Divergent Synthesis of α,γ-Disubstituted γ-Butyrolactones through Diastereoselective Bromolactonization with Alkali Metal Bromide: Asymmetric Total Synthesis of (+)-Dubiusamine C

Article abstract of DOI:10.1021/acs.joc.5b01497

A divergent synthesis of α-substituted bromomethyl γ-lactones was developed, which involves the diastereoselective bromolactonization of α-substituted 4-pentenoic acids and 4-pentenamides via umpolung of bromide by use of alkali metal bromide and Oxone (p

Full text of DOI:10.1021/acs.joc.5b01497

Article
pubs.acs.org/joc
Divergent Synthesis of α,γ-Disubstituted γ‑Butyrolactones through
Diastereoselective Bromolactonization with Alkali Metal Bromide:
Asymmetric Total Synthesis of (+)-Dubiusamine C
Katsuhiko Moriyama,* Toru Sugiue, Chihiro Nishinohara, and Hideo Togo*
Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
S
* Supporting Information
ABSTRACT: A divergent synthesis of α-substituted bromomethyl γ-lactones was developed, which involves the
diastereoselective bromolactonization of α-substituted 4-pentenoic acids and 4-pentenamides via umpolung of bromide by
use of alkali metal bromide and Oxone (potassium peroxymonosulfate mixture, 2KHSO5·KHSO4·K2SO4) to obtain mainly cis-
products from α-substituted 4-pentenoic acids and trans-products from α-substituted 4-pentenamides, and it was found that the
bromonium species generated from KBr and Oxone had higher activity than N-bromosuccinimide. Furthermore, the asymmetric
total synthesis of (+)-dubiusamine C, which was isolated as a minor diastereomer from Pandanus dubius, was accomplished for
the first time through the cis-selective bromolactonization of (S)-α-methyl-4-pentenoic acid in nine linear steps and 36% overall
yield.
on earth, are stable in air, easy to handle, neutral, and nontoxic.
Meanwhile, the oxidation of bromide (Br−) into bromonium
ion (Br+) is a very important tool for the biosynthesis of
halogenated natural products.9 In particular, the bromonium
ion species generated from bromide with Oxone (potassium
peroxymonosulfate mixture, 2KHSO5·KHSO4·K2SO4) is antici-
pated to exhibit higher electrophilicity than organic bromo
reagents due to the stability of the counteranion. We report
here the divergent synthesis of α-substituted bromolactones
through diastereoselective bromolactonization that uses the
highly electrophilic bromonium ion species generated from
oxidation of alkali metal bromide upon treatment with Oxone
(Figure 1) and the asymmetric total synthesis of (+)-dubius-
amine C.
INTRODUCTION
■
α,γ-Disubstituted γ-butyrolactones are very important building
blocks of natural products and biologically active products,1 and
the halolactonization of alkenyl carboxylic acid derivatives is a
powerful tool for construction of the substituted lactone
framework.2 However, the use of an organic bromo reagent,
such as N-bromosuccinimide (NBS), for the bromolactoniza-
tion results in low reactivity. To overcome this drawback,
organocatalysts that increase the electrophilicity of bromonium
ion3 and chiral catalysts4 have been developed for this reaction.
On the other hand, little work has been done on the
diastereoselective halolactonization of α-substituted alkenyl
carbonyl compounds. In 1984, Yoshida and co-workers5
reported the 1,3-trans-selective halolactonization of α-alkyl-
N,N-dimethyl-4-pentenamide with N-halosuccinimide (NXS)
as the halogen reagent. Since then, the 1,3-trans-selective
halolactonization of chiral α-alkyl-1-oxo-4-pentenyl carbonyl
compounds bearing a chiral 2-oxazolidinone framework,
derived from the method of Evans et al.,6 has been extensively
utilized for the asymmetric synthesis of biological products.7
We have developed various oxidative transformations via
umpolung of bromide from alkali metal bromide instead of
organic bromo reagents,8 and our approach has shown that
alkali metal halides, one of the most abundant natural resources
RESULTS AND DISCUSSION
■
First, we screened for solvent and temperature for the
diastereoselective bromolactonization of α-methyl-4-pentenoic
acid (1a) and N,N-dimethyl-α-methyl-4-pentenamide (2a) by
use of the KBr/Oxone system (Table 1).
Received: July 1, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01497
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To evaluate the activity of the KBr/Oxone system in
bromolactonization, we investigated the bromolactonization of
2a with NBS under previously published conditions,5 and we
found that 3 days of reaction was required to obtain desired
product 3a in 53% yield (cis/trans = 10/90), together with
recovered 2a in 20% yield.10 The high performance of the KBr/
Oxone system is due to the high electrophilicity of the
bromonium ion species, a conjugate acid of hypobromate
(H2OBr+) formed by the protonation11 of hypobromate
(HOBr) that is generated via the oxidation of KBr with
Oxone to stabilize H2O as a weak conjugate base (H3O+; pKa =
−1.7 vs succinimide; pKa = 9.612 in H2O) (Figure 2).
Figure 1. Divergent synthesis involving diastereoselective bromolacto-
nization with alkali metal bromide.
Table 1. Screening for Diastereoselective
Bromolactonization of 1a and 2a by Use of Alkali Metal
Bromide
a
b
temp
(°C)
time
(h)
yield
dr (cis/
Figure 2. Effect of electrophilicity on bromonium ion species by
conjugate base.
entry substrate
solvent
MeNO2
(%)
trans)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
2a
2a
2a
rt
rt
18
12
12
12
12
12
12
5
99
99
99
98
99
93
88
86
78
92
67/33
72/28
72/28
77/23
71/29
73/27
75/25
12/88
11/89
15/85
AcOEt
MeNO2
AcOEt
dioxane
MeCN
acetone
MeCN
CH2Cl2
Then, to investigate the effect of substituent on the amide
groups, various amides (4a−6a) were used as substrates under
optimum conditions for trans-selective bromolactonization.
However, those reactions were much less reactive and
diastereoselective than the reaction of 2a (Scheme 1). From
−10
−10
−10
−10
−10
rt
c
c
Scheme 1. Effect of Substituent on Amide Group for trans-
Selective Bromolactonization
rt
5
c
c
c
c
c
10
11
12
13
14
CH2Cl2/H2O
(9/1)
rt
5
2a
2a
2a
2a
CH2Cl2/H2O
(20/1)
rt
rt
rt
5
5
5
5
91
87
84
72
10/90
12/88
15/85
17/83
MeCN/H2O
(20/1)
dioxane/H2O
(20/1)
AcOEt/H2O
(20/1)
rt
a
b
Number indicates an isolated yield. Diastereomeric ratio of 3a was
c
1
determined by H NMR analysis. KBr (1.2 equiv) was used.
Treatment of 1a with KBr (1.5 equiv) and Oxone (1.2 equiv)
in MeNO2 at room temperature provided α-methyl-γ-
butyrolactone (3a) in 99% yield with cis-selectivity (cis/trans
= 67/33) (entry 1). The use of AcOEt as solvent gave
improved cis-selectivity compared to the reaction run in
MeNO2, and decreasing the reaction temperature further
increased the cis-selectivity for the bromolactonization of 1a
(entries 1−4). Other solvents, such as 1,4-dioxane, MeCN, and
acetone, were much less effective than AcOEt in the present
reaction (entries 5−7). When 2a was used as the substrate with
KBr/Oxone in MeCN at room temperature, the desired
product trans-3a was obtained in 86% yield as the major isomer
(cis/trans = 12/88) (entry 8). The addition of H2O improved
the yield of 3a, whereas CH2Cl2 alone was not suitable for
transformation of 2a into trans-3a (entries 9 and 10).
Decreasing the amount of H2O in CH2Cl2 as the solvent
mixture slightly increased the diastereoselectivity of trans-3a in
the present reaction (entry 11). The use of MeCN, 1,4-dioxane,
and AcOEt gave similar reactivities and trans-selectivities to the
use of CH2Cl2 (entries 12−14).
a
1
Diastereomeric ratio of 3a was determined by H NMR analysis.
these results, the presence of water and the N-substituent on
the amide group have an important role for bromolactonization
of 4-pentenamide (2). Therefore, we suggest that this reaction
depends largely on the reactivity of hydrolysis of iminium
cation intermediate formed by bromocyclization.
To explore the substrate scope for divergent synthesis of α-
substituted bromolactones through diastereoselective bromo-
lactonization by use of the KBr/Oxone system, various α-
substituted 4-pentenoic acids (1) and 4-pentenamides (2) were
examined under optimum conditions (Scheme 2).
For the bromolactonization of 1 (condition A), substrates
bearing i-Pr (1b), n-octyl (1c), cyclopentyl (1d), cyclohexyl
(1e), cyclooctyl (1f), benzyl (1g), 4-bromobenzyl (1h), and
phenethyl (1i) groups at the α-position gave desired products
(3b−3i) in high yields (92−99%) with cis-selectivity (cis/trans
= 72/28 to 85/15). The use of 4-pentenoic acids bearing
functional groups such as propargyl (1j), sulfonamide (1k), and
B
DOI: 10.1021/acs.joc.5b01497
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The Journal of Organic Chemistry
Article
bromolactonization via the KBr/Oxone system, α-methyl-δ-
bromomethyl-δ-valerolactone (9a) was obtained as mainly a
trans-isomer in each case (Table 2).
