.1–4 The various substituted
γ-lactam derivatives have been prepared stereospecifically
via ring expansion from their corresponding β-lactam
derivatives.5–13 However, few examples have been reported
about the effects of substituents on the α-position in
β-lactam derivatives via ring expansion to lead γ-lactam
derivatives stereospecifically. We herein have shown the
effects of substituents on the α-position and stereochemistry
in β-lactam derivatives 1a, 1b, 3a, and 3b via ring expan-
sion to lead γ-lactam derivatives 2, 4a, and 4b (Schemes 1
and 2). In the case of aryl substituents such as phenyl and
thiophenyl in β-lactam derivatives 1a, 1b, only one
γ-lactam derivative 2 was obtained (Scheme 1).
7b were determined by H NMR coupling constant, where
the coupling constant of cis β-lactam is larger than that of
trans β-lactam.14 The coupling constant of trans β-lactam
7a was 2.6 and the coupling constant of cis β-lactam 7b
was 5.4.
Furthermore, the trans isomer 7a reacted with LDA in
THF to obtain (3R,4R,5S)-3,4,5-triphenylpyrrolidin-2-one,
(8) in 50% yield. In the same manner, the cis isomer (7b)
provided the compound 8 in 35% yield. In the case of the
Ph substituent on α-carbon of β-lactam derivatives, a single
diastereomer 8 was obtained from trans β-lactam 7a and
cis β-lactam 7b (Scheme 3). The stereochemistry of anti,
anti-3,4,5-triphenyl-2-pyrolidine(8) was established by
NMR techniques, particularly by vicinal proton coupling
constant and NOE difference spectra.12a
Scheme 4 illustrates S-pyridin-2-yl 2-(thiophen-2-yl)etha-
nethioate (9) reacted with imine 6 by treatment with TiCl4
and triethyl amine to provide the mixtures of trans β-lactam
10a in 20% and cis β-lactam 10b in 17% yields.14 Isolated
(3S,4R)-1-benzyl-4-phenyl-3-(thiophen-2-yl)azetidin-2-one
(10a) was treated under basic condition, LDA in THF to
give (3S,4R,5S)-4,5-diphenyl-3-(thiophen-2-yl)pyrrolidin-2-
one (11) in 53% yield. In the same manner, (3S,4S)-1-ben-
zyl-4-phenyl-3-(thiophen-2-yl)azetidin-2-one (10b) yielded
On the other hand, the γ-lactam derivatives 4a, 4b were
obtained stereospecifically from the alkyl substituents such
as methyl, and ethyl in β-lactam derivatives 3a, 3b
(Scheme 2).
Two isomers of (3S,4R)-1-benzyl-3,4-diphenylazetidin-2-
one (7a) in 57% yield and the (3S,4S)-1-benzyl-3,4-diphe-
nylazetidin-2-one (7b) in 21% yield were prepared by
treatment of S-pyridin-2-yl 2-phenylethanethioate (5) and
(E)-N-benzylidene-1-phenylmethanamine (6) with TiCl4 in
triethyl amine at room temperature.
Each isomer of trans β-lactam 7a and cis β-lactam 7b
was separated by column chromatography, respectively.
R
Ph
Ph
R
O
Ph
LDA
LDA
Ph
R
O
LDA
LDA
N
O
N
H
Ph
N
Ph
3a
R
Ph
Ph
4a
1a
O
N
H
R
Ph
Ph
R
O
Ph
R
O
Ph
Ph
2
N
O
N
N
H
Ph
3b
1b
4b
R=Ph, Thiophenyl
Scheme 1. The formation of γ-lactam derivatives 2
R=Me, Et
Scheme 2. The formation of γ-lactam derivatives 4a, 4b
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KOREAN CHEMICAL SOCIETY
Ph
Ph
Ph
O
Ph
Ph
LDA
LDA
O
N
Ph
O
N
H
8
Ph
N
S
7a
(57%)
5
(50%)
TiCl4
Et3N
+
+
Ph
O
Ph
Ph
Ph
N
8
N
Ph
(35%)
7b
6
(21%)
Scheme 3. The formation of γ-lactam 8
Ph
S
Ph
S
LDA
O
Ph
Ph
N
O
N
H
11
O
10a
(20%)
N
S
S
9
TiCl4
Et3N
(53%)
+
+
Ph
N
Ph
Ph
S
Ph
11
LDA
6
(45%)
N
O
10b
(17%)
Scheme 4. The formation of γ-lactam 11
45% of the anti, anti γ-lactam 11. Surprisingly, in the case
of thiophenyl substituent, only a single stereoisomer, anti,
anti γ-lactam diastereomer 11 was observed. The structure
