Alkyl 2-(2-benzothiazolylsulfinyl)acetates as useful synthetic reagents for alkyl 4-hydroxyalk-2-enoates by sulfinyl-Knoevenagel reaction

Article abstract of DOI:10.1016/j.tet.2012.01.057

Isopropyl, ethyl, and methyl 2-(2-benzothiazolylsulfinyl)acetates have been found to be useful synthetic reagents for sulfinyl-Knoevenagel reaction with various aldehydes to give directly the corresponding 4-hydroxyalk-2-enoates [R′CH(OH)CHCHCO₂R], which are ubiquitous structures in biologically active natural products and useful building blocks for organic synthesis of chiral compounds. From the optically pure (R)-2-(2- benzothiazolylsulfinyl)acetates (>99% ee) prepared by the enzymatic kinetic resolution of (±)-2-(2-benzothiazolylsulfinyl)acetates, optically active 4-hydroxyalk-2-enoates (up to 91% ee) have been obtained in good yields.

Full text of DOI:10.1016/j.tet.2012.01.057

Tetrahedron 68 (2012) 2471e2480
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Tetrahedron
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Alkyl 2-(2-benzothiazolylsulfinyl)acetates as useful synthetic reagents for alkyl
4-hydroxyalk-2-enoates by sulfinyl-Knoevenagel reaction
*
Zhenjun Du, Toshihiro Kawatani, Kazuhide Kataoka, Rikiya Omatsu, Junzo Nokami
Department of Applied Chemistry, Faculty of Engineering, Okayama University of Science, 1-1 Ridai-cho, Kita-ku, Okayama 700-0005, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Isopropyl, ethyl, and methyl 2-(2-benzothiazolylsulfinyl)acetates have been found to be useful synthetic
reagents for sulfinyl-Knoevenagel reaction with various aldehydes to give directly the corresponding 4-
hydroxyalk-2-enoates [R0CH(OH)CH]CHCO2R], which are ubiquitous structures in biologically active
natural products and useful building blocks for organic synthesis of chiral compounds. From the optically
pure (R)-2-(2-benzothiazolylsulfinyl)acetates (>99% ee) prepared by the enzymatic kinetic resolution of
(ꢀ)-2-(2-benzothiazolylsulfinyl)acetates, optically active 4-hydroxyalk-2-enoates (up to 91% ee) have
been obtained in good yields.
Received 21 December 2011
Received in revised form 16 January 2012
Accepted 18 January 2012
Available online 24 January 2012
Keywords:
Knoevenagel reaction
Alkyl 2-(2-benzothiazolylsulfinyl)acetate
Alkyl 4-hydroxy-2-alkenoate
MisloweEvans rearrangement
Kinetic resolution
Ó 2012 Elsevier Ltd. All rights reserved.
Porcine pancreatic lipase
(PPL, Sigma Type II)
Asymmetric synthesis
1. Introduction
methylene compounds where oxidation of a-carbon of the starting
aldehyde occurred due to the characteristic sigmatropic reaction
(MisloweEvans rearrangement)6 of the sulfinyl group (Scheme 1).
Since then, these reactions have been applied not only for the
synthesis of various 3-hydroxyalk-1-enyl ketones, sulfones, sulf-
oxides, and diethyl phosphonates [R0CH(OH)CH]CHeEWG;
EWG¼COR,7 SO2Ar,8 SOAr,9 PO(OEt)210], but also for that of the
optically active compounds starting from the corresponding opti-
cally active sulfoxides.11 For example, we carried out several
asymmetric sulfinyl-Knoevenagel reactions of optically active
sulfinyl-activated methylene compounds with aldehydes in the
presence of piperidine in acetonitrile and discovered that (R)-2-(p-
chlorophenylsulfinyl)acetonitrile gave the corresponding optically
active 4-hydroxyalk-2-enenitrile in 77% yield with higher optical
yield (75% ee) than that obtained using (R)-2-(p-tolylsulfinyl)ace-
tonitrile in 64% yield with 54% ee.11a Burgess and his co-workers
reported that sulfinyl-Knoevenagel reaction of (R)-methyl 2-(aryl-
sulfinyl)acetates (aryl¼phenyl, p-chlorophenyl, and p-nitrophenyl)
with pentanal gave the desired (R)-methyl 4-hydroxyhept-2-
enoate in moderate yields with 61% ee, 72% ee, and 79% ee,
respectively.11c,e Thus, we thought that an electron-withdrawing
substituent on sulfinyl group might give the desired products in
good yields with higher optical yields. Actually, (S)-ethyl 2-(p-
chlorophenylsulfinyl)acetate was successfully applied to the syn-
thesis of biologically active natural compounds (þ)-brefeldin A.2l
Alkyl 4-hydroxyalk-2-enoates [R0CH(OH)CH]CHCO2R] are quite
useful functional groups in organic synthesis, because there are
many bioactive natural compounds such as macrolides bearing
these functional groups in a side chain1 or in a macrolide ring.2
Although the structureeactivity relationship of those compounds
has not yet been clear, it seems to be plausible that these functional
groups play an important role to show bioactivity by reacting with
eSH moiety of a binding site in receptors of enzymes.
In the beginning of 1980s, we3a and Tanikaga’s group4b in-
dependently discovered that Knoevenagel-type reactions5 of
sulfinyl-activated methylene compounds such as 2-(phenylsulfinyl)
acetonitrile [PhS(O)CH2CN]3 and methyl 2-(p-chlorophenylsulfinyl)
acetate [p-ClC6H4S(O)CH2CO2Me]4 with aldehyde (R0CH2CHO) in
the presence of a base directly gave a sulfur free highly function-
alized product, 4-hydroxyalk-2-enenitrile [R0CH(OH)CH]CHCN]
and methyl 4-hydroxyalk-2-enoate [R0CH(OH)CH]CHCO2Me], re-
spectively, in good yield. We may call this reaction ‘sulfinyl-Knoe-
venagel reaction’, because 4-hydroxyalk-2-enenitriles and alkyl 4-
hydroxyalk-2-enoates were directly obtained conveniently by
Knoevenagel reaction of aldehyde with sulfinyl-activated
* Corresponding author. Tel.: þ81 86 256 9569; fax: þ81 86 252 6891; e-mail
address: nogami@dac.ous.ac.jp (J. Nokami).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.057

2472
Z. Du et al. / Tetrahedron 68 (2012) 2471e2480
Scheme 1. Sulfinyl-Knoevenagel reaction of sulfinyl-activated methylene compounds with aldehyde.
Although organosulfur chemistry is quite useful in organic
In order to investigate the reactivity of newly developed sulfinyl-
activated methylene compounds bearing 2-BTsulfinyl group, we
treated ethyl 2-(2-BTsulfinyl)acetate (2) with 3-phenylpropanal (4a)
under Knoevenagel conditions (Table 1). It was revealed that 2 gave
the desired ethyl 4-hydroxy-5-phenylpent-2-enoate (6a) in higher
yields in shorter reaction time than those of similar reactions using