Scheme 2. Divergent Synthesis of α-Substituted
Bromolactones via Diastereoselective Bromolactonization in
a KBr/Oxone System
Table 2. Synthesis of α-Substituted Bromomethyl-δ-
valerolactone by Diastereoselective Bromolactonization via
the KBr/Oxone System
a
dr
KBr
yield of
9a (%)
(cis/
trans)
substrate (equiv)
conditions
7a
1.5
TsOH (20 mol %),
86
30/70
MeNO2/ toluene (3/1), 0 °C,
8 h
8a
1.2
CH2Cl2/H2O (20/1), −10 °C, 5 h
82
35/65
a
1
Diastereomeric ratio of 9a was determined by H NMR analysis.
Regarding the diastereoselectivity of the bromolactonization,
Kurth and co-workers13 reported the calculation of some
transition states for electrophilic cyclization. On the basis of
their results, the difference in diastereoselectivity for
bromolactonization is suggested through the plausible tran-
sition states shown in Figure 3. In the trans-selective reaction of
Figure 3. Plausible transition states for diastereoselective bromolacto-
nization.
a
Diastereomeric ratio of 3 was determined by 1H NMR analysis.
bTsOH·H2O (10 mol %) was added. The reaction was carried out in
MeCN/H2O (20/1). TsOH·H2O (1.2 equiv) was added.
c
amides (2), the substituent at α-position takes the axial form
due to the steric hindrance of the dimethylamino moiety, and
therefore axial olefin (B) prevails over equatorial olefin (A) to
avoid interaction between the substituents. By contrast, the cis-
selective reaction of carboxylic acid (1) favors diequatorial form
(C) over diaxial form (D), where there is not so much energy
difference between the two transition states (C is more stable
by 0.307 kcal/mol than D, when R′ = Me13) to induce lower
selectivity than the trans-selective reaction.
To demonstrate the present reaction, we attempted to
perform the asymmetric total synthesis of (+)-dubiusamine C
(Scheme 3). Dubiusamine C was isolated as a minor
diastereomer of dubiusamine A (diastereomeric ratio dr = 4/
1) from the crude base of Pandanus dubius, and its racemic total
synthesis was reported by Takayama and co-workers.14
d
silyl ether (1l), alkenoic acids with disubstituted olefin (1m and
1n), and 4-pentenoic acids with an acidic proton at α-position
(1o and 1p) gave also corresponding cis-products (3j−3p) in
high yields (87% to >99%). On the other hand, the
bromolactonization of 2 proceeded with high diastereoselec-
tivity (cis/trans = 29/71 to 6/94) to obtain the trans-products
(3) in high yields (81−97%) in many cases. Two notable
exceptions are the lowered diastereoselectivity found with 3m
and 3p (cis/trans = 44/56).
When α-methyl-5-hexenoic acid (7a) and N,N-dimethyl-5-
hexenamide (8a) were used for the six-membered ring in
C
DOI: 10.1021/acs.joc.5b01497
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The Journal of Organic Chemistry
Article
methyl-4-pentenoic acid in nine linear steps and 36% overall
yield.:
Scheme 3. Asymmetric Total Synthesis of (+)-Dubiusamine
C
EXPERIMENTAL SECTION
General Procedure. H NMR spectra were measured on a 400
■
1
MHz spectrometer. Chemical shifts are reported as follows: chemical
shift in parts per million (ppm) from internal tetramethylsilane on the
δ scale, multiplicity (s = singlet; d = doublet; t = triplet; q = quartet; m
= multiplet; br = broad), coupling constant (hertz), integration, and
assignment. 13C NMR spectra were measured on a 100 MHz
spectrometer. Chemical shifts were recorded in ppm from the solvent
resonance employed as the internal standard (deuterochloroform at
77.0 ppm). High-resolution mass spectra (HRMS) were performed by
Orbitrap mass spectrometers. Characteristic peaks in the Infrared (IR)
spectra are recorded in wavenumbers (cm−1) by use of attenuated total
reflectance (ATR). Melting points are reported as uncorrected. Thin-
layer chromatography (TLC) was performed on 0.25 mm silica gel
plates (60F-254). The products were purified by column chromatog-
raphy on silica gel 60 (63−200 mesh). Visualization was accomplished
by UV light (254 nm), anisaldehyde, KMnO4, and phosphomolybdic
acid.
Condition A for Bromolactonization of α-Substituted
Alkenylcarboxylic Acids by Use of a KBr/Oxone System
(Table 1, entry 4, and Scheme 2). To a solution of 1a (28.5 mg,
0.25 mmol) and KBr (44.6 mg, 0.375 mmol) in AcOEt (1.0 mL) was
added Oxone (184.4 mg, 0.30 mmol) at −10 °C. After the mixture was
stirred at −10 °C for 12 h, saturated Na2SO3 aqueous solution (10
mL) was added and the product was extracted with AcOEt (10 mL ×
3). The combined extracts were washed with brine (10 mL) and dried
over Na2SO4. The organic phase was concentrated under reduced
pressure and the crude product was purified by silica gel column
chromatography (eluent hexane/AcOEt = 3/1) to give desired
product 3a (47.3 mg, 98% yield, cis/trans = 77/23).
Condition B for Bromolactonization of α-Substituted
Alkenylamides by Use of a KBr/Oxone System (Table 1,
entry 11, and Scheme 2). To a solution of 2a (35.3 mg, 0.25 mmol)
and KBr (35.7 mg, 0.30 mmol) in a mixture of CH2Cl2 (1.0 mL) and
H2O (50.0 μL) was added Oxone (184.4 mg, 0.30 mmol) at room
temperature. After the mixture was stirred at room temperature for 5
h, saturated NaHCO3 aqueous solution (5 mL) was added, and the
reaction mixture was stirred for 2 h. The product was extracted with
AcOEt (10 mL × 3), and then the combined extracts were washed
with brine (10 mL) and dried over Na2SO4. The organic phase was
concentrated under reduced pressure and the crude product was
purified by silica gel column chromatography (eluent hexane/AcOEt =
3/1) to give desired product 3a (44.1 mg, 91% yield, cis/trans = 10/
90).
5-(Bromomethyl)-3-methyldihydrofuran-2(3H)-one (3a). Cis iso-
mer: colorless oil; 1H NMR (400 MHz, CDCl3) δ 1.31 (d, J = 7.1 Hz,
3H), 1.65−1.78 (m, 1H), 2.64 (ddd, J = 12.8, 9.1, 6.1 Hz, 1H), 2.69−
2.83 (m, 1H), 3.51 (dd, J = 11.0, 6.3 Hz, 1H), 3.59 (dd, J = 11.0, 4.8
Hz, 1H), 4.52−4.63 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 15.0,
33.3, 35.5, 35.6, 75.9, 178.4. IR (neat) 2973, 1766, 1454, 1344, 1154,
1014 cm−1; [α]D23 = −16.3 (c 1.5, CHCl3, (S)); MS (atmospheric
pressure chemical ionization, APCI) calcd for C6H10BrO2 [M + H]+
192.9859, found 192.9861.
However, its asymmetric total synthesis has never been
accomplished. Asymmetric alkylation, according to Evans et
al.,6 of 10 with sodium bis(trimethylsilyl)amide (NaHMDS)
and MeI in THF at −78 °C afforded alkylated product 11 in
97% yield (dr = 93/7), and (S)-1a was obtained by cleavage of
the chiral auxiliary from 11 with LiOH and aqueous H2O2.15 As
the key step, cis-selective bromolactonization of (S)-1a by use
of the KBr/Oxone system provided mainly chiral cis-
bromolactone (S)-3a in 98% yield with 77/23 diastereomeric
ratio, which could be separated by column chromatography.
Alkyl−allyl coupling reaction16 of (S)-3a with allyltributyltin in
the presence of V-40 [1,1′-azobis(cyclohexane-1-carbonitrile)]
as the radical initiator provided allylated compound 12 in 81%
yield. This was followed by hydroboration with BH3·THF
complex and oxidation with NaBO3·4H2O17 to obtain alcohol
13 in 89% yield in two steps. After the Mitsunobu reaction18 of
13 with NsNH2, PPh3, and diethyl azodicarboxylate (DEAD) in
a mixture of THF and toluene (7/3) at room temperature,
resultant amide 14 was subjected to the second Mitsunobu
reaction with 13, PPh3, and DEAD in toluene at 60 °C to give
symmetrical amide 15 in 85% yield. Cleavage of the nosyl
group18 with PhSH and K2CO3 in a mixture of DMF and
MeCN (4/3) provided (+)-dubiusamine C in 95% yield.
Spectral data of the synthesized product were in good
agreement with those reported previously,14 and the optical
rotation was [α]1D8 +28.8 (c 1.07, CHCl3).
Trans isomer: colorless oil; 1H NMR (400 MHz, CDCl3) δ 1.31 (d,
J = 7.6 Hz, 3H), 2.10 (dt, J = 13.8, 8.5 Hz, 1H), 2.41 (ddd, J = 13.8,
9.7, 4.0 Hz, 1H), 2.77−2.90 (m, 1H), 3.50 (dd, J = 11.0, 6.2 Hz, 1H),
3.55 (dd, J = 11.0, 4.5 Hz, 1H), 4.71−4.80 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 16.1, 33.8 (2C), 33.9, 75.7, 179.1; IR (neat) 2973,
1766, 1455, 1343, 1158, 1012 cm−1; MS (APCI) calcd for C6H10BrO2
[M + H]+ 192.9859, found 192.9868.
In conclusion, we developed a divergent synthesis of α-
substituted bromolactones through the diastereoselective
bromolactonization of α-substituted 4-pentenoic acids and 4-
pentenamides via oxidative umpolung of bromide ion by use of
alkali metal bromide with Oxone. Furthermore, the asymmetric
total synthesis of (+)-dubiusamine C was accomplished for the
first time through cis-selective bromolactonization of (S)-α-
5-(Bromomethyl)-3-isopropyldihydrofuran-2(3H)-one (3b). Con-
dition A, 54.2 mg, 98%; condition B, 48.0 mg, 87%.
