Gold(I)-catalyzed synthesis of optically active 1,4-oxazepan-7-ones

Article abstract of DOI:10.1021/jo501254x

Optically active seven-membered lactones, dimethyleneoxazepanones, were readily prepared in good yields from chiral β-(N-propargylic)amino-α- methylene carboxylic acid tert-butyl esters in the presence of catalytic amounts of Ph₃PAuCl and Cu(OTf)₂. A smooth 7-exo-dig cyclization was observed.

Full text of DOI:10.1021/jo501254x

Note
pubs.acs.org/joc
Gold(I)-Catalyzed Synthesis of Optically Active 1,4-Oxazepan-7-ones
Akio Kamimura,*,† Yu Yamane,† Ryuichiro Yo,† Toshiyuki Tanaka,† and Hidemitsu Uno‡
†Department of Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University, Ube 755-8611, Japan
‡Department of Chemistry, Graduate School of Science and Engineering, Ehime University, Matsuyama 790-8577, Japan
S
* Supporting Information
ABSTRACT: Optically active seven-membered lactones, dimethyleneoxaze-
panones, were readily prepared in good yields from chiral β-(N-propargylic)-
amino-α-methylene carboxylic acid tert-butyl esters in the presence of catalytic
amounts of Ph3PAuCl and Cu(OTf)2. A smooth 7-exo-dig cyclization was
observed.
1,4-Oxazepane, a seven-membered heterocyclic compound, is a
structural motif often observed in natural and biologically active
compounds such as holstine,1 apohemeanthamine,2 batracho-
toxin,3 and calvine.4 These oxaaza-heterocyclic compounds are
also recognized as one-carbon homologues of morpholines, a
structural feature observed among many biologically active
compounds.5 Thus, the development of methods for the
efficient synthesis of these compounds has been of interest in
organic synthesis.
compound 2a in low yield (Table 1, entry 2). When the
reaction was catalyzed by Ph3PAuCl in the presence of AgSbF6,
the yield of 2a increased to 40% (Table 1, entry 3). Use of
AgNTf2 instead of AgSbF6 enhanced the yield to 62%, while
AgBF4 did not promote the reaction (Table 1, entries 4 and 5).
Only a moderate yield of 2a was observed on elevating the
reaction temperature in the presence of Ag(I) salt as cocatalyst
(Table 1, entry 6). When Ag(I) salts were replaced by
Cu(OTf)2,15 known as an effective cocatalyst in some Au(I)-
catalyzed reactions, the yield of 2a was improved to 70% under
1,2-dichloroethane reflux conditions, although the reaction at
room temperature failed the formation of 2a (Table 1, entries
7−9). Use of toluene instead of 1,2-dichloroethane afforded 2a
in comparable yield (Table 1, entry 10). We next examined the
influence of the amount of gold catalyst. When the load of
Ph3PAuCl was reduced to 1 mol %, the yield of 2a was
dependent on the amount of Cu(OTf)2. Compound 2a was
obtained in 80% yield when 6 mol % of Cu(OTf)2 was used
(Table 1, entries 11 and 12). HPLC analysis using
CHIRALPAK ID revealed that the optical purity of 2a was
94% ee, which was similar to that of the starting material 1a.
Thus, no significant racemization at chiral carbon occurred
during the reaction. The presence of gold(I) catalyst was
required to effectively promote the formation of 2a. For
example, the use of catalytic amounts of CuCl and CuCl2 in the
absence of Ph3PAuCl did not promote the transformation;
instead, the substrate 1a was recovered completely (Table 1,
entries 13 and 14). The presence of catalytic amounts of
Cu(OTf)2, on the other hand, consumed 1a and N-
propargyltosylamide was isolated in 18% yield (Table 1, entry
15). This decomposition of 1a might be caused by the hidden
Brønsted acid catalyst generated from Cu(OTf)2.16 However,
treatment of 1a with catalytic amounts of TfOH resulted in the
formation of a complex mixture. Under these conditions,
AgOTf was less effective in comparison with Cu(OTf)2, and
compound 2a was isolated in moderate to poor yields (Table 1,
entries 16 and 17).
We have recently developed a facile method for the synthesis
of enantiomerically enriched aza-Morita−Baylis−Hillman (aza-
MBH) adducts, which are regarded as useful synthetic building
blocks.6 For example, we have employed the chiral N-allylic and
N-propargylic β-amino-α-methylene esters for the synthesis of
various heterocyclic compounds via the RCM reaction,7 the
Pauson-Khand reaction,8 and the domino radical cyclization
reaction.9 A 1,6-enyne motif in the N-propargylic aza-MBH
adducts prompted us to explore their potential as substrates in
Au(I)-catalyzed reactions. Transition-metal-catalyzed cyclo-
isomerization, a reaction characteristic of 1,6-enyne com-
pounds, has been extensively studied.10 Carbo- and heterocyclic
compounds are prepared in a one-step reaction from 1,6-
enynes in the presence of catalytic amounts of an Au(I)
complex.11 Echavarren and co-workers have extensively
investigated the scope of this reaction and proposed reaction
mechanisms.12 If an ester motif is strategically located relative
to an enyne moiety, the activation of the alkyne moiety can
initiate an attack on the ester to yield the lactone. While this
strategy can be used to effectively generate five- and six-
membered heterocyclic compounds, its utility in the production
of seven-membered lactones remains low, resulting in moderate
yields.13 Interestingly, our N-propargylic aza-MBH products
retain a tert-butyl carboxylic ester functionality at the other
terminus,14 appropriately oriented for the synthesis of
oxazepanes. Here we report a facile synthesis of chiral seven-
membered heterocyclic lactones, i.e., oxazepanones, from N-
propargyl-β-amino-α-methylene esters.
First, we examined the transformation of compound 1a in
the presence of Ph3PAuCl and AgSbF6 (Table 1). No reaction
was observed in the absence of silver cocatalyst (Table 1, entry
1). Addition of both JohnPhosAuCl and AgSbF6 gave
Received: June 4, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo501254x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. Optimization of the Conditions for 7-Exo Cyclization
a
entry
Au cat. (amt (mol %))
cocat. (amt (mol %))
solvent
CH2Cl2
temp
yield of 2a (%)
b
1
Ph3PAuCl (7)
[(JohnPhos)AuCl] (10)
Ph3PAuCl (10)
Ph3PAuCl (6)
Ph3PAuCl (10)
Ph3PAuCl (6)
Ph3PAuCl (6)
Ph3PAuCl (6)
Ph3PAuCl (6)
Ph3PAuCl (6)
Ph3PAuCl (1)
Ph3PAuCl (1)
none
none
room temp
room temp
room temp
room temp
room temp
reflux
nr
4
2
AgSbF6 (15)
AgSbF6 (15)
AgNTf2 (9)
AgBF4 (30)
AgNTf2 (9)
Cu(OTf)2 (18)
Cu(OTf)2 (18)
Cu(OTf)2 (18)
Cu(OTf)2 (18)
Cu(OTf)2 (15)
Cu(OTf)2 (6)
CuCl2 (8)
CH2Cl2
3
CH2Cl2
40
62
14
50
4
CH2Cl2
5
CH2Cl2
6
CH2Cl2
b
7
CH2Cl2
room temp
reflux
nr
8
CH2Cl2
13
70
62
60
80
9
ClCH2CH2Cl
toluene
reflux
10
11
12
13
14
15
16
17
reflux
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
reflux
reflux
b
reflux
nr
nr
b
none
CuCl (8)
reflux
c
none
Cu(OTf)2 (8)
AgOTf (6)
reflux
0
Ph3PAuCl (1)
Ph3PAuCl (1)
reflux
49
14
AgOTf (12)
reflux
a
b
c
Isolated yield. Recovery of starting material. Compound 1a was consumed. N-Propargyltosylamide was isolated in 18% yield instead.
