Equilibrium shift induced by chiral nanoparticle precipitation in rhodium-catalyzed disulfide exchange reaction

Article abstract of DOI:10.1016/j.tet.2015.05.106

Chiral silica (P)-nanoparticles grafted with (P)-helicene recognize the molecular structure of a chiral diol disulfide in the presence of monool disulfide and dibutyl disulfide. The (P)-nanoparticles selectively adsorb the diol disulfide, aggregate, and precipitate from solution. Under rhodium-catalyzed equilibrium among three disulfides, the diol disulfide is removed from solution by precipitation, which induces an equilibrium shift in the solution. By conducting the precipitation experiment twice, we obtained the diol disulfide in 37% yield from a statistical 1:2:1 equilibrium mixture of three disulfides. The method is applied to a racemic monool disulfide, and an optically active diol disulfide is obtained via kinetic resolution and equilibrium shift.

Full text of DOI:10.1016/j.tet.2015.05.106

Tetrahedron 71 (2015) 4920e4926
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Equilibrium shift induced by chiral nanoparticle precipitation in
rhodium-catalyzed disulfide exchange reaction
*
Masamichi Miyagawa, Mieko Arisawa, Masahiko Yamaguchi
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral silica (P)-nanoparticles grafted with (P)-helicene recognize the molecular structure of a chiral diol
disulfide in the presence of monool disulfide and dibutyl disulfide. The (P)-nanoparticles selectively
adsorb the diol disulfide, aggregate, and precipitate from solution. Under rhodium-catalyzed equilibrium
among three disulfides, the diol disulfide is removed from solution by precipitation, which induces an
equilibrium shift in the solution. By conducting the precipitation experiment twice, we obtained the diol
disulfide in 37% yield from a statistical 1:2:1 equilibrium mixture of three disulfides. The method is
applied to a racemic monool disulfide, and an optically active diol disulfide is obtained via kinetic res-
olution and equilibrium shift.
Received 22 March 2015
Received in revised form 27 May 2015
Accepted 28 May 2015
Available online 4 June 2015
Keywords:
Equilibrium shift
Helical structure
Molecular recognition
Nanoparticles
Ó 2015 Elsevier Ltd. All rights reserved.
Precipitation
1. Introduction
exceptions are reported for the equilibrium shift by the removal of
an ester product in an acid/base-catalyzed transesterification re-
Catalysis is a phenomenon in which a chemical substance,
a catalyst, changes a reaction course without affecting the relative
thermodynamic stability of substrates and products.1 When prod-
ucts are thermodynamically stable than substrate, a product can be
obtained, in principle, in a high yield; when the relative stability is
comparable between substrates and products or favors substrates,
a product cannot be obtained in a high yield. Then, devices are
needed to shift the equilibrium to products according to the prin-
ciple of Le Chatelier.2,3 Reaction conditions are adjusted, or alter-
natively, one of the products is removed from the system. Because
the reaction conditions available for a catalytic reaction are gen-
erally limited, particularly in solution, the removal method has
a broader applicability.
Conventional methods of removing a product under equilibrium
reaction employ the removal of inorganic byproducts such as water
and metal salts from reaction mixture to the gas phase (reactive
distillation),4 to the aqueous phase,5 or to the solid phase (pre-
cipitation).6 These methods, however, have a limitation of being
highly dependent on the physical properties of the inorganic
byproducts such as boiling point, vapor pressure, and solubility. It is
not applicable to catalytic reactions forming only organic products,
action by membrane permeation.7 Polymer imprinting was exam-
ined in an enzyme-catalyzed amide formation reaction.8 These
methods, however, suffer from low molecular recognition ability
and a limited substrate scope. The development of a versatile
method of recognizing a certain structure of an organic molecule in
a catalytic equilibrium reaction in solution and of removing
a product from the solution is desired. Note that such a method
must be compatible with catalysis.
We have recently reported the use of chiral silica (P)-nanoparticles
(P)-1 loaded with (P)-1,12-dimethyl-8-methoxycarbonylbenzo[c]
phenanthrene for the optical resolution of aromatic secondary alco-
hols.9 Up to 61% ee of (S)-isomer was obtained, which was induced by
chiral recognition, adsorption, aggregation, and precipitation of the
enantiomer by (P)-1. We also described that the double-helix struc-
ture of an ethynylhelicene oligomer was adsorbed and precipitated by
(P)-1 in the presence of a random-coil form,10 which shifted the
equilibrium from a random-coil to a double-helix in solution. It has
then become a subject of interest whether the nanoparticle method
can be applied to the equilibrium shift of small organic molecules
with molecular weights of several hundreds daltons under metal
catalysis.
where the physical properties are relatively similar.
A
few
We have been developing metal-catalyzed transformations of
organoheteroatom compounds,11 which often provide equilibrium
reactions. In the rhodium-catalyzed organic disulfide exchange
reaction,12 three disulfides, namely R1SSR1, R1SSR2, and R2SSR2, are
formed in a statistical 1:2:1 mixture under equilibrium. To obtain
* Corresponding author. Tel.: þ81 22 795 6812; fax: þ81 22 795 6811; e-mail
address: yama@m.tohoku.ac.jp (M. Yamaguchi).
http://dx.doi.org/10.1016/j.tet.2015.05.106
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

M. Miyagawa et al. / Tetrahedron 71 (2015) 4920e4926
4921
a single product in a higher yield, the equilibrium needs to be
shifted. In this paper, we describe such reaction using the (P)-
nanoparticles by the molecular recognition of R1SSR1, adsorption,
aggregation, and precipitation (Fig. 1). The reaction provides
products in higher chemical yields than those determined by
equilibrium. The equilibrium shift with concomitant kinetic reso-
lution was also conducted in this study under disulfide exchange
reaction catalyzed by an achiral rhodium catalyst.
The equilibrium state of the disulfides in chlorobenzene was
determined as a statistical mixture of (R)-2:(R,R)-3:4¼1:2:1 by in-
dependent forward and backward reaction experiments, from,
which an equilibrium constant K¼[(R,R)-3][4]/[(R)-2]2¼0.25 was
obtained (Scheme S4).
