Study for diastereoselective aldol reaction in flow: synthesis of (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid, a key component of cyclodepsipeptide HDAC inhibitors

Article abstract of DOI:10.1016/j.tet.2015.05.051

Abstract Flow synthesis of (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (5), a key component of cyclodepsipeptide histone deacetylase inhibitors was achieved. An efficient flow system for the synthesis of α, β-unsaturated ester 8 was established using a flow reactor column packed with polymer-supported 1,4-diazabicyclo[2.2.2]octane and a fast mixing accessible flow reactor (Comet X-01). Enal 9 was efficiently prepared by a partial reduction of the α, β-unsaturated ester 8 using diisobutylaluminium hydride in the flow system, and the continuous-flow diastereoselective aldol reaction was performed at low temperature, giving a good yield and diastereoselectivity of the desired aldol 10.

Full text of DOI:10.1016/j.tet.2015.05.051

Tetrahedron xxx (2015) 1e8
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Study for diastereoselective aldol reaction in flow: synthesis of (E)-
(
S)-3-hydroxy-7-tritylthio-4-heptenoic acid, a key component of
cyclodepsipeptide HDAC inhibitors
*
Takayuki Doi , Hiroyuki Otaka, Koji Umeda, Masahito Yoshida
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aramaki, Aoba-ku, 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:
Flow synthesis of (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (5), a key component of cyclo-
Received 14 March 2015
Received in revised form 14 May 2015
Accepted 15 May 2015
Available online xxx
depsipeptide histone deacetylase inhibitors was achieved. An efficient flow system for the synthesis of
-unsaturated ester 8 was established using a flow reactor column packed with polymer-supported 1,4-
diazabicyclo[2.2.2]octane and a fast mixing accessible flow reactor (Comet X-01). Enal 9 was efficiently
prepared by a partial reduction of the -unsaturated ester 8 using diisobutylaluminium hydride in the
a,
b
a, b
This paper is dedicated to Honorary Pro-
fessor Jiro Tsuji on the occasion of his Tet-
rahedron Prize
flow system, and the continuous-flow diastereoselective aldol reaction was performed at low temper-
ature, giving a good yield and diastereoselectivity of the desired aldol 10.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Aldol reaction
Flow synthesis
Diastereoselective
Histone deacetylase inhibitor
Cyclodepsipeptide
1
. Introduction
tritylthio-4-heptenoic acid (5), which is a key component of the
5
natural product histone deacetylase (HDAC) inhibitors, FK228 (1),
6
7
8
The use of flow synthesis in the current organic synthesis has
been investigated extensively in recent decades because of the
advantages flow synthesis offers over the conventional batch syn-
thesis. These advantages include the ability to strictly control the
reaction temperature through an efficient heat transfer and the
spiruchostatins (2), burkholdacs (3) and largazole (4) (Fig. 1).
HDAC inhibitors have been found to be novel anticancer drug
candidates, because the inhibition of HDACs causes apoptosis to be
9
induced in cancer cells. The naturally occurring cyclodepsipeptide
FK228 (1) has recently been approved for treating human cutane-
ous T-cell lymphoma. Synthetic analogues of 1 containing the b-
1
ability to mix reactants quickly using miniaturized flow devices.
Flow systems can also allow a synthesis to be performed re-
producibly at different scales with a specified reaction time, and
this can be achieved using a continuous-flow system without the
need to further optimize the reaction conditions though it is nec-
essary in batch systems. The potential for using flow systems to
perform reactions that are difficult to regulate in the batch systems
has been investigated by several research groups, i.e., metalation of
haloarenes,2 photochemical reactions, and the multi-step pro-
cesses such as natural product synthesis have also been attempted
3
4
utilizing the flow reactor. We have focused on developing a flow
system for reproducibly synthesizing (E)-(S)-3-hydroxy-7-
*
Corresponding author. E-mail address: doi_taka@mail.pharm.tohoku.ac.jp
Fig. 1. Naturally occurring cyclodepsipeptide HDAC inhibitors containing a 3-hydroxy-
(
T. Doi).
7-thio-4-heptenoic acid moiety.
http://dx.doi.org/10.1016/j.tet.2015.05.051
040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
0
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2
T. Doi et al. / Tetrahedron xxx (2015) 1e8
hydroxy acid derivative 5 described above could therefore also be
attractive for discovering anticancer agents. The synthesis of a va-
riety of cyclodepsipeptide analogues described above would re-
quire an efficient method for supplying sufficient quantities of 5.
reaction and decreased the yield of the corresponding a, b-un-
saturated ester 8.
The synthesis of the desired
previously been reported by several groups, and we have also
b-hydroxy acid derivative 5 has
10
established the solution-phase synthesis of 5 from acrolein (6) and
11
trityl thiol as shown in Fig. 2. The method involves (1) 1,4-
addition of thiol, (2) HornereWadswortheEmmons (HWE) re-
action, (3) reduction of a, b-unsaturated ester, (4) oxidation to the
enal, (5) diastereoselective aldol reaction and (6) removal of the
chiral auxiliary.
Scheme 1. Initial attempt of the one-pot synthesis of 8 in a batch system.
We therefore planned to synthesize 8 using a flow reactor, de-
scribed in Fig. 3. The first step in the planned synthesis was the 1,4-
addition of thiol to acrolein (6), performing by passing through
15
a column containing polymer-supported DABCO. The resulting
aldehyde 7 could be combined with deprotonated phosphonoace-
tate in the flow reactor (Comet X-01-T) to afford the desired a, b-
unsaturated ester 8. The solutions of the substrates and phospho-
noacetate were to be independently introduced to the flow reactor
using syringe pumps, and the resulting reaction mixture was to be
poured directly into aqueous HCl to terminate the reaction.
Fig. 2. Current synthesis of (E)-(S)-3-hydroxy-7-tritylthio-heptenoic acid (5).
We believed that our synthetic scheme could be improved to
produce 5 more reproducibly by developing it for use in one-pot
synthesis or the flow synthesis methods. For instance, we re-
cently succeeded in improving the synthesis of enal 9 by a partial
reduction of
a, b-unsaturated esters 8 using commercially available
diisobutylaluminium hydride (DIBAL-H) in flow, providing some
12
hundreds of milligrams of enal 9. The desired
b-hydroxy acid
derivative 5 can be produced by basic hydrolysis of 10, followed by
removal of the resulting chiral auxiliary by simple filtration.
Therefore, we subsequently aimed to establish an integrated flow
Fig. 3. Flow system for the synthesis of a, b-unsaturated esters 8 and 11.
system for synthesizing the
0 as a step toward reliably producing sufficient quantities of 5.