With the optimized reaction conditions in hand, we
in moderate to good yields. For example, 4-fluoro-, 4-chloro-,
and 4-CF3-substituted aromatic derivatives of 1 gave the
corresponding oxazepanones 2b−d in good yields, respectively.
Enantiomeric excesses of the cyclic products were close to
those of the starting materials, indicating no loss in optical
purity during the reaction. The reaction of 1 containing other
aromatic substituents progressed smoothly, but the yields of
2e−j were moderate. The reaction of 1k, which had a p-
methoxyphenyl substituent, underwent decomposition, giving
N-tosylpropargylamine in 32% yield instead of the correspond-
ing cyclic product 2k. Compounds 1 containing aliphatic
substituents at the R group led to the formation of
corresponding compounds 2l−o in moderate yields. The
enantiomeric excesses of these compounds were almost at the
same level as those of the starting materials, and the reaction
progressed without the loss of optical purity. Conversion of
tert-butyl derivative 1p provided the expected 2p in 30% yield
along with the formation of dihydropyrrole 3p in 18% yield.
The internal alkyne derivative 1q underwent a similar
reaction to produce the corresponding 2q as a single isomer,
although the reaction progressed sluggishly and the yield was
only 12% (Scheme 1). Note that NOESY spectrum of 2q
revealed cross peaks between the vinylic H and the NCH2
group, indicating the selective formation of (Z)-2q. α-Methyl
precursor 1r underwent a smooth cyclization reaction, giving
the corresponding oxazepane 2r in 76% yield.
examined the 7-exo-dig cyclization reaction of various N-
propargylic aza-MBH products 1b−p. The results are
summarized in Table 2. Oxazepanones 2b−p were prepared
a b
,
Table 2. Preparation of Chiral Oxazepanones 2a−p
Oxazepanone 2a underwent the cleavage of the lactone bond
to give ketone 4 in 68% yield by treatment with 1.0 equiv of
NaOMe. Acid-catalyzed hydrolysis of oxazepanone 2a also
provided 4 in 56% yield (Scheme 2).
The hydrogenation reaction of 2a gave the saturated
oxazepine 5 in 67% yield (Scheme 3). Compound 5 contained
two diastereomers whose ratio was almost 1:1. The two
diastereomers 5a,b were separated by a recycle GPC apparatus,
and their configuration was determined by NOE experiments;
a
b
Isolated yield. The enantiomeric excess was determined by chiral
HPLC analyses.
B
dx.doi.org/10.1021/jo501254x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 1
Scheme 5
Scheme 2
reagent Ph3PAuX (X = OTf, SbF6) is generated from
Ph3PAuCl in the presence of the cocatalyst AgSbF6 or
Scheme 3
Cu(OTf)2. Lafollee and Gandon have reported that the
́
presence of Cu(OTf)2 gradually generates the active
[PPh3AuI]+ and that this process slowly reaches equilibrium.15
This slow conversion of PPh3AuCl provides a preferable
generation of the active catalyst in a high-temperature reaction.
The active Au(I) catalyst attacks the terminal alkyne unit in
compound 1 to generate active intermediate A, wherein an
internal 7-exo-dig cyclization by the oxygen in the ester gives
intermediate B.14 Subsequent elimination of isobutene or tert-
butyl cation generates intermediate C, which is protonated to
give product 2 and regenerates active Au(I) catalyst.
In conclusion, we have developed a new route for the
preparation of 1,4-oxazepan-7-ones 2 in one step from optically
active alkynyl esters 1 using catalytic amounts of Ph3PAuCl and
Cu(OTf)2. The conversion is efficient, and oxazepanones are
prepared in moderate to good yields. Oxazepanones 2 contain
two exo methylenes that are poised for further synthetic
modifications and are also regarded to be efficient precursors in
the synthesis of optically active calvine4 and the nitrogen
analogue of the floresolide B structural motif.17
strong signal enhancements for H2 (15%) and H5 (9%) were
observed when H6 in 5a was irradiated, while signal
enhancement was observed for only H2 (19%) when H6 in
5b was irradiated. These results clearly indicated that 5a has an
all-cis configuration but that 5b has a 2,6-cis-5,6-trans
configuration. It is surprising that the steric bias expected by
the phenyl group at C5 position provided no effects on the
stereocontrol during the hydrogenation reaction at the C6
position. Note that very high 2,6-cis selectivity was observed in
the hydrogenation.
The reaction in the presence of NBS gave the oxazepanone
6, with a bromine atom introduced at the vinyl ether moiety of
the molecule (Scheme 4). When the same reaction was
conducted in the absence of the gold catalyst, the starting
material 1a was recovered in 79% yield.
EXPERIMENTAL SECTION
■
Preparation of Compound 1a. Under a nitrogen atmosphere, 1a
(405.3 mg, 1,05 mmol) was added to a mixture of K2CO3 (1.46 g, 10.5
mmol) and propargyl bromide (0.32 mL, 4.2 mmol) in dry DMF (2
mL), and the resulting mixture was strirred at room temperature for 24
h. The reaction mixture was diluted with water (10 mL), and the
resulting mixture was extracted with ether (3 × 10 mL). The organic
layer was combined, washed with brine (1 × 20 mL), and dried over
Na2SO4. After filtration, the filtrate was concentrated under reduced
pressure. The crude residue was purified through flash chromatog-
raphy (silica gel, hexane/EtOAc 10/1 then 5/1, v/v) to give 1a in 83%
yield (371.0 mg, 0.8725 mmol): white solid, mp 57.7−58.5 °C; [α]D =
+86.1° (c 0.97, CHCl3). The enantiomeric purity was determined as
99% ee by HPLC analysis (230 nm, 30 °C): tR 15.6 min (major); tR
16.7 min (minor) [DAICEL CHIRALPAK IC (0.46 cm × 250 mm)
(from Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 82/18, 1,0 mL/
We postulate that Scheme 5 depicts the mechanism for the
Au(I)-catalyzed formation of oxazepanones. At first, the active
Scheme 4
1
min]. H NMR (500 MHz, CDCl3): δ 7.74 (d, J = 8.3 Hz, 2H), 7.24
(d, J = 8.1 Hz, 2H), 7.20−7.15 (m, 3H), 6.99 (dd, J = 7.5, 2.1 Hz, 2H),
6.35 (d, J = 1.6 Hz, 1H), 6.05 (d, J = 1.7 Hz, 1H), 5.83 (d, J = 1.8 Hz,
C
dx.doi.org/10.1021/jo501254x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1H), 4.00 (dd, J = 18.4, 2.5 Hz, 1H), 3.82 (dd, J = 18.4, 2.5 Hz, 1H),
2.39 (s, 3H), 1.92 (t, J = 2.4 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ
165.0, 143.6, 140.3, 137.4, 136.7, 129.5 (2C), 128.8 (2C), 128.6 (2C),
128.2, 127.7 (2C), 126.8, 81.4, 79.1, 72.4, 62.2, 34.9, 27.7 (3C), 21.6.
HRMS (ESI-TOF): calcd for C24H28NO4S 426.1739 [M + H+], found
426.1738.
Preparation of (S)-2,6-Dimethylene-4-tosyl-5-(4-
(trifluoromethyl)phenyl)-1,4-oxazepan-7-one (2d). Under a
nitrogen atmosphere, a mixture of 1d (88.5 mg, 0.179 mmol),
Ph3PAuCl (1.0 mg, 0.002 mmol), and Cu(OTf)2 (4.0 mg, 0.011
mmol) in 1,2-dichloroethane (dried over CaH2 and distilled, 2 mL) in
a 30 mL round-bottom flask was heated at reflux temperature for 45
min. After it was cooled, the reaction mixture was concentrated by
rotary evaporator and then purified through flash chromatography
(silica gel, hexane/EtOAc 7/1 then 3/1 v/v), giving 2d in 77% yield
(60.5 mg, 0.138 mmol): colorless oil; [α]D = −31.2° (c 2.02, CHCl3).
