3,3-Dimethoxypropylsulfonyl Group: A new versatile protecting and activating group for amine synthesis

Article abstract of DOI:10.1016/j.tet.2018.04.088

3,3-Dimethoxypropylsulfonyl (Dimps) chloride was prepared and used as a new versatile sulfonating agent for ammonia, primary and secondary amines to afford corresponding Dimps-amides in excellent yields. The resulting N-nonsubstituted and N-monosubstituted Dimps-amides, activated amines, were alkylated satisfactorily under new Mitsunobu conditions. The Dimps group was removed by treatment in aqueous solution under acidic followed by basic conditions. Furthermore, epilachnene, the defensive droplets from the Mexican bean beetle, Epilachna varivestis, was synthesized utilizing this Dimps methodology in short steps.

Full text of DOI:10.1016/j.tet.2018.04.088

Accepted Manuscript
3,3-Dimethoxypropylsulfonyl Group: A new versatile protecting and activating group
for amine synthesis
Izumi Sakamoto, Kazuya Iwaoka, Yuta Kawada, Takanori Naito, Kazuyoshi Makida,
Yuki Takeuchi, Takeshi Nishii, Mitsuyo Horikawa, Hiroto Kaku, Tetsuto Tsunoda
PII:
S0040-4020(18)30500-3
10.1016/j.tet.2018.04.088
TET 29503
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 April 2018
Revised Date: 26 April 2018
Accepted Date: 28 April 2018
Please cite this article as: Sakamoto I, Iwaoka K, Kawada Y, Naito T, Makida K, Takeuchi Y, Nishii T,
Horikawa M, Kaku H, Tsunoda T, 3,3-Dimethoxypropylsulfonyl Group: A new versatile protecting and
activating group for amine synthesis, Tetrahedron (2018), doi: 10.1016/j.tet.2018.04.088.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
3,3-Dimethoxypropylsulfonyl Group: A New
Leave this area blank for abstract info.
Versatile Protecting and Activating Group
for Amine Synthesis
a
a
a
a
a
a
Izumi Sakamoto , Kazuya Iwaoka , Yuta Kawada , Takanori Naito , Kazuyoshi Makida , Yuki Takeuchi ,
a
a
a,
a,
Takeshi Nishii , Mitsuyo Horikawa , Hiroto Kaku * and Tetsuto Tsunoda *
Faculty of Pharmaceutical Sciences, Tokushima Bunri University
Dimps-Cl
NH
3
Dimps NH
2
OMe
R OH, CMBP
Dimps N R
MeO
SO
Dimps
2
Dimps-Cl
H+, H O then –OH
R-NH
2
2
H
R' OH, CMMP
Bu
3
P
CN (CMBP)
CN (CMMP)
Dimps-Cl
H+, H O then –OH
HN R
R'
Dimps N R
3
Me P
2
R'
or TMSOTf
Dimps methodorogy

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
3
,3-Dimethoxypropylsulfonyl Group: A New Versatile Protecting and Activating
Group for Amine Synthesis
a
a
a
a
a
a
Izumi Sakamoto , Kazuya Iwaoka , Yuta Kawada , Takanori Naito , Kazuyoshi Makida , Yuki Takeuchi ,
a
a
a,∗
a,*
Takeshi Nishii , Mitsuyo Horikawa , Hiroto Kaku , and Tetsuto Tsunoda
a
b
Faculty of Pharmaceutical and Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima city, Tokushima, 770-8514, JAPAN
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
3,3-Dimethoxypropylsulfonyl (Dimps) chloride was prepared and used as a new versatile
sulfonating agent for ammonia, primary and secondary amines to afford corresponding Dimps-
amides in excellent yields. The resulting N-nonsubstituted and N-monosubstituted Dimps-
amides, activated amines, were alkylated satisfactorily under new Mitsunobu conditions. The
Dimps group was removed by treatment in aqueous solution under acidic followed by basic
conditions. Furthermore, epilachnene, the defensive droplets from the Mexican bean beetle,
Epilachna varivestis, was synthesized utilizing this Dimps methodology in short steps.
Available online
Keywords:
Amines
Mitsunobu reaction
Phosphorane
Protecting group
Sulphonamide
2
009 Elsevier Ltd. All rights reserved.
1
. Introduction
to be the same as that of aliphatic sulfonamides (e.g., MsNHMe:
6
pK = 11.8).
a
In the synthesis of nitrogen-containing molecules with a wide
variety of interesting biological activities, protection and/or
activation of the nitrogen atom followed by deprotection
procedures are common processes in the construction of nitrogen
functional groups. Thus, many protecting and/or activating
groups have been developed and applied to various stages of
1
organic syntheses. Among them, the Fukuyama method utilizing
the o-nitrobenzenesulfonyl (Ns) group has been widely accepted
and applied to amine synthesis because of its sufficient stability
toward various reagents and mild and easy conditions to remove
2
the group. Further, the o-anisylsulfonyl (Ans) group was
developed as an alternative activating/protecting group of the
nitrogen functionality.
3
Fig. 1. Dios and Dimps Groups.
2
. Results and Discussion
In the course of our studies on the Mitsunobu chemistry
utilizing (cyanomethylene)tributylphosphorane (CMBP) and/or
4,5
Dimps chloride (7), a sulfonyl agent, was prepared by the
(cyanomethylene)trimethylphosphorane (CMMP), we proposed
following reaction sequence: 1) commercially available 3,3-
dimethoxypropylchloride (5) was converted to the corresponding
sodium 3,3-dimethoxypropylsulfonate (6) using Na SO (DME-
H O, 110 °C, 72 h in an Ace pressure tube with vigorous
stirring), and then 2) the sulfonate 6 was treated with 2.0 equiv of
the 2-(1,3-dioxan-2-yl)ethylsulfonyl (Dios) group (1) (Figure 1)
as a new versatile sulfonyl group for amino activation/protection
and employed it for the preparation of a wide variety of primary
2
3
5
2
and secondary amines. To expand this chemistry, we recently
designed 3,3-dimethoxypropylsulfonyl (Dimps) group (3), which
could be removed more easily than the Dios group (1). Even so,
the reactivity of Dimps-amides (4) activated amines under the
Mitsunobu reaction conditions was expected to be similar to that
PPh and 2.2 equiv of sulfuryl chloride (CH Cl , −10 °C, 2 h).
3
2
2
The agent 7 could be purified by rapid chromatography (n-hex. /
ether = 1 / 1) on silica gel and stored at −15 °C for at least one
month (Scheme 1).
of Dios-amides (2), because the pK values of both are estimated
a
—
——
∗
Corresponding author. Tel.: +81-88-602-8454; fax: +81-88-655-3051; e-mail: kaku@ph.bunri-u.ac.jp, tsunoda@ph.bunri-u.ac.jp

2
Tetrahedron
ACCEPTED MANUSCRIPT
Na SO3
(1.25 equiv)
SO Cl (2.2 equiv)
2 2
2
OMe
OMe
OMe
PPh (2.0 equiv)
3
MeO
Cl
DME / H O
MeO
SO Na
CH Cl / DMF
MeO
SO Cl
2
2
3
2
2
(
1:2)
10 °C , 72 h
in a pressure tube
(4:1)
–10 °C , 2 h
7
5
6
1
74% (2 steps)
Scheme 1. Preparation of 7.
The reaction of 7 with ammonia afforded water-soluble N-
secondary amines were also sulfonated in excellent yields (1.1
nonsubstituted Dimps-amide (8) in 95% yield (NH3 aqueous,
equiv of 7, 1.5 equiv of NEt , CH Cl , 0 °C to room temperature,
3
2
2
CH CN, 0 °C to room temperature, 10 min). Primary and
10~30 min), as listed in Table 1.