Cis isomer: colorless oil; 1H NMR (400 MHz, CDCl3) δ 0.95 (d, J
= 7.1 Hz, 3H), 1.06 (d, J = 7.1 Hz, 3H), 1.72−1.91 (m, 1H), 2.16−
2.30 (m, 1H), 2.39 (ddd, J = 13.0, 9.3, 6.2 Hz, 1H), 2.65 (ddd, J =
12.4, 9.3, 5.2 Hz, 1H), 3.49 (dd, J = 10.9, 6.6 Hz, 1H), 3.60 (dd, J =
10.9, 4.8 Hz, 1H), 4.50−4.58 (m, 1H); 13C NMR (100 MHz, CDCl3)
D
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Article
δ 18.2, 20.5, 27.6, 29.1, 33.4, 46.8, 75.7, 176.9; IR (neat) 2961, 1766,
1467, 1335, 1152, 1011 cm−1; MS (APCI) calcd for C8H14BrO2 [M +
H]+ 221.0172, found 221.0167.
3.50 (dd, J = 11.0, 6.4 Hz, 1H), 3.60 (dd, J = 11.0, 4.7 Hz, 1H), 4.47−
4.57 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 25.1, 25.8, 26.4 (2C),
26.7, 29.46, 29.51, 32.5, 33.4, 36.4, 48.2, 75.8, 177.1; IR (neat) 2917,
1770, 1446, 1337, 1160, 1022 cm−1; MS (APCI) calcd for C13H22BrO2
[M + H]+ 289.0798, found 289.0791.
Trans isomer: colorless oil; 1H NMR (400 MHz, CDCl3) δ 0.96 (d,
J = 6.9 Hz, 3H), 1.04 (d, J = 6.9 Hz, 3H), 2.13−2.30 (m, 3H), 2.70
(ddd, J = 10.3, 7.8, 5.1 Hz, 1H), 3.49 (dd, J = 11.0, 6.3 Hz, 1H), 3.54
(dd, J = 11.0, 4.3 Hz, 1H), 4.64−4.73 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 18.3, 20.3, 27.9, 28.9, 34.5, 45.2, 76.1, 177.7; IR (neat) 2962,
1766, 1469, 1334, 1155, 1010 cm−1; MS (APCI) calcd for C8H14BrO2
[M + H]+ 221.0172, found 221.0167.
1
Trans isomer: colorless oil; H NMR (400 MHz, CDCl3) δ 1.32−
1.80 (m, 14H), 2.10−2.30 (m, 3H), 2.76 (ddd, J = 10.3, 8.7, 4.6 Hz,
1H), 3.49 (dd, J = 10.9, 6.0 Hz, 1H), 3.52 (dd, J = 10.9, 4.4 Hz, 1H),
4.65−4.74 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 25.2, 25.9, 26.39
(2C), 26.43, 28.1, 29.4, 32.3, 34.6, 37.7, 46.4, 76.0, 178.0; IR (neat)
2918, 1768, 1446, 1340, 1155, 1022 cm−1; MS (APCI) calcd for
C13H22BrO2 [M + H]+ 289.0798, found 289.0789.
5-(Bromomethyl)-3-octyldihydrofuran-2(3H)-one (3c). Condition
A, 72.4 mg, 99%; condition B, 65.5 mg, 90%.
Cis isomer: white solid, mp 37.0−37.5 °C; H NMR (400 MHz,
1
3-Benzyl-5-(bromomethyl)dihydrofuran-2(3H)-one (3g). Condi-
tion A, 65.0 mg, 97%; condition B, 61.4 mg, 91%.
CDCl3) δ 0.88 (t, J = 6.8 Hz, 3H), 1.16−1.53 (m, 13H), 1.65−1.78(m,
1H), 1.86−1.98 (m, 1H), 2.53−2.72 (m, 2H), 3.49 (dd, J = 10.8, 6.6
Hz, 1H), 3.59 (dd, J = 10.8, 4.7 Hz, 1H), 4.51−4.62 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 14.1, 22.6, 27.3, 29.2, 29.29, 29.34, 30.3,
31.8, 33.4, 33.6, 40.7, 76.1, 177.9; IR (neat) 2917, 1756, 1465, 1365,
1164, 1013 cm−1; MS (APCI) calcd for C13H24BrO2 [M + H]+
291.0954, found 291.0948.
Cis isomer: colorless oil; 1H NMR (400 MHz, CDCl3) δ 1.78 (ddd,
J = 13.0, 11.4, 9.6 Hz, 1H), 2.42 (ddd, J = 13.0, 9.2, 6.4 Hz, 1H), 2.80
(dd, J = 14.0, 9.2 Hz, 1H), 2.99 (dtd, J = 11.4, 9.2, 4.4 Hz, 1H), 3.28
(dd, J = 14.0, 4.4 Hz, 1H), 3.34 (dd, J = 11.0, 6.5 Hz, 1H), 3.48 (dd, J
= 11.0, 4.7 Hz, 1H), 4.49−4.58 (m, 1H), 7.17−7.22 (m, 2H), 7.22−
7.28 (m, 1H), 7.28−7.36 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
32.9, 33.1, 36.1, 42.5, 76.2, 126.8, 128.75 (2C), 128.83 (2C), 138.1,
177.0; IR (neat) 2925, 1769, 1453, 1336, 1159, 1013 cm−1; MS
(APCI) calcd for C12H14BrO2 [M + H]+ 269.0172, found 269.0166.
Trans isomer: colorless oil; 1H NMR (400 MHz, CDCl3) δ 0.88 (t,
J = 7.0 Hz, 3H), 1.17−1.54 (m, 13H), 1.78−1.92 (m, 1H), 2.13 (dt, J
= 13.5, 8.2 Hz, 1H), 2.33 (ddd, J = 13.5, 9.7, 4.6 Hz, 1H), 2.66−2.80
(m, 1H), 3.49 (dd, J = 11.0, 6.4 Hz, 1H), 3.54 (dd, J = 11.0, 4.4 Hz,
1H), 4.68−4.77 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 14.0, 22.6,
27.1, 29.1, 29.2, 29.3, 31.1, 31.8, 31.9, 34.1, 39.0, 76.0, 178.5; IR (neat)
2923, 1769, 1468, 1338, 1151, 1018 cm−1; MS (APCI) calcd for
C13H24BrO2 [M + H]+ 291.0954, found 291.0945.
1
Trans isomer: colorless oil; H NMR (400 MHz, CDCl3) δ 2.13−
2.26 (m, 2H), 2.83 (dd, J = 14.0, 9.1 Hz, 1H), 3.03−3.14 (m, 1H),
3.19 (dd, J = 14.0, 4.6 Hz, 1H), 3.44 (dd, J = 11.0, 6.0 Hz, 1H), 3.47
(dd, J = 11.0, 4.6 Hz, 1H), 4.47−4.57 (m, 1H), 7.17−7.23 (m, 2H),
7.23−7.29 (m, 1H), 7.29−7.36 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 31.0, 34.0, 36.6, 40.8, 76.0, 126.9, 128.8 (2C), 128.9 (2C),
137.7, 177.8; IR (neat) 2927, 1770, 1454, 1338, 1150, 1015 cm−1; MS
(atmospheric pressure photoionization, APPI) calcd for C12H14BrO2
[M + H]+ 269.0172 found 269.0164.
5-(Bromomethyl)-3-cyclopentyldihydrofuran-2(3H)-one (3d).
Condition A, 61.5 mg, 99%; condition B, 55.4 mg, 90%.
Cis isomer: colorless oil; 1H NMR (400 MHz, CDCl3) δ 1.21−1.38
(m, 2H), 1.50−1.72 (m, 4H), 1.72−1.88 (m, 2H), 1.99−2.10 (m, 1H),
2.12−2.26 (m, 1H), 2.50 (ddd, J = 12.8, 8.9, 6.0 Hz, 1H), 2.71 (ddd, J
= 11.9, 8.9, 7.3 Hz, 1H), 3.49 (dd, J = 10.9, 6.5 Hz, 1H), 3.59 (dd, J =
10.9, 4.7 Hz, 1H), 4.50−4.59 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 24.9, 25.3, 29.7, 30.6, 31.8, 33.4, 40.2, 44.8, 75.8, 177.1; IR (neat)
2950, 1769, 1451, 1337, 1153, 1018 cm−1; MS (APCI) calcd for
C10H16BrO2 [M + H]+ 247.0328, found 247.0322.
3-(4-Bromobenzyl)-5-(bromomethyl)dihydrofuran-2(3H)-one
(3h). Condition A, 84.1 mg, 97%; condition B, 77.5 mg, 89%.
Cis isomer: colorless oil; 1H NMR (400 MHz, CDCl3) δ 1.75 (ddd,
J = 13.0, 11.9, 9.8 Hz, 1H), 2.42 (ddd, J = 13.0, 9.0, 6.2 Hz, 1H), 2.77
(dd, J = 14.2, 9.3 Hz, 1H), 2.91−3.02 (m, 1H), 3.21 (dd, J = 14.2, 4.3
Hz, 1H), 3.40 (dd, J = 11.0, 6.4 Hz, 1H), 3.51 (dd, J = 11.0, 4.6 Hz,
1H), 4.50−4.60 (m, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 32.8, 33.1, 35.3, 42.3, 76.1,
120.7, 130.6 (2C), 131.8 (2C), 137.0, 176.6; IR (neat) 2926, 1769,
1487, 1335, 1158, 1011 cm−1; MS (APCI) calcd for C12H13Br2O2 [M
+ H]+ 346.9277, found 346.9293.