Herein, we describe the development of the method for synthe-
sizing the -hydroxy acid derivative 5 using an integrated flow
system involving a polymer-supported reagent-packed column
a, b-unsaturated ester 8 and the aldol
1
d,e
1
b
The synthesis of
a, b-unsaturated esters 8 using the above
designed flow system was investigated, and the results are shown
in Table 1. A mixture of trityl thiol (1 equiv, 0.4 M) and acrolein (6)
1.4 equiv, 0.56 M) in THF was pumped at a flow rate of 2 mL min
through the polymer-supported DABCO using a syringe pump, and
,4-addition of the thiol to 6 was complete within 75 sec to give the
aldehyde 7. The resulting 7 generated in situ was subsequently
introduced into the reactor and mixed with a solution of the
deprotonated HWE reagent (1.3 equiv, 0.52 M) in THF, supplied by
13
reactor and a fast mixing accessible flow reactor Comet X-01.
ꢀ1
(
2
2
. Results and discussion
1
.1. Continuous synthesis of
a
,
b-unsaturated ester by se-
quential 1,4-additioneHWE reaction
Before attempting to develop a flow synthesis, we initially in-
vestigated a one-pot method for synthesizing -unsaturated
another syringe pump, at room temperature to afford a, b-un-
a
,
b
saturated ester 8 in the short residence time (12 sec) (69%, entry 1).
With the good reaction conditions in hand, we further scoped the
HWE reagents in the continuous-flow synthesis of the esters 11.
ester 8 through the 1,4-addition of trityl thiol to acrolein (6), fol-
lowed by HornereWadswortheEmmons reaction in a conventional
batch system (Scheme 1). The 1,4-addition of thiol to 6 smoothly
occurred within 75 sec in the presence of 1,4-diazabicyclo[2.2.2]
octane (DABCO),14 and the HWE reaction was subsequently per-
formed on the resulting aldehyde 7 using deprotonated triethyl
Reactions using
in flow occurred smoothly to provide the corresponding
saturated esters 11a and 11b, respectively, in moderate yields (en-
a
-bromo and
a
-chloro-substituted HWE reagents
a, b-un-
16
tries 2 and 3), whereas the yield of the fluoro-substituted 11c was
low because the high viscosity of the deprotonated -fluoro HWE
reagent led to mixing occurring slowly and the reaction not
reaching completion (entry 4). Moderate yields of the -alkyl-
phosphonoacetate. However, the yield of the
was only moderate (59%), whereas HWE reaction of the isolated
aldehyde 7 smoothly proceeded to provide the corresponding ester
in 97% yield. These observations led us to conclude that the
presence of DABCO in the reaction mixture could inhibit the HWE
a,
b-unsaturated ester
a
8
a
8
substituted 11d and 11e were found using the reaction conditions
described above. This is because that nucleophilic addition to the
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T. Doi et al. / Tetrahedron xxx (2015) 1e8
3
Table 1
Synthesis of the a, b-unsaturated esters 8 and 11 using the integrated flow system
Entry
1
Product
Yielda
69%
Ratio of E/Zb
>95:5
2
3
72%
74%
19:81
19:81
Fig. 4. Flow system for a partial DIBAL-H reduction of a, b-unsaturated ester 8.
4
5
36%
55%
91:9
economical18 for synthesizing a desired enal from the corre-
sponding a, b-unsaturated ester 8 in the gram scale.
87:13
Table 2
Selective synthesis of enal 9 by a partial reduction of 8 in flow
6
54%
56:44
Conditions: A: a mixture of 0.4 M TrtSH and 0.56 M acrolein (6) in THF. B: a 0.52 M
solution of the deprotonated HWE reagent in THF.
a
Isolated yield.
b
The ratio was determined by crude 1H NMR.
aldehyde 7 would occur slowly because of steric hindrance of the a-
alkyl-substituted HWE reagents. It would therefore be necessary to
Conv. Ratio of 9:12a Yield
Entry Conditions
a
of 9 (%)b
(%)
adjust the residence time for the HWE reaction in the flow syn-
ꢁ
1
2
3
Flow (ꢀ97 C, 18 nL/min, RT¼1 sec) >95
89:11
45:55
d
82
33
67
thesis of
a-substituted
a
,
b-unsaturated esters 11.
Batch slow addition (1.1 equiv)
Batch 2 steps 1) DIBAL-H, 2) Swern.
75
c
d
Conditions: A: a 0.1 M solution of a, b-unsaturated ester 8 in toluene. B: a 0.3 M
2
.2. A partial reduction of the
a, b-unsaturated ester 8 to the
solution of DIBAL-H in toluene.
a
The ratio of 9:12 was determined by crude 1H NMR.
Isolated yield.
see Ref. 10a.
enal 9 in flow
b
c
We next performed a partial reduction of 8 to give the enal 9
once the flow synthesis of -unsaturated ester 8 had been ach-
ieved.12 The flow system we used to achieve this partial reduction is
shown in Fig. 4. The flow reactor (Comet X-01-SS) and tubing,
made of stainless steel, were used because of its good thermal
conductivity. Solutions of the substrate and DIBAL-H in toluene
were prepared and independently introduced into the reactor at
the desired flow rate using rotary piston pumps. The reaction
mixture was subsequently quenched with EtOH in a T-shaped
mixer connected to the outlet of the flow reactor. The reaction was
a, b
17
2.3. A continuous-flow diastereoselctive aldol reaction with
the enal 9
The continuous-flow diastereoselective aldol reaction of an ac-
19
etate derivative with 9 was next attempted. The key to achieving
the diastereoselective aldol reaction was rapidly generating the
enolate in the flow reactor and achieving high conversion efficiency
and a high stereoselectivity. We have previously reported the
ꢁ
performed at ꢀ97 C, which was achieved by immersing the system
synthesis of
b-hydroxy acid derivative 10 through a diaster-
2
in a liquid N /MeOH cooling bath.
1
2
eoselective aldol reaction using the Zr-enolate of acetylox-
As we have previously reported,
a, b-unsaturated ester 8 was
2
0
azolidinone 13, but it is conceivable that it could be difficult to
prepare the Zr-enolate for the large-scale synthesis of 10 because of
the poor solubility of the zirconium salt in organic solvents. On the
other hand, we have previously reported the aldol reaction using Li-
enolate of 13 afforded good yield and moderate diastereoselectivity
partially reduced by DIBAL-H in the flow system in a ratio of 89:11,
and the desired enal 9 was afforded in 82% isolated yield (Table 2,
entry 1). On the other hand, the yield of 9 was moderate using
conventional methods such as slow addition of DIBAL-H and two-
step procedure (entries 2 and 3). In addition, 264 mg of the de-
sired enal 9 per minute was afforded in a single step; therefore we
concluded that the method we developed is an efficient and redox-
11a
in the aldol reaction (89%, S:R¼77:23). Therefore, we investigated
the diastereoselective aldol reaction in flow using soluble and
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4
T. Doi et al. / Tetrahedron xxx (2015) 1e8
commercially available LiHMDS. The details of the flow system used
for the aldol reaction are shown in Fig. 5. A Comet X-01-T (Teflon)
flow reactor was used for the enolate formation and a Comet X-01-
SS (Stainless steel) was used for the aldol reaction, respectively.