3
Table 1. Reaction of Amines with 7.
entry
1
amine
Solvent
Dimps-amide
Yield (%)
95
a
NH
3
aq.
8
Dimps NH2
CH
3
CN
2
3
CH
2
Cl
2
2
Dimps
N
H
Ph
99
99
9
a
CH
CH
CH
CH
2
2
2
2
Cl
Dimps
Dimps
N
H
9
b
4
5
Cl
2
Cl
2
Cl
2
96
84
84
N
H
Hex
9
c
Dimps
Dimps
N
H
9
1
d
6
N
Ph
0a
a
3
Reaction was carried out without NEt .
The feature of the reaction of 8 in the presence of CMBP was
quite similar to that of the Dios-amide reported previously.
Thus, the Mitsunobu alkylation of 8 proceeded in satisfactory
yields to give 9 even with secondary alcohols (Table 2), even
though benzylic and allylic alcohols gave overreacted product 10
(double alkylation products) to some extent because of their high
reactivity.
5
Table 2. Mitsunobu Alkylation of 8.
CMBP (1.5 equiv)
Tol., temp., 24 h
R
R
Dimps
N
H
Dimps N
R OH + Dimps NH
(1.5 equiv)
+
2
R
8
9
10
R-OH
Temp. (°C)
Yield (%)
9
10

3
ACCEPTED MANUSCRIPT
Dimps
N
H
Ph
Dimps
Dimps
N
N
Ph
Ph
Ph
OH
rt
rt
rt
9a: 67
1
0b: 25
OH
2
10c: 12
9
e: 78
(
)14
a
OH
—
9
9
f: 89
c: 79
OH
Hex
Double alkylated product was not obtained.
a
1
00
—
a
7
As shown in Table 3, N-monosubstituted Dimps-amides (9)
could also be subjected to the Mitsunobu alkylation utilizing
CMMP which possessed sufficient reactivity to afford N,N-
disubstituted Dimps-amides (10) in excellent yields.
Table 3. Mitsunobu Alkylation of 9.
CMMP (1.5 equiv)
R
R
Dimps
+
N
H
Dimps
N
R' OH
Tol., temp., 24 h
R'
9
(1.5 equiv)
10
9
: R—
R’-OH
Temp. (°C)
rt
10
Yield (%)
95
Dimps
N
N
OH
2
9
e
10c
OH
9
e
80
90
Dimps
Hex
Hex
Hex
1
0d
OH
8
0
86
92
93
Dimps
Dimps
N
N
Hex
9
b
1
0e
Ph
Ph
Ph
OH
9
d
80
Hex
Hex
1
0f
9
a
8
0
OH
Dimps
Dimps
N
N
Ph
1
0g
Ph
Hex
OH
9
a
80
89
93
Hex
1
0h
Ph
OH
8
0
10h
Hex
9
c

4
Tetrahedron
ACCEPTED MANUSCRIPT
We reported previously that the Dios group (1) was cleaved
temperature and with less amounts of trifluoroacetic acid (50%)
(e.g., Scheme 2).
by the treatment in hot 80% aqueous trifluoroacetic acid to afford
5
primary and secondary amines in high yields. However, the
deprotection of substances with trisubstituted olefins such as the
geranyl group failed to give desired amines even at room
Ph
Ph
CF COOH / H O
3
2
(
1 / 1)
N
SO2
N
SO2
OH
+
11
+
others
O
rt, 20 h
O
12
11
O
O
38%
23%
Scheme 2. Reaction of N-geranyl Dios-amide (11) under acidic conditions.
Table 5. Deprotection of N,N-Disubstituted Dimps-amide
(10).
We expected that the Dimps group (3) could be removed more
easily than 1. Eventually, the deprotection of 3 was accomplished
with a two-step operation in one pot as follows: 1) acid-catalyzed
hydrolysis of the acetal moiety to the aldehyde in an aqueous
acetone or acetonitrile solution of p-tolenesulfonic acid (p-TsOH)
at room temperature, and then 2) basification with the addition of
R
p-TsOH (3.0 equiv.)
CH CN / H O (2 / 1)
K CO / H O
2
3
2
R
Dimps
N
R'
HN
R'
3
2
0 °C to rt, 1 h
10
0 °C then rt, ~ 12 h
Yield of Amine (%)
1
M NaOH or solid K CO with a small amount of water for a
2 3
8
retro-Michael reaction, giving the corresponding primary and
secondary amines in high yields (Tables 4 and 5). N-
9
HN
Ph
99
98
Monosubstituted Dimps-amides 9 could be cleaved more easily
than N,N-disubstituted Dimps-amides 10. Under these conditions,
the geranyl group could survive satisfactorily. Furthermore, we
confirmed that Dios-amide was sufficiently stable under these
aqueous acidic conditions to recover itself (only 2% hydrolysis
after 14 h). Otherwise, the Dimps group could also be cleaved by
treatment with TMSOTf in good yield (Scheme 3).
13
HN
Hex
14
9
5
Table 4. Deprotection of N-Monosubstituted Dimps-amide
HN
HN
2
(
9).
15
R
p-TsOH (3.0 equiv.) 1M NaOH / MeOH
Dimps
N
H
H N R
2
Acetone / H O (2 / 1)
0 °C to rt, 1 h
2
9
0
°C then rt, ~ 6 h
94
Ph
Yield of Amine (%)
16
9
8
Ph
NH2
TMSOTf (3.0 equiv)
CH Cl , 0 °C , 10 min
HN
Ph
Dimps
N
Ph
2
2
NH2
85
10a
87%
13
Hex
Scheme 3. Cleavage of Dimps group using TMSOTf.
1
0
8
9
8
2
We prepared compound 17 bearing the Dimps group with
tert-butoxycarbonyl (Boc) and Ns groups on nitrogen atoms and
examined the selective deprotection of each group as follows: 1)
acid-catalyzed hydrolysis followed by basification cleaved the
Dimps group to afford 18, 2) treatment with thiophenol-K CO
NH2
2
3
NH2
cleaved the Ns group to give 19, and 3) treatment with conc.
H SO in MeOH removed the Boc group quite significantly to
2
4
yield 20. Thus, the Dimps group can be utilized not only as an
activating group but also as a new amine-protecting group. In
conclusion, the order of the stability of Boc, Dios and Dimps
11
group under aqueous acidic conditions is Dios > Boc > Dimps.

5
ACCEPTED MANUSCRIPT
Dimps
N
NBoc
Ns
p-TsOH (3.0 equiv)
K
CO
0 °C to rt, 1 h
quant.
/ H
O
HN
NBoc
Ns
2
3
2
CH CN / H O (4 / 1)
Ph
3
2
Ph
0
°C then rt, 12 h
18
17
PhSH, K CO
Dimps
Dimps
N
NHBoc
2
3
DMF, rt, 1 h
Ph
1
9
9
6%
conc. H SO
N
NH
Ns
2
4
MeOH, 0 °C to rt, 2 h
7%
Ph
0
2
9
Scheme 4. Selective Deprotection of Dimps, Nosyl or Boc groups
1
0
To demonstrate the usefulness of the Dimps methodology, we
synthesized epilachnene (21) again. In the previous synthesis,
This time, Dimps-amide 27 was utilized to overcome this
12
13
14
problem (Scheme 6). Alcohol 22 was subjected to the
tosylamide 23 was employed as a nitrogen nucleophile under
Mitsunobu conditions (CMMP) followed by lactonization to
afford 25, whose tosyl group was removed smoothly by reductive
conditions using sodium naphthalenide at –40 °C in DME.
However, the product of the reaction was undesired lactam 26
generated by intramolecular acyl migration. So, trans-
lactonization of 26 was carried out by treatment with p-
toluenesulfonic acid (Scheme 5).