of anti, anti-4,5-diphenyl-3-(thiophen-2-yl)pyrrolidin-2-one
(11) was expected by vicinal proton coupling which was
compared with compound 8. In compound 8, the coupling
constant (J) of anti, anti vicinal protons (C2 C3, C3 C4)
has large values, which are 8.4 and 11.6 Hz. The vicinal
proton coupling constants of C2 C3 and C3 C4 in
(3S,4R,5S)-4,5-diphenyl-3-(thiophen-2-yl)pyrrolidin-2-one
(11) are 12.8 and 14.8 Hz which are large values. From
these results, we expected the structure of γ-lactam 11
should have anti, anti relationship with one another.12a
Scheme 5 illustrates S-pyridin-2-yl propanethioate (12)
reacted with (E)-N-benzylidene-1-phenylmethanamine (6)
by treatment with TiCl4 in triethyl amine to provide the
mixtures of trans β-lactam 15a in 50% and cis β-lactam
15b in 15% yield.14 Under the LDA in THF condition,
trans β-lactam 15a leads to anti, anti γ-lactam 16a in 60%
yield, and cis β-lactam 15b leads to syn, anti γ-lactam 16b
in 52% yield. Unlike phenyl or thiophenyl substituents,
methyl substituent on the α-carbon in the trans β-lactam
15a generated the anti, anti γ-lactam 16a, and cis β-lactam
15b, which gave the syn, anti γ-lactam 16b. The structure
of anti, anti and syn, anti relationships in γ-lactams (16a,
J = 10.5, 8.4 Hz and 16b, J = 9.0, 6.0 Hz) was established
based on a relative vicinal coupling constant determining
stereochemistry of γ-lactam 8.12a
Scheme 6 illustrates S-pyridin-2-yl propanethioate (17)
reacted with (E)-N-benzylidene-1-phenylmethanamine (6)
by treatment with TiCl4 in triethyl amine to provide the
mixtures of trans β-lactam 18a in 52% and cis β-lactam
18b in 21% yield.14 Under the LDA in THF condition,
trans β-lactam 18a leads to anti, anti γ-lactam 19a in 74%
yield, and cis β-lactam 18b leads to syn, anti γ-lactam 19b
in 42% yield. Unlike phenyl or thiophenyl substituent, the
ethyl substituent on the α-carbon in trans β-lactam 18a gen-
erated the anti, anti γ-lactam 19a, and cis β-lactam 18b
gave the syn, anti γ-lactam 19b. The structures of anti, anti
and syn, anti relationships in γ-lactams (19a, J = 9.0,
4.2 Hz and 19b, J = 3.0, 3.0 Hz) were established based
on a relative vicinal coupling constant determining stereo-
chemistry of γ-lactam 8.12a
Further studies are underway to prove the mechanism in
forming the γ-lactam derivatives stereospecifically from cis
and trans β-lactam derivatives via ring expansion.
Experimental
General. Nuclear magnetic resonance (1H and 13C NMR)
spectra were recorded on a Brucker Avance 400 spectrome-
ter. Chemical shifts are reported in parts per million (δ)
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Me
Ph
Me
O
Ph
Ph
LDA
O
N
Ph
N
O
Me
N
S
H
15a
(50%)
16a
12
(60%)
TiCl4
Et3N
+
+
Ph
Me
O
Ph
Ph
Me
Ph
Ph
N
LDA
Ph
N
6
O
N
H
15b
(15%)
16b
(52%)
Scheme 5. The formation of γ-lactam 16a, 16b
Et
Ph
Ph
Et
Ph
Ph
LDA
O
N
O
N
H
19a
Et
O
S
N
18a
(52%)
17
(74%)
TiCl4
Et3N
+
+
Ph
Et
O
Ph
Ph
Et
Ph
Ph
N
LDA
Ph
N
6
O
N
H
19b
18b
(21%)
(42%)
Scheme 6. The formation of γ-lactam 19a, 19b
downfield from tetramethylsilane. Coupling constant
(J values) are given in hertz (Hz).
(3S,4R,5S)-4,5-Diphenyl-3-(thiophen-2-yl)pyrrolidin-
2-one (11): IR (ATR) : 3235 (w), 2900 (w), 1662 (s); H
1
Infrared spectra were recorded on a Jasco FT/IR-6300
spectrometer. Band positions are given in reciprocal centi-
meters (cm−1) and relative intensities are listed as br
(broad), s (strong), m (medium), or w (weak).