Syringe pumps were used to independently deliver the substrate
Table 3
Investigation of diastereoselective aldol reaction with the enal 9 in flow
13, and LiHMDS dissolved in THF into the first flow reactor at the
specified flow rate and at the appropriate temperature. The
resulting enolate was directly introduced into the next reactor, in
which the aldol reaction was performed by treatment with the enal
9
pumped by another syringe pump. Finally, the resulting reaction
Entry Flow rate
Residence time (sec) Temp Conv. Ratio of Yield of
mixture was then poured into saturated aqueous NH Cl to termi-
nate the reaction, and allow the desired aldol adduct 10 to be
afforded.
4
ꢀ1
ꢁ
a
10S:10Ra 10 (%)
(V mL$min
)
( C)
(%)
RT
1
RT
7.5
30
30
2
1
2
3
2
1
1
150
300
300
ꢀ40 >95
78:22
91:9
85b
b
ꢀ60
ꢀ78
82
51
33
c
65 >95:5
Conditions: A: a 0.13 M solution of acetyl oxazolidinone 13 in THF. B: a 0.15 M
solution of LiHMDS in THF. C: a 0.05 M solution of the enal 9 in THF.
a
Determined by crude 1H NMR.
Combined yield of a mixture of S- and R-isomers.
Isolated yield.
b
c
conversion of the enal 9 was decreased to 82%, conceivably because
the reaction temperature was slightly lower to allow for the suffi-
cient enolate formation (entry 2). On the other hand, excellent di-
ꢁ
astereomeric ratio was observed at ꢀ78 C (10S:10R¼ >95:5), and
the desired S-isomer was afforded in 33% yield as a sole product
(entry 3). Note that this observation is a first example of the aldol
reaction being performed using the lithium enolate of non-
substituted-acetyl oxazolidinone derivatives and giving 10 with
excellent diastereoselectivity. The aldol product 10 obtained using
these conditions was easily converted into the desired
b-hydroxy
acid derivative 5 by hydrolysis under basic condition and by simple
11
purification using a short pad silica gel column chromatography.
As can be seen from the descriptions above, we found that
ꢁ
performing the reaction at the lower temperature such as ꢀ78 C
was required to improve the diastereoselectivity of the reaction,
but a higher conversion was achieved when the reaction was
ꢁ
conducted at a higher temperature (up to ꢀ40 C). We therefore
expected that a high conversion and good diastereoselectivity
could be achieved by performing the enolate formation and the
aldol reaction under different conditions; therefore, we redesigned
the flow system used for the aldol reaction. In the redesigned
system, two flow reactors were immersed in separate cryogenic
Fig. 5. Flow system for a diastereoselective aldol reaction of 13 with the enal 9.
ꢁ
ꢁ
baths, at ꢀ40 C for the enolate formation and ꢀ78 C for the aldol
reaction, and the reagents including 13 and LiHMDS were both
ꢀ1
dispensed at a flow rate of 1 mL min . The enolate formation of 13
We initially investigated the aldol reaction of the enal 9 in the
flow system at different temperatures, and the results are sum-
marized in Table 3. The enolate formation and the aldol reaction
ꢁ
proceeded at ꢀ40 C by mixing with LiHMDS in the reactor, and the
resulting enolate was immediately introduced into the next flow
reactor, in which the aldol reaction with enal 9 was performed at
ꢁ
were performed at ꢀ40 C by immersing the flow reactor into dry
ꢁ
21
ꢀ78 C. The aldol reaction smoothly proceeded with good con-
ice/acetone cryogenic bath.
A 0.13 M solution of acetylox-
version as same as the reaction in the batch system, and the desired
product 10 was afforded in 73% yield with acceptably high dia-
stereoselectivity (Table 4, entry 1, 10S:10R¼86:14). We also found
that the reaction reached completion with a shorter residence time
azolidinone 13 in THF was combined with a 0.15 M solution of
LiHMDS in THF in the flow reactor Comet X-01-T, both solutions
ꢀ1
being delivered at a flow rate of 2 mL min . The enolate formation
was allowed to proceed for 150 sec, and then the resulting enolate
was subsequently introduced into the next reactor Comet X-01-SS
and mixed with a 0.05 M solution of the enal 9 in THF, dispensed
ꢀ1
when a higher flow rate (e.g., 3 mL min ) was used, affording the
desired 9 without decreasing the yield and the diastereoselectivity
(entry 2). Therefore, it is conceivable that the flow system we
established could be used in the scalable synthesis of 10, because
the system allows the reaction temperature to be controlled, which
is difficult to achieve in a large scale batch system.
ꢀ1
at 4 mL min by a syringe pump, to perform the aldol reaction at
the same temperature. Enal 9 was completely consumed within
a shorter residence time (7.5 sec), and the desired aldol product 10
was obtained in 85% yield with a moderate diastereoselectivity
(
10S:10R¼78:22, entry 1). We next performed the reaction at
a lower temperature to improve a diastereoselectivity in the aldol
reaction, and the residence time allowed for the enolate formation
and the aldol reaction were extended using a lower flow rate
3. Conclusion
We have developed a flow synthesis method for producing b-
hydroxy acid derivative 5, which is a key component of the natural
product HDAC inhibitors, FK228 (1), spiruchostatins (2),
ꢀ
1
(
1 mL min ). It was found that a diastereomeric ratio was in-
ꢁ
creased to 91:9 when the reaction was performed at ꢀ60 C, but
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T. Doi et al. / Tetrahedron xxx (2015) 1e8
5
Table 4
abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), m
multiplet) dd (double doublet), dt (double triplet), ddt (double
Investigation of diastereoselective aldol reaction of 13 with the enal 9 in flow
(
double triplet), brs (broad singlet), J (coupling constants in Herts).
Mass spectra and high-resolution mass spectra were measured
with JEOL JMS-DX303 (EI), MS-AX500 (FAB), or BRUKER microTOF-
II (ESI) instruments. IR spectra were recorded with a Shimadzu
ꢀ
1
FTIR-8400, and data are given in cm . Only the strongest and/or
structurally important absorptions are reported. Melting points
were measured using a Round Science Inc. RFS-10 instrument and
are not corrected.
Entry Flow rate
Residence time (sec)
Conv. Ratio of
Yield of
V mL$minꢀ1)
(%)
a
10S:10R
a
10 (%)b
(
RT
1
RT
2
4
.2. Synthesis of ethyl (E)-5-(triphenylmethylthio)-2-
1
2
1
3
300
100
30
10
91
91
86:14
83:17
73
76
11
pentenoate (8) by one-pot procedure in the batch system
Conditions: A: a 0.13 M solution of acetyl oxazolidinone 13 in THF.B: a 0.15 M so-
lution of LiHMDS in THF. C: a 0.05 M solution of the enal 9 in THF.