Mitsunobu reaction with 27 in the presence of CMMP to yield
Dimps-amide 28, which was treated with base in hot aqueous
ethanol to provide seco-acid 29. The lactonization of 29 was
successfully achieved by the reaction of 2-chloro-1-
methylpyridinium iodide (30) under highly dilute conditions to
afford 31. Finally, the Dimps group was cleaved easily by
treatment with TMSOTf.
15
Ts
OTBDMS
CN
N
CN Ts
H
2 steps
2
3
OH
N
OTBDMS
CMMP
(S)-22
24
O
O
OH
Na / Naph
O
p-TsOH
O
O
N
N
NH
Ts
56% (2 steps)
2
5
26
(R)-21
Scheme 5. Previous Synthesis of (R)-Epilachnene (21).
Scheme 6. Synthesis of (±)-21.
Thus, because the Dimps group can be used as a versatile
activating/protecting group for amines, the reactions presented
herein would be widely employed as useful methodologies in the
synthesis of nitrogen-containing molecules.
3
. Conclusion
To conclude, the complete reaction sequence is illustrated in
Scheme 7. The Dimps group was introduced onto an amino
group, and the resulting Dimps-amide was alkylated under the
new Mitsunobu conditions. Finally, the Dimps group was
cleaved/deprotected under acidic followed by basic conditions.

6
Tetrahedron
ACCEPTED MA74
N
%
U
in
S
2
C
s
R
te
I
ps). 7 was stored at −15 °C for a month without
P
T
1
decomposition. H NMR (CDCl ) δ 4.53 (1H, t, J = 4.9 Hz),
3
1
3
3
.80-3.75 (2H, m), 3.38 (6H, s), 2.35-2.28 (2H, m); C NMR
(
1
2
CDCl ) δ 101.8, 60.7, 54.2, 27.9; IR (ATR) 2938, 2837, 1366,
167, 1119, 1070 cm ; MS (FAB) m/z 201 ([M-H] ); HRMS m/z
3
-
1
+
01.0008 (200.9988 calcd for C H ClO S).
5
10
4
4
.3. Dimps-amide (8)
To a cooled solution of 7 (1.01 g, 4.96 mmol) in acetonitrile (5
mL) was added dropwise aqueous ammonia (15 mL) over a
period of 3 min at 0 °C. The resulting mixture was stirred for 10
min at room temperature, and concentrated in vacuo. The crude
product was purified by silica gel column chromatography
Scheme 7. Conclusion of Dimps Methodology.
(
eluent: n-hexane/AcOEt, 1/1, v/v) to yield 8 as a colorless solid
4
. Experimental
(861 mg, 95%). m.p. 49.9-51.0 °C (colorless needles, n-hexane-
AcOEt); H NMR (CDCl ) δ 4.89 (2H, br.s), 4.50 (1H, t, J = 5.1
Hz), 3.37 (6H, s), 3.19-3.26 (2H, m), 2.12-2.21 (2H, m);
1
3
4
.1. General
13
C
NMR (CDCl ) δ 102.8, 53.9, 50.6, 27.6; IR (KBr) 3343, 3266,
Melting points (m.p.) were determined with a Yanaco MP3
apparatus. Infrared (IR) spectra were recorded using the ATR
attenuated total reflectance) technique with a JASCO Model
3
-
1
+
1
376, 1365, 1170 cm ; MS (CI) m/z 184 ([M+H] ), 152, 123, 71
(
100); HRMS m/z 184.0619 (184.0644 calcd for C H NO S).
(
5
14
4
FTIR-410 spectrophotometer. Proton nuclear magnetic resonance
spectra ( H NMR) were recorded with a Mercury 300 (300 MHz)
4
.4. General procedure for sulfonylation of amines
1
spectrometers in CDCl . Chemical shifts are reported in parts per
4.4.1. N-Benzyl-3,3-dimethoxypropylsulfonamide
(9a): (Reaction of 7 with benzylamine)
3
million on the δ scale relative to internal Me Si (δ = 0.00 ppm),
4
13
and coupling constants are given in Hertz. C NMR spectra were
obtained with a Mercury 300 (75 MHz) instrument, and chemical
To a cooled solution (0 °C) of benzylamine (220 µL, 2.0
mmol) and Et N (420 µL, 3.0 mmol) in CH Cl (10 mL) was
3
2
2
shifts are referenced to the residual solvent signal (CDCl : δ =
added 7 (446 mg, 2.2 mmol) slowly with stirring. The mixture
3
7
7.0 ppm). Mass spectra, including high-resolution mass spectra,
was stirred at room temperature for 1 h and then quenched with a
were recorded with a JEOL AX-500 spectrometer. Analytical
thin layer chromatography (TLC) was performed on precoated
silica gel 60 F-254 plates (0.2 mm layers) on glass with a
fluorescent indicator, supplied by E. Merck. For column
chromatography, Fuji Silysia BW-127ZH (100–270 mesh) silica
was used. Reagents and solvents were commercial grades and
were used without further purification unless otherwise stated.
Air- and/or moisture-sensitive reactions were carried out under
argon.
sat. NH Cl aq. sol. (15 mL). The reaction mixture was extracted
4
with CH Cl (3 x 25 mL), and the combined organic extracts
2
2
were dried over Na SO , filtered, and concentrated under reduced
2
4
pressure. The residue was subjected to purification by column
chromatography on silica gel (eluent: n-hexane/AcOEt, 3/1 - 1/1,
v/v) to give 542 mg (99%) of 9a as colorless solid. m.p. 56.4-
1
57.2 °C (colorless needles, n-hexane-AcOEt); H NMR (CDCl )
3
δ 7.27-7.41 (5H, m), 4.81 (1H, br.t, J = 6.0 Hz), 4.40 (1H, t, J =
5.2 Hz), 4.29 (2H, d, J = 6.3 Hz), 3.31 (6H, s), 3.00-3.08 (2H, m),
1
3
2
1
1
9
.01-2.11 (2H, m); C NMR (CDCl ) δ 136.8, 128.9, 128.1,
3
4
.2. Dimps chloride (7)
27.9, 102.7, 53.7, 48.2, 47.3, 27.2; IR (KBr) 3261, 2960, 2940,
359, 1193 cm ; MS (CI) m/z 272 ([M-H] ), 242, 210, 146, 106,
1, 75 (100); HRMS m/z 272.0948 (272.0956 calcd for
-
1
+
A mixture of 3,3-dimethoxypropylchloride (5) (5.00 g, 36.1
mmol) and sodium sulfite (5.70 g, 45.1 mmol) in DME (15 mL)
and water (30 mL) was heated at 110 °C in an Ace pressure tube
with vigorous stirring for 3 days. The resulting mixture was
C H NO S).
12 18
4
4
.5. General procedure for Mitsunobu alkylation
concentrated in vacuo, and then the residue was dried over P O5
2
under reduced pressure (5 mmHg) for 48 h to afford 10.4 g of
4.5.1. N-(Oct-2-yl)-3,3-dimethoxypropylsulfonamide
crude sodium 13,3-dimethoxypropylsulfonate (6) containing
(9c): (Reaction of 8 with octan-2-ol)
inorganic salts. H NMR (D O, acetone as an internal standard
2
An Ace pressure tube was used as a reaction vessel. To a
solution of 8 (279 mg, 1.5 mmol) and octan-2-ol (160 µL, 1.0
mmol) in dry toluene (5 mL) was added CMBP (380 µL, 1.5
mmol) at room temperature under an argon atmosphere. The
resulting mixture was sealed and stirred for 24 h at 100 °C. After
concentrating in vacuo, the residue was purified by silica gel
(2.22 ppm)) δ 4.65 (1H, t, J = 5.6 Hz), 3.40 (6H, s), 2.94 (2H, t-
like m), 2.05 (2H, m).