NMR (CDCl3) : 1.25 (bs,1H), 3.35 (d, J = 14.8 Hz, 1H),
3.69 (dd, J = 12.8, 14.8 Hz, 1H), 4.45 (d, J = 12.8 Hz,
1H), 5.94–6.92 (m, 3H), 7.26–7.44 (m, 10H); 13C NMR
(CDCl3) : 32.26, 47.45, 57.15, 121.16, 127.44, 128.12,
128.43, 128.57, 128.69, 128.90, 129.35, 137.18, 137.44,
138.64, 140.62, 175.01.
(3S,4R,5S)-3-Methyl-4,5-diphenyl-2-pyrrolidinone (16a):
IR (KBr): 3045 (w), 2915 (w), 2800 (m), 1702 (s), 1586 (w),
1486 (w), 1430 (m); 1H NMR (CDCl3): δ 1.20 (d,
J = 5.1 Hz, 3H), 2.81 (m, 1H), 2.8 (dd, 1H, J = 8.4,
10.5 Hz), 4.6 (d, 1H, J = 8.4 Hz), 5.9 (s, 1H), 7.08–7.33 (m,
10H); 13C NMR: 13.9, 44.4, 60.8, 63.8, 126.1, 127.4, 128.0,
128.1, 128.7, 128.8, 138.3, 140.0, 178.4.
(3R,4R,5S)-3-Methyl-4,5-diphenyl-2-pyrrolidinone (16b):
IR (KBr): 3055 (w), 2915 (w), 2800 (m), 1702 (s), 1586 (w),
1486 (w), 1430 (m); 1H NMR (CDCl3): δ 0.86 (d,
J = 7.5 Hz, 3H), 2.88 (m, 1H), 3.51 (dd, J = 4.2, 9.0 Hz,
1H), 4.95 (d, J = 4.2 Hz, 1H), 6.26 (s, 1H), 7.12–7.37 (m,
10H); 13C NMR (CDCl3): 11.7, 39.7, 54.7, 61.7, 125.6,
127.2, 127.9, 128.2, 128.6, 128.8, 139.0, 141.4, 180.1.
(3S,4R,5S)-3-Ethyl-4,5-diphenyl-2-pyrrolidinone (19a):
IR (KBr): 3177 (w), 3091 (w), 2913 (w), 2864 (w), 1713 (s),
General Procedure for Preparation of γ-Lactam Deriva-
tives. LDA (1.5 M in cyclohexane, 1.5 equiv) was added
at room temperature to a solution containing β-lactam deri-
vatives 7a, 7b, 10a, 10b, 15a, 15b, 18a, 18b (1 equiv) in
THF. The reaction mixture was stirred at room temperature
for 1 h and then quenched with saturated aq. NH4Cl. The
reaction mixture was extracted with EtOAc after evaporat-
ing THF in the rotavapor. The organic layer was dried
(Na2SO4), and concentrated in vacuo to give crude solid.
Purification by flash chromatography (80% EtOAc/hexane)
for γ-lactam derivatives 8, 11, 16a, 16b, 19a, 19b.
(3R,4R,5S)-3,4,5-Triphenyl-2-pyrrolidinone (8): IR
(KBr): 3170 (m), 3080 (m), 3027 (w), 2915 (m), 2380 (m),
1702 (s), 1432 (w); 1H NMR (CDCl3): δ 3.37 (dd,
J = 8.5 Hz, 14.6, 1H), 4.04 (d, J = 14.6 Hz, 1H), 4.75 (d,
J = 8.5 Hz, 1H), 6.16–7.38 (m, 15H); 13C NMR (CDCl3):
56.0, 61.4, 63.6, 111.7, 129.1, 127.3, 127.5, 128.0, 128.3,
128.5, 128.7, 128.8, 137.0, 137.6, 139.6, 176.1.
Bull. Korean Chem. Soc. 2016, Vol. 37, 580–583
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1594 (m); H NMR (CDCl3): δ 0.86 (t, J = 9.0 Hz, 3H),
1.63–1.77 (m, 2H), 2.75 (m, 1H), 3.0 (dd, J = 6.0, 9.0 Hz,
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1
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1H), 4.85 (d, J = 3.0 Hz, 1H), 6.17 (s, 1H), 7.10–7.39 (m,
10H); 13C NMR (CDCl3): 12.1, 19.4, 45.8, 54.1, 62.3, 125.5,
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Acknowledgments. This work is financially supported by
Changwon National University in 2015–2017.
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Bull. Korean Chem. Soc. 2016, Vol. 37, 580–583
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