To a solution of HSTrt (442 mg, 1.60 mmol, 1.0 equiv) and DABCO
(
246
added acrolein (6) (150
ature, and the mixture was stirred at the same temperature for
5 sec. To the reaction mixture was added a solution of deproto-
nated triethyl phosphonoacetate (580 L, 2.91 mmol, 1.3 equiv) in
mL, 2.24 mmol, 1.4 equiv) in THF (3.6 mL, 2.25 mL/mmol) was
a
1
Determined by crude H NMR.
Combined yield of a mixture of S- and R-isomers.
b
mL, 2.24 mmol, 1.4 equiv) at room temper-
7
burkholdacs (3) and largazole (4). An integrated flow system in-
m
volving 1,4-addition of thiol and HWE reaction was established for
THF (3.6 mL, 2.25 mL/mmol) at room temperature. After the alde-
synthesizing the
a,
b
-unsaturated ester 8. In the system, 1,4-
hyde 6 was completely consumed (<1 min), the reaction mixture
addition of trityl thiol to acrolein (6) was achieved with a high ef-
ficiency using polymer-supported DABCO, and the subsequent
HWE reaction smoothly proceeded at ambient temperature to af-
ford the corresponding esters 8 in moderate yield (scalability:
was quenched with H O, and the aqueous layer was extracted with
ethyl acetate. The organic layer was washed with brine, dried with
2
MgSO , filtered, and concentrated in vacuo. The residue was puri-
4
fied by column chromatography on silica gel (eluting with hexane/
ꢀ
1
2
09 mg min ), not less than the yield by one-pot synthesis in
EtOAc¼98:2) to give the
(59%, 381 mg, 0.946 mmol). Mp 81e82 C; H NMR (400 MHz,
CDCl ):
7.41e7.19 (m, 15H), 6.75 (dt, 1H, J¼16.0, 6.8 Hz), 5.69 (d,
1H, J¼16.0 Hz), 4.15 (q, 2H, J¼7.6 Hz), 2.28 (t, 2H, J¼7.2 Hz), 2.18 (dt,
a, b-unsaturated ester 8 as a white solid
ꢁ
1
solution-phase. Partial reduction of the resulting -unsaturated
a, b
ester 8 was achieved in the flow system by strictly controlling the
flow rate, the residence time and the reagent concentration. The
scalable synthesis of desired enal 9 was also achieved, and it is
noteworthy that the flow system we developed efficiently provided
some hundreds milligram of enal 9 per minute (scalability:
d
3
1
3
2H, J¼7.2, 6.8 Hz), 1.26 (t, 3H, J¼7.6 Hz); C NMR (100 MHz, CDCl ):
3
d
166.3, 146.5, 144.6, 129.5, 127.9, 126.6, 122.3, 66.8, 60.2, 31.3, 30.2,
14.2; FTIR (Neat): 3056, 3030, 2980, 1719, 1654, 1594, 1489, 1444,
ꢀ1
ꢀ1
2
64 mg min ). A continuous-flow diastereoselective aldol reaction
1367, 1335, 1309, 1270, 1196, 1143, 1035, 743, 701, 622 cm ; HRMS
(ESI) calcd for C24H22NaOS [MþNa]þ 425.1551, found 425.1526.
with the above enal 9 was then attempted, and excellent diaster-
eoselectivity was observed when the reaction was performed at
ꢁ
ꢀ
78 C. The scalable synthesis of 10 could also be achieved using
4.3. HWE reaction of the isolated aldehyde 7 with triethyl
phosphonoacetate
ꢀ
1
the flow system when a high flow rate (3 mL min ) was used with
controlling the reaction temperature (scalability: 155 mg min ).
The methods we developed together offer a simple, reproducible
ꢀ
1
To a solution of a suspension of NaH (60% in mineral oil, 16 mg,
0.389 mmol, 1.3 equiv) in THF (0.75 mL, 2.5 mL/mmol) was added
and reliable way of synthesizing b-hydroxy acid derivative 5. We
ꢁ
are currently investigating the application of these methods to
multi-step processes, such as natural product synthesis, and the
results of our investigations will be reported in due course.
triethyl phosphonoacetate (89 mL, 0.449 mmol, 1.5 equiv) at 0 C
under argon, and the mixture was stirred at the same temperature
for 30 min. To the reaction mixture was added a solution of alde-
hyde 6 (99 mg, 0.299 mmol,1 equiv) in THF (0.75 mL, 2.5 mL/mmol)
ꢁ
4
4
. Experimental section
dropwise at 0 C. After being stirred at room temperature, the re-
action mixture was quenched with H
extracted with ethyl acetate. The organic layer was washed with
brine, dried with MgSO , filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(eluting with hexane/EtOAc¼98:2) to give the -unsaturated
ester 8 as a white solid (97%, 117 mg, 0.290 mmol).
2
O and the aqueous layer was
.1. General techniques
4
All commercially available reagents were used as received. Dry
THF (Kanto Chemical Co.) was obtained by passing commercially
available pre-dried, oxygen-free formulations through activated
alumina columns. MeOH was distilled from iodine and magnesium
turnings. Toluene was distilled from sodium. DMF was purchased
from Wako. All reactions in solution-phase were monitored by
thin-layer chromatography carried out on 0.25 mm E. Merck silica
gel plates (60F-254) with UV light, and visualized with anisalde-
hyde, 10% ethanolic phosphomolybdic acid. Silica gel 60N (Kanto
a, b
4.4. General procedure for the synthesis of a, b-unsaturated
ester 8 and 11aee in flow
The flow system was established with a syringe pumps
Ò
(HIIe10B, Techno applications ), Teflon tube, the flow reactor
Ò
Chemical Co. 100e210
m
m) was used for column chromatography.
(Comet X-01-T, Techno applications ), polymer-supported DABCO
1
13
H NMR spectra (400 MHz) and C NMR spectra (100 MHz) were
recorded on a JEOL JNM-AL400 spectrometer. Chemical shifts (
are reported in units parts per million (ppm) relative to signal for
(2.2 g, 2.3 mmol) packed column flow reactor (20 mm boreꢂ38 mm
length). Before use, the flow system was flushed with THF and dried
under vacuum. A solution of the trityl thiol (0.4 M) and acrolein (6)
(0.56 M) in THF was then loaded into a Teflon sample loop (Tube 1),
and a solution of deprotonated HWE reagents (0.52 M) in THF was
loaded into another Teflon sample loop (Tube 3). Both two solutions
d)
1
internal tetramethylsilane (0 ppm for H) for solutions in CDCl
3
.