To a solution of triphenylphosphine (26.4 g, 101 mmol) in
CH Cl (100 mL) under an argon atmosphere was added slowly
2
2
sulfuryl chloride (9.0 mL, 111 mmol) at 0 °C. After stirring for
0 min, DMF (25 mL) was added and the resulting mixture was
cooled to −10 °C. To this mixture was added the crude product 6
above) rapidly. After vigorous stirring for 2 h, the reaction
column chromatography (eluent: n-hexane/AcOEt, 2/1 - 1/1 - 1/2
1
1
-
(
1/5, v/v) to yield 9c as a colorless oil (235 mg, 79%). H NMR
CDCl ) δ 4.48 (1H, t, J = 5.2 Hz), 4.07 (1H, br.d, J = 8.5 Hz),
3
(
3
.40-3.51 (1H, m), 3.36 (6H, s), 3.05-3.12 (2H, m), 2.05-2.14
mixture was carefully poured into a mixture of water (100 mL)
and n-hexane (100 mL). The organic layer was separated and the
aqueous layer was extracted with n-hexane (2 x 100 mL). The
combined organic layers were washed with water (5 x 100 mL),
(
2H, m), 1.25-1.52 (10H, m), 1.23 (3H, d, J = 6.6 Hz), 0.88 (3H,
13
t, J = 6.9 Hz); C NMR (CDCl ) δ 102.8, 53.7, 50.4, 49.2, 38.0,
3
3
1
1.7, 29.0, 27.4, 25.7, 22.6, 22.4, 14.0; IR (neat) 3280, 2931,
124 cm ; MS (CI) m/z 296 ([M+H] ), 264 (100), 232; HRMS
-
1
+
dried (MgSO ), filtered, and concentrated in vacuo. The residue
4
m/z 296.1888 (296.18954 calcd for C H NO S).
13
30
4
was dissolved in n-hexane (100 mL), and then insoluble material
(
O=PPh ) was filtered off. The filtrate was concentrated in vacuo,
4.5.2. N-(Geranyl)-N-(oct-2-yl)-3,3-
dimethoxypropylsulfonamide (10d): (Reaction of 9e
3
and the crude product was subjected to quick purification through
a short silica gel column chromatography (eluent: ether/n-hexane,
with octan-2-ol)
1
/1, v/v) to yield Dimps chloride (7) as a colorless oil (5.44 g,

7
An Ace pressure tube was used as a reac
A
tio
C
n
C
ve
E
ss
P
el
T
. T
E
o
D
a
MA(1
N
H,
U
m
S
),
C
4.
R
58
I
(
P
1H
T
, t, J = 5.2 Hz), 4.38 (2H, s), 3.70 (2H, d, J =
solution of 9e (320 mg, 1.5 mmol) and octan-2-ol (160 µL, 1.0
mmol) in dry toluene (5 mL) was added CMMP (170 mg, 1.5
mmol) at room temperature under an argon atmosphere. The
resulting mixture was sealed and stirred for 24 h at 80 °C. After
concentrating in vacuo, the residue was purified by silica gel
6.9 Hz), 3.35 (6H, s), 2.99-3.07 (2H, m), 2.05-2.15 (2H, m), 1.71
(3H, dd, J = 6.5, 1.2 Hz); C NMR (CDCl ) δ 136.3, 131.4,
128.6, 128.4, 127.8, 125.1, 102.9, 53.7, 49.8, 48.5, 48.4, 27.0,
17.6; IR (neat) 2938, 1332, 1193, 1123 cm ; MS (CI) m/z 328
13
3
−1
+
(([M+H] ), 296, 242, 210 (100), 159, 91; HRMS m/z 328.1600
column chromatography (eluent: n-hexane/AcOEt, 5/1 - 1/1, v/v)
(328.15824 calcd for C H NO S).
16
26
4
1
to yield 10d as a colorless oil (392 mg, 90%). H NMR (CDCl ) δ
3
4
.5.8. N,N-Dibenzyl-3,3-
5
.21 (1H, br.t, J = 6.8 Hz), 5.07 (1H, br.t, J = 6.6 Hz), 4.46 (1H,
t, J = 5.4 Hz), 3.74-3.90 (3H, m), 3.34 (6H, s), 2.93-3.01 (2H, m),
.96-2.14 (6H, m), 1.68 (6H, s), 1.60 (3H, br.s), 1.24-1.33 (10H,
dimethoxypropylsulfonamide (10b)
1
The title compound was isolated as a colorless oil. H NMR
1
13
(CDCl ) δ 7.27-7.39 (10H, m), 4.41 (1H, s), 4.35 (4H, s), 3.32
3
m), 1.20 (3H, d, J = 6.9 Hz), 0.8 (3H, br.t, J = 6.3Hz); C NMR
CDCl ) δ 138.1, 131.7, 123.9, 122.1, 103.0, 54.0, 53.6, 49.0,
1
3
(6H, s), 2.94-3.02 (2H, m), 2.04-2.12 (2H, m); C NMR (CDCl3)
(
3
δ 135.6, 128.7, 128.7, 128.0, 102.6, 53.6, 50.0, 48.8, 26.8; IR
4
1
4
0.7, 39.6, 35.7, 31.7, 29.1, 27.2, 26.8, 26.3, 25.6, 22.6, 20.1,
−
1
+
−1
(neat) 2937, 2832, 1332, 1124 cm ; MS (CI) m/z 362 ([M-H] ),
332, 300, 268, 244, 210 (100), 195, 181, 131, 120, 91, 71, 44;
HRMS m/z 362.1433 (362.14259 calcd for C H NO S).
7.6, 16.1, 14.0; IR (neat) 2930, 1334, 1194 cm ; MS (CI) m/z
+
31 (M ), 400, 367, 264, 232, 137 (100); HRMS m/z 431.3072
+
19
24
4
(M ) (431.30691 calcd for C H NO S).
23
45
4
4
.5.9. N,N-Digeranyl-3,3-
4
.5.3. N-2-(Cyclohex-1-enyl)ethyl-3,3-
dimethoxypropylsulfonamide (10c)
dimethoxypropylsulfonamide (9b)
1
1
The title compound was isolated as a colorless oil. H NMR
The title compound was isolated as a colorless oil. H NMR
(CDCl ) δ 5.19 (2H, br.t, J = 6.6 Hz), 5.04-5.11 (2H, m), 4.47
3
(CDCl ) δ 5.52 (1H, br.s), 4.48 (1H, t, J = 5.2 Hz), 4.22 (1H, br.t,
3
(1H, t, J = 5.5 Hz), 3.83 (4H, d, J = 6.9 Hz), 3.35 (6H, s), 2.95-
J = 5.5 Hz), 3.36 (6H, s), 3.18 (2H, dd, J = 12.3, 6.6 Hz), 3.05-
3
1
NMR (CDCl ) δ 133.6, 124.8, 102.8, 53.8, 47.7, 40.8, 38.3, 27.8,
2
3
.03 (2H, m), 1.99-2.15 (10H, m), 1.68 (6H, br.s), 1.64 (6H,
.13 (2H, m), 2.19 (2H, br.t, J = 6.6 Hz), 2.05-2.13 (2H, m),
.97-2.04 (2H, m), 1.87-1.94 (2H. m), 1.57-1.68 (4H, m);
13
13
br.s), 1.61 (6H, br.s); C NMR (CDCl ) δ 140.4, 131.8, 123.8,
1
IR (neat) 2925, 1376, 1337, 144, 1124 cm ; MS (CI) m/z 455
(M ), 424, 392, 360, 256, 137 (100); HRMS m/z 455.3070
3
C
19.4, 103.0, 53.7, 48.2, 44.0, 39.7, 27.0, 26.4, 25.6, 17.7, 16.1;
−1
3
−1
7.3, 25.2, 22.7, 22.2; IR (neat) 3287, 2930, 2834 cm ; MS
+
+
(
FAB) m/z 314 ([M+Na] ), 289, 260, 228 (100); HRMS m/z
(455.30691 calcd for C H NO S).