On the basis of the above results, the rhodium-catalyzed equi-
librium reaction among (R)-2, (R,R)-3, and 4 was examined, where
(R,R)-3 was removed by taking advantage of its higher affinity to
Fig. 1. Equilibrium shift in rhodium-catalyzed disulfide exchange reaction by removal of R1SSR1.
2. Result and discussion
(P)-1 (Fig. 2). A mixture of (R)-2 (0.25 mmol) in chlorobenzene was
treated with RhH(PPh3)4 (20 mol %), trifluoromethanesulfonic acid
(40 mol %), and (p-tolyl)3P (80 mol %) at room temperature for 24 h.
3-Aminopropylated silica nanoparticles of 70 nm average di-
ameter were grafted with (P)-1,12-dimethyl-8- methox-
ycarbonylbenzo[c]phenanthrene-5-carboxylate, and the resulting
nanoparticles (P)-1 were used in this study. To know the molecular
recognition ability of (P)-1, a precipitation experiment was con-
ducted. (P)-1 in chlorobenzene was sonicated and mixed with (R)-2-
hydroxy-2-phenylethyl butyl disulfide (R)-2 in the same solvent. The
suspension was allowed to settle at 25 ꢀC. The top of the suspension
cleared after 25 h, and the precipitation was completed after 29 h,
which is noted as [25 h/29 h] in this work. In the absence of (R)-2, (P)-
1 started to precipitate only after 48 h and completed after 52 h,
[48 h/52 h]. To determine the effect of the molecular structure on the
precipitation, the same experiments were conducted using sym-
metric disulfides, bis{(R)-2-hydroxy-2-phenylethyl} disulfide (R,R)-3
and dibutyl disulfide 4, where precipitation occurred by [20 h/24 h]
and [52 h/59 h], respectively. (P)-1 was found to recognize and
precipitate (R,R)-3 over (R)-2 and 4 (Fig. 2). When the enantiomeric
(S,S)-3 and (S)-2 were treated, precipitation occurred by [33 h/36 h]
and [36 h/40 h], respectively. Chiral recognition in the precipitation
of disulfides by (P)-1 favored the (R)-isomers.
Then, (P)-1 (13 mg, containing 2.0
mmol of helicene) in chloro-
benzene was sonicated for 3 min and added to the solution. The
mixture was allowed to settle for another 24 h, and precipitates
were separated from the supernatant by centrifugation. The su-
pernatant contained (R,R)-3 (6%), (R)-2 (30%), and 4 (33%) (Table 1,
entry 1), which are under equilibrium as determined by the cal-
culated K¼0.22. The precipitates were suspended in chloroform
and sonicated to liberate (R,R)-3 (27%) and (R)-2 (3%), where 4 was
not detected. The yield of (R,R)-3 increased from 25% under equi-
librium to 33% against the maximum yield of 50%; the 27% yield of
(R,R)-3 was obtained in the precipitate and 6% remained in the
supernatant. The selectivity of precipitation for (R,R)-3 and (R)-2
turned out to be 9:1. The results revealed substantial molecular
recognition for disulfides by (P)-1 and the selective removal of
(R,R)-3 from solution. Note that rhodium-catalysis was not affected
by (P)-1.
Equilibrium can still be shifted by repeating the precipitation
experiment on the supernatant. The disulfides formed in the su-
pernatant were treated with (P)-1 in chlorobenzene for 24 h. Then,
from the precipitate, (R,R)-3 (8%) and (R)-2 (2%) were obtained, and
(R)-2 (17%), (R,R)-3 (2%), and 4 (39%) remained in the supernatant.
Thus, from an equilibrium mixture containing (R,R)-3 at 25%, the
(R,R)-3 was separated in 35% (27þ8%) yield by precipitating twice
with 2% remaining in solution, and (R,R)-3 in a total yield of 37%
was obtained. In principle, repeating the procedures can shift the
equilibrium to the theoretical 50% yield of (R,R)-3.
The scale of the once-precipitation reaction could be slightly
increased for (R)-2 (0.4 mmol) and (P)-1 (21 mg, containing
3.2 mmol of helicene) to confirm the stiochiometry of the hetero-
geneous reaction, where (R,R)-3 was obtained in the precipitates in
26% (0.10 mmol) isolated yield and 8% (0.032 mmol) in the super-
natant. Note that the amount of silica nanoparticles (P)-1 used here
is comparable to that of substrates, which contrasts to silica gel
chromatography that uses a large excess of silica gel relative to the
amount of substrates. It is also notable that (P)-1 with 3.2
mmol of
helicene removed 100 mol of (R,R)-3 from solution. This is an
m
advantage of this method, although the mechanism is not clear at
present.
Solvent effect was examined in 1,2-dichlorobenzene, 1,3-
bis(trifluoromethyl)benzene, bromobenzene, and toluene, where
Fig. 2. Molecular recognition and equilibrium shift in rhodium-catalyzed disulfide
exchange reaction.

4922
M. Miyagawa et al. / Tetrahedron 71 (2015) 4920e4926
Table 1
precipitate (entry 7), and chiral recognition was ascribed to dif-
ferent rates of precipitation.
Equilibrium shift in rhodium-catalyzed disulfide exchange reactiona
The reaction of racemic (ꢁ)-2 is notable in terms of the equi-
librium shift with concomitant kinetic resolution using an achiral
catalyst (Table 1, entry 8). After the reaction for 45 h, symmetric
disulfides 3 (20%) were obtained in the precipitate at a ratio of (R,R)-
3:meso-3:(S,S)-3¼37:48:15, along with the recovered (R)-2 (3%, 30%
ee). The enantiomeric excess for (R,R)-3 is then calculated as 42% ee.