1
Trans isomer: colorless oil; H NMR (400 MHz, CDCl3) δ 1.21−
1.42 (m, 2H), 1.51−1.74 (m, 4H), 1.74−1.84 (m, 1H), 1.89−2.00 (m,
1H), 2.10−2.33 (m, 3H), 2.73 (dt, J = 9.6, 7.7 Hz, 1H), 3.48 (dd, J =
11.0, 6.5 Hz, 1H), 3.54 (dd, J = 11.0, 4.4 Hz, 1H), 4.66−4.75 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 24.8, 25.2, 29.9, 30.3, 30.6, 34.3, 41.0,
43.1, 75.9, 177.8; IR (neat) 2952, 1769, 1468, 1356, 1158, 1020 cm−1;
MS (APCI) calcd for C10H16BrO2 [M + H]+ 247.0328, found
247.0322.
1
Trans isomer: colorless oil; H NMR (400 MHz, CDCl3) δ 2.09−
2.28 (m, 2H), 2.81 (dd, J = 13.8, 8.6 Hz, 1H), 3.02−3.17 (m, 2H),
3.46 (dd, J = 11.0, 5.7 Hz, 1H), 3.49 (dd, J = 11.1, 4.6 Hz, 1H), 4.51−
4.60 (m, 1H), 7.08 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 30.9, 34.2, 36.1, 40.6, 76.1, 121.0, 130.8
(2C), 132.0 (2C), 136.8, 177.6; IR (neat) 2928, 1770, 1487, 1338,
1150, 1011 cm−1; MS (APPI) calcd for C12H13Br2O2 [M + H]+
346.9277, found 346.9264.
5-(Bromomethyl)-3-cyclohexyldihydrofuran-2(3H)-one (3e). Con-
dition A, 67.1 mg, 92%; condition B, 52.9 mg, 81%.
Cis isomer: colorless oil; 1H NMR (400 MHz, CDCl3) δ 1.00−1.21
(m, 3H), 1.22−1.38 (m, 2H), 1.52−1.93 (m, 7H), 2.39 (ddd, J = 13.0,
9.4, 6.2 Hz, 1H), 2.63 (ddd, J = 12.4, 9.3, 5.0 Hz, 1H), 3.48 (dd, J =
10.8, 6.6 Hz, 1H), 3.59 (dd, J = 10.8, 4.6 Hz, 1H), 4.48−4.58 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 26.0, 26.1, 26.2, 28.5, 29.7, 31.2, 33.4,
37.5, 46.1, 75.8, 176.9; IR (neat) 2924, 1768, 1448, 1339, 1164, 1021
cm−1; MS (APCI) calcd for C11H18BrO2 [M + H]+ 261.0485, found
261.0479.
5-(Bromomethyl)-3-phenethyldihydrofuran-2(3H)-one (3i). Con-
dition A, 70.4 mg, 99%; condition B, 68.4 mg, 97%.
Cis isomer: colorless oil; 1H NMR (400 MHz, CDCl3) δ 1.68−1.86
(m, 2H), 2.22−2.34 (m, 1H), 2.50−2.75 (m, 3H), 2.75−2.86 (m, 1H),
3.49 (dd, J = 11.0, 6.4 Hz, 1H), 3.58 (dd, J = 11.0, 4.6 Hz, 1H), 4.48−
4.59 (m, 1H), 7.16−7.25 (m, 3H), 7.26−7.33 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 31.8, 33.1, 33.4, 33.6, 39.7, 76.0, 126.3, 128.4
(2C), 128.5 (2C), 140.5, 177.6; IR (neat) 2919, 1763, 1455, 1372,
1161, 1019 cm−1; MS (APCI) calcd for C13H16BrO2 [M + H]+
283.0328, found 283.0324.
1
Trans isomer: colorless oil; H NMR (400 MHz, CDCl3) δ 1.01−
1.21 (m, 3H), 1.21−1.37 (m, 2H), 1.54−1.64 (m, 1H), 1.64−1.72 (m,
1H), 1.72−1.88 (m, 4H), 2.17 (ddd, J = 13.9, 10.6, 5.5 Hz, 1H), 2.27
(ddd, J = 13.9, 8.2, 7.3 Hz, 1H), 2.68 (ddd, J = 10.6, 7.3, 5.0 Hz, 1H),
3.48 (dd, J = 11.0, 6.4 Hz, 1H), 3.53 (dd, J = 11.0, 4.5 Hz, 1H), 4.62−
4.72 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 26.0 (2C), 26.1, 28.6
(2C), 30.8, 34.4, 38.8, 44.9, 76.3, 177.8; IR (neat) 2924, 1764, 1449,
1340, 1156, 1018 cm−1; MS (APCI) calcd for C11H18BrO2 [M + H]+
261.0485, found 261.0478.
Trans isomer: white solid, mp 53.5−54.0 °C; 1H NMR (400 MHz,
CDCl3) δ 1.73−1.86 (m, 1H), 2.08−2.27 (m, 2H), 2.34 (ddd, J = 13.9,
9.8, 4.3 Hz, 1H), 2.66−2.84 (m, 3H), 3.47 (dd, J = 11.0, 6.3 Hz, 1H),
3.52 (dd, J = 11.0, 4.4 Hz, 1H), 4.70−4.78 (m, 1H), 7.16−7.24 (m,
3H), 7.27−7.34 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 32.0. 32.9,
33.2, 34.0, 38.2, 76.0, 126.3, 128.4 (2C), 128.6 (2C), 140.5, 178.2; IR
(neat) 2950, 1764, 1455, 1373, 1153, 1018 cm−1; MS (APCI) calcd for
C13H16BrO2 [M + H]+ 283.0328, found 283.0320.
5-(Bromomethyl)-3-cyclooctyldihydrofuran-2(3H)-one (3f). Con-
dition A, 71.9 mg, 99%; condition B, 65.1 mg, 90%.
Cis isomer: colorless oil; 1H NMR (400 MHz, CDCl3) δ 1.31−1.78
(m, 14H), 1.85 (dt, J = 12.6, 10.1 Hz, 1H), 2.13−2.25 (m, 1H), 2.41
(ddd, J = 12.6, 9.2, 6.2 Hz, 1H), 2.71 (ddd, J = 12.6, 9.2, 4.4 Hz, 1H),
E
DOI: 10.1021/acs.joc.5b01497
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
5-(Bromomethyl)-3-(prop-2-yn-1-yl)dihydrofuran-2(3H)-one (3j).
cm−1; MS (APCI) calcd for C12H14BrO2 [M + H]+ 269.0172, found
269.0167.
Trans isomer: H NMR (400 MHz, CDCl3) δ 1.24 (d, J = 7.1 Hz,
Condition A, 53.5 mg, 99%; condition B, 44.7 mg, 82%.
1
1
Cis isomer: white solid, mp 51.5−52.0 °C; H NMR (400 MHz,
CDCl3) δ 1.98−2.08 (m, 1H), 2.04 (t, J = 2.7 Hz, 1H), 2.56 (ddd, J =
17.4, 7.8, 2.7 Hz, 1H), 2.61−2.72 (m, 2H), 2.91 (dddd, J = 12.0, 9.2,
7.8, 4.5 Hz, 1H), 3.51 (dd, J = 10.8, 6.5 Hz, 1H), 3.62 (dd, J = 10.8, 4.8
Hz, 1H), 4.59−4.68 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 19.4,
32.5, 33.0, 39.9, 71.0, 76.2, 79.9, 175.8; IR (neat) 3263, 2921, 1771,
1421, 1353, 1152, 1009 cm−1; MS (APCI) calcd for C8H10BrO2 [M +
H]+ 216.9859, found 216.9857.
3H), 2.16−2.30 (m, 1H), 3.05−3.20 (m, 2H), 3.66 (d, J = 11.4 Hz,
1H), 3.71 (d, J = 11.4 Hz, 1H), 7.32−7.46 (m, 5H); 13C NMR (100
MHz, CDCl3) δ 16.6, 35.7, 40.7, 41.1, 84.4, 124.8 (2C), 128.5, 128.7
(2C), 141.8, 178.5; IR (neat) 2973, 1767, 1450, 1313, 1191, 1026
cm−1; MS (APCI) calcd for C12H14BrO2 [M + H]+ 269.0172, found
269.0170.
5-(1-Bromobutyl)-3-methyldihydrofuran-2(3H)-one (3n). Condi-
tion A, 55.4 mg, 94%; condition B, 54.1 mg, 92%.
Trans isomer: colorless oil; 1H NMR (400 MHz, CDCl3) δ 2.05 (t,
J = 2.6 Hz, 1H), 2.38−2.52 (m, 2H), 2.56−2.70 (m, 2H), 2.96−3.07
(m, 1H), 3.55 (d, J = 5.0 Hz, 2H), 4.79−4.88 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 20.3, 30.6, 34.4, 38.3, 71.0, 76.1, 79.7, 176.7; IR (neat)
3289, 2924, 1770, 1424, 1358, 1156, 1015 cm−1; MS (APCI) calcd for
C8H10BrO2 [M + H]+ 216.9859, found 216.9856.
Cis isomer: colorless oil; 1H NMR (400 MHz, CDCl3) δ 0.95 (t, J =
7.5 Hz, 3H), 1.30 (d, J = 6.9 Hz, 3H), 1.38−1.53 (m, 1H), 1.60−1.83
(m, 3H), 2.01 (dddd, J = 14.6, 9.7, 6.2, 3.2 Hz, 1H), 2.63−2.78 (m,
2H), 3.99 (ddd, J = 9.8, 8.0, 3.2 Hz, 1H), 4.38 (ddd, J = 10.0, 8.0, 5.7
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.3, 15.0, 20.2, 35.5, 35.9,
36.9, 57.1, 79.2, 178.7; IR (neat) 2961, 1772, 1455, 1343, 1167, 1013
cm−1; MS (APCI) calcd for C9H16BrO2 [M + H]+ 235.0328, found
235.0325.