25 45 4
3
14.1420 (314.14019 calcd for C H NO SNa).
13 25 4
4
3
.5.10. N-2-(Cyclohex-1-enyl)ethyl-N-(oct-2-yl)-
4
.5.4. N-Phenyl-3,3-dimethoxypropylsulfonamide
,3-dimethoxypropylsulfonamide (10e)
The title compound was isolated as a colorless oil. H NMR
(
9d)
1
1
The title compound was isolated as a colorless oil. H NMR
(CDCl ) δ 5.45 (1H, br.s), 4.47 (1H, t, J = 5.2 Hz), 3.75 (1H,
3
(CDCl ) δ 7.15-7.39 (5H, m), 6.61 (1H, br.s), 4.47 (1H, t, J = 5.2
3
1
3
sextet, J = 6.9 Hz), 3.36 (6H, s), 3.15 (2H, dd, J = 7.8, 10.0 Hz),
.42-1.66 (6H, m), 1.24-1.40 (8H, m), 1.21 (3H, d, J = 6.9 Hz),
Hz), 3.31 (6H, s), 3.16-3.22 (2H, m), 2.08-2.16 (2H, m);
NMR (CDCl ) δ 136.7, 129.6, 125.3, 120.8, 102.6, 53.7, 47.0,
2
C
1
3
13
−1
0.88 (3H, t, J = 6.6 Hz); C NMR (CDCl ) δ 134.9, 123.0, 102.9,
54.1, 53.7, 48.2, 42.3, 40.1, 35.9, 31.7, 29.1, 28.4, 27.1, 26.8,
2
cm ; MS (CI) m/z 403 (M ), 372, 308, 212, 142, 71 (100);
HRMS m/z 402.2674 (402.26779 calcd for C H NO S).
3
7.0 IR (neat) 3260, 2939, 1344 cm ; MS (CI) m/z 260
+
([M+H] ), 228 (100), 132, 196; HRMS m/z 259.0866 (259.08782
5.2, 22.8, 22.6, 22.3, 19.8, 14.1; IR (neat) 2929, 1379, 1334
calcd for C H NO S).
11
17
4
−
1
+
4
.5.5. N-Geranyl-3,3-dimethoxypropylsulfonamide
21
40
4
(
9e)
1
4.5.11. N-(Oct-2-yl)-N-phenyl-3,3-
dimethoxypropylsulfonamide (10f)
The title compound was isolated as a colorless oil. H NMR
(CDCl ) δ 5.22(1H, br.t, J = 7.1 Hz), 5.06 (1H, br.t, J = 6.6 Hz),
3
1
The title compound was isolated as a colorless oil. H NMR
4
3
.47 (1H, t, J = 5.1 Hz), 4.14 (1H, br.s), 3.72 (2H, t, J = 6.6 Hz),
(CDCl ) δ 7.36-7.45 (3H, m), 7.25-7.31 (2H, m), 4.45 (1H, t, J =
3
.36 (6H, s), 3.06-3.13 (2H, m), 1.98-2.15 (6H, m), 1.68 (6H, br.
13
5.1Hz), 4.27 (1H, sextet, J = 6.9 Hz), 3.34 (2H, m), 2.05-2.17
2H, m), 1.20-1.55 (10H, m), 1.17 (3H, d, J = 6.9 Hz), 0.88 (3H,
s), 1.60 (3H, br.s); C NMR (CDCl ) δ 141.1, 131.9, 123.6,
1
3
(
19.3, 102.8, 53.7, 48.1, 41.0, 39.4, 27.3, 26.3, 25.6, 17.7, 16.3;
13
−
1
+
br.t, J = 6.3 Hz); C NMR (CDCl ) δ 135.3, 132.3, 129.0, 128.6,
3
IR (neat) 3286, 2930, 1381, 1193 cm ; MS (CI) m/z 320 (M ),
88, 256, 137 (100); HRMS m/z 319.1824 (319.18172 calcd for
C H NO S).
1
1
3
02.9, 55.6, 53.7, 48.0, 35.9, 31.7, 29.0, 27.2, 26.7, 22.5, 20.7,
−1 +
4.0; IR (neat) 2931, 1338, 1153 cm ; MS (CI) m/z 371 (M ),
40 (100), 286, 252; HRMS m/z 371.2120 (371.21301 calcd for
2
15
29
4
4
.5.6. N-Hexadecanyl-3,3-
C H NO S).
19 33 4
dimethoxypropylsulfonamide (9f)
1
4.5.12. N-Benzyl-N-geranyl-3,3-
dimethoxypropylsulfonamide (10g)
m.p. 67-69 °C (colorless needles, n-hexane-AcOEt); H NMR
(CDCl ) δ 4.48 (1H, t, J = 5.1 Hz), 4.21(1H, br.t, J = 6.0 Hz),
3
1
The title compound was isolated as a colorless oil. H NMR
3
.36 (6H, s), 3.05-3.15 (4H, m), 2.06-2.14 (2H, m), 1.48-1.60
13
(CDCl ) δ 7.28-7.40 (5H, m), 5.19 (1H, br.t J = 7.6 Hz), 5.03-
3
(4H, m), 1.18-1.40 (14H, br.s), 0.88 (3H, t, J = 6.6 Hz); C NMR
5
=
.11 (1H, m), 4.47 (1H, t, J = 5.4 Hz), 4.38 (2H, s), 3.78 (2H, t, J
7.1 Hz), 3.35 (6H, s), 2.29-3.08 (2H, m), 1.98-2.17 (6H, m),
1.69 (3H, br.d, J = 1.2 Hz), 1.61 (3H, br.s), 1.49 (3H, br.d, J =
(CDCl ) δ 102.8, 53.8, 47.7, 43.4, 32.9, 30.3, 29.7, 29.7, 29.7,
3
2
9.6, 29.6, 29.6, 29.5, 29.5, 29.3, 29.1, 27.3, 26.6, 22.7, 14.1; IR
−1
(
(
KBr) 3273, 2917, 2849, 1310, 1131 cm ; MS (CI) m/z 408
[M+H] ), 376 (100), 348, 280, 278, 252, 164, 110; HRMS m/z
13
+
1.5 Hz); C NMR (CDCl ) δ 141.2, 136.3, 131.9, 128.6, 128.3,
1
2
3
27.7, 123.8, 118.3, 102.8, 53.7, 49.9, 48.3, 43.9, 39.6, 26.9,
4
08.3137 (408.31473 calcd for C H NO S).
21 46 4
−1
6.2, 25.7, 17.7, 16.1; IR (neat) 2929, 1143 cm ; MS (CI) m/z
+
4
.5.7. N-(Benzyl)-N-crotyl-3,3-
409 (M ), 378, 345, 242, 210, 137 (100); HRMS m/z 409.2286
dimethoxypropylsulfonamide (10a)
(409.22866 calcd for C H NO S).
22 35 4
1
m.p. 51.0-52.0 °C (colorless needles, n-hexane-AcOEt). H
NMR (CDCl ) δ 7.26-7.39 (5H, m), 5.54-5.67 (1H, m), 5.37-5.50
3

8
Tetrahedron
−1
+
4
.5.13. N-Benzyl-N-(oct-2-yl)-3,3-
2925, 2856 cm ; MS (CI) m/z 238 ([M+H] , 100), 236, 193, 156,
ACCEPTED MANUSCRIPT
dimethoxypropylsulfonamide (10h)
142, 89; HRMS m/z 238.2534 (238.25346 calcd for C H N).