NMR spectral data are reported as follows: chloroform (7.26 ppm
1
13
for H) or chloroform-d (77.0 ppm for C) when internal standard
ꢀ
1
is not indicated. Multiplicities are reported by the following
were pumped at flow rate of 2 mL min , and mixed in the reactor
Please cite this article in press as: Doi, T.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.051

6
T. Doi et al. / Tetrahedron xxx (2015) 1e8
(
Comet X-01-T and Tube 4) at the room temperature. The resulting
1288, 1288, 1244, 743, 701 cmꢀ1; HRMS (ESI): calcd for
mixture was quenched by 1 M aqueous HCl, and the aqueous layer
was extracted with ethyl acetate. The organic layer was washed
C
28
H30NaO
2
S [MþNa]þ 453.1864, found 453.1857.
with brine, dried MgSO
residue was purified by column chromatography on silica gel
eluting with hexane/EtOAc¼98:2) to give the -unsaturated
esters 8 and 11aee.
4
, filtered, and concentrated in vacuo. The
4
.5. General procedure for the synthesis of enal 9 in flow
(
a, b
The flow system was established with two rotary piston pumps
Ò
(Reglo-CPF Digital/ISM 321 and RH0.CKC-LF/FMI013, ISMATEC ),
Ò
a syringe pump (HIIe10B, Techno applications ), stainless steel
tube, Teflon tube, the flow reactor (Comet X-01-SS, Techno
applications ) and a methanol/liquid N
4.4.1. Ethyl (E)-5-(triphenylmethylthio)-2-pentenoate (8). Collection
Ò
volume: 6 mL; colorless oil 334 mg, 0.83 mmol, 69%, E/Z¼>95:5).
2
cryogenic bath. Before use,
the flow system was flushed with dry toluene. A solution of the
substrate in toluene (0.1 M) was then loaded into a stainless steel
sample loop (Tube 1), and a solution of DIBAL-H in toluene (0.3 M)
was loaded into another stainless steel sample loop (Tube 2). The
two sample solutions were pumped at a combined flow rate of
4
.4.2. Ethyl (Z)-2-bromo-5-(triphenylmethylthio)-2-pentenoate
(11a). Collection volume:
6
mL; colorless oil (417 mg,
H NMR (400 MHz, CDCl ):
3
1
0
d
1
.866 mmol, 72%, E/Z¼19:81).
7.44e7.38 (m, 6H), 7.32e7.26 (m, 6H), 7.24e7.18 (m, 3H), 7.14 (t,
H, J¼6.8 Hz), 4.25 (q, 2H, J¼7.2 Hz), 2.40e2.31 (m, 4H), 1.31 (t, 3H,
ꢀ
1
1
8.0 mL min , and mixed in the reactor (Comet and Tube 3) at
13
J¼7.2 Hz); C NMR (100 MHz, CDCl
3
):
d
162.1, 144.5, 143.6, 129.5,
ꢁ
97 C. The output of the reactor was connected with a T-shaped
ꢀ
ꢀ
1
127.9,126.7,117.4, 66.9, 62.4, 31.2, 29.6,14.1; FTIR (Neat) 3083, 3056,
mixer to quench the reaction with EtOH (2 mL min ). The resulting
mixture was collected for 4.5 min, and the collected mixture was
diluted with water, and the mixture was extracted with diethyl
ꢀ
1
3
030, 2980, 2928, 1727, 1489, 1444, 1254, 1045, 743, 701 cm
;
7
9
S [MþNa]þ 503.0656, found
HRMS (ESI): calcd for C26H25 BrNaO
2
5
03.0650.
4
ether. The organic layer was washed with brine, dried with MgSO ,
filtered, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (eluting with hexane/
EtOAc¼96:4) to give 9 (82%, 1.19 g, 3.32 mmol) as a white solid.
4
.4.3. Ethyl (Z)-2-chloro-5-(triphenylmethylthio)-2-pentenoate
(11b). Collection volume:
6
mL; colorless oil (386 mg,
H NMR (400 MHz, CDCl ):
3
1
0
d
1
.883 mmol, 74%, E/Z¼19:81).
4
.5.1. (E)-5-(Triphenylmethylthio)-2-pentenal (9).11 Mp 141e142 C;
ꢁ
7.48e7.36 (m, 6H), 7.32e7.24 (m, 6H), 7.23e7.16 (m, 3H), 6.91 (t,
H, J¼6.8 Hz), 4.23 (q, 2H, J¼7.0 Hz), 2.40e2.28 (m, 4H), 1.29 (t, 3H,
1
H NMR (400 MHz, CDCl
6
3
):
d
9.42 (d, 1H, J¼8.0 Hz), 7.47e7.38 (m,
13
J¼7.0 Hz); C NMR (100 MHz, CDCl
3
): d 162.0, 144.5, 139.7, 129.4,
H), 7.32e7.19 (m, 9H), 6.61 (dt, 1H, J¼16.0, 6.4 Hz), 6.13 (dd, 1H,
13
127.8, 126.6, 125.6, 66.8, 62.1, 29.7, 28.5, 14.0; FTIR (Neat): 3056,
J¼16.0, 8.0 Hz), 2.34e2.27 (m, 4H); C NMR (100 MHz, CDCl
3
):
ꢀ
1
3
030, 2981, 2627, 1731, 1489, 1444, 1259, 1049, 743, 701 cm
;
d
193.6, 155.6, 144.5, 133.5, 129.4, 127.9, 126.7, 66.9, 31.6, 29.9; FTIR
HRMS (ESI): calcd for C26
4
H
25ClNaO
2
S [MþNa]þ 459.1161, found
(
7
Neat) 3056, 3030, 2980, 2929, 1719, 1444, 1269, 1195, 743,
ꢀ1
þ
59.1157.
00 cm ; HRMS (ESI): calcd for C24H22NaOS [MþNa] 381.1289,
found 381.1275.
4
.4.4. Ethyl (E)-2-fluoro-5-(triphenylmethylthio)-2-pentenoate
mL; colorless oil (175 mg,
.416 mmol, 36%, E/Z¼91:9). H NMR (400 MHz, CDCl ): 7.38e7.28
(11c). Collection volume:
6
ꢁ
4
.6. Procedure for the synthesis of aldol 10 in flow at L78 C
1
0
3
d
(Table 3, entry 3)
(
7
(
d
m, 6H), 7.22e7.15 (m, 6H), 7.14e7.06 (m, 3H), 5.67 (dt, 1H, J¼20.4,
.4 Hz), 4.15 (q, 2H, J¼7.2 Hz), 2.48 (ddt, 2H, J¼7.6, 7.4, 1.6 Hz), 2.17
The flow system was established with two syringe pumps
13
t, 2H, J¼7.6 Hz), 1.21 (t, 3H, J¼7.2 Hz); C NMR (100 MHz, CDCl
3
):
Ò
(
(
(
HIIe10B, Techno applications ), Teflon tube, the flow reactor
160.6 (d, J¼35.9 Hz), 147.4 (d, J¼252.4 Hz), 144.6, 129.4, 127.8,
Ò
Comet X-01-T, Techno applications ), stainless steel flow reactor
Comet X-01-SS, Techno applications ) and an acetone/dry-ice
1
26.6, 121.3 (d, J¼19.8 Hz), 66.7, 61.3, 31.3 (d, J¼2.5 Hz), 24.5 (d,
Ò
J¼5.3 Hz), 14.0; FTIR (Neat): 3056, 2981, 1728, 1489, 1444, 1375,
bath. Before use, the flow system was flushed with THF and dried
under vacuum. A solution of the acetyloxazolidinone 13 in THF
ꢀ1
1320, 1241, 743, 701 cm ; HRMS (ESI): calcd for C26
H
25FNaO
2
S
þ
[MþNa] 443.1452, found 443.1460.