N-[2-(5-(Bromomethyl)-2-oxotetrahydrofuran-3-yl)ethyl]-N-
methylbenzenesulfonamide (3k). Condition A, 81.6 mg, 87%;
condition B, 80.4 mg, 85%.
1
Trans isomer: colorless oil; 1H NMR (400 MHz, CDCl3) δ 0.95 (t,
J = 7.5 Hz, 3H), 1.31 (d, J = 7.6 Hz, 3H), 1.37−1.53 (m, 1H), 1.58−
1.74 (m, 1H), 1.74−1.84 (m, 1H), 1.88−2.00 (m, 1H), 2.08 (dt, J =
13.7, 8.0 Hz, 1H), 2.48 (ddd, J = 13.7, 9.8, 5.0 Hz, 1H), 2.74−2.87 (m,
1H), 4.05 (ddd, J = 10.3, 7.2, 3.4 Hz, 1H), 4.54 (ddd, J = 8.0, 7.2, 5.0
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.3, 16.4, 20.3, 33.5, 34.1,
36.6, 57.2, 79.3, 179.3; IR (neat) 2961, 1773, 1455, 1345, 1171, 1009
cm−1; MS (APPI) calcd for C9H16BrO2 [M + H]+ 235.0328, found
235.0324.
Cis isomer: white solid, mp 102.5−103.0 °C; H NMR (400 MHz,
CDCl3) δ 1.60−1.73 (m, 1H), 1.73−1.85 (m, 1H), 2.15−2.28 (m,
1H), 2.74 (s, 3H), 2.82 (ddd, J = 12.6, 9.2, 6.0 Hz, 1H), 2.87−2.96 (m,
1H), 2.99 (dt, J = 13.5, 5.5 Hz, 1H), 3.27 (ddd, J = 13.5, 9.2, 5.5 Hz,
1H), 3.59 (d, J = 5.0 Hz, 2H), 4.60−4.69 (m, 1H), 7.51−7.59 (m,
2H), 7.59−7.66 (m, 1H), 7.75−7.81 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 28.1, 33.2, 33.5, 34.6, 38.0, 47.8, 76.3, 127.2 (2C), 129.2
(2C), 132.8, 136.7, 177.6; IR (neat) 2934, 1769, 1446, 1334, 1156,
1018 cm−1; MS (APCI) calcd for C14H19BrNO4S [M + H]+ 376.0213,
found 376.0204.
5-(Bromomethyl)-3-phenyldihydrofuran-2(3H)-one (3o). Condi-
1
Trans isomer: white solid, mp 82.5−83.0 °C; H NMR (400 MHz,
tion A, 58.4 mg, 92%; condition B, 58.6 mg, 92%.
1
CDCl3) δ 1.66−1.79 (m, 1H), 2.08−2.19 (m, 1H), 2.21 (dt, J = 13.5,
8.8 Hz, 1H), 2.54 (ddd, J = 13.5, 9.8, 3.4 Hz, 1H), 2.75 (s, 3H), 2.89−
3.01 (m, 1H), 3.08 (dt, J = 13.9, 6.2 Hz, 1H), 3.21 (ddd, J = 13.9, 7.9,
6.2 Hz, 1H), 3.54 (d, J = 5.2 Hz, 2H), 4.77−4.85 (m, 1H), 7.51−7.58
(m, 2H), 7.59−7.65 (m, 1H), 7.76−7.82 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 29.1, 31.5, 34.0, 35.0, 36.2, 47.8, 76.2, 127.3 (2C),
129.2 (2C), 132.8, 136.9, 178.2; IR (neat) 2929, 1768, 1446, 1334,
1156, 1022 cm−1; MS (APCI) calcd for C14H19BrNO4S [M + H]+
376.0213, found 376.0202.
Cis isomer: white solid, mp 70.0−70.5 °C; H NMR (400 MHz,
CDCl3) δ 2.22−2.36 (m, 1H), 2.88 (ddd, J = 13.1, 9.4, 6.0 Hz, 1H),
3.59 (dd, J = 11.0, 6.3 Hz, 1H), 3.66 (dd, J = 11.0, 4.6 Hz, 1H), 3.94
(dd, J = 12.6, 9.4 Hz, 1H), 4.66−4.75 (m, 1H), 7.28−7.35 (m, 3H),
7.35−7.42 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 33.1, 36.3, 46.9,
75.7, 127.8, 128.1 (2C), 128.9 (2C), 136.0, 175.7; IR (neat) 2951,
1767, 1450, 1352, 1146, 1015 cm−1; MS (APPI) calcd for C11H11BrO2
[M]+ 253.9937, found 253.9936.
1
Trans isomer: colorless oil; H NMR (400 MHz, CDCl3) δ 2.58
5-(Bromomethyl)-3-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}-
dihydrofuran-2(3H)-one (3l). Condition A, 114.8 mg, 99%; condition
B, 102.8 mg, 89%.
Cis isomer: white solid, mp 110.0−110.5 °C; H NMR (400 MHz,
CDCl3) δ 1.06 (s, 9H), 1.57−1.75 (m, 2H), 2.18−2.30 (m, 1H), 2.47
(ddd, J = 12.8, 9.2, 6.2 Hz, 1H), 2.88 (dtd, J = 12.1, 9.4, 4.1 Hz, 1H),
3.44 (dd, J = 10.8, 6.4 Hz, 1H), 3.55 (dd, J = 10.8, 4.6 Hz, 1H), 3.70
(ddd, J = 10.5, 7.8, 4.6 Hz, 1H), 3.85 (dt, J = 10.5, 5.7 Hz, 1H), 4.48−
4.58 (m, 1H), 7.35−7.47 (m, 6H), 7.62−7.69 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 19.1, 26.8 (3C), 33.1, 33.3, 33.9, 38.0, 61.4, 76.2,
127.7 (4C), 129.8 (2C), 133.3, 133.4, 135.5 (4C), 177.9; IR (neat)
2930, 1777, 1471, 1362, 1164, 1107, 1020 cm−1; MS (APCI) calcd for
C23H30BrO3Si [M + H]+ 461.1142, found 461.1133.
(dt, J = 13.9, 7.8 Hz, 1H), 2.67 (ddd, J = 13.9, 10.1, 5.3 Hz, 1H),
3.57−3.63 (m, 2H), 4.03 (dd, J = 10.1, 7.8 Hz, 1H), 4.83−4.92 (m,
1H), 7.24−7.34 (m, 3H), 7.34−7.41 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 33.9, 34.8, 45.4, 76.1, 127.5 (2C), 127.7, 129.0 (2C), 136.8,
176.3; IR (neat) 2958, 1768, 1452, 1334, 1149, 1011 cm−1; MS
(APCI) calcd for C11H12BrO2 [M + H]+ 255.0015, found 255.0019.
N-[5-(Bromomethyl)-2-oxotetrahydrofuran-3-yl]-N-methylbenze-
nesulfonamide (3p). Condition A, 82.1 mg, 94%; condition B, 81.1
mg, 93%.
1
Cis isomer: colorless oil; 1H NMR (400 MHz, CDCl3) δ 2.16−2.28
(m, 1H), 2.61 (ddd, J = 13.0, 9.3, 6.0 Hz, 1H), 2.80 (s, 3H), 3.58 (dd, J
= 11.4, 4.1 Hz, 1H), 3.63 (dd, J = 11.4, 5.3 Hz, 1H), 4.56−4.67 (m,
1H), 5.14 (dd, J = 12.1, 9.3 Hz, 1H), 7.50−7.58 (m, 2H), 7.58−7.65
(m, 1H), 7.86−7.94 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 30.0,
30.3, 33.3, 57.5, 74.2, 127.4 (2C), 129.1 (2C), 133.1, 138.4, 171.0; IR
(neat) 2944, 1782, 1446, 1335, 1153, 980 cm−1; MS (APCI) calcd for
C12H15BrNO4S [M + H]+ 347.9900, found 347.9902.
Trans isomer: colorless oil; 1H NMR (400 MHz, CDCl3) δ 1.06 (s,
9H), 1.60−1.72 (m, 1H), 2.06−2.22 (m, 2H), 2.28 (ddd, J = 13.6, 9.6,
3.9 Hz, 1H), 2.97 (qd, J = 9.6, 4.6 Hz, 1H), 3.47 (dd, J = 10.8, 6.0 Hz,
1H), 3.51 (dd, J = 10.8, 4.4 Hz, 1H), 3.70 (ddd, J = 10.8, 7.6, 4.8 Hz,
1H), 3.82 (dt, J = 10.8, 5.7 Hz, 1H), 4.66−4.75 (m, 1H), 7.36−7.48
(m, 6H), 7.62−7.70 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 19.3,
26.9 (3C), 31.9, 33.7, 34.1, 36.3, 61.4, 76.1, 127.9 (4C), 129.9 (2C),
133.4 (2C), 135.6 (4C), 178.8; IR (neat) 2930, 1775, 1471, 1361,
1158, 1110, 1023 cm−1; MS (APCI) calcd for C23H30BrO3Si [M + H]+
461.1142, found 461.1131.