16 32
1
The title compound was isolated as a colorless oil. H NMR
4
.6.4. Desulfurization of 10a using TMSOTf
To a solution of 10a (327 mg, 1.0 mmol) in dry CH Cl (5
(CDCl ) δ 7.22-7.46 (5H, m), 4.40 (1H, t, J = 5.1 Hz), 4.38 (1H,
3
2
2
d, J = 15.6 Hz), 4.29 (1H, d, J = 15.6 Hz), 3.86 (1H, sextet, J =
mL) was added TMSOTf (550 µL, 3.0 mmol) at 0 °C under an
argon atmosphere. After stirring for 10 min, a saturated NaHCO3
aqueous solution (10 mL) was added and extracted with CH Cl
6
1
1
3
1
2
.9 Hz), 3.32 (6H, s), 2.76-2.96 (2H, m), 1.98-2.11 (2H, m),
.10-1.52 (13H, m), 0.86 (3H, t, J = 6.6 Hz); C NMR (CDCl ) δ
38.1, 128.4, 128.3,127.5, 102.7, 54.6, 53.6, 48.5, 46.9, 35.7,
1.6, 28.9, 26.9, 26.7, 22.5, 19.8, 14.0; IR (neat) 2931, 2857,
334, 1139, 1124 cm ; MS (CI) m/z 384 ([M-H] ), 354 (100),
90, 266, 232, 210, 204, 174, 134, 71; HRMS m/z 384.2210
13
3
2
2
(3 x 20 mL). The combined organic layers were dried over
−1
+
K CO , filtrated and evaporated. The residue was purified by
2
3
silica gel column chromatography (eluent: n-hexane/AcOEt, 1/1,
/3, v/v) to yield 13 as a pale yellow oil (140 mg, 87%), whose
spectra data were identified with an authentic sample.
1
(384.22084 calcd for C H NO S).
20 34 4
4
.6. General procedure for Desulfurization
4
.7. Selective Cleavage of Protective Group
4
.6.1. Desulfurization of N-geranyl-3,3-
4
.7.1. N-Benzyl-N’-Boc-N’-Ns-propane-1,3-diamine
dimethoxypropylsulfonamide (9e)
(
18): (Selective cleavage of Dimps group)
To a solution of 9e (639 mg, 2.00 mmol) in acetone (4 mL)
and water (2 mL) was added slowly p-toluenesufonic acid
monohydrate (1.14 g, 6.00 mmol) at 0 °C. After 5 min, the
reaction mixture was allowed to warm to room temperature and
stirred for 6 h. After completion of the reaction was checked by
TLC, the mixture was cooled again at 0 °C, and then MeOH (10
mL) and a 1M aqueous solution of NaOH (3 mL) were added to
the mixture. After stirring for 5 min at 0 °C and 1 h at room
temperature, water (15 mL) was added and the mixture was
extracted with CH Cl (3 x 20 mL). The combined organic
1
The title compound was isolated as a colorless oil. H NMR
(CDCl ) δ 8.31-8.27 (1H, m), 7.76-7.70 (3H, m), 7.34-7.21 (5H,
3
m), 3.87 (2H, t, J = 7.0 Hz), 3.81 (2H, s), 2.75 (2H, t, J = 7.0 Hz),
2
NMR (CDCl ) δ 150.4, 147.5, 140.1, 134.1, 133.5, 133.2, 131.7,
1
1
3
.29 (1H, br.s), 1.97 (2H, quintet, J = 7.0 Hz), 1.34 (9H, s);
C
3
28.4, 128.2, 126.9, 124.3, 85.0, 53.8, 46.2, 46.1, 30.3, 27.8; IR
(ATR) 3335, 2979, 2934, 2360, 2341, 1729, 1541, 1454, 1361,
−1
+
1
282, 1256, 1149, 1120 cm ; MS (FAB) m/z 450 ([M+H] );
HRMS m/z 450.1707 (450.16987 calcd for C H N O S).
21
28
3
6
2
2
extracts were dried over MgSO , filtered, and concentrated under
reduced pressure. The residue was subjected to purification by
4.7.2. N-Benzyl-N-Dimps-N’-Boc-propane-1,3-
diamine (19): (Selective cleavage of Nosyl group)
4
column chromatography (treated by NH ) on silica gel (eluent: n-
3
To a mixture of 17 (123 mg, 0.20 mmol) and K CO (55 mg,
0.40 mmol) in DMF (2 mL) was added PhSH (26.5 µL, 0.26
2
3
hexane, AcOEt/Et N = 99/1, then MeOH/Et N = 99/1, v/v) to
3
3
afford 282 mg (92 %) of geranylamine as a pale yellow oil,
whose spectra data were identified with an authentic sample.
mmol) at rt. After stirring for 1 h, a saturated NaHCO aqueous
3
solution (10 mL) was added and extracted with ether (3 x 10
mL). The combined organic layers were washed with brine, dried
4
.6.2. Desulfurization of N-benzyl-N-geranyl-3,3-
over MgSO , filtrated and evaporated. The residue was purified
dimethoxypropylsulfonamide (10g)
4
by silica gel column chromatography (eluent: n-hexane/AcOEt,
To a solution of 10g (306 mg, 0.748 mmol) in acetonitrile (5
mL) and water (2.5 mL) was added slowly p-toluenesufonic acid
monohydrate (450 mg, 2.37 mmol) at 0 °C. After 5 min, the
reaction mixture was allowed to warm to room temperature and
stirred for 10 h. After completion of the reaction was checked by
TLC, the mixture was cooled again at 0 °C, and then water (2
mL) and K CO (550 mg, 3.98 mmol) were added slowly to the
2
5
(
/1, v/v) to yield 19 as a colorless solid (85.2 mg, 96%). m.p.
1
8.0-59.0 °C (colorless needles, n-hexane-EtOAc); H NMR
300MHz, CDCl ) δ 7.37-7.31 (5H, m), 4.80 (1H, s), 4.45 (1H, t,
3
J = 5.3 Hz), 4.38 (2H, s), 3.35 (6H, s), 3.24 (2H, t, J = 6.9 Hz),
3
1
1
(
1
4
.05 (2H, m), 3.03-2.98 (2H, m), 2.13-2.06 (2H, m) 1.57 (2H, m),
13
.42 (9H, s); C NMR (CDCl ) δ 156.0, 136.2, 128.8, 128.5,
3
2
3
28.1, 102.7, 79.1, 53.8, 51.7, 47.2, 45.1, 36.9, 28.4, 26.8; IR
mixture. After stirring for 10 min at 0 °C and 1 h at room
temperature, water (20 mL) was added and the mixture was
extracted with CH Cl (3 x 20 mL). The combined organic
ATR) 3427, 2940, 2359, 1712, 1508, 1313, 1239, 1160, 1120,
−
1
+
068, 1022 cm ; MS (FAB) m/z 453 ([M+Na] ); HRMS m/z
2
2
53.2062 (453.20351 calcd for C H N O SNa).