Note that the ratio of isomeric 3, (R,R)-3, meso-3, and (S,S)-3, in the
precipitate is asymmetric, where compared with symmetric equi-
librium, (R,R)-3:meso-3:(S,S)-3¼1:2:1. In the supernatant, 4 (33%)
and (S)-2 (32%, 36% ee) are the major components along with a small
amount of (S,S)-3 (8%, 43% ee), where the calculated K¼0.26 is
consistent with the equilibrium among 2, 3, and 4. It was found that
the reaction time affected the yield and selectivity of (R,R)-3 in the
precipitate: 4% yield and 56% ee after 42 h; 24% yield and 31% ee
after 48 h. Enantiomeric excess can be increased by shortening the
reaction time. This reaction provides an optically active symmetric
disulfide (R,R)-3 starting from a racemic unsymmetric disulfide
(ꢁ)-2, which is due to the kinetic resolution and equilibrium shift
exerted by (P)-1. A notable feature of this kinetic resolution is the
use of an achiral catalyst and chiral recognition. Unlike conventional
kinetic resolution, the same chemical structure of the products with
the different absolute configurations are obtained. Although
enantio-selectivity and catalyst-loading need improvement, the
study shows a new concept to obtain optically active compounds.
Amine derivatives were also subjected to the equilibrium shift in
the rhodium-catalyzed reaction. When (S)-(2-pyrrolidylmethyl)
butyl disulfide (S)-8 was reacted with (P)-1 for 48 h, diamine
disulfide (S,S)-9 was obtained in 26% yield in the precipitate along
with the recovered (S)-8 (4%) (Table 2, entry 1). In the supernatant,
(S,S)-9 (8%), (S)-8 (32%), and 4 (30%) were formed, which showed an
equilibrium state from the calculated K¼0.23. Substantial chiral
recognition was observed in the reaction of the enantiomer (R)-8,
and a low yield of (R,R)-9 (5%) was obtained in the precipitate (Table
S4). It was found that the (R)-isomer showed a high affinity to (P)-1
in the reaction of alcohol 2 and the (S)-isomer in amine 8. The N-(t-
butoxycarbonyl) derivative (S)-10 underwent an equilibrium shift
giving the symmetric disulfide (S,S)-11 in 24% yield in the pre-
cipitate, which indicated the applicability of this method to amide
derivatives lacking the NH group.
Entry
R1
R2
Stateb
Yield (%)c
R1 SSR1
R1 SSR2
R2SSR2
1
2
3
4
5
n-Bu (R)-2
n-Bu
P
S
27
6
3
30
0
33
P
S
0
24
0
50
0
23
Me
P
S
21
8
5
34
0
31f
n-Oct
P
S
30
6
3
30
0
32
n-Bu
P
S
28
6
3
32
0
32
6
n-Bu (S)-2
P
S
P
S
3
22
25
7
2
49
4
0
23
0
7d
30
32
8e
n-Bu (ꢁ)-2g
P
S
20h
3j
0
33
8i
32k
a
The reaction was conducted using the substrate (0.25 mmol) and (P)-1 (13 mg)
in chlorobenzene (2.0 mL) in the presence of RhH(PPh3)4 (20 mol %), p-tol3P (80 mol
%), and trifluoromethanesulfonic acid (40 mol %) for 48 h.
b
P, precipitate; S, supernatant.
Maximum yield, 50%.
Reaction time, 60 h.
Reaction time, 45 h.
Dimethyl disulfide was obtained by careful evaporation of hexane at 0 ꢀC after
c
d
e
f
chromatography.
g
The reaction from (ꢁ)-2 was conducted, and (R,R)-3, meso-3, (S,S)-3, 4, (R)-2, and
(S)-2 were obtained.
The structure of helicene on the silica nanoparticles was ex-
amined using (P)-nanoparticles (P)-5, (P)-6, and (P)-7 grafted with
h
Yield of 3 ((R,R)-3:meso-3:(S,S)-3¼37:48:15, 42% ee).
i
Yield of 3 ((R,R)-3:meso-3:(S,S)-3¼16:44:40, 43% ee).
j
Yield of 2 ((R)-2:(S)-2¼65:35, 30% ee).
k
Yield of 2 ((R)-2:(S)-2¼32:68, 36% ee).
Table 2
Equilibrium shift in the reaction of (S)-8, and (S)-10a
yields and selectivity slightly decreased compared with those in
chlorobenzene (Table S1). In polar solvents such as ether, tetrahy-
drofuran (THF), acetone, methanol, and N,N-dimethylformamide
(DMF), precipitates contained (R,R)-3 in less than 3% yield.
The effect of disulfide structure on precipitation of (P)-1 was
examined in the equilibrium shift using the once-precipitating
procedures (Table 1). The reaction of (R)-2 acetate and (P)-1 gave
no disulfide in the precipitate (entry 2), and the hydroxyl group is
essential for the molecular recognition and precipitation. With
regard to the effect of the alkylthio moiety in the substrate, the
yield of (R,R)-3 increased in the order of methyl, butyl, and octyl
derivatives (entries 1, 3, and 4). The reaction can be applied to al-
iphatic alcohols as well as aromatic alcohols (entry 5).
Entry
R1
R2
Stateb
Yield (%)c
R1SSR1
R1SSR1
R2SSR2
1
n-Bu (S)-8
P
S
26
8
4
0
32
30
2d
n-Bu (S)-10
P
S
24
7
4
0
33
31
Notable chiral recognition was observed in an experiment of
enantiomeric (S)-2. The reaction of the enantiomer (S)-2 for 48 h
gave (S,S)-3, only in 3% yield in the precipitates, which contrasted to
a 27% yield of (R)-2 under the same conditions (entry 6). The results
are in accordance with the precipitation experiments noted above.
The reaction of (S)-2 for 60 h provided a 25% yield of (S,S)-3 in the
a
The reaction was conducted using the substrate (0.25 mmol) and (P)-1 (13 mg)
in chlorobenzene (2.0 mL) in the presence of RhH(PPh3)4 (20 mol %), p-tol3P (80 mol
%), and trifluoromethanesulfonic acid (40 mol %) for 48 h.
b
P, precipitate; S, supernatant.
Maximum yield, 50%.