1
Trans isomer: colorless oil; H NMR (400 MHz, CDCl3) δ 2.39−
2.59 (m, 2H), 2.75 (s, 3H), 3.53 (dd, J = 11.4, 3.9 Hz, 1H), 3.59 (dd, J
= 11.4, 5.2 Hz, 1H), 4.81−4.90 (m, 1H), 5.13 (t, J = 10.3 Hz, 1H),
7.50−7.57 (m, 2H), 7.57−7.65 (m, 1H), 7.86−7.94 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 29.0, 30.9, 34.4, 56.3, 75.2, 127.6 (2C),
129.1 (2C), 133.2, 138.4, 171.9; IR (neat) 2961, 1779, 1446, 1335,
1156, 980 cm−1; MS (APCI) calcd for C12H15BrNO4S [M + H]+
347.9900, found 347.9892.
5-(Bromomethyl)-3-methyl-5-phenyldihydrofuran-2(3H)-one
(3m). Condition A, 62.8 mg, 93%; condition B, 58.7 mg, 87%.
1
Cis isomer: white solid, mp 101.5−102.0 °C; H NMR (400 MHz,
6-(Bromomethyl)-3-methyltetrahydro-2H-pyran-2-one (9a).
CDCl3) δ 1.31 (d, J = 7.1 Hz, 3H), 2.46 (t, J = 12.1 Hz, 1H), 2.52−
2.65 (m, 1H), 2.78 (dd, J = 12.1, 8.5 Hz, 1H), 3.68 (d, J = 11.4 Hz,
1H), 3.76 (d, J = 11.4 Hz, 1H), 7.32−7.46 (m, 5H); 13C NMR (100
MHz, CDCl3) δ 14.5, 34.7, 40.2, 40.4, 84.0, 125.1 (2C), 128.7, 128.8
(2C), 139.8, 177.9; IR (neat) 2971, 1769, 1450, 1316, 1195, 1026
Condition A, 44.5 mg, 86%; condition B, 42.6 mg, 82%.
Cis isomer: colorless oil; 1H NMR (400 MHz, CDCl3) δ 1.25 (d, J
= 6.9 Hz, 3H), 1.53−1.67 (m, 1H), 1.73−1.88 (m, 1H), 2.07−2.20 (m,
2H), 2.55−2.68 (m, 1H), 3.44 (dd, J = 11.0, 6.3 Hz, 1H), 3.54 (dd, J =
11.0, 5.0 Hz, 1H), 4.47−4.57 (m, 1H); 13C NMR (100 MHz, CDCl3)
F
DOI: 10.1021/acs.joc.5b01497
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The Journal of Organic Chemistry
Article
δ 16.2, 25.0, 25.1, 33.0, 33.3, 76.7, 174.8; IR (neat) 2935, 1737, 1460,
1374, 1160, 1015 cm−1; MS (APCI) calcd for C7H12BrO2 [M + H]+
207.0015, found 207.0015.
2.50 (m, 1H), 2.56 (sextet, J = 7.1 Hz, 1H), 5.02−5.14 (m, 2H), 5.70−
5.85 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 16.3, 37.4, 39.1, 117.2,
135.1, 182.4; IR (neat) 2979, 1703, 1463, 1286, 1244, 916 cm−1; [α]D20
= +10.6 (c 1.0, CHCl3, (S)).
Trans isomer: colorless oil; 1H NMR (400 MHz, CDCl3) δ 1.32 (d,
J = 7.1 Hz, 3H), 1.54−1.70 (m, 1H), 1.73−1.87 (m, 1H), 2.02−2.20
(m, 2H), 2.42−2.55 (m, 1H), 3.50 (dd, J = 11.0, 6.0 Hz, 1H), 3.53
(dd, J = 11.0, 4.6 Hz, 1H), 4.46−4.57 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 17.1, 27.5, 27.7, 34.4, 36.0, 79.3, 173.3; IR (neat) 2936,
1728, 1459, 1379, 1163, 1013 cm−1; MS (APCI) calcd for C7H12BrO2
[M + H]+ 207.0015, found 207.0014.
(3S,5R)-5-(But-3-en-1-yl)-3-methyldihydrofuran-2(3H)-one (12).
To a solution of (S)-3a (193.0 mg, 1.0 mmol) and V-40 (48.9 mg,
0.2 mmol) in degassed toluene (3.1 mL) was added allyltributyltin
(6.13 mL, 20.0 mmol) at room temperature. After the solution was
stirred at 80 °C for 22 h, it was cooled to room temperature and the
solvent was removed under reduced pressure. The crude product was
purified by silica gel column chromatography (10% w/w anhydrous
K2CO3−silica gel; eluent hexane/AcOEt = 6/1) to give desired
product 12 (124.1 mg, 81% yield): colorless oil; 1H NMR (400 MHz,
CDCl3) δ 1.27 (d, J = 7.1 Hz, 3H), 1.52 (td, J = 12.5, 10.6 Hz, 1H),
1.65−1.76 (m, 1H), 1.79−1.92 (m, 1H), 2.12−2.32 (m, 2H), 2.50
(ddd, J = 12.5, 8.7, 5.5 Hz, 1H), 2.68 (ddd, J = 12.1, 8.7, 7.1 Hz, 1H),
4.36 (ddt, J = 10.6, 7.8, 5.5 Hz, 1H), 4.98−5.11 (m, 2H), 5.81 (ddt, J =
17.2, 10.3, 6.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 15.0, 29.5,
34.6, 35.8, 37.2, 77.8, 115.5, 137.1, 179.5; IR (neat) 2935, 1766, 1453,
1357, 1188, 1010, 913 cm−1; [α]D23 = +23.7 (c 1.2, CHCl3, (S)); MS
(electrospray ionization, ESI) calcd for C9H15O2 [M + H]+ 155.1067,
found 155.1061.
Asymmetric Total Synthesis of (+)-Dubiusamine C. (S)-4-
Benzyl-3-(pent-4-enoyl)oxazolidin-2-one (10). To a solution of 4-
pentenoic acid (1.00 g, 10.0 mmol) and Et3N (1.52 mL, 11.0 mmol) in
THF (25.0 mL) was added pivaloyl chloride (1.52 mL, 10.5 mmol)
dropwise over 5 min at −78 °C, and the mixture was stirred at 0 °C for
1 h. To obtain (S)-4-benzyl-2-oxazolidione lithium salt, n-BuLi (1.6 M
in n-hexane, 6.56 mL, 10.5 mmol) was added to a solution of (S)-4-
benzyl-2-oxazolidione (1.86 g, 10.5 mmol) in THF (25.0 mL)
dropwise over 5 min at −78 °C and the mixture was stirred for 30 min.
This was added to the first solution dropwise over 5 min at −78 °C,
and the resulting mixture was stirred at −78 °C for 15 min and then
allowed to warm to 0 °C. After stirring at 0 °C for 1 h, the reaction
mixture was quenched with saturated NH4Cl aqueous solution (30
mL) and extracted with AcOEt (30 mL × 3). The combined extracts
were washed with saturated NaHCO3 aqueous solution (30 mL) and
brine (30 mL) and dried over Na2SO4. The organic phase was
concentrated under reduced pressure and the crude product was
purified by silica gel column chromatography (eluent hexane/AcOEt =
(3S,5R)-5-(4-Hydroxybutyl)-3-methyldihydrofuran-2(3H)-one
(13). To a solution of 12 (38.6 mg, 0.25 mmol) in THF (1.0 mL) was
added BH3·THF (0.92 M in THF, 270 μL, 0.25 mmol) at 0 °C. After
the mixture was stirred at 0 °C for 3 h, H2O (1 mL) was added
dropwise over 10 min at 0 °C. Then NaBO3·4H2O (57.7 mg, 0.375
mmol) was added to this mixture at room temperature. After the
reaction mixture was stirred at room temperature for 2 h, it was
extracted with AcOEt (20 mL × 3). The combined extracts were
washed with brine (10 mL), dried over Na2SO4, and concentrated
under reduced puressure. The crude product was purified by silica gel
column chromatography (eluent hexane/AcOEt = 1/3) to give desired
1
3/1) to give desired product 10 (2.46 g, 95% yield): colorless oil; H
NMR (400 MHz, CDCl3) δ 2.41−2.52 (m, 2H), 2.76 (dd, J = 13.8, 9.8
Hz, 1H), 3.02 (dt, J = 17.7, 7.6 Hz, 1H), 3.11 (dd, J = 17.7, 7.6 Hz,
1H), 3.30 (dd, J = 13.8, 3.3 Hz, 1H), 4.14−4.24 (m, 2H), 4.63−4.72
(m, 1H), 5.00−5.16 (m, 2H), 5.89 (ddt, J = 17.4, 10.3, 6.8 Hz, 1H),
7.18−7.24 (m, 2H), 7.25−7.31 (m, 1H), 7.31−7.37 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 28.2, 34.8, 37.9, 55.1, 66.2, 115.7, 127.3,
129.0 (2C), 129.4 (2C), 135.2, 136.7, 153.5, 172.5; IR (neat) 2974,
1775, 1698, 1384, 1351, 1209 cm−1; [α]D19 = +56.3 (c 1.3, CHCl3, (S)).
(S)-4-Benzyl-3-[(S)-2-methylpent-4-enoyl]oxazolidin-2-one (11).