(0.13 M) was then loaded into a Teflon sample loop (Tube 1), and
a solution of LiHMDS in THF (0.15 M) was loaded into an another
4
.4.5. Ethyl (E)-2-methyl-5-(triphenylmethylthio)-2-pentenoate
Teflon sample loop (Tube 2). Both two solutions were pumped at
(11d). Collection volume: 6 mL; colorless oil (275 mg, 0.66 mmol,
ꢀ1
a combined flow rate of 2 mL min , and mixed in the reactor
1
5
7
1
5%, E/Z¼87:13). H NMR (400 MHz, CDCl
.32e7.25 (m, J¼8.8 Hz, 2H), 7.23e7.18 (m, 3H), 6.57 (dt, 1H, J¼6.8,
.0 Hz), 4.16 (q, 2H, J¼7.0 Hz), 2.31e2.27 (m, 2H), 2.21e2.17 (m, 2H),
3
):
d
7.42e7.39 (m, 6H),
ꢁ
(
Comet X-01-T and Tube 3) at ꢀ78 C. The output of the reactor was
connected with another reactor (Comet X-01-SS) and Tube 5 to mix
the reaction mixture with a solution of the enal 9 in THF (0.05 M,
13
1
.71 (d, 3H, J¼1.0 Hz), 1.27 (t, 3H, J¼7.0 Hz); C NMR (100 MHz,
CDCl ): 167.8, 144.7, 139.4, 129.5, 129.0, 127.8, 126.6, 66.7, 60.4,
0.7, 27.9, 14.2, 12.4; FTIR (Neat): 3056, 3030, 2979, 2927, 1709,
ꢀ1
2
mL min , Tube 4). The reaction mixture was collected for 60 sec,
3
d
and the resulting mixture was quenched with saturated aqueous
NH Cl, and the aqueous layer was extracted with ethyl acetate. The
organic layer was washed with brine, dried MgSO , filtered, and
3
4
ꢀ
1
1489, 1444, 1259, 1108, 743, 701 cm . HRMS (ESI): calcd for
4
þ
C
27
H28NaO
2
S [MþNa] 439.1708, found 439.1707.
concentrated in vacuo. The residue was purified by column chro-
matography on silica gel (eluting with hexane/EtOAc¼91:9) to give
4
.4.6. Ethyl (E)-2-ethyl-5-(triphenylmethylthio)-2-pentenoate
10 as a white solid (22.4 mg, 33%, S/R¼>95:5).
(11e). Collection volume:
6
mL; colorless oil (278 mg,
H NMR (400 MHz, CDCl ):
3
1
0
d
1
.645 mmol, 54%, E/Z¼56:44).
4
.6.1. (E)-(S)-3-Hydroxyl-1-[(R)-4-isopropyl-5,5-diphenyl-2-
7.44e7.38 (m, 6H), 7.32e7.25 (m, 6H), 7.24e7.17 (m, 3H), 6.52 (t,
H, J¼7.2 Hz), 4.16 (q, 2H, J¼7.0 Hz), 2.30e2.14 (m, 6H), 1.27 (t, 3H,
11
19
D
oxazolidinone-3-yl]-7-trityl-4-thiohepten-1-one (10S).
½
a
ꢃ
þ89.9
ꢁ
1
(c 0.745, CHCl
3
); mp 61e62 C; H NMR (400 MHz, CDCl
3
):
1
3
J¼7.0 Hz), 0.92 (t, 3H, J¼8.0 Hz); C NMR (100 MHz, CDCl
3
): d 167.5,
d
7.60e7.10 (m, 25H), 5.50 (dt, 1H, J¼15.6, 7.2 Hz), 5.36 (d, 1H,
144.7, 139.0, 135.2, 129.5, 127.8, 126.6, 66.7, 60.3, 30.9, 27.6, 20.0,
J¼3.2 Hz), 5.35 (dd, 1H, J¼15.6, 6.0 Hz), 4.46 (m, 1H), 3.15 (dd, 1H,
J¼16.8, 3.2 Hz), 2.82 (dd, 2H, J¼16.8, 8.8 Hz), 2.74 (d, 1H, J¼4.0 Hz),
14.2, 13.8; FTIR (Neat): 3057, 2975, 2933, 2873, 1709, 1489, 1444,
Please cite this article in press as: Doi, T.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.051

T. Doi et al. / Tetrahedron xxx (2015) 1e8
7
2
0
.17 (t, 2H, J¼7.2 Hz), 2.06e1.90 (m, 2H), 0.876 (d, 3H, J¼6.8 Hz),
References and notes
13
.74 (d, 3H, J¼6.8 Hz); C NMR (100 MHz, CDCl
3
): d 171.8, 152.8,
1
. (a) Yoshida, J.; Nagaki, A.; Yamada, T. Chem.dEur. J. 2008, 14, 7450e7459; (b)
Artman, R. L.; Jensen, K. F. Lab. Chip 2009, 9, 2495e2507; (c) Yoshida, J. Chem.
Rec. 2010, 10, 332e341; (d) Suga, S.; Yamada, D.; Yoshida, J. Chem. Lett. 2010, 39,
404e406; (e) Yoshida, J.; Saito, K.; Nagaki, A. Synlett 2011, 1189e1194; (f)
Wegner, J.; Ceylan, S.; Kirschning, A. Adv. Synth. Catal. 2012, 354, 17e57; (g)
McQuade, D. T.; Seeberger, P. H. J. Org. Chem. 2013, 78, 6384e6389; (h) Yoshida,
J.; Takahashi, Y.; Nagaki, A. Chem. Commun. 2013, 9896e9904.
1
1
44.8,142.0,137.9,131.6,130.1,129.5,128.9,128.7,128.3,127.9,127.8,
26.5, 125.8, 125.4, 89.5, 68.5, 66.5, 64.5, 42.1, 31.3, 29.8, 21.7, 16.2;
FTIR (Neat): 3518, 3058, 3029, 2965, 1784, 1700, 1492, 1449, 1366,
ꢀ1
1319, 1212, 1175, 1035, 1001, 983, 752, 701 cm ; HRMS (ESI): calcd
S [MþNa]þ 704.2810, found 704.2787.
for C44H43NNaO
4
2
. (a) Nagaki, A.; Tomida, Y.; Usutani, H.; Kim, H.; Takabayashi, N.; Nokami, T.;
Okamoto, H.; Yoshida, J. Chem.dAsian. J. 2007, 2, 1513e1523; (b) Usutani, H.;
Tomida, Y.; Nagaki, A.; Okamoto, H.; Nokami, T.; Yoshida, J. J. Am. Chem. Soc.