Reaction time, 60 h.
c
d

M. Miyagawa et al. / Tetrahedron 71 (2015) 4920e4926
4923
(P)-helicene decyl ester, triethyleneglycolyl ester, and trifluoroethyl
ester, respectively (Table 3). (P)-1 showed a higher yield of (R,R)-3
(27%) in the precipitates than the other (P)-nanoparticles, (P)-5, (P)-
6, and (P)-7. It is shown that the molecular recognition properties of
the nanoparticle can be tuned using different loading groups on the
surface.
spectropolarimeter. Elemental analyses were conducted with
Yanaco CHN CORDER MT-6.
4.2. Equilibrium shift of rhodium catalyzed disulfide ex-
change reaction
Under an argon atmosphere, a solution of RhH(PPh3)4 (58 mg,
0.050 mmol), tris(p-tolyl)phosphine (60 mg, 0.20 mmol), and tri-
fluoromethanesulfonic acid (11 mL, 0.10 mmol) in chlorobenzene
Table 3
Equilibrium shift using nanoparticles grafted with helicene derivativesa
(0.5 mL) was added to a solution of (R)-2 (60 mg, 0.25 mmol) in
chlorobenzene (0.5 mL), and the mixture was allowed to settle for
24 h at room temperature. Then, (P)-1 (13 mg, containing 2.0 mmol
of helicene) in chlorobenzene (1.0 mL) was sonicated for 3 min, and
was added to the solution. The mixture was allowed to settle for
another 24 h at room temperature. The mixture was centrifuged to
separate supernatant and precipitates. The supernatant was con-
centrated, and dried in vacuo. Then, (R)-2 (18 mg, 30%), (R,R)-3
(5 mg, 6%), and 4 (15 mg, 33%) were separated by silica gel chro-
matography. Chloroform (2.0 mL) was added to the precipitates,
and the mixture was sonicated for 3 min (P)-nanoparticles were
separated, and (R)-2 (2 mg, 3%) and (R,R)-3 (21 mg, 27%) were
separated by silica gel chromatography.
Entry
X
Stateb
Yield (%)c
(R,R)-3
(R)-2
4
1
2
3
4
OMe
(P)-1
O-nC10H21
(P)-5
O(CH2CH2O)3Me
(P)-6
P
S
P
S
P
S
P
S
27
6
3
30
8
36
7
35
3
36
0
33
0
25
0
25
0
27
15
13
15
12
18
10
(P)-1 (9.1 mg) in chlorobenzene (0.70 mL) was sonicated for
3 min, and was added to the supernatant obtained in the above
experiment. Then, RhH(PPh3)4 (40 mg, 0.035 mmol), tris(p-tolyl)
phosphine (43 mg, 0.14 mmol), and trifluoromethanesulfonic acid
OCH2CF3
(P)-7
(7 mL, 0.070 mmol) in chlorobenzene (0.70 mL) were added, and the
a
The reaction was conducted using the substrate (0.25 mmol) and (P)-nano-
particles in chlorobenzene (2.0 mL) in the presence of RhH(PPh3)4 (20 mol %), p-
tol3P (80 mol %), and trifluoromethanesulfonic acid (40 mol %) for 48 h.
mixture was allowed to settle for 24 h at room temperature. The
mixture was centrifuged to separate supernatant and precipitates.
The supernatant was concentrated, and dried in vacuo. (R)-2
(10 mg, 17%), (R,R)-3 (2 mg, 2%), and 4 (17 mg, 39%) were separated
by silica gel chromatography. Chloroform (1.0 mL) was added to the
precipitates and the mixture was sonicated for 3 min, and centri-
fuged. (R)-2 (1 mg, 2%) and (R,R)-3 (7 mg, 8%) were separated by
silica gel chromatography.
The same first experiment was conducted to confirm re-
producibility, and disulfides were isolated as follows: (R)-2 (32%),
(R,R)-3 (7%), and 4 (33%) in supernatant; (R)-2 (3%) and (R,R)-3
(25%) in precipitate.
b
P, precipitate; S, supernatant.
Maximum yield, 50%.
c
3. Conclusion
To summarize, (P)-nanoparticles recognize the structure of op-
tically active organic disulfides, and selectively adsorb diol/diamine
disulfides, aggregate, and precipitate from solution. Under a rho-
dium-catalyzed disulfide exchange reaction, diol/diamine disul-
fides are removed from solution by precipitation without
interfering with catalysis, which induces an equilibrium shift. Note
that the reaction gives products in higher yields than those de-
termined by equilibrium, and such method will provide a new
concept in synthetic methodology.
4.3. Synthesis and characterization
4.3.1. (R)-2-Hydroxy-2-phenylethyl butyl disulfide, (R)-2. In a two-
necked flask equipped with a reflux condenser were placed (R,R)-
3 (920 mg, 3.0 mmol), 4 (1.7 mL, 9.0 mmol), RhH(PPh3)4 (100 mg,
0.090 mmol), tris(p-tolyl)phosphine (110 mg, 0.36 mmol), and tri-
4. Experimental section
4.1. General methods
fluoromethanesulfonic acid (16 mL, 0.18 mmol) in acetone (12 mL)
under an argon atmosphere, and the solution was heated at reflux
for 2 h. Then, the solvent was removed under reduced pressure, and
(R)-2 (1.1 g, 74%) was separated by silica gel chromatography. Col-
Melting points were determined with a Yanagimoto micro
melting point apparatus without correction. Optical rotations were
measured on a JASCO P-1010 digital polarimeter. IR spectra were
measured on a JASCO FT/IR-400 spectrophotometer. 1H NMR, 13C
NMR, and 19F NMR spectra were recorded on a Varian-MR spec-
trometer (1H, 400 MHz; 13C, 100 MHz; 19F, 376 MHz) with tetra-
methylsilane as an internal standard. 13C NMR spectrum taken in
CDCl3
spectra taken in DMSO-d6
DMSO-d6 (
39.7) were referenced to the residual solvents.19F NMR
spectra was recorded with trifluoroacetic acid as an external stan-
dard (
orless oil. 1H NMR (400 MHz, CDCl3)
d
0.93 (3H, t, J¼7.2 Hz), 1.43
(2H, sext., J¼7.6 Hz), 1.68 (2H, quint., J¼7.6 Hz), 2.73 (1H, s), 2.75
(2H, t, J¼7.2 Hz), 2.90 (1H, dd, J¼9.6 Hz, 14 Hz), 3.03 (1H, dd,
J¼3.2 Hz, 14 Hz), 4.97 (1H, dd, J¼9.6 Hz, 3.2 Hz), 7.27e7.41 (5H, m).