To a solution of 10 (129.7 mg, 0.50 mmol) in THF (2.5 mL) was
added NaHMDS (1.1 M in THF, 682 μL, 0.75 mmol) dropwise over 5
min at −78 °C. After the mixture was stirred at −78 °C for 1 h, MeI
(125 μL, 2.0 mmol) was added dropwise over 5 min at −78 °C and
the mixture was stirred at −78 °C for 7 h. Saturated NH4Cl aqueous
solution (20 mL) was added to the reaction mixture, and the product
was extracted with AcOEt (20 mL × 3). The combined extracts were
washed with brine (20 mL) and dried over Na2SO4. The organic phase
was concentrated under reduced pressure, and the crude product was
purified by silica gel column chromatography (eluent hexane/AcOEt =
5/1) to give desired product 11 (131.9 mg, 97% yield): colorless oil;
1H NMR (400 MHz, CDCl3) δ 1.24 (t, J = 7.1 Hz, 3H), 2.13−2.26
(m, 1H), 2.42−2.54 (m, 1H), 2.77 (dd, J = 13.6, 9.7 Hz, 1H), 3.27
(dd, J = 13.6, 3.3 Hz, 1H), 3.83 (sextet, J = 7.1 Hz, 1H), 4.13−4.24 (m,
2H), 4.62−4.71 (m, 1H), 5.00−5.12 (m, 2H), 5.78 (ddt, J = 17.4, 10.3,
7.2 Hz, 1H), 7.19−7.24 (m, 2H), 7.25−7.30 (m, 1H), 7.30−7.37 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 17.0, 37.4, 37.5, 37.9, 55.3, 66.0,
117.0, 127.3, 128.9 (2C), 129.4 (2C), 135.2, 135.5, 153.0, 176.4; IR
(neat) 2978, 1774, 1695, 1383, 1349, 1208 cm−1; [α]D19 = +79.5 (c 1.0,
CHCl3, (S)).
1
product 13 (32.9 mg, 76% yield): white solid, mp 65.5−66.0 °C; H
NMR (400 MHz, CDCl3) δ 1.27 (d, J = 7.1 Hz, 3H), 1.36−1.71 (m,
7H), 1.72−1.83 (m, 1H), 2.50 (ddd, J = 12.8, 8.7, 5.5 Hz, 1H), 2.61−
2.75 (m, 1H), 3.67 (t, J = 6.4 Hz, 2H), 4.35 (ddt, J = 10.8, 7.7, 5.5 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 15.0, 21.6, 32.2, 35.2, 35.9, 37.2,
62.4, 78.5, 179.6; IR (neat) 3385, 2947, 1747, 1361, 1190, 1047, 989
cm−1; [α]D23 = +20.0 (c 1.0, CHCl3, (S)); MS (ESI) calcd for C9H17O3
[M + H]+ 173.1172, found 173.1170.
N-{4-[(2R,4S)-4-Methyl-5-oxotetrahydrofuran-2-yl]butyl}-2-nitro-
benzenesulfonamide (14). To a solution of 13 (68.9 mg, 0.40 mmol),
NsNH2 (202.3 mg, 1.0 mmol), and Ph3P (136.4 mg, 0.52 mmol) in a
mixture of THF (5.6 mL) and toluene (2.4 mL) was added DEAD
(2.2 M in toluene, 236 μL, 0.52 mmol) dropwise over 5 min at 0 °C.
After the mixture was stirred at room temperature for 25 h, the solvent
was removed under reduced pressure. The crude product was purified
by silica gel column chromatography (eluent hexane/AcOEt = 2/3) to
give desired product 14 (106.0 mg, 74% yield): colorless oil; 1H NMR
(400 MHz, CDCl3) δ 1.26 (d, J = 7.1 Hz, 3H), 1.38−1.74 (m, 7H),
2.47 (ddd, J = 12.7, 8.7, 5.5 Hz, 1H), 2.58−2.73 (m, 1H), 3.04−3.18
(m, 2H), 4.29 (ddt, J = 10.8, 7.7, 5.5 Hz, 1H), 5.29 (t, J = 6.2 Hz, 1H),
7.70−7.80 (m, 2H), 7.84−7.92 (m,1H), 8.10−8.18 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 15.0, 22.4, 29.3, 34.8, 35.8, 37.2, 43.5,
78.2, 125.4, 131.0, 132.8, 133.5, 133.6, 148.0, 179.4; IR (neat) 3327,
2936, 1758, 1539, 1340, 1163, 1080 cm−1; [α]D19 = +6.5 (c 1.5, CHCl3,
(S)); MS (ESI) calcd for C15H21N2O6S [M + H]+ 357.1115, found
357.1104.
N,N-Bis{4-[(2R,4S)-4-methyl-5-oxotetrahydrofuran-2-yl]butyl}-2-
nitrobenzenesulfonamide (15). To a solution of 14 (56.1 mg, 0.16
mmol), 13 (38.7 mg, 0.22 mmol), and Ph3P (51.1 mg, 0.20 mmol) in
toluene (0.94 mL) was added DEAD (2.2 M in toluene, 89 μL, 0.19
mmol) dropwise over 5 min at 0 °C. After the mixture was stirred at
60 °C for 3 h, it was filtreted through Celite and the organic layer was
concentrated under reduced pressure. The crude product was purified
by silica gel column chromatography (eluent hexane/AcOEt = 1/1 to
2/5) to give desired product 15 (68.6 mg, 85% yield): colorless oil; 1H
NMR (400 MHz, CDCl3) δ 1.26 (d, J = 7.1 Hz, 6H), 1.33−1.74 (m,
14H), 2.47 (ddd, J = 12.7, 8.7, 5.5 Hz, 2H), 2.59−2.73 (m, 2H), 3.21−
(S)-2-Methylpent-4-enoic acid ((S)-1a). To a solution of 11 (273.3
mg, 1.0 mmol) in a mixture of THF (7.5 mL) and H2O (2.5 mL) was
added a solution of 30% aqueous H2O2 (511.0 μL, 5.0 mmol) and
LiOH (47.9 mg, 2.0 mmol) in H2O (2.0 mL) dropwise over 5 min at 0
°C. After the mixture was stirred at 0 °C for 1 h, THF was removed
under reduced pressure. The aqueous layer was adjusted to pH 2 with
1 N HCl aqueous solution and then extracted with AcOEt (20 mL ×
3). The combined extracts were dried over Na2SO4 and concentrated
under reduced pressure. The crude product was purified by silica gel
column chromatography (eluent hexane/ether = 1/1) to give desired
1
product (S)-1a (101.5 mg, 89% yield): colorless oil; H NMR (400
MHz, CDCl3) δ 1.19 (d, J = 7.1 Hz, 3H), 2.15−2.27 (m, 1H), 2.39−
G
DOI: 10.1021/acs.joc.5b01497
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3.36 (m, 4H), 4.30 (ddt, J = 10.7, 7.4, 5.3 Hz, 2H), 7.58−7.66 (m,
1H), 7.66−7.74 (m, 2H), 7.97−8.04 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 14.9 (2C), 22.4 (2C), 27.8 (2C), 34.8 (2C), 35.7 (2C), 37.1
(2C), 47.1 (2C), 78.2 (2C), 124.0, 130.4, 131.6, 133.2, 133.5, 147.8,
179.4 (2C); IR (neat) 2936, 1760, 1543, 1345, 1160, 997 cm−1; [α]D19
= +22.5 (c 0.9, CHCl3, (S)); MS (ESI) calcd for C24H35N2O8S [M +
H]+ 511.2109, found 511.2098.
12416. (j) Nam, G.; Ko, S. Y. Helv. Chim. Acta 2012, 95, 1937−1945.
(k) Nilsson, J.; Gidlof, R.; Johansson, M.; Sterner, O. Tetrahedron
̈
2012, 68, 3336−3341. (l) Alliot, J.; Gravel, E.; Pillon, F.; Buisson, D.-
A.; Nicolas, M.; Doris, E. Chem. Commun. 2012, 48, 8111−8113.
(m) Nonn, M.; Kiss, L.; Sillanpaa, R.; Fulop, F. Tetrahedron 2012, 68,
̈
̈
̈
̈
9942−9948. (n) Burch, P.; Binaghi, M.; Scherer, M.; Wentzel, C.;
Bossert, D.; Eberhardt, L.; Neuburger, M.; Scheiffele, P.; Gademann,
K. Chem. - Eur. J. 2013, 19, 2589−2591. (o) Tsuna, K.; Noguchi, N.;
Nakada, M. Chem. - Eur. J. 2013, 19, 5476−5486.
(+)-Dubiusamine C. To a solution of 15 (57.9 mg, 0.11 mmol) and
K2CO3 (30.1 mg, 2.2 mmol) in a mixture of MeCN (159 μL) and
DMF (119 μL) was added PhSH (14.5 μL, 0.14 mmol) at room
temperature. After the mixture was stirred at room temperature for 2
h, it was filtered through Celite and concentrated under reduced
pressure. The crude product was purified by silica gel column
chromatography (eluent CHCl3/MeOH/Et3N = 100/10/1) to give
(+)-dubiusamine C (35.0 mg, 95% yield): white solid, mp 83.0−83.5
(3) (a) Cambie, R. C.; Rutledge, P. S.; Somerville, R. F.; Woodgate,
P. D. Synthesis 1988, 1988, 1009−1011. (b) Mellegaard, S. R.; Tunge,
J. A. J. Org. Chem. 2004, 69, 8979−8981. (c) Braddock, D. C.; Cansell,
G.; Hermitage, S. A. Chem. Commun. 2006, 2483−2485. (d) Melle-
gaard-Waetzig, S. R.; Wang, C.; Tunge, J. A. Tetrahedron 2006, 62,
7191−7198. (e) Ahmad, S. M.; Braddock, D. C.; Cansell, G.;
Hermitage, S. A.; Redmond, J. M.; White, A. J. P. Tetrahedron Lett.
2007, 48, 5948−5952. (f) Ahmad, S. M.; Braddock, D. C.; Cansell, G.;
Hermitage, S. A. Tetrahedron Lett. 2007, 48, 915−918. (g) Chen, F.;
Jiang, X.; Er, J. C.; Yeung, Y.-Y. Tetrahedron Lett. 2010, 51, 3433−
3435. (h) Balkrishna, S. J.; Prasad, C. D.; Panini, P.; Detty, M. R.;
Chopra, D.; Kumar, S. J. Org. Chem. 2012, 77, 9541−9552. (i) Cheng,
Y. A.; Chen, T.; Tan, C. K.; Heng, J. J.; Yeung, Y.-Y. J. Am. Chem. Soc.
2012, 134, 16492−16495.