The enantiomeric purity was determined as 84% ee by HPLC analysis
(230 nm, 30 °C): tR 10.0 min (minor); tR 11.4 min (major)
[CHIRALPAK AD (0.46 cm × 250 mm) (from Daicel Chemical Ind.,
Preparation of (S)-2,6-dimethylene-5-phenyl-4-tosyl-1,4-ox-
azepan-7-one (2a). Under a nitrogen atmosphere, a mixture of 1a
(84.1 mg, 0.198 mmol), Ph3PAuCl (1.0 mg, 0.002 mmol), and
Cu(OTf)2 (4.0 mg, 0.011 mmol) in 1,2-dichloroethane (dried over
CaH2 and distilled, 2 mL) in a 30 mL round-bottom flask was heated
at reflux temperature for 100 min. After it was cooled, the reaction
mixture was concentrated by a rotary evaporator and then purified
through flash chromatography (silica gel, hexane/EtOAc 5/1 then 3/1
v/v), giving 2a in 80% yield (58.5 mg, 0.158 mmol): white solid; mp
153−154 °C; [α]D = −37.9° (c 1.48, CHCl3). The enantiomeric purity
was determined as 94% ee by HPLC analysis (230 nm, 40 °C): tR 12.1
min (minor); tR 13.0 min (major) [CHIRALPAK ID (0.46 cm × 250
mm) (from Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 70/30, 1.00
1
Ltd.) hexane/i-PrOH, 80/20, 0.80 mL/min]. H NMR (500 MHz,
CDCl3): δ 7.72 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 7.53 (d, J
= 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 6.30 (s, 1H), 6.06 (s, 1H),
5.51 (s, 1H), 4.88 (s, 1H), 4.65 (s, 1H), 4.22 (d, J = 14.8 Hz, 1H), 3.85
(d, J = 14.8 Hz, 1H), 2.46 (s, 3H). 13C NMR (126 MHz, CDCl3): δ
164.6, 149.1, 144.8, 140.4, 137.8, 135.9, 132.4, 130.8 (d, J = 32.8 Hz),
130.2 (2C), 128.2 (2C), 127.5 (2C), 125.8 (d, J = 3.5 Hz, 2C), 123.9
(d, J = 272.1 Hz), 106.8, 60.2, 46.6, 21.6. HRMS (ESI-TOF): calcd for
C21H18F3NNaO4S 460.0806 [M + Na+], found 460.0801.
1
mL/min]. H NMR (500 MHz, CDCl3): δ 7.72 (d, J = 7.9 Hz, 2H),
7.39 (d, J = 7.3 Hz, 2H), 7.37−7.31 (m, 5H), 6.24 (s, 1H), 6.07 (s,
1H), 5.50 (s, 1H), 4.89 (s, 1H), 4.64 (s, 1H), 4.26 (d, J = 14.9 Hz,
1H), 3.80 (d, J = 15.0 Hz, 1H), 2.45 (s, 3H). 13C NMR (126 MHz,
CDCl3): δ 165.3, 149.4, 144.4, 138.6, 136.2, 135.9, 131.4, 130.0 (2C),
128.8(2C), 128.4, 127.8 (2C), 127.4 (2C), 106.8, 60.3, 46.3, 21.7.
HRMS (ESI-TOF): calcd for C20H19NNaO4S 392.0933 [M + Na+],
found 392.0939.
Preparation of (S)-5-(3-Chlorophenyl)-2,6-dimethylene-4-
tosyl-1,4-oxazepan-7-one (2e). Under a nitrogen atmosphere, a
mixture of 1e (91.7 mg, 0.200 mmol), Ph3PAuCl (1.0 mg, 0.002
mmol), and Cu(OTf)2 (4.0 mg, 0.011 mmol) in 1,2-dichloroethane
(dried over CaH2 and distilled, 2 mL) in a 30 mL round-bottom flask
was heated at reflux temperature for 30 min. After it was cooled, the
reaction mixture was concentrated by rotary evaporator and then
purified through flash chromatography (silica gel, hexane/EtOAc 5/1
then 3/1 v/v), giving 2e in 75% yield (60.8 mg, 0.151 mmol):
colorless oil; [α]D = −35.0° (c 1.05, CHCl3). The enantiomeric purity
was determined as 91% ee by HPLC analysis (230 nm, 30 °C): tR 9.7
min (minor); tR 11.6 min (major) [CHIRALPAK AD (0.46 cm × 250
mm) (from Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 80/20, 0.50
Preparation of (S)-5-(4-Fluorophenyl)-2,6-dimethylene-4-
tosyl-1,4-oxazepan-7-one (2b). Under a nitrogen atmosphere, a
mixture of 1b (88.0 mg, 0.199 mmol), Ph3PAuCl (1.0 mg, 0.002
mmol), and Cu(OTf)2 (4.0 mg, 0.011 mmol) in 1,2-dichloroethane
(dried over CaH2 and distilled, 2 mL) in a 30 mL round-bottom flask
was heated at reflux temperature for 75 min. After it was cooled, the
reaction mixture was concentrated by a rotary evaporator and then
purified through flash chromatography (silica gel, hexane/EtOAc 8/1
then 3/1 v/v), giving 2b in 82% yield (63.0 mg, 0.163 mmol): white
solid; mp 129−130 °C; [α]D = −46.0° (c 0.85, CHCl3). The
enantiomeric purity was determined as 96% ee by HPLC analysis (230
nm, 30 °C): tR 21.2 min (minor); tR 23.0 min (major) [CHIRALPAK
AD (0.46 cm × 250 mm) (from Daicel Chemical Ind., Ltd.) hexane/i-
PrOH, 80/20, 0.50 mL/min]. 1H NMR (500 MHz, CDCl3): δ 7.71 (d,
J = 8.1 Hz, 2H), 7.38 (dd, J = 8.4, 5.4 Hz, 2H), 7.33 (d, J = 8.3 Hz,
2H), 7.04 (t, J = 8.5 Hz, 2H), 6.23 (s, 1H), 6.02 (s, 1H), 5.47 (s, 1H),
4.89 (s, 1H), 4.67 (s, 1H), 4.23 (d, J = 14.9 Hz, 1H), 3.81 (d, J = 14.9
Hz, 1H), 2.45 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 165.0, 162.7
(d, J = 247.0 Hz), 149.3, 144.6, 138.6, 136.0, 131.8 (d, J = 3.2 Hz),
131.6, 130.1 (2C), 129.7 (d, J = 8.2 Hz, 2C), 127.4 (2C), 115.8 (d, J =
8.2 Hz. 2C), 106.7, 59.8, 46.3, 21.7. HRMS (ESI-TOF): calcd for
C20H18FNNaO4S 410.0838 [M + Na+], found 410.0831.
1
mL/min]. H NMR (500 MHz, CDCl3): δ 7.72 (d, J = 8.1 Hz, 2H),
7.34 (d, J = 8.5 Hz, 3H), 7.28 (d, J = 14.3 Hz, 3H), 6.28 (s, 1H), 6.01
(s, 1H), 5.50 (s, 1H), 4.91 (s, 1H), 4.68 (s, 1H), 4.25 (d, J = 14.9 Hz,
1H), 3.84 (d, J = 14.9 Hz, 1H), 2.46 (s, 3H). 13C NMR (126 MHz,
CDCl3): δ 164.7, 149.1, 144.6, 138.3, 137.9, 135.9, 134.8, 132.2, 130.1
(2C), 128.7, 127.9, 127.4, 127.4 (2C), 126.0, 106.9, 60.0, 46.5, 21.7.
HRMS (ESI-TOF): calcd for C20H1935ClNO4S 404.0723 [M + H+],
found 404.0747; calcd for C20H1937ClNO4S 406.0694 [M + H+], found
406.0706.
Preparation of (S)-2,6-Dimethylene-5-(p-tolyl)-4-tosyl-1,4-
oxazepan-7-one (2f). Under a nitrogen atmosphere, a mixture of
1f (86.6 mg, 0.198 mmol), Ph3PAuCl (1.0 mg, 0.002 mmol), and
Cu(OTf)2 (4.0 mg, 0.011 mmol) in 1,2-dichloroethane (dried over
CaH2 and distilled, 2 mL) in a 30 mL round-bottom flask was heated
at reflux temperature for 30 min. After it was cooled, the reaction
mixture was concentrated by rotary evaporator and then purified
through flash chromatography (silica gel, hexane/EtOAc 5/1 then 3/1
v/v), giving 2f in 57% yield (43.3 mg, 0.113 mmol): colorless oil; [α]D
= −33.2° (c 1.39, CHCl3). The enantiomeric purity was determined as
97% ee by HPLC analysis (230 nm, 30 °C: tR 15.7 min (minor); tR
16.9 min (major) [YMC Chiral Amylose-C (0.46 cm × 250 mm)
(from YMC Co., Ltd.) hexane/i-PrOH, 90/10, 1.00 mL/min]. 1H
NMR (500 MHz, CDCl3): δ 7.72 (d, J = 7.8 Hz, 2H), 7.33 (d, J = 7.9
Hz, 2H), 7.14 (d, J = 7.8 Hz, 2H), 6.21 (s, 1H), 6.03 (s, 1H), 5.48 (s,
1H), 4.90 (s, 1H), 4.66 (s, 1H), 4.26 (d, J = 15.0 Hz, 1H), 3.77 (d, J =
15.0 Hz, 1H), 2.45 (s, 3H), 2.34 (s, 3H). 13C NMR (126 MHz,
CDCl3): δ 165.5, 149.5, 144.3, 139.0, 138.3, 136.3, 132.8, 130.9, 130.0
(2C), 129.5 (2C), 127.8 (2C), 127.4 (2C), 106.7, 60.1, 46.2, 21.7,
21.1. HRMS (ESI-TOF): calcd for C21H21NNaO4S 406.1089 [M +
Na+], found 406.1088.
Preparation of (S)-5-(4-Chlorophenyl)-2,6-dimethylene-4-
tosyl-1,4-oxazepan-7-one (2c). Under a nitrogen atmosphere, a
mixture of 1c (92.7 mg, 0.202 mmol), Ph3PAuCl (1.0 mg, 0.002
mmol), and Cu(OTf)2 (4.0 mg, 0.011 mmol) in 1,2-dichloroethane
(dried over CaH2 and distilled, 2 mL) in a 30 mL round-bottom flask
was heated at reflux temperature for 70 min. After it was cooled, the
reaction mixture was concentrated by a rotary evaporator and then
purified through flash chromatography (silica gel, hexane/EtOAc 5/1
then 3/1 v/v), giving 2c in 86% yield (69.3 mg, 0.172 mmol): colorless
oil; [α]D = −31.5° (c 1.43, CHCl3). The enantiomeric purity as 91%
ee was determined by HPLC analysis (230 nm, 30 °C): tR 56.1 min
(minor); tR 61.2 min (major) [CHIRALPAK AD (0.46 cm × 250
mm) (from Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 80/20, 0.20
1
mL/min]. H NMR (500 MHz, CDCl3): δ 7.72 (d, J = 8.1 Hz, 2H),
7.34 (d, J = 8.1 Hz, 6H), 6.26 (s, 1H), 6.01 (s, 1H), 5.48 (s, 1H), 4.89
(s, 1H), 4.66 (s, 1H), 4.22 (d, J = 14.9 Hz, 1H), 3.81 (d, J = 14.9 Hz,
1H), 2.45 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 164.8, 149.1,
144.6, 138.2, 136.0, 134.6, 134.5, 131.9, 130.1 (2C), 129.2 (2C), 129.0
(2C), 127.4 (2C), 106.8, 59.9, 46.4, 21.7. HRMS (ESI-TOF): calcd for
C20H1935ClNO4S 404.0723 [M + H+], found 404.0719; calcd for
C20H1937ClNO4S 406.0694 [M + H+], found 406.0692.
Preparation of (S)-2,6-Dimethylene-5-(o-tolyl)-4-tosyl-1,4-
oxazepan-7-one (2g). Under a nitrogen atmosphere, a mixture of
1g (88.1 mg, 0.201 mmol), Ph3PAuCl (1.0 mg, 0.002 mmol), and
Cu(OTf)2 (4.0 mg, 0.011 mmol) in 1,2-dichloroethane (dried over
CaH2 and distilled, 2 mL) in a 30 mL round-bottom flask was heated
D
dx.doi.org/10.1021/jo501254x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
at reflux temperature for 35 min. After it was cooled, the reaction
mixture was concentrated by rotary evaporator and then purified
through flash chromatography (silica gel, hexane/EtOAc 5/1 then 3/1
v/v), giving 2g in 50% yield (38.5 mg, 0.100 mmol): colorless oil; [α]D
= −18.2° (c 1.28, CHCl3). The enantiomeric purity was determined as
96% ee by HPLC analysis (230 nm, 30 °C): tR 42.3 min (minor); tR
45.0 min (major) [DAICEL CHIRALPAK ID (0.46 cm × 250 mm)
(from Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 80/20, 0.50 mL/
min]. 1H NMR (500 MHz, CDCl3): δ 7.61 (d, J = 8.2 Hz, 2H), 7.32−
7.18 (m, 5H), 7.09 (t, J = 6.8 Hz, 1H), 6.20 (s, 1H), 6.09 (s, 1H), 5.28
(s, 1H), 4.97 (s, 1H), 4.70 (s, 1H), 4.47 (d, J = 16.0 Hz, 1H), 3.89 (d, J
= 16.1 Hz, 1H), 2.47 (s, 3H), 2.43 (s, 3H). 13C NMR (126 MHz,
CDCl3): δ 165.4, 150.2, 144.3, 140.2, 137.7, 136.1, 134.6, 131.3, 129.9
(2C), 129.5, 128.7, 128.6, 127.5 (2C), 125.9, 105.1, 58.5, 46.6, 21.7,
19.9. HRMS (ESI-TOF): calcd for C21H21NNaO4S 406.1089 [M +
Na+], found 406.1096.
Preparation of (S)-5-(2-Bromophenyl)-2,6-dimethylene-4-
tosyl-1,4-oxazepan-7-one (2h). Under a nitrogen atmosphere, a
mixture of 1h (100.5 mg, 0.200 mmol), Ph3PAuCl (1.0 mg, 0.002
mmol), and Cu(OTf)2 (4.0 mg, 0.011 mmol) in 1,2-dichloroethane
(dried over CaH2 and distilled, 2 mL) in a 30 mL round-bottom flask
was heated at reflux temperature for 45 min. After it was cooled, the
reaction mixture was concentrated by rotary evaporator and then
purified through flash chromatography (silica gel, hexane/EtOAc 5/1
then 2/1 v/v), giving 2h in 40% yield (35.5 mg, 0.079 mmol):
colorless oil; [α]D = −30.9° (c 1.18, CHCl3). The enantiomeric purity
was determined as 97% ee by HPLC analysis (230 nm, 30 °C): tR 30.0
min (minor); tR 32.4 min (major) [DAICEL CHIRALPAK ID (0.46
cm × 250 mm) (from Daicel Chemical Ind., Ltd.) hexane/i-PrOH,
80/20, 1.00 mL/min]. 1H NMR (500 MHz, CDCl3): δ 7.66 (d, J = 8.3
Hz, 2H), 7.54 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.27 (d, J
= 8.3 Hz, 4H), 7.16 (t, J = 7.3 Hz, 1H), 6.08 (s, 1H), 6.00 (s, 1H), 5.24
(s, 1H), 4.98 (s, 1H), 4.80 (s, 1H), 4.39 (q, J = 15.8 Hz, 2H), 2.42 (s,
3H). 13C NMR (126 MHz, CDCl3): δ 1164.7, 150.6, 144.4, 138.4,
136.3, 135.4, 133.6, 130.1, 129.9 (2C), 129.3, 127.9, 127.6 (2C), 124.1,
102.8, 77.1, 61.8, 47.4, 21.6. HRMS (ESI-TOF): calcd for
C20H1979BrNO4S 448.0218 [M + H+], found 448.0193; calcd for
C20H1981BrNO4S 450.0198 [M + H+], found 450.0203.
was determined as 95% ee by HPLC analysis (230 nm, 30 °C): tR 13.9
min (minor); tR 15.6 min (major) [DAICEL CHIRALPAK AD (0.46
cm × 250 mm) (from Daicel Chemical Ind., Ltd.) hexane/i-PrOH,
80/20, 1.00 mL/min]. 1H NMR (500 MHz, CDCl3): δ 7.86−7.82 (m,
2H), 7.78−7.73 (m, 4H), 7.55−7.49 (m, 3H), 7.34 (d, J = 8.2 Hz,
2H), 6.33 (s, 1H), 6.23 (s, 1H), 5.58 (s, 1H), 4.90 (s, 1H), 4.62 (s,
1H), 4.32 (d, J = 15.0 Hz, 1H), 3.80 (d, J = 15.0 Hz, 1H), 2.45 (s, 3H).
13C NMR (126 MHz, CDCl3): δ 165.2, 149.5, 144.5, 138.6, 136.3,
133.3, 133.1, 133.0, 131.7, 130.1 (2C), 128.8, 128.2, 127.7, 127.5 (2C),
127.4, 126.8, 126.6, 125.3, 106.9, 60.5, 46.5, 21.7. HRMS (ESI-TOF):
calcd for C24H21NNaO4S 442.1089 [M + Na+], found 442.1094.
Preparation of (S)-5-Butyl-2,6-dimethylene-4-tosyl-1,4-oxa-
zepan-7-one (2l). Under a nitrogen atmosphere, a mixture of 1l
(81.0 mg, 0.200 mmol), Ph3PAuCl (1.0 mg, 0.002 mmol), and
Cu(OTf)2 (4.0 mg, 0.011 mmol) in 1,2-dichloroethane (dried over
CaH2 and distilled, 2 mL) in a 30 mL round-bottom flask was heated
at reflux temperature for 5 min. After it was cooled, the reaction
mixture was concentrated by rotary evaporator and then purified
through flash chromatography (silica gel, hexane/EtOAc 8/1 then 6/1
v/v), giving 2l in 56% yield (38.7 mg, 0.111 mmol): colorless oil; [α]D
= −3.47° (c 1.27, CHCl3). The enantiomeric purity was determined as
91% ee by HPLC analysis (230 nm, 30 °C): tR 33.8 min (minor); tR
35.4 min (major) [DAICEL CHIRALPAK ID (0.46 cm × 250 mm)
(from Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 85/15, 0.50 mL/
1
min]. H NMR (500 MHz, CDCl3): δ 7.68 (d, J = 8.2 Hz, 2H), 7.30
(d, J = 8.1 Hz, 2H), 5.88 (s, 1H), 5.41 (s, 1H), 4.99 (d, J = 1.4 Hz,
1H), 4.90 (s, 1H), 4.71−4.61 (m, 1H), 4.29 (d, J = 15.1 Hz, 1H), 3.90
(d, J = 15.1 Hz, 1H), 2.43 (s, 3H), 1.85−1.76 (m, 1H), 1.68 (dt, J =
12.6, 6.3 Hz, 1H), 1.34−1.26 (m, 4H), 0.88 (dd, J = 9.0, 4.5 Hz, 3H).
13C NMR (126 MHz, CDCl3): δ 166.0, 150.6, 144.1, 141.3, 136.6,
129.9 (2C), 128.4, 127.4 (2C), 106.5, 57.7, 45.5, 32.3, 28.1, 22.2, 21.7,
13.9. HRMS (ESI-TOF): calcd for C18H23NNaO4S 372.1246 [M +
Na+], found 372.1254.
Preparation of (S)-2,6-Dimethylene-5-pentyl-4-tosyl-1,4-ox-
azepan-7-one (2m). Under a nitrogen atmosphere, a mixture of 1m
(83.9 mg, 0.200 mmol), Ph3PAuCl (1.0 mg, 0.002 mmol), and
Cu(OTf)2 (4.0 mg, 0.011 mmol) in 1,2-dichloroethane (dried over
CaH2 and distilled, 2 mL) in a 30 mL round-bottom flask was heated
at reflux temperature for 50 min. After it was cooled, the reaction
mixture was concentrated by rotary evaporator and then purified
through flash chromatography (silica gel, hexane/EtOAc 8/1 then 5/1
v/v), giving 2m in 68% yield (49.4 mg, 0.136 mmol): white solid; mp
82−83 °C; [α]D = −11.1° (c 1.65, CHCl3). The enantiomeric purity
was determined as 86% ee by HPLC analysis (230 nm, 30 °C): tR 11.1
min (major); tR 12.1 min (minor) [YMC Chiral Cellulose-C (0.46 cm
× 250 mm) (from YMC Co., Ltd.) hexane/i-PrOH, 80/20, 0.50 mL/
Preparation of (S)-2,6-Dimethylene-5-(m-tolyl)-4-tosyl-1,4-
oxazepan-7-one (2i). Under a nitrogen atmosphere, a mixture of 1i
(87.1 mg, 0.198 mmol), Ph3PAuCl (1.0 mg, 0.002 mmol), and
Cu(OTf)2 (4.0 mg, 0.011 mmol) in 1,2-dichloroethane (dried over
CaH2 and distilled, 2 mL) in a 30 mL round-bottom flask was heated
at reflux temperature for 45 min. After it was cooled, the reaction
mixture was concentrated by rotary evaporator and then purified
through flash chromatography (silica gel, hexane/EtOAc 5/1 then 3/1
v/v), giving 2i in 60% yield (45.1 mg, 0.118 mmol): pale yellow oil;
[α]D = −41.5° (c 1.50, CHCl3). The enantiomeric purity was
determined as 95% ee by HPLC analysis (230 nm, 30 °C): tR 8.8 min
(minor); tR 10.2 min (major) [DAICEL CHIRALPAK AD (0.46 cm ×
250 mm) (from Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 80/20,
1
min]. H NMR (500 MHz, CDCl3): δ 7.67 (d, J = 7.7 Hz, 2H), 7.30
(d, J = 7.7 Hz, 2H), 5.88 (s, 1H), 5.42 (s, 1H), 4.99 (s, 1H), 4.90 (s,
1H), 4.65 (t, J = 7.7 Hz, 1H), 4.29 (d, J = 15.1 Hz, 1H), 3.89 (d, J =
15.1 Hz, 1H), 2.42 (s, 3H), 1.79 (dt, J = 18.7, 7.0 Hz, 1H), 1.70−1.62
(m, 1H), 1.27 (d, J = 3.5 Hz, 6H), 0.87 (s, 3H). 13C NMR (126 MHz,
CDCl3): δ 166.0, 150.6, 144.1, 141.3, 136.6, 129.9 (2C), 128.3, 127.4
(2C), 106.5, 57.7, 45.5, 32.6, 31.3, 25.6, 22.5, 21.6, 14.0. HRMS (ESI-
TOF): calcd for C19H25NNaO4S, 386.1402 [M + Na+], found
386.1395.
1
1.00 mL/min]. H NMR (500 MHz, CDCl3): δ 7.72 (d, J = 8.2 Hz,
2H), 7.33 (d, J = 8.1 Hz, 2H), 7.21 (q, J = 7.8 Hz, 1H), 7.15 (d, J = 7.3
Hz, 2H), 7.11 (d, J = 7.4 Hz, 1H), 6.22 (s, 1H), 6.02 (s, 1H), 5.49 (s,
1H), 4.90 (s, 1H), 4.65 (s, 1H), 4.28 (d, J = 15.0 Hz, 1H), 3.80 (d, J =
15.0 Hz, 1H), 2.45 (s, 3H), 2.31 (s, 3H). 13C NMR (126 MHz,
CDCl3): δ 165.4, 149.6, 144.3, 138.8, 138.6, 136.4, 135.8, 131.3, 130.0
(2C), 129.2, 128.6, 128.6, 127.5 (2C), 124.9, 106.7, 60.4, 46.3, 21.7,
21.5. HRMS (ESI-TOF): calcd for C21H21NNaO4S 406.1089 [M +
Na+], found 406.1094.
Preparation of (S)-2,6-Dimethylene-5-(naphthalen-2-yl)-4-
tosyl-1,4-oxazepan-7-one (2j). Under a nitrogen atmosphere, a
mixture of 1j (88.9 mg, 0.187 mmol), Ph3PAuCl (0.9 mg, 0.002
mmol), and Cu(OTf)2 (4.0 mg, 0.011 mmol) in 1,2-dichloroethane
(dried over CaH2 and distilled, 1.9 mL) in a 30 mL round-bottom flask
was heated at reflux temperature for 15 min. After it was cooled, the
reaction mixture was concentrated by rotary evaporator and then
purified through flash chromatography (silica gel, hexane/EtOAc 8/1
then 5/1 v/v), giving 2j in 49% yield (38.0 mg, 0.091 mmol): pale
yellow oil; [α]D = −31.9° (c 1.27, CHCl3). The enantiomeric purity
Preparation of (S)-5-Isopropyl-2,6-dimethylene-4-tosyl-1,4-
oxazepan-7-one (2n). Under a nitrogen atmosphere, a mixture of 1n
(78.1 mg, 0.200 mmol), Ph3PAuCl (1.0 mg, 0.002 mmol), and
Cu(OTf)2 (4.0 mg, 0.011 mmol) in 1,2-dichloroethane (dried over
CaH2 and distilled, 2 mL) in a 30 mL round-bottom flask was heated
at reflux temperature for 60 min. After it was cooled, the reaction
mixture was concentrated by rotary evaporator and then purified
through flash chromatography (silica gel, hexane/EtOAc 8/1 then 5/1
v/v), giving 2n in 56% yield (37.7 mg, 0.112 mmol): colorless oil;
[α]D = −34.8° (c 1.24, CHCl3). The enantiomeric purity was
determined as 90% ee by HPLC analysis (230 nm, 30 °C): tR 17.8 min
(major); tR 20.4 min (minor) [DAICEL CHIRALPAK IC (0.46 cm ×
250 mm) (from Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 80/20,
1
0.80 mL/min]. H NMR (500 MHz, CDCl3): δ 7.69 (d, J = 8.2 Hz,
2H), 7.30 (d, J = 8.1 Hz, 2H), 5.88 (s, 1H), 5.40 (s, 1H), 4.95 (s, 1H),
E
dx.doi.org/10.1021/jo501254x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
4.80 (s, 1H), 4.18 (d, J = 14.9 Hz, 1H), 4.09 (d, J = 11.2 Hz, 1H), 3.87
(d, J = 14.9 Hz, 1H), 2.42 (s, 3H), 2.08−1.90 (m, 1H), 0.97 (d, J = 6.6
Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ
165.8, 151.0, 144.1, 139.3, 136.7, 130.4, 129.8 (2C), 127.8 (2C), 106.7,
65.3, 45.5, 28.9, 21.5, 19.8, 19.5. HRMS (ESI-TOF): calcd for
C17H21NNaO4S 358.1089 [M + Na+], found 358.1097.
Hz, 1H), 2.44 (s, 3H), 1.42 (dd, J = 6.9, 1.6 Hz, 3H). 13C NMR (126
MHz, CDCl3): δ 165.7, 144.3, 142.0, 138.6, 136.6, 136.4, 131.3, 130.0
(2C), 128.7 (2C), 128.3, 127.5 (2C), 127.4 (2C), 118.2, 60.2, 47.1,
21.7, 10.5. HRMS (ESI-TOF): calcd for C21H22NO4S 384.12670 [M +
H+], found 384.1272.
Preparation of (5R,6R)-6-Methyl-2-methylene-5-phenyl-4-
tosyl-1,4-oxazepan-7-one (2r). Under a nitrogen atmosphere, a
mixture of 1r (82.7 mg, 0.194 mmol), Ph3PAuCl (1.4 mg, 0.0028
mmol), and Cu(OTf)2 (4.4 mg, 0.0121 mmol) in 1,2-dichloroethane
(dried over CaH2 and distilled, 2 mL) in a 30 mL round-bottom flask
was heated at 75 °C temperature for 100 min. After it was cooled, the
reaction mixture was concentrated by rotary evaporator and then
purified through flash chromatography (silica gel, hexane/EtOAc 15/1
then 7/1 v/v), giving 2r in 76% yield (54.4 mg, 0.147 mmol): colorless
semisolid; [α]D = +29.9° (c 1.48, CHCl3). 1H NMR (500 MHz,
CDCl3): δ 7.49 (d, J = 8.2 Hz, 2H), 7.27−7.06 (m, 7H), 5.02 (s, 1H),
5.01 (s, 1 H), 4.99 (d, J = 3.8 Hz, 1 H), 4.53 (d, J = 15.2 Hz, 1H), 3.56
(d, J = 15.3 Hz, 1H), 3.21 (qd, J = 7.0, 3.1 Hz, 1H), 2.32 (s, 3H), 1.16
(d, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 172.1, 151.6,
144.1, 136.8, 134.6, 129.9 (2C), 129.0 (2C), 128.7, 128.5 (2C), 127.5
(2C), 107.9, 60.9, 45.6, 43.1, 21.6, 16.5. HRMS (ESI-TOF): calcd for
C20H21NNaO4S 394.1089 [M + Na+], found 394.1089.
Preparation of (S)-5-Cyclohexyl-2,6-dimethylene-4-tosyl-
1,4-oxazepan-7-one (2o). Under a nitrogen atmosphere, a mixture
of 1o (86.0 mg, 0.199 mmol), Ph3PAuCl (1.0 mg, 0.002 mmol), and
Cu(OTf)2 (4.0 mg, 0.011 mmol) in 1,2-dichloroethane (dried over
CaH2 and distilled, 2 mL) in a 30 mL round-bottom flask was heated
at reflux temperature for 120 min. After it was cooled, the reaction
mixture was concentrated by rotary evaporator and then purified
through flash chromatography (silica gel, hexane/EtOAc 8/1 then 6/1
v/v), giving 2o in 61% yield (45.6 mg, 0.122 mmol): colorless oil; [α]D
= −24.4° (c 1.52, CHCl3). The enantiomeric purity was determined as
98% ee by HPLC analysis (230 nm, 30 °C): tR 20.1 min (major); tR
21.2 min (minor) [DAICEL CHIRALPAK ID (0.46 cm × 250 mm)
(from Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 90/10, 0.80 mL/
1
min]. H NMR (500 MHz, CDCl3): δ 7.68 (d, J = 8.1 Hz, 2H), 7.29
(d, J = 8.0 Hz, 2H), 5.86 (s, 1H), 5.38 (s, 1H), 4.95 (s, 1H), 4.77 (s,
1H), 4.20−4.14 (m, 2H), 3.84 (d, J = 15.0 Hz, 1H), 2.42 (s, 3H),
1.88−1.61 (m, 6H), 1.22−1.09 (m, 3H), 0.93 (dd, J = 22.6, 10.8 Hz,
1H), 0.81 (dd, J = 17.1, 8.0 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ
165.8, 150.8, 143.9, 138.9, 136.6, 130.4, 129.7 (2C), 127.6 (2C), 106.7,
63.9, 45.5, 37.4, 30.3, 29.6, 26.0, 25.7, 25.7, 21.5. HRMS (ESI-TOF):
calcd for C20H25NNaO4S 398.1402 [M + Na+], found 398.1397.
Preparation of (S)-5-(tert-Butyl)-2,6-dimethylene-4-tosyl-
1,4-oxazepan-7-one (2p). Under a nitrogen atmosphere, a mixture
of 1p (94.3 mg, 0.233 mmol), Ph3PAuCl (1.1 mg, 0.0022 mmol), and
Cu(OTf)2 (4.8 mg, 0.013 mmol) in 1,2-dichloroethane (dried over
CaH2 and distilled, 2.4 mL) in a 30 mL round-bottom flask was heated
at reflux temperature for 40 min. After it was cooled, the reaction
mixture was concentrated by rotary evaporator and then purified
through flash chromatography (silica gel, hexane/EtOAc 12/1 then 5/
1 v/v), giving 2p in 30% yield (24.6 mg, 0.0705 mmol) along with 3p
in 18% yield (17.1 mg, 0.0422 mmol). Compound 2p: colorless oil;
[α]D = +11.5° (c 0.82, CHCl3). The enantiomeric purity was
determined as 99% ee by HPLC analysis (230 nm, 30 °C): tR 23.6 min
(major); tR 26.3 min (minor) [DAICEL CHIRALPAK AD (0.46 cm ×
250 mm) (from Daicel Chemical Ind., Ltd.) hexane/i-PrOH, 80/20,
Basic Hydrolysis of Compound 2a. Under a nitrogen
atmosphere, a solution of 2a (56.8 mg, 0.154 mmol) and NaOMe
(8.1 mg, 0.15 mmol) in MeOH (1.5 mL) was stirred at room
temperature for 3 h. The solution was diluted with aqueous NH4Cl
(10 mL), and the resulting mixture was extracted with EtOAc (3 × 20
mL). The organic layer was combined, washed with brine (1 × 20
mL), and dried over Na2SO4. After filtration, the filtrate was
concentrated under reduced pressure. The crude residue was purified
through flash chromatography (silica gel, hexane/EtOAc 10/1 then 3/
1, v/v) to give 4 in 68% yield (41.6 mg, 0.104 mmol): white solid, mp
1
133−134 °C; [α]D = +139.0° (c 0.74, CHCl3). H NMR (500 MHz,
CDCl3): δ 7.78 (d, J = 7.2 Hz, 2H), 7.35−7.19 (m, 5H), 7.08 (s, 2H),
6.31 (s, 1H), 6.11 (s, 1H), 5.68 (s, 1H), 3.97 (dd, J = 37.8, 18.2 Hz,
2H), 3.60 (s, 3H), 2.44 (s, 3H), 1.82 (s, 3H). 13C NMR (126 MHz,
CDCl3): δ 203.6, 166.2, 143.8, 138.5, 136.5, 136.4, 129.5 (2C), 128.7
(2C), 128.6 (2C), 128.4, 128.1 (2C), 127.8, 61.7, 54.3, 52.1, 26.6, 21.7.
HRMS (ESI-TOF): calcd for C21H23NNaO5S 424.1195 [M + Na+],
found 424.1197.
Acidic Hydrolysis of Compound 2a. Under a nitrogen
atmosphere, a solution of 2a (36.5 mg, 0.099 mmol) in MeOH/12
M HCl (10/1, 10 mL) in a 30 mL round-bottom flask was stirred at
room temperature for 16 h. The solution was diluted with water (10
mL,) and the resulting mixture was extracted with CH2Cl2 (3 × 15
mL). The organic layer was combined, washed with water (1 × 20
mL) and brine (1 × 20 mL), and dried over Na2SO4. After filtration,
the filtrate was concentrated under reduced pressure. The crude
residue was purified through flash chromatography (silica gel, hexane/
EtOAc 2/1, v/v) to give 4 in 56% yield (22.2 mg, 0.055 mmol).
Hydrogenation Reaction of 2a. A mixture of 2a (51.1 mg, 13.8
mmol) and Pd/C (29.7 mg) in MeOH (2 mL) was charged in a
pressure bottle (90 mL) and stirred vigorously under 5 MPa of
hydrogen atmosphere for 24 h at room temperature. The reaction
mixture was filtered, and the filtrate was concentrated in vacuo to give
5 in 67% yield (34.3 mg, 0.092 mmol). The product contained two
diastereomers which were separated by a recycle GPC apparatus.
1
0.30 mL/min]. H NMR (500 MHz, CDCl3): δ 7.70 (d, J = 8.3 Hz,
2H), 7.29 (d, J = 8.2 Hz, 2H), 5.79 (s, 1H), 5.44 (s, 1H), 4.84 (s, 1H),
4.49 (d, J = 1.7 Hz, 1H), 4.46 (d, J = 16.0 Hz, 1H), 4.42 (s, 1H), 4.08
(d, J = 16.0 Hz, 1H), 2.42 (s, 3H), 1.06 (s, 9H). 13C NMR (126 MHz,
CDCl3): δ 168.3, 150.8, 144.1, 138.6, 136.8, 130.4, 129.7 (2C), 128.1
(2C), 108.07, 67.87, 47.11, 36.7, 28.6 (3C), 21.6. HRMS (ESI-TOF):
calcd for C18H23NNaO4S 372.1246 [M + Na+], found 372.1242.
Compound 3p: colorless oil; [α]D = +16.4° (c 0.55, CHCl3). 1H NMR
(500 MHz, CDCl3): δ 7.65 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.3 Hz,
2H), 6.91 (dd, J = 17.9, 10.9 Hz, 1H), 5.32 (d, J = 10.9 Hz, 1H), 5.23
(d, J = 17.8 Hz, 1H), 4.56 (d, J = 2.6 Hz, 1H), 4.37 (d, J = 17.4 Hz,
1H), 4.21 (dd, J = 17.4, 2.7 Hz, 1H), 2.37 (s, 3H), 1.42 (s, 9H), 0.98
(s, 9H). 13C NMR (126 MHz, CDCl3): δ 162.9, 144.6, 143.6, 134.0,
130.5, 129.5 (2C), 128.3, 127.7 (2C), 121.1, 81.5, 56.2, 38.7, 30.7, 28.0
(3C), 26.9 (3C), 21.6. HRMS (ESI-TOF): calcd for C22H31NNaO4S
428.1866 [M + Na+], found 428.1872.
1
5a: colorless oil; [α]D = −18.1° (c 0.70, CHCl3). H NMR (500
Preparation of (S)-6-Methylene-5-phenyl-2-(Z)-propylidene-
4-tosyl-1,4-oxazepan-7-one (2q). Under a nitrogen atmosphere, a
mixture of 1q (147.3 mg, 0.33 mmol), Ph3PAuCl (1.7 mg, 0.0034
mmol), and Cu(OTf)2 (7.1 mg, 0.020 mmol) in 1,2-dichloroethane
(dried over CaH2 and distilled, 3 mL) in a 30 mL round-bottom flask
was heated at reflux temperature for 6 h. After it was cooled, the
reaction mixture was concentrated by rotary evaporator and then
purified through flash chromatography (silica gel, hexane/EtOAc 5/1
v/v), giving (Z)-2q in 15% yield as a single isomer (15.0 mg, 0.039
MHz, CDCl3): δ 7.50−7.16 (m, 9H), 5.20 (d, J = 2.9 Hz, 1H), 4.69
(dt, J = 14.2, 6.6 Hz, 1H), 3.88 (d, J = 15.9 Hz, 1H), 3.33 (qd, J = 7.0,
3.2 Hz, 1H), 3.20 (dd, J = 15.0, 8.8 Hz, 1H), 2.39 (s, 3H), 1.37 (d, J =
6.5 Hz, 3H), 1.24 (d, J = 7.0 Hz, 3H). 13C NMR (126 MHz, CDCl3):
δ 174.5, 143.9, 136.8, 134.7, 129.9 (2C), 128.9 (2C), 128.6, 128.5
(2C), 127.1 (2C), 77.4, 75.9, 60.8, 49.6, 44.2, 21.6, 19.6, 16.4. HRMS
(ESI-TOF): calcd for C20H23NNaO4S 396.1246 [M + Na+], found
396.1237.
1
1
mmol): colorless oil; [α]D = −35.1° (c 0.65, CHCl3). H NMR (500
5b: colorless oil; [α]D = +4.08° (c 0.64, CHCl3). H NMR (500
MHz, CDCl3): δ 7.71 (d, J = 8.3 Hz, 2H), 7.38−7.26 (m, 7H), 6.28 (d,
J = 1.2 Hz, 1H), 6.06 (s, 1H), 5.47 (d, J = 1.4 Hz, 1H), 4.90 (qd, J =
6.7, 1.0 Hz, 1H), 4.16 (ddd, J = 14.5, 2.7, 1.4 Hz, 1H), 3.74 (d, J = 14.5
MHz, CDCl3): δ 7.69−7.26 (m, 9H), 5.18 (d, J = 8.3 Hz, 1H), 4.51
(hept, J = 6.3 Hz, 1H), 3.54 (dt, J = 14.0, 6.7 Hz, 1H), 3.46 (dd, J =
13.5, 10.8 Hz, 1H), 3.20 (dd, J = 13.9, 4.5 Hz, 1H), 2.42 (s, 3H), 1.29
F
dx.doi.org/10.1021/jo501254x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(d, J = 6.6 Hz, 3H), 1.24 (d, J = 6.3 Hz, 3H). 13C NMR (126 MHz,
CDCl3): δ 172.6, 144.1, 136.5, 136.2, 129.8 (2C), 129.4 (2C), 128.6,
127.6 (2C), 127.3 (2C), 69.4, 60.6, 48.1, 41.6, 21.7, 19.0, 16.7. HRMS
(ESI-TOF): calcd for C20H23NNaO4S 396.1246 [M + Na+], found
396.1246.
(6) Kamimura, A.; Okawa, H.; Morisaki, Y.; Ishikawa, S.; Uno, H. J.
Org. Chem. 2007, 72, 3569.
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3578.
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Lett. 2010, 51, 2329.
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(b) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239.
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Preparation of Compound 6. Under a nitrogen atmosphere, a
mixture of 1a (83.0 mg, 0.195 mmol), Ph3PAuCl (1.0 mg, 0.002
mmol), Cu(OTf)2 (4.0 mg, 0.011 mmol), and NBS (35.0 mg, 0.197
mmol) in 1,2-dichloroethane (dried over CaH2 and distilled, 2.0 mL)
in a 30 mL round-bottom flask was heated at reflux until the
disappearance of 1a. After it was cooled, the reaction mixture was
concentrated by rotary evaporator and then purified through flash
chromatography (silica gel, hexane/EtOAc 8/1 then 5/1 v/v), giving 6
in 22% yield (18.9 mg, 0.0423 mmol): white semisolid; [α]D = + 47.5°
(c 0.16, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.72 (d, J = 8.3 Hz,
2H), 7.42−7.32 (m, 7H), 6.26 (d, J = 1.7 Hz, 1H), 6.20 (d, J = 1.4 Hz,
1H), 6.11 (s, 1H), 5.51 (d, J = 1.7 Hz, 1H), 4.20 (dd, J = 34.6, 15.6 Hz,
2H), 2.45 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 164.6, 145.9,
144.5, 138.5, 136.2, 135.4, 131.5, 130.1 (2C), 129.1 (2C), 128.7, 128.2
(2C), 127.5 (2C), 102.4, 60.2, 43.6, 21.7. HRMS (ESI-TOF): calcd for
C20H1879BrNNaO4S 470.0038 [M + Na+], found 470.0044; calcd for
C20H1881BrNNaO4S 472.0017 [M + 2 + Na+], found 472.0034.
(d) Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410.
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ASSOCIATED CONTENT
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S
* Supporting Information
1
Figures and a CIF file giving H and 13C NMR spectra for
(12) (a) Obradors, C.; Echavarren, A. M. Acc. Chem. Res. 2014, 47,
compounds 1a, 2, 3p, 4, 5, and 6, an ORTEP drawing and
crystallographic data for 2a, and chiral HPLC data for 1a and 2.
This material is available free of charge via the Internet at
http://pubs.acs.org.
902. (b) Amijs, C. H. M.; Lop
Galan, P.; Ferrer, C.; Echavarren, A. M. J. Org. Chem. 2008, 73, 7721.
(c) Cabello, N.; Jimenez-Nunez, E.; Bunuel, E.; Cardenas, D. J.;
Echavarren, A. M. Eur. J. Org. Chem. 2007, 4217. (d) Lopez, S.;
Herrero-Gomez, E.; Perez-Galan, P.; Nieto-Oberhuber, C.;
Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 6029. (e) Nieto-
Oberhuber, C.; Munoz, M. P.; Lopez, S.; Jimenez-Nunez, E.; Nevado,
ez, E.; Raducan, M.; Echavarren, A. M. Chem. Eur. J.
2006, 12, 1677. (f) Nieto-Oberhuber, C.; Lopez, S.; Munoz, M. P.;
Jimenez-Nunez, E.; Bunuel, E.; Cardenas, D. J.; Echavarren, A. M.
Chem. Eur. J. 2006, 12, 1694. (g) Nieto-Oberhuber, C.; Munoz, M. P.;
́ ́
ez-Carrillo, V.; Raducan, M.; Perez-
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́
AUTHOR INFORMATION
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Corresponding Author
*E-mail for A.K.: ak10@yamaguchi-u.ac.jp.
C.; Herrero-Gom
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Notes
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The authors declare no competing financial interest.
Buæuel, E.; Nevado, C.; Car
Chem., Int. Ed. 2004, 43, 2402.
(13) Harkat, H.; Dembele,
Tetrahedron 2009, 65, 1871.
́
denas, D. J.; Echavarren, A. M. Angew.
ACKNOWLEDGMENTS
́
A. Y.; Weibel, J.-M.; Blanc, A.; Pale, P.
■
We are grateful for financial aid from Yamaguchi University
under The YU Strategic Program for Fostering Research
Activities (2010−2011 and 2013−2014). We are also grateful
to Drs. Tsuyoshi Arai and Yousuke Oota, UBE Scientific
Analysis Laboratory Inc., for the NMR analyses of several
compounds.
(14) (a) Nguyen, K. H.; Tomasi, S.; Le Roch, M.; Toupet, L.;
Renault, J.; Uriac, P.; Gouault, N. J. Org. Chem. 2013, 78, 7809.
(b) Shu, C.; Liu, M.-Q.; Wang, S.-S.; Li, L.; Ye, L.-W. J. Org. Chem.
2013, 78, 3292. (c) Nguyen, K. H.; Tomasi, S.; Le Roch, M.; Toupet;
Renault, J.; Uriac, P.; Gouault, N. J. Org. Chem. 2013, 78, 7809.
(d) Gregory, A. W.; Jakubec, P.; Turner, P.; Dixon, D. J. Org. Lett.
2013, 15, 4330. (e) Hashmi, A. S. K.; Jaimes, M. C. B.; Schuster, A. M.;
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Lee, J. H.; Na, Y. J. Chem. Commun. 2008, 5794. (g) Buzas, A.; Gagosz,
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dx.doi.org/10.1021/jo501254x | J. Org. Chem. XXXX, XXX, XXX−XXX