13C NMR (100 MHz, CDCl3)
d 13.7, 21.6, 31.2, 38.7, 48.1, 72.0, 125.9,
127.9, 128.6, 142.1. IR (neat) 3378, 2927 cmꢂ1. LRMS (EI, 70 eV) m/z
(
d
77.0) were referenced to the residual solvents. 1H NMR
242 (Mþ, 26%). HRMS Calcd for C12H18OS2: 242.0799. Found:
(
d
2.49) and 13C NMR spectra taken in
242.0797. [
a
]
24 ꢂ89 (c 0.57, CHCl3).
D
d
4.3.2. Bis{(R)-2-hydroxy-2-phenylethyl} disulfide, (R,R)-3.13 To a so-
lution of (R)-styrene oxide (1.3 g, 10 mmol) and bis(trimethylsilyl)
sulfide (2.7 mL, 13 mmol) was added tetrabutylammonium fluoride
(10 mL, 1.0 M THF solution) at 0 ꢀC, and the mixture was stirred for
2 h at 0 ꢀC. The reaction was quenched by adding 20% citric acid
aqueous solution, and the organic materials were extracted with
diethyl ether twice. The combined organic layers were washed with
d
ꢂ79.0). Low- and High-resolution mass spectra were
recorded on a JEOL JMS DX-303, or a JEOL JMS AX-700 spectrometer.
HPLC analysis was conducted with Agilent 1120 compact LC,
25 cmꢃ0.46 cm CHIRALPAK IC-3 column, hexane/2-propanol (95/
5), 0.5 mL/min. Measurement wavelength was 290 nm. CD and
UVevis spectra were measured on
a
JASCO J-720

4924
M. Miyagawa et al. / Tetrahedron 71 (2015) 4920e4926
water and brine, and dried over magnesium sulfate. The solvents
were evaporated in vacuo, and the residue was dissolved in hexane
(67 mL) and toluene (67 mL). Sodium iodate (3.9 g) and alumina
(10 g) were added to the solution, and the mixture was vigorously
stirred for 24 h at room temperature. The mixture was filtered, and
the residue was washed with ethyl acetate. The solution was evap-
orated, and the residue was purified by silica gel chromatography to
give (R,R)-3 (1.1 g, 72%). Colorless oil. 1H NMR (400 MHz, CDCl3)
silica gel chromatography. Colorless oil. 1H NMR (400 MHz, CDCl3)
2.44 (3H, s), 2.72 (1H, s) 2.90 (1H, dd, J¼8.8 Hz, 14 Hz), 3.05 (1H,
dd, J¼4 Hz, 14 Hz), 4.96 (1H, dd, J¼4 Hz, 8.8 Hz), 7.27e7.40 (5H, m).
13C NMR (100 MHz, CDCl3)
23.0, 47.3, 72.0, 125.9, 128.0, 128.6,
d
d
142.1. IR (neat) 3417, 2913 cmꢂ1. LRMS (EI, 70 eV) m/z 200 (Mþ,11%).
HRMS Calcd for C9H12OS2: 200.0330. Found: 200.0323. [
0.36, CHCl3).
a
]
24 ꢂ78 (c
D
d
2.72 (2H, s), 2.87 (2H, dd, J¼8.8 Hz, 14 Hz), 2.96 (2H, dd, J¼4 Hz,
4.3.8. (R)-2-Hydroxy-2-phenylethyl octyl disulfide. In a two-necked
flask equipped with a reflux condenser were placed (R,R)-3
(110 mg, 0.35 mmol), dioctyl disulfide (0.33 mL, 1.1 mmol),
RhH(PPh3)4 (12 mg, 0.011 mmol), tris(p-tolyl)phosphine (13 mg,
14 Hz), 4.86 (2H, dd, J¼4 Hz, 8.8 Hz), 7.26e7.33 (10H, m). 13C NMR
(100 MHz, CDCl3)
d 47.5, 71.9, 125.8, 127.8, 128.4, 142.0. IR (neat)
3374, 2911 cmꢂ1. LRMS (EI, 70 eV) m/z 306 (Mþ,18%). HRMS Calcd for
C
16H18O2S2: 306.0748. Found: 306.0725. [
a]
20 ꢂ178 (c 1.71, CHCl3).
0.042 mmol), and trifluoromethanesulfonic acid (2 mL, 0.021 mmol)
D
in acetone (1.4 mL) under an argon atmosphere, and the solution
was heated at reflux for 2 h. Then, the solvent was removed under
reduced pressure, and the product (156 mg, 75%) was separated by
silica gel chromatography. Colorless oil. 1H NMR (400 MHz, CDCl3)
4.3.3. (R)-2-Acetoxy-2-phenylethyl butyl disulfide. To a solution of
(R)-2 (48 mg, 0.2 mmol) in dichloromethane (0.40 mL), acetyl an-
hydride (0.040 mL, 0.40 mmol) and triethylamine (0.060 mL,
0.40 mmol) were added at room temperature, and the mixture was
stirred for 1 h. The reaction was quenched by adding 2 M hydro-
chloric acid, and the organic materials were extracted with ethyl
acetate twice. The combined organic layers were washed with
water and brine, and dried over magnesium sulfate. The solvent
was evaporated in vacuo, and the residue was purified by silica gel
chromatography to give the product (52 mg, 91%). ColoBreakrless
d
0.88 (3H, t, J¼6.8 Hz), 1.20e1.42 (10H, m), 1.68 (2H, quint.,
J¼6.8 Hz), 2.72 (2H, t, J¼7.2 Hz), 2.88 (1H, dd, J¼8.8 Hz, 14 Hz), 3.00
(1H, dd, J¼3.2 Hz,13.6 Hz), 4.94 (1H, dd, J¼3.2 Hz, 8.8 Hz), 7.28e7.39
(5H, m). 13C NMR (100 MHz, CDCl3)
d 14.1, 22.6, 28.4 (2 peaks), 29.1
(2 peaks), 31.7, 39.0, 48.0, 72.0, 125.9, 127.8, 128.5, 142.1. IR (neat)
3419, 2925 cmꢂ1. LRMS (EI, 70 eV) m/z 298 (Mþ, 100%). HRMS Calcd
for C16H26OS2: 298.1425. Found: 298.1437. [
a
]
24 ꢂ66 (c 0.42, CHCl3).