1
°C; H NMR (400 MHz, CDCl3) δ 1.27 (d, J = 7.3 Hz, 6H), 1.30−
1.58 (m, 11H), 1.58−1.69 (m, 2H), 1.69−1.81 (m, 2H), 2.49 (ddd, J =
12.8, 8.7, 5.5 Hz, 2H), 2.61 (t, J = 6.8 Hz, 4H), 2.60−2.74 (m, 2H),
4.34 (ddt, J = 10.6, 7.6, 5.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
15.1 (2C), 23.2 (2C), 29.8 (2C), 35.4 (2C), 35.9 (2C), 37.3 (2C),
49.7 (2C), 78.5 (2C), 179.5 (2C); IR (neat) 3311, 2926, 1762, 1456,
1353, 1193, 987 cm−1; [α]D18 = +28.8 (c 1.1, CHCl3, (S)); MS (ESI)
calcd for C18H32NO4 [M + H]+ 326.2326, found 326.2312.
(4) (a) Zhou, L.; Tan, C. K.; Jiang, X.; Chen, F.; Yeung, Y.-Y. J. Am.
Chem. Soc. 2010, 132, 15474−15476. (b) Murai, K.; Matsushita, T.;
Nakamura, A.; Fukushima, S.; Shimura, M.; Fujioka, H. Angew. Chem.,
Int. Ed. 2010, 49, 9174−9177. (c) Whitehead, D. C.; Fhaner, M.;
Borhan, B. Tetrahedron Lett. 2011, 52, 2288−2291. (d) Tan, C. K.;
Zhou, L.; Yeung, Y.-Y. Org. Lett. 2011, 13, 2738−2741. (e) Tan, C. K.;
Chen, F.; Yeung, Y.-Y. Tetrahedron Lett. 2011, 52, 4892−4895.
(f) Chen, J.; Zhou, L.; Tan, C. K.; Yeung, Y.-Y. J. Org. Chem. 2012, 77,
999−1009. (g) Tan, C. K.; Le, C.; Yeung, Y.-Y. Chem. Commun. 2012,
48, 5793−5795. (h) Paull, D. H.; Fang, C.; Donald, J. R.; Pansick, A.
D.; Martin, S. F. J. Am. Chem. Soc. 2012, 134, 11128−11131. (i) Jiang,
X.; Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Angew. Chem., Int. Ed. 2012, 51,
7771−7775.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01497.
■
S
1H and 13C NMR spectra of compounds in the
diastereoselective bromolactonization and asymmetric
total synthesis of (+)-dubiusamine C (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail moriyama@faculty.chiba-u.jp.
*E-mail togo@faculty.chiba-u.jp.
Notes
■
(5) Tamaru, Y.; Mizutani, M.; Furukawa, Y.; Kawamura, S.; Yoshida,
Z.; Yanagi, K.; Minobe, M. J. Am. Chem. Soc. 1984, 106, 1079−1085.
(6) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737−1739.
The authors declare no competing financial interest.
(7) (a) Herold, P.; Duthaler, R.; Rihs, G.; Angst, C. J. Org. Chem.
1989, 54, 1178−1185. (b) Bradbury, R. H.; Revill, J. M.; Rivett, J. E.;
Waterson, D. Tetrahedron Lett. 1989, 30, 3845−3848. (c) Bradbury, R.
H.; Major, J. S.; Oldham, A. A.; Rivett, J. E.; Roberts, D. A.; Slater, A.
M.; Timms, D.; Waterson, D. J. Med. Chem. 1990, 33, 2335−2342.
(d) Ghosh, A. K.; Xu, X. Org. Lett. 2004, 6, 2055−2058.
(e) Yamaguchi, Y.; Menear, K.; Cohen, N.-C.; Mah, R.; Cumin, F.;
Schnell, C.; Wood, J. M.; Maibaum, J. Bioorg. Med. Chem. Lett. 2009,
19, 4863−4867. (f) Nam, G.; Ko, S. Y. Helv. Chim. Acta 2012, 95,
1937−1945. (g) Michida, M.; Takayanagi, Y.; Imai, M.; Furuya, Y.;
Kimura, K.; Kitawaki, T.; Tomori, H.; Kajino, H. Org. Process Res. Dev.
2013, 17, 1430−1439.
(8) (a) Moriyama, K.; Izumisawa, Y.; Togo, H. J. Org. Chem. 2011,
76, 7249−7255. (b) Moriyama, K.; Takemura, M.; Togo, H. Org. Lett.
2012, 14, 2414−2417. (c) Moriyama, K.; Ishida, K.; Togo, H. Chem.
Commun. 2012, 48, 8574−8576. (d) Moriyama, K.; Takemura, M.;
Togo, H. J. Org. Chem. 2014, 79, 6094−6104. (e) Moriyama, K.;
Nakamura, Y.; Togo, H. Org. Lett. 2014, 16, 3812−3815.
(9) (a) Gribble, G. W. Chemosphere 2003, 52, 289−297. (b) Butler,
A.; Carter-Franklin, J. N. Nat. Prod. Rep. 2004, 21, 180−188.
(c) Neumann, C. S.; Fujimori, D. G.; Walsh, C. T. Chem. Biol.
2008, 15, 99−109.
ACKNOWLEDGMENTS
■
Financial support in the form of a Grant-in-Aid for Scientific
Research (20550033) from the Ministry of Education, Culture,
Sports, Science and Technology in Japan (K.M.) and the Naito
Foundation in Japan (K.M.) is gratefully acknowledged.
REFERENCES
■
(1) For review on γ-butyrolactones: (a) Hoffmann, H. M. R.; Rabe, J.
Angew. Chem., Int. Ed. Engl. 1985, 24, 94−110. (b) Koch, S. S. C.;
Chamberlin, A. R. In Studies in Natural Products Chemistry, Vol. 16;
Atta-ur-Rahman, Ed.; Elsevier Science: Amsterdam, 1995; pp 687−
725; DOI: 10.1016/S1572-5995(06)80065-7. (c) Bandichhor, R.;
Nosse, B.; Reiser, O. Top. Curr. Chem. 2005, 243, 43−72.
(2) (a) Ghosh, A. K.; Xu, X. Org. Lett. 2004, 6, 2055−2058.
(b) Noguchi, X.; Nakada, M. Org. Lett. 2006, 8, 2039−2042.
(c) Williams, D. R.; Patnaik, S.; Cortez, G. S. Heterocycles 2007, 72,
́
213−219. (d) Carret, S.; Depres, J.-P. Angew. Chem., Int. Ed. 2007, 46,
6870−6873. (e) Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T.
Angew. Chem., Int. Ed. 2007, 46, 5734−5736. (f) Breder, A.; Chinigo,
G. M.; Waltman, A. W.; Carreira, E. M. Angew. Chem., Int. Ed. 2008,
47, 8514−8517. (g) Rye, C. E.; Barker, D. J. Org. Chem. 2011, 76,
6636−6648. (h) Miles, T. J.; Barfoot, C.; Brooks, G.; Brown, P.; Chen,
D.; Dabbs, S.; Davies, D. T.; Downie, D. L.; Eyrisch, S.; Giordano, I.;
Gwynn, M. N.; Hennessy, A.; Hoover, J.; Huang, J.; Jones, G.;
Markwell, R.; Rittenhouse, S.; Xiang, H.; Pearson, N. Bioorg. Med.
Chem. Lett. 2011, 21, 7483−7488. (i) Breder, A.; Chinigo, G. M.;
Waltman, A. W.; Carreira, E. M. Chem. - Eur. J. 2011, 17, 12405−
(10) Treatment of 2a with NBS (1.1 equiv) in a solution mixture of
DME and H2O (1/1) at room temperature for 3 days gave the desired
product 3a in 53% yield (cis/trans = 10/90), together with recovery of
2a.
(11) Edwards, J. O.; Fleischauer, P. D. Inorg. Chim. Acta, Rev. 1968, 2,
53−63.
H
DOI: 10.1021/acs.joc.5b01497
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(12) Walton, H. F.; Schilt, A. A. J. Am. Chem. Soc. 1952, 74, 4995−
4996.
(13) Moon, H.-S.; Eisenberg, S. W. E.; Wilson, M. E.; Schore, N. E.;
Kurth, M. J. J. Org. Chem. 1994, 59, 6504−6505.
(14) (a) Tan, M. A.; Kitajima, M.; Kogure, N.; Nonato, M. G.;
Takayama, H. Tetrahedron 2010, 66, 3353−3359. (b) Tan, M. A.;
Kogure, N.; Kitajima, M.; Takayama, H. Philippine Sci. Lett. 2011, 2,
98−102.
(15) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987,
28, 6141−6144.
(16) (a) Kosugi, M.; Kurino, K.; Takayama, K.; Migita, T. J.
Organomet. Chem. 1973, 56, C11−C13. (b) Grignon, J.; Pereyre, M. J.
Organomet. Chem. 1973, 61, C33−C35. (c) Grignon, J.; Servens, C.;
Pereyre, M. J. Organomet. Chem. 1975, 96, 225−235. (d) Keck, G. E.;
Enholm, E. J.; Yates, J. B.; Wiley, M. R. Tetrahedron 1985, 41, 4079−
4094.
(17) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. Tetrahedron
Lett. 1989, 30, 1483−1486.
(18) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 40, 353−359.
I
DOI: 10.1021/acs.joc.5b01497
J. Org. Chem. XXXX, XXX, XXX−XXX