4
.7. Procedure for the synthesis of aldol 10 in flow using
a high flow rate (Table 4, entry 2)
2
2
007, 129, 3046e3047; (c) Nagaki, A.; Kim, H.; Yoshida, J. Angew. Chem., Int. Ed.
008, 47, 7833e7836; (d) Browne, D. L.; Baumann, M.; Hariji, B. H.; Baxendale,
The flow system was established with two syringe pumps
I. R.; Ley, S. V. Org. Lett. 2011, 13, 3312e3315; (e) Shu, W.; Pellegatti, L.; Oberli,
M. A.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 10665e10669; (f) Brod-
mann, T.; Koos, P.; Metzger, A.; Knochel, P.; Ley, S. V. Org. Process Res. Dev. 2012,
Ò
(
(
(
HIIe10B, Techno applications ), Teflon tube, the flow reactor
Ò
Comet X-01-T, Techno applications ), stainless steel flow reactor
1
6, 1102e1113; (g) Nagaki, A.; Ichinari, D.; Yoshida, J. Chem. Commun. 2013,
3242e3244; (h) Nagaki, A.; Ichinari, D.; Yoshida, J. J. Am. Chem. Soc. 2014, 136,
2245e12248.
. (a) Fukuyama, T.; Hino, Y.; Kamata, N.; Ryu, I. Chem. Lett. 2004, 33, 1430e1431;
b) Hook, B. D. A.; Dohle, W.; Hirst, P. R.; Pickworth, M.; Berry, M. B.; Booker-
Ò
Comet X-01-SS, Techno applications ) and an acetone/dry-ice
1
bath. Before use, the flow system was flushed with THF and dried
under vacuum. A solution of the acetyloxazolidinone 13 in THF
3
(
(
0.13 M) was then loaded into a Teflon sample loop (Tube 1), and
Milburn, K. I. J. Org. Chem. 2005, 70, 7558e7564; (c) Sugimoto, A.; Sumino, Y.;
Takagi, M.; Fukuyama, T.; Ryu, I. Tetrahedron Lett. 2006, 47, 6197e6200; (d)
Tsutsumi, K.; Terao, K.; Yamaguchi, H.; Yoshimura, S.; Morimoto, T.; Kakiuchi,
K.; Fukuyama, T.; Ryu, I. Chem. Lett. 2010, 39, 828e829; (e) Fuse, S.; Tanabe, N.;
Yoshida, M.; Yoshida, H.; Doi, T.; Takahashi, T. Chem. Commun. 2010,
8722e8724; (f) L eꢀ vesque, F.; Seeberger, P. H. Org. Lett. 2011, 13, 5008e5011; (g)
L eꢀ vesque, F.; Seeberger, P. H. Angew. Chem., Int. Ed. 2012, 51, 1706e1709; (h)
a solution of LiHMDS in THF (0.15 M) was loaded into an another
Teflon sample loop (Tube 2). Both two solutions were pumped at
a combined flow rate of 3 mL min , and mixed in the reactor
ꢀ1
ꢁ
(
Comet X-01-T and Tube 3) at ꢀ40 C. The output of the reactor was
connected with another reactor (Comet X-01-SS) and Tube 5 to mix
Bou-Hamdan, F. R.; Seeberger, P. H. Chem. Sci. 2012, 3, 1612e1616; (i) Asano, K.;
Uesugi, Y.; Yoshida, J. Org. Lett. 2013, 15, 2398e2401; (j) Zhang, Y.; Blackman, M.
L.; Leduc, A. B.; Jamison, T. F. Angew. Chem., Int. Ed. 2013, 52, 4251e4255; (k)
Cantillo, D.; de Frutos, O.; Rinc oꢀ n, J. A.; Mateos, C.; Kappe, C. O. Org. Lett. 2014,
the reaction mixture with a solution of the enal 9 in THF (0.05 M,
ꢀ1
ꢁ
6
mL min , Tube 4) at ꢀ78 C. The reaction mixture was collected
for 60 sec, and the resulting mixture was quenched with saturated
aqueous NH Cl, and the aqueous layer was extracted with ethyl
acetate. The organic layer was washed with brine, dried MgSO
1
6, 896e899; (l) Cantillo, D.; de Frutos, O.; Rinc oꢀ n, J. A.; Mateos, C.; Kappe, C. O.
4
J. Org. Chem. 2014, 79, 8486e8490; (m) Ushakov, D. B.; Gilmore, K.; Kopetzki,
D.; McQuade, D. T.; Seeberger, P. H. Angew. Chem., Int. Ed. 2014, 53, 557e561; (n)
Straathof, N. J. W.; Genoets, H. P. L.; Wang, X.; Schouten, J. C.; Hessel, V.; No e€ l, T.
4
,
filtered, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (eluting with hexane/
EtOAc¼91:9) to give 10 as a white solid (155 mg, 76%, S/R¼83:17).
ChemSusChem 2014, 7, 1612e1617.
4
. (a) Baxendale, I. R.; Griffiths-Jones, C. M.; Ley, S. V.; Tranmer, G. K. Synlett 2006,
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S.; Tranmer, G. K. Chem. Commun. 2006, 2566e2568; (c) Tanaka, K.; Motomatsu,
S.; Koyama, K.; Tanaka, S.-I.; Fukase, K. Org. Lett. 2007, 9, 299e302; (d) Tanaka,
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kayabu, A.; Fukase, K. Chem.dAsian. J. 2009, 4, 574e580; (e) Kim, H.; Nagaki, A.;
Yoshida, J. Nat. Commun. 2011, 2, 1e6; (f) Riva, E.; Rencurosi, A.; Gagliardi, S.;
Passarella, D.; Martinelli, M. Chem.dEur. J. 2011, 17, 6221e6226; (g) Fuse, S.;
Mifune, Y.; Takahashi, T. Angew. Chem., Int. Ed. 2014, 53, 851e855; (h) Newton,
S.; Carter, C. F.; Pearson, C. M.; de C. Alves, L.; Lange, H.; Thansandote, P.; Ley, S.
V. Angew. Chem., Int. Ed. 2014, 53, 4915e4920.
. Furumai, R.; Matsuyama, A.; Kobashi, N.; Lee, K.-H.; Nishiyama, M.; Nakajima,
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2002, 62, 4916e4921.