D
oil. 1H NMR (400 MHz, CDCl3)
d
0.92 (3H, t, J¼7.6 Hz), 1.41 (2H, sext.,
J¼7.2 Hz), 1.64 (2H, quint., J¼7.6 Hz), 2.11 (3H, s), 2.69 (2H, t,
J¼7.6 Hz), 3.04 (1H, dd, J¼5.2 Hz, 14 Hz), 3.16 (1H, dd, J¼8.4 Hz,
14 Hz), 6.00 (1H, dd, J¼5.2 Hz, 8.4 Hz), 7.28e7.38 (5H, m). 13C NMR
4.3.9. Bis{(R)-2-hydroxybutyl} disulfide. To a solution of (R)-1,2-
epoxybutane (720 mg, 10 mmol) and bis(trimethylsilyl)sulfide
(2.7 mL,13 mmol) was added tetrabutylammonium fluoride (10 mL,
1.0 M THF solution) at 0 ꢀC, and the mixture was stirred for 2 h at
0 ꢀC. The reaction was quenched by adding 20% citric acid aqueous
solution, and the organic materials were extracted with diethyl
ether twice. The combined organic layers were washed with water
and brine, and dried over magnesium sulfate. The solvent was
evaporated in vacuo, and the residue was dissolved in hexane
(67 mL) and toluene (67 mL). Sodium iodate (3.9 g) and alumina
(10 g) were added to the solution, and the mixture was vigorously
stirred for 24 h at room temperature. The mixture was filtered, and
the residue was washed with ethyl acetate. The solution was
evaporated, and the residue was purified by silica gel chromatog-
raphy to give bis{(R)-2-hydroxybutyl} disulfide (580 mg, 55%).
(100 MHz, CDCl3) d 13.7, 21.1, 21.6, 31.2, 38.8, 45.3, 74.1, 126.7, 128.4,
128.6, 139.0, 170.0. IR (neat) 2927, 1746 cmꢂ1. LRMS (EI, 70 eV) m/z
284 (Mþ, 10%). HRMS Calcd for C14H20O2S2: 284.0905. Found:
284.0919. [
a
]
24 ꢂ57 (c 0.66, CHCl3).
D
4.3.4. Bis{(R)-2-acetoxy-2-phenylethyl} disulfide. To a solution of
(R,R)-3 (60 mg, 0.20 mmol) in dichloromethane (0.40 mL), acetyl
anhydride (0.08 mL, 0.80 mmol) and triethylamine (0.11 mL,
0.80 mmol) were added at room temperature, and the mixture was
stirred for 1 h. The reaction was quenched by adding 2 M hydro-
chloric acid, and the organic materials were extracted with ethyl
acetate twice. The combined organic layers were washed with
water and brine, and dried over magnesium sulfate. The solvent
were evaporated in vacuo, and the residue was purified by silica gel
chromatography to give the product (69 mg, 88%). Colorless oil. 1H
Colorless oil. 1H NMR (400 MHz, CDCl3)
d
1.00 (6H, t, J¼7.6 Hz),
1.53e1.62 (4H, m), 2.34 (2H, s), 2.67 (2H, dd, J¼8.8 Hz, 14 Hz), 2.92
(2H, dd, J¼3.2 Hz, 14 Hz), 3.80e3.84 (2H, m). 13C NMR (100 MHz,
NMR (400 MHz, CDCl3)
d
2.09 (6H, s) 3.03 (2H, dd, J¼5.2 Hz, 14 Hz),
CDCl3) d
9.9, 29.0, 45.9, 71.1. IR (neat) 3375, 2925 cmꢂ1. LRMS (EI,
3.16 (2H, dd, J¼8.4 Hz, 14 Hz), 5.98 (2H, dd, J¼5.2 Hz, 8.4 Hz),
70 eV) m/z 210 (Mþ, 27%). HRMS Calcd for C8H18O2S2: 210.0748.
7.28e7.38 (10H, m). 13C NMR (100 MHz, CDCl3)
d
20.9, 45.0, 73.8,
Found: 210.0744. [
a
]
23 ꢂ68 (c 0.30, CHCl3).
D
126.6, 128.3, 128.5, 138.7, 169.8. IR (neat) 2925, 1742 cmꢂ1. LRMS (EI,
70 eV) m/z 390 (Mþ, 7%). HRMS Calcd for C20H22O4S2: 390.0960.