20
34
2
6
extracts were dried over MgSO , filtered, and concentrated under
4
reduced pressure. The residue was subjected to purification by
column chromatography on silica gel (eluent: n-hexane/AcOEt,
4.7.3. N-Benzyl-N-Dimps-N’-Ns-propane-1,3-
diamine (20): (Selective cleavage of Boc group)
1
1
0/1 - 4/1 - 1/1, v/v then AcOEt only) to afford 172 mg (94 %) of
6 as a colorless oil. H NMR (CDCl ) δ 7.4-7.2 (5H, m), 5.26
3
To a solution of 17 (123 mg, 0.20 mmol) in MeOH (1 mL)
1
was added conc. H SO4 (32 µL, 0.60 mmol) at 0 °C. After
2
(1H, br.t, J = 6.7 Hz), 5.10 (1H, br.t, J = 6.6 Hz), 3.78 (2H, s),
stirring for 2 h at room temperature, a saturated NaHCO aqueous
3
3
.25 (2H, d, J = 6.6 Hz), 2.15-1.95 (4H, m), 1.68 (3H, s), 1.61
solution (10 mL) was added and extracted with ether (3 x 10
mL). The combined organic layers were washed with brine, dried
13
(6H, s); C NMR (CDCl ) δ 140.5, 137.8, 131.4, 128.3, 128.1,
3
1
26.8, 124.1, 122.8, 53.4, 46.6, 39.6, 26.5, 25.6, 17.6, 16.2; IR
−1 +
over MgSO , filtrated and evaporated. The residue was purified
4
(
(
ATR) 3275, 3061, 2967 cm ; MS (EI) m/z 243 (M ) 174, 91
100); HRMS m/z 243.1992 (243.1987 calcd for C H N).
by silica gel column chromatography (eluent: n-hexane/AcOEt,
1
17
25
2/1, v/v) to yield 20 as a colorless oil (100 mg, 97%). H NMR
(
CDCl ) δ 8.08-8.03 (1H, m), 7.86-7.81 (1H, m), 7.74-7.69 (2H,
3
4
.6.3. N-(Oct-2-yl)-2-(cyclohex-1-enyl)ethylamine
m), 7.38-7.30 (5H, m), 5.74 (1H, t, J = 6.5 Hz), 4.45 (1H, t, J =
5.1 Hz), 4.35 (2H, s), 3.36 (6H, s), 3.31 (2H, t, J = 6.5 Hz), 3.08-
(
14)
1
The title compound was isolated as a colorless oil. H NMR
2
.99 (4H, m), 2.12-2.05 (2H, m), 1.53 (2H, quintet, J = 6.5 Hz);
(CDCl ) δ 5.47(1H, br s), 2.71(1H, dt, J = 11.1, 6.9 Hz), 2.60
3
13
C NMR (CDCl ) δ 148.0, 136.1, 133.9, 133.4, 132.7, 130.7,
3
(2H, dt, J = 11.4, 6.9 Hz), 2.13 (2H, t, J = 6.9 Hz), 1.95-2.04 (2H,
1
28.8, 128.5, 128.3, 125.3, 102.7, 53.9, 52.4, 46.7, 45.2, 40.0,
m), 1.87-1.95 (2H, m), 1.50-1.67 (4H, m), 1.24-1.34 (10H, m),
1
13
28.9, 26.8; IR (ATR) 3336, 2939, 1732, 1540, 1442, 1415, 1335,
1
.03 (3H, d, J = 6.3 Hz), 0.88 (3H, t, J = 6.6 Hz); C NMR
−1
239, 1214, 1165, 1142, 1120, 1072 cm ; MS (FAB) m/z 538
(CDCl ) δ 135.4, 122.8, 53.2, 44.8, 38.4, 37.1, 31.9, 29.5, 28.0,
3
+
([M+Na] ); HRMS m/z 538.1317 (538.12936 calcd for
2
6.1, 25.2, 22.9, 22.6, 22.5, 20.4, 14.1; IR (neat) 3310, 2956,
C H N O S Na).
21
29
3
8 2

9
4
.8. Application of Dimps-amide: the Synthesis of (±)-
1.98-2.30 (2H, m), 1.80-1.96 (1H, m), 1.10-1.78 (12H, m), 0.93
13
ACCEPTED MANUSCRIPT
Epilachnene
(3H, t, J = 7.2 Hz); C NMR (CDCl ) δ 173.3, 131.3, 129.4,
3
1
2
1
4
02.8, 63.5, 61.2, 53.6, 49.4, 44.9, 36.4, 33.5, 31.6, 28.8, 26.8,
6.4, 25.6, 25.3, 23.3, 20.3, 14.0; IR (KBr) 2954, 2935, 2870,
736, 1330, 1146, 1123 cm ; MS (CI) m/z 474, 433 (M ), 432,
02, 390, 338 (100), 306, 266, 224, 71; HRMS m/z 433.2513
4
.8.1. Dimps-amide 28
To a solution of 27 (496 mg, 1.5 mmol) and 22 (222 mg, 1.0
−1
+
mmol) in dry toluene (6 mL) was added CMMP (182 mg, 1.6
mmol) at room temperature under an argon atmosphere. The
resulting mixture was stirred for 24 h at room temperature. After
concentrating in vacuo, the residue was purified by silica gel
(433.24979 calcd for C H NO S).
21 39 6
4
.8.4. (±)-Epilachnene (21)
column chromatography (eluent: n-hexane/AcOEt, 5/1 - 4/1, v/v)
To a solution of 31 (217 mg, 0.50 mmol) in dry CH Cl (10
2 2
mL) was added TMSOTf (270 µL, 1.5 mmol) at 0 °C under an
1
to yield 28 as a colorless oil (490 mg, 90%). H NMR (CDCl ) δ
3
5
1
.47(1H, dtt, J = 10.8, 7.2, 1.5 Hz), 5.29(1H, dtt, J = 10.8, 7.2,
.5 Hz), 4.49 (1H, t, J = 5.4 Hz), 3.66-3.80 (2H, m), 3.54-3.65
argon atmosphere. After stirring for 4 h, a saturated NaHCO
aqueous solution (10 mL) was added and extracted with CH Cl
3
2
2
(
1H, m), 3.35 (6H, s), 3.14-3.22 (2H, m), 2.97-3.05 (2H, m), 2.34
(3 x 20 mL). The combined organic layers were dried over
CO , filtrated and evaporated. The residue was purified by
(2H, t, J = 7.2 Hz), 2.20 (2H, qd, J = 7.4, 1.2 Hz), 2.05-2.17 (4H,
K
2
3
m), 1.72 (2H, quintet, J = 7.2 Hz), 1.28-1.55 (13H, m), 0.90(9H,
silica gel column chromatography (eluent: n-hexane/AcOEt, 2/1,
13
m), 0.07(6H, s); C NMR (CDCl ) δ 132.0, 127.1, 119.8, 102.8,
v/v and then AcOEt) to yield (±)-21 as a colorless oil (121 mg,
3
1
6
2
2
2.6, 58.5, 53.6, 48.3, 45.2, 36.2, 33.9, 29.4, 27.1, 27.0, 26.4,
5.9, 25.9, 25.3, 20.1, 18.1, 16.4, 14.0, -5.4; IR (neat) 2954,
91%). H NMR (C
6
D
6
) δ 5.38 (1H, dtt, J = 18.5, 8.1, 1.8 Hz),
5.14-5.26 (1H, m), 4.18 (1H, ddd, J = 11.3, 7.5, 2.1 Hz), 3.85
(1H, ddd, J = 11.3, 6.5, 2.1 Hz), 2.68 (1H, ddd, J = 14.0, 7.5, 2.1
Hz), 2.48 (1H, ddd, J = 14.0, 6.5, 2.1 Hz), 2.31 (1H, m), 2.06-
2.24 (4H, m), 1.92-2.04 (2H, m), 1.46-1.60 (1H, m), 1.60-1.76
−1
933, 2857, 2245, 1335, 1145, 1123 cm ; MS (CI) m/z 564, 545
+
(
[M-H] ), 532, 489, 451 (100), 419, 381, 352, 326, 278, 235, 206,
56, 106, 71; HRMS m/z 545.3434 (545.34442 calcd for
C H N O SSi).