. (a) Masuoka, Y.; Nagai, A.; Shin-ya, K.; Furihata, K.; Nagai, K.; Suzuki, K.-i.;
Hayakawa, Y.; Seto, H. Tetrahedron Lett. 2001, 42, 41e44; (b) Shindo, N.; Terada,
A.; Mori, M.; Amino, N.; Hayata, K.; Nagai, K.; Hayakawa, Y.; Shin-ya, K. Ma-
suoka, Y. (Yamanouchi Pharmaceutical, Japan), 2001, JP 348340A. (c) Nagai, K.;
Taniguchi, M.; Shindo, N.; Terada, A.; Mori, M.; Amino, N.; Suzunuma, I.; Ta-
kahashi, I.; Amase, M. (Yamanouchi Phamaceutical, Japan), 2004, PCT
WO20460 A1.
4
.8. (E)-(S)-3-Hydroxyl-7-tritylthio-4-heptenoic acid (5).11
To a solution of 10S (22 mg, 0.032 mmol, 1 equiv) in MeOH
(
0
1.0 mL, 30 mL/mmol) was added 2 M aqueous NaOH (32
.064 mmol, 2 equiv) at 0 C. After being stirred at room temper-
m
L,
ꢁ
ature for 1 h, the reaction mixture was quenched with 1 M aqueous
HCl. The aqueous layer was extracted with ethyl acetate. The or-
ganic layer was washed with brine, dried over MgSO , filtered and
4
5
6
concentrated in vacuo. The residue was purified by column chro-
matography on silica gel (eluting with hexane/EtOAc¼1:1) to give 5
2
3
(
58%, 7.8 mg, 0.019 mmol) as a white solid. ½
a
ꢃ
e3.11 (c 0.388
D
ꢁ
1
CHCl
1
(
6
1
3
7
3
); mp 133e135 C; H NMR (400 MHz, CDCl
3
):
d
7.41e7.18 (m,
5H), 5.58 (dt, 1H, J¼15.2, 6.8 Hz), 5.41 (dd, 1H, J¼15.2, 6.4 Hz), 4.45
dd, 1H, J¼12.0, 6.4 Hz), 2.52 (d, 2H, J¼12.0 Hz), 2.19 (dt, 2H, J¼15.2,
7
. Biggins, J. B.; Gleder, C. D.; Brady, S. F. Org. Lett. 2011, 13, 1536e1539.
8. Taori, K.; Paul, V. J.; Luesch, H. J. Am. Chem. Soc. 2008, 130, 1806e1807.
. Bolden, J. E.; Peart, M. J.; Johnstone, R. W. Nat. Rev. Drug Discov. 2006, 5,
69e784.
0. (a) Li, K. W.; Wu, J.; Xing, W.; Simon, J. A. J. Am. Chem. Soc. 1996, 118,
13
3
.8 Hz), 2.07 (m, 2H); C NMR (100 MHz, CDCl ): d 176.9, 144.8,
9
31.6, 130.7, 129.6, 127.8, 126.6, 68.5, 66.6, 41.1, 31.4; FTIR (Neat)
7
379, 3056, 2924, 1714, 1489, 1443, 1261, 1181, 1083, 1034, 742,
1
ꢀ1
S [MþNa]þ 441.1503,
00 cm ; HRMS (ESI): calcd for C26
H26NaO
3
7237e7238; (b) Chen, Y.; Gambs, C.; Abe, Y.; Wentworth, P., Jr.; Janda, K. D. J.
Org. Chem. 2003, 68, 8902e8905; (c) Yurek-George, A.; Habens, F.; Brimmell,
M.; Packham, G.; Ganesan, A. J. Am. Chem. Soc. 2004, 126, 1030e1031; (d)
Greshock, T. J.; Johns, D. M.; Noguchi, Y.; Williams, R. M. Org. Lett. 2008, 10,
613e616; (e) Takizawa, T.; Watanabe, K.; Narita, K.; Oguchi, T.; Abe, H.; Katoh, T.
Chem. Commun. 2008, 1677e1679.
found 441.1495.
Acknowledgements
1
1. (a) Doi, T.; Iijima, Y.; Shin-ya, K.; Ganesan, A.; Takahashi, T. Tetrahedron Lett.
006, 47, 1177e1180; (b) Fuse, S.; Okada, K.; Iijima, Y.; Munakata, A.; Machida,
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3. The flow reactor Comet X-01 was purchased from Techno applications.
34e16e204 Denenchofuhoncho, Ota-ku, Tokyo 145-0072, Japan.
This work was supported by a Grant-in-Aid for Scientific Re-
search on Innovative Areas (No. 2105), and partially supported by
Platform for Drug Discovery, Informatics, and Structural Life Sci-
ence from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan (No. 2105).
2
3
1
1
1
4. We found that DABCO and DBU smoothly promoted 1,4-addition of thiol to the
acrolein (6), and DABCO was used as an additive for 1,4-addition of thiol be-
cause the multiple spots on TLC were observed in the presence of DBU.
Supplementary data
1
5. (a) Anand, R. V.; Singh, V. K. Synlett 2000, 807e808; (b) Li, J.-H.; Hu, X.-C.; Xie,
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Supplementary data (Copies of 1H and 13C NMR spectra for
1aee. This material is available free of charge via the internet)
related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2015.05.051.
1
16. The
HornereWadswortheEmmons
reaction using
triethyl 2-fluo-
rophosphonoacetate provides (E)-
a
-fluoro-a, b
-unsaturated esters, see Liu, R. S.
Please cite this article in press as: Doi, T.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.051

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T. Doi et al. / Tetrahedron xxx (2015) 1e8
H.; Matsumoto, H.; Asato, A. E.; Denny, M.; Shichida, Y.; Yoshizawa, T.; Dahl-
quist, F. W. J. Am. Chem. Soc. 1981, 103, 7195e7201.
7. A partial reduction of the saturated esters using a flow reactor has been re-
ported; (a) Ducry, L.; Roberge, D. M. Org. Process Res. Dev. 2008, 12, 163e167; (b)
Chiba, H.; Tagami, K. J. Synth. Org. Chem. Jpn. 2011, 69, 600e610; (c) Webb, D.;
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19. Cross aldol reactions in aqueous biphasic medium were performed under mi-
crofluidic conditions utilizing a Comet X-01 micromixer, see Tanaka, K.; Mo-
tomatsu, S.; Koyama, K.; Fukase, K. Tetrahedron Lett. 2008, 49, 2010e2012.
20. The substrate 13 was prepared according to the reported procedure, see Ref. 11b.
21. Ley et al. has reported that the enolate formation of acyloxazolidinone is
completely performed at room temperature in the continuous-flow diaster-
eoselective electrophilic fluorination, see Nakayama, K.; Browne, D. L.; Bax-
endale, I. R.; Ley, S. V. Synlett 2013, 1298e1302.
1
18. Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem., Int. Ed. 2009, 48,
2854e2867.
Please cite this article in press as: Doi, T.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.051