4.3.10. (R)-2-Hydroxybutyl butyl disulfide. In a two-necked flask
equipped with reflux condenser were placed bis{(R)-2-
Found: 390.0936. [
a
]
D
24 ꢂ96 (c 0.38, CHCl3).
a
hydroxybutyl} disulfide (110 mg, 0.50 mmol), dibutyl disulfide
(0.28 mL, 1.5 mmol), RhH(PPh3)4 (17 mg, 0.015 mmol), tris(p-tolyl)
phosphine (18 mg, 0.060 mmol), and trifluoromethanesulfonic acid
4.3.5. (S)-2-Hydroxy-2-phenylethyl butyl disulfide (S)-2. (S)-2 was
prepared by the method used for the synthesis of (R)-2. [
0.60, CHCl3).
a
]
24 þ88 (c
D
(3 mL, 0.030 mmol) in acetone (1.0 mL) under an argon atmosphere,
and the solution was heated at reflux for 2 h. Then, the solvent was
removed under reduced pressure, and the product (136 mg, 70%)
was separated by silica gel chromatography. Colorless oil. 1H NMR
4.3.6. Bis{(S)-2-hydroxy-2-phenylethyl} disulfide, (S,S)-3. (S,S)-3
19
was prepared by the method used for the synthesis of (R,R)-3. [a]
D
22
þ171 (c 1.01, CHCl3); lit. [
a]
þ164 (c 2.13, CHCl3).13
(400 MHz, CDCl3)
d
0.93 (3H, t, J¼7.6 Hz), 1.00 (3H, t, J¼7.6 Hz), 1.42
D
(2H, sext., J¼7.6 Hz), 1.54e1.62 (2H, m), 1.67 (2H, quint., J¼7.6 Hz),
2.36 (1H, s), 2.64 (1H, dd, J¼8.8 Hz, 14 Hz), 2.73 (2H, t, J¼7.6 Hz),
2.88 (1H, dd, J¼3.2 Hz, 14 Hz), 3.77e3.83 (1H, m). 13C NMR
4.3.7. (R)-2-Hydroxy-2-phenylethyl methyl disulfide. In
a two-
necked flask equipped with a reflux condenser were placed (R,R)-
3 (100 mg, 0.33 mmol), dimethyl disulfide (0.089 mL, 1.0 mmol),
RhH(PPh3)4 (11 mg, 0.010 mmol), tris(p-tolyl)phosphine (12 mg,
(100 MHz, CDCl3) d 9.9,13.6, 21.6, 28.9, 31.2, 38.7, 46.0, 71.1. IR (neat)
3404, 2928 cmꢂ1. LRMS (EI, 70 eV) m/z 194 (Mþ, 100%). HRMS Calcd
0.040 mmol), and trifluoromethanesulfonic acid (2
mL, 0.020 mmol)
for C8H18OS2: 194.0799. Found: 194.0794. [
a
]
23 ꢂ41 (c 0.37, CHCl3).
D
in acetone (1.0 mL) under an argon atmosphere, and the solution
was heated at reflux for 2 h. Then, the solvent was removed under
reduced pressure, and the product (95 mg, 72%) was separated by
4.3.11. (ꢁ)-2-Hydroxy-2-phenylethyl butyl disulfide, (ꢁ)-2. (ꢁ)-2
was prepared by the method used for the synthesis of (R)-2.

M. Miyagawa et al. / Tetrahedron 71 (2015) 4920e4926
4925
Colorless oil. 1H NMR (400 MHz, CDCl3)
d
0.93 (3H, t, J¼7.2 Hz), 1.42
J¼7.2 Hz), 1.43 (9H, s), 1.64 (2H, quint., J¼7.2 Hz), 1.74e1.88 (3H, m),
1.96e2.01 (1H, m), 2.75 (2H, t, J¼7.2 Hz), 2.80 (1H, dd, J¼8.8,
12.8 Hz), 3.07 (1H, dd, J¼2.8, 12.8 Hz), 3.24 (1H, ddd, J¼3.2, 5.6,
12.8 Hz), 3.31 (1H, ddd, J¼6.0, 7.6, 10.8, Hz), 3.97 (1H, tt, J¼3.2,
(2H, sext., J¼7.6 Hz), 1.69 (2H, quint., J¼7.6 Hz), 2.72 (1H, s), 2.75
(2H, t, J¼7.2 Hz), 2.92 (1H, dd, J¼9.6 Hz, 14 Hz), 3.03 (1H, dd,
J¼3.2 Hz, 14 Hz), 4.98 (1H, dd, J¼9.6 Hz, 3.2 Hz), 7.28e7.43 (5H, m).
13C NMR (100 MHz, CDCl3)
d
13.7, 21.7, 31.2, 38.8, 48.2, 72.0, 126.0,
8.0 Hz). 13C NMR (100 MHz, DMSO-d6)
d 13.1, 20.4, 22.6, 28.0, 28.2,
127.9, 128.7, 142.0. IR (neat) 3380, 2925 cmꢂ1. LRMS (EI, 70 eV) m/z
242 (Mþ, 17%). HRMS Calcd for C12H18OS2: 242.0799. Found:
242.0792.
29.0, 30.4, 38.1, 46.2, 56.3, 78.3, 153.3. IR (neat) 2925, 1696 cmꢂ1
.
LRMS (EI, 70 eV) m/z 305 (Mþ, 15%). HRMS Calcd for C14H27NO2S2:
305.1483. Found: 305.1467. [
a]
24 ꢂ112 (c 0.38, CHCl3).
D
4.3.12. Bis(2-hydroxy-2-phenylethyl) disulfide, 3. 3 (diastereomer
mixture of (R,R)-3, meso-3, and (S,S)-3) was prepared by the
method used for the synthesis of (R,R)-3. Ratio was determined by
chiral HPLC; (R,R)-3:meso-3:(S,S)-3¼26:51:23. Colorless oil. 1H
4.3.16. Bis{(S)-N-(tert-Butoxycarbonyl)-2-pyrrolidylmethyl}
disul-
fide, (S,S)-11. To a solution of (S)-2-(acetylsulfanyl)methyl-N-(tert-
butoxycarbonyl)-pyrrolidine (S)-2414 (3.7 g, 14 mmol) in methanol
(56 mL) and water (28 mL) was added potassium carbonate (3.87 g)
at room temperature. The mixture was stirred under air for 24 h.