1
1
3
(1H, m), 1.02-1.42 (10H, m), 0.88-0.94 (3H, t-like m); C NMR
27
53
2
5
(
C D ) δ 172.9, 131.6, 129.8, 63.8, 56.5, 45.9, 38.7, 34.8, 32.0,
6 6
4
.8.2. Seco-acid 29
2
2
1
9.3, 27.9, 26.0, 25.8, 24.3, 19.3, 14.8; IR (KBr) 2928, 2855,
−1 +
360, 1736, 1459, 1159 cm ; MS (EI) m/z 267 (M ), 252, 224,
70, 157, 116, 97; HRMS m/z 267.2203 (267.21981 calcd for
An Ace pressure tube was used as a reaction vessel. A mixture
of 28 (896 mg, 1.6 mmol) in 2M KOH solution (15 mL) and
EtOH (15 mL) was sealed and stirred for 18 h at 95 °C. After
cooling, the resulting mixture was poured into hexane (50 mL)
and extracted with 1M NaOH solution (3 x 30 mL). The
combined basic aqueous layers were acidified with 2M HCl
C H NO ).
16
29
2
Acknowledgments
solution (pH 1) and extracted with CH Cl (4 x 30 mL), dried
2
2
This work was supported partially by JSPS KAKENHI Grant
Number JP25460030.
over MgSO , filtrated and evaporated. The residue was purified
4
by silica gel column chromatography (eluent: n-hexane/AcOEt,
2
/1 - 1/1, v/v, then AcOEt with 1% AcOH) to yield 29 as a
References and notes
1
colorless oil (724 mg, 100%). H NMR (CDCl ) δ 5.27-5.48 (2H,
3
m), 4.51(1H, t, J = 5.4 Hz), 3.74 (2H, t, J = 5.7 Hz), 3.62 (1H,
quintet, J = 6.3 Hz), 3.37 (6H, s), 3.30 (2H, dd, J = 12.5, 5.7 Hz),
1
.
For selected references, see: a) Wuts, P. G. M.; Greene, T. W.
Greene’s Protective Group in Organic Synthesis, 4th ed.; John
Wiley and Sons: New Jersey, 2007; pp 696-926. b) Qian, L.; Sun,
Z.; Mertes, M. P.; Mertes, K. B. J. Org. Chem. 1991, 56, 4904–
4907. c) Vedejs, E.; Lin, S.; Klapars, A.; Wang, J. J. Am. Chem.
Soc. 1996, 118, 9796–9797. d) Sun, P.; Weinreb, S. M.; Shang, M.
J. Org. Chem. 1997, 62, 8604–8608.
3
1
.01-3.10 (2H, m), 2.35 (2H, t, J = 6.9 Hz), 1.96-2.18 (6H, m),
.62-1.75 (2H, m), 1.25-1.58 (11H, m), 0.93 (3H, t, J = 6.9 Hz);
1
3
C NMR (CDCl ) δ 178.1, 130.7, 128.6, 102.7, 62.2, 58.9, 53.7,
3
4
2
7.7, 45.1, 36.0, 33.8, 33.0, 29.4, 26.9, 26.9, 26.5, 26.2, 24.4,
−1
0.0, 13.9; IR (neat) 3460, 2936, 2871, 1709, 1320, 1123 cm ;
2. For a review of Ns chemistry, see: a) Kan, T.; Fukuyama, T. J.
Synth. Org. Chem. Jpn. 2001, 59, 779–789. b) Kan, T.; Fukuyama,
T. Chem. Commun. 2004, 353-359, and references therein.
+
MS (CI) m/z 469, 450 ([M-H] ), 437, 420, 388, 356 (100), 324,
82, 254, 242, 181, 164, 137, 116, 71; HRMS m/z 450.2542
450.25253 calcd for C H NO S).
2
(
3
.
Milburn, R. R.; Snieckus, V. Angew. Chemie Int. Ed. 2004, 43,
92–894.
a) Tsunoda, T.; Ozaki, Fumie; Ito, S. Tetrahedron Lett. 1994, 35,
081–5082. b) Tsunoda, T.; Yamamoto, H.; Goda, K.; Itô, S.
21
40
7
8
4
.
4
.8.3. N-Dimps-epilachnene 31
5
The reaction was carried out under a dry argon atmosphere in
Tetrahedron Lett. 1996, 37, 2457–2458. c) Tsunoda, T.; Itô, S. J.
Synth. Org. Chem. Jpn. 1997, 55, 631–641. d) Itô, S.; Tsunoda, T.
Pure Appl. Chem. 1999, 71, 1053–1057. e) Uemoto, K.;
Kawahito, A.; Matsushita, N.; Sakamoto, I.; Kaku, H.; Tsunoda,
T. Tetrahedron Lett. 2001, 42, 905–907. f) Sakamoto, I.; Kaku,
H.; Tsunoda, T. Chem. Pharm. Bull. 2003, 51, 474-476. g)
Tsunoda, T.; Kaku, H.; Itô, S. TCIMail 2005, 123, 1–10. h)
Sakamoto, I.; Nishii, T.; Ozaki, F.; Kaku, H.; Tanaka, M.;
Tsunoda, T. Chem. Pharm. Bull. 2005, 53, 1508-1509.
a 500-mL three-necked round-bottomed flask equipped with a
reflux condenser, a septum for adding the reagents and sampling
the reaction mixture, and an inlet for purging the flask with dried
argon. A mixture of 29 (215 mg, 0.48 mmol) and dry Et N (840
3
µL, 6.0 mmol) in dry CH CN (8 mL) was added dropwise using a
3
syringe over 60 min to a refluxing solution of 30 (767 mg, 3.0
mmol) in dry CH CN (170 mL), and the resulting mixture was
3
5
.
Sakamoto, I.; Izumi, N.; Yamada, T.; Tsunoda, T. Org. Lett. 2006,
refluxing for 3 h. After cooling to 0 °C, water (100 mL) and ether
8
, 71–74.
(200 mL) were added. The resulting mixture was separated, and
6
.
King, J. F.; Rathore, R.; Lam, J. Y. L.; Guo, Z. R.; Klassen, D. F.
J. Am. Chem. Soc. 1992, 114, 3028–3033.
the ethereal solution was washed with water (3 x 100 mL) and
brine (100 mL), dried over MgSO , filtrated and evaporated. The
4
7. TMAD-PBu
3
and CMBP can be also used for this conversion. See
residue was purified by silica gel column chromatography
ref. 4a and 5.
8
.
.
Acrolein generated as a coproduct did not react with amines
produced under these aqueous conditions. So, ref. numbers were
changed.
(eluent: n-hexane/AcOEt, 4/1 - 3/1 - 2/1, v/v, and then AcOEt) to
yield 31 as a colorless solid (125 mg, 60%). m.p. 71.0-72.0 °C
1
(
colorless needles, n-hexane-ether); H NMR (CDCl ) δ 5.31-
3
9
1
A plausible reaction pathway is shown in ref 5.
5
4
.43 (1H, m), 5.20-5.31 (1H, m), 4.49 (1H, t, J = 5.1 Hz), 4.24-
.36 (1H, m), 4.06 (1H, ddd, J = 12.5, 4.2, 2.7 Hz), 3.25-3.60
0. See Supplementary Material for spectra data.
11. The order of stability of Dios and Boc group was mentioned in ref
5
.
(2H, m), 3.36 (6H, s), 2.96-3.17 (2H, m), 2.33-2.44 (2H, m),

10
Tetrahedron
1
2. Attygalle, A. B.; McCormick, K. D.; Blankespoor, C. L.; Eisner,
ACCEPTED MANUSCRIPT
T.; Meinwald, J. Proc. Natl. Acad. Sci. U. S. A. 1993, 90, 5204–
208.
3. Kaku, H.; Okamoto, N.; Nakamaru, A.; Tsunoda, T. Chem. Lett.
004, 33, 516–517.
5
1
2
1
1
4. Racemic 22 was prepared following the previous paper. See ref 11
5. Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 5, 49–50.
Supplementary Material
1
H NMR spectra of 6-8, 9a-f, 10a-h, 14, 16-20, 27-29, 31 and
(±)-epilachnene (21); Spectra data of 17 and 27.