The reaction was quenched by adding 4 M hydrochloric acid, and
the organic materials were extracted with ethyl acetate twice. The
combined organic layers were washed with water and brine, and
dried over sodium sulfate. The solvents were evaporated in vacuo,
and the residue was purified by silica gel chromatography to give
(S,S)-11 (2.5 g, 82%). Mp 95e96 ꢀC (hexane). 1H NMR (400 MHz,
NMR (400 MHz, CDCl3)
d
2.68 (4H, s), 2.86 (2H, dd, J¼8.8 Hz, 14 Hz),
2.89 (2H, dd, J¼8.8 Hz, 14 Hz), 2.94 (2H, dd, J¼4 Hz, 14 Hz), 2.96 (2H,
dd, J¼4 Hz, 14 Hz), 4.82e4.90 (4H, m), 7.26e7.33 (20H, m). 13C NMR
(100 MHz, CDCl3)
d 47.5, 47.6, 72.1 72.5, 125.8, 125.9, 128.0, 128.1,
128.6, 128.7, 142.0, 142.2. IR (neat) 3386, 2925 cmꢂ1. LRMS (EI,
70 eV) m/z 306 (Mþ, 24%). HRMS Calcd for C16H18O2S2: 306.0748.
Found: 306.0740.
DMSO-d6) d 1.42 (18H, s), 1.71e1.90 (6H, m), 1.94e2.03 (2H, m), 2.88
4.3.13. (S)-(2-Pyrrolidylmethyl) butyl disulfide, (S)-8. In
a
two-
(2H, dd, J¼9.2, 13.2 Hz), 3.10 (2H, dd, J¼3.2, 13.2 Hz), 3.24 (2H, ddd,
necked flask equipped with a reflux condenser were placed (S,S)-
9 (120 mg, 0.50 mmol), dibutyl disulfide (0.28 mL, 1.5 mmol),
RhH(PPh3)4 (17 mg, 0.015 mmol), tris(p-tolyl)phosphine (18 mg,
J¼2.8, 5.6, 12.8 Hz), 3.31 (2H, ddd, J¼6.0, 7.6, 10.8, Hz), 3.97 (2H, tt,
J¼3.2, 8.0 Hz). 13C NMR (100 MHz, DMSO-d6)
d 22.7, 28.1, 28.5, 29.0,
46.2, 56.4, 78.3, 153.5. IR (neat) 2925, 1685 cmꢂ1. LRMS (EI, 70 eV)
0.060 mmol), and trifluoromethanesulfonic acid (3
mL, 0.030 mmol)
m/z 432 (Mþ, 1%). HRMS Calcd for C20H36N2O4S2: 432.2117. Found:
27
in acetone (1.0 mL) under an argon atmosphere, and the solution
was heated at reflux for 2 h. Then, the solvent was removed under
reduced pressure, and (S)-8 (140 mg, 69%) was separated by silica
432.2112. [
a
]
ꢂ120 (c 0.93, CHCl3).
D
Acknowledgements
gel chromatography. Colorless oil. 1H NMR (400 MHz, CDCl3)
d 0.92
(3H, t, J¼7.2 Hz), 1.41 (2H, sext., J¼7.2 Hz), 1.43e1.47 (1H, m) 1.66
(2H, quint., J¼7.2 Hz), 1.73e1.81 (2H, m), 1.89e1.98 (1H, m), 2.13
(1H, s), 2.70 (2H, t, J¼7.2 Hz), 2.73e2.81 (2H, m), 2.89 (1H, ddd,
J¼6.8, 7.6, 14.4 Hz), 2.98 (1H, ddd, J¼6.0, 8.0, 13.6 Hz), 3.36 (1H,
Financial support from JSPS (No. 25249108) is acknowledged.
M.A. expresses her appreciation to the financial support provided
by Grants-in-Aid for Scientific Research (Nos. 25109503 and
15H00911) and the Asahi Glass Foundation. M.M. acknowledges
a fellowship from the Japan Society for Young Japanese Scientists
(No. 25-7469).
quint., J¼7.2 Hz). 13C NMR (100 MHz, CDCl3)
d 13.7, 21.7, 25.2, 30.9,
31.2, 38.8, 45.3, 46.3, 57.7. IR (neat) 3330, 2925 cmꢂ1. LRMS (EI,
70 eV) m/z 205 (Mþ, 1%). HRMS Calcd for C9H19NS2: 205.0959.
Found: 205.0965. [
a
]
24 ꢂ125 (c 0.52, CHCl3).
D
Supplementary data
4.3.14. Bis{(S)-(2-pyrrolidylmethyl)} disulfide, (S,S)-9. To a solution
of (S,S)-11 (320 mg, 0.74 mmol) in dichloromethane (1.5 mL) was
added trifluoroacetic acid (0.83 mL, 11 mmol) at 0 ꢀC, and the
mixture was stirred for 1 h. The reaction was quenched by adding
saturated aqueous sodium hydrogen carbonate, and the organic
materials were extracted with ethyl acetate twice. The combined
organic layer were washed with water and brine, and dried over
sodium sulfate. The solvents were evaporated in vacuo, and the
residue was purified by silica gel chromatography to give (S,S)-9
(120 mg, 70%). Colorless oil. 1H NMR (400 MHz, DMSO-d6)
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.05.106.
References and notes
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d
1.70e1.90 (6H, m), 1.94e2.02 (2H, m), 2.90 (2H, dd, J¼9.2,13.2 Hz),
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d 22.3, 28.3, 29.7, 48.2, 59.5. IR (neat) 3340,
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ꢀ
ꢀ
ꢁ
ꢀ
ꢀ
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denser were placed (S,S)-11 (220 mg, 0.50 mmol), dibutyl disulfide
(0.28 mL, 1.5 mmol), RhH(PPh3)4 (17 mg, 0.015 mmol), tris(p-tolyl)
phosphine (18 mg, 0.060 mmol), and trifluoromethanesulfonic acid
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ꢀ
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ꢀ
Chem. Res. 2007, 46, 52e58; (b) Dube, M. A.; Tremblay, A. Y.; Liu, J. Bioresour.
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separated by silica gel chromatography. Colorless oil. 1H NMR
ꢀ
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(400 MHz, DMSO-d6)
d
0.90 (3H, t, J¼7.2 Hz), 1.42 (2H, sext.,

4926
M. Miyagawa et al. / Tetrahedron 71 (2015) 4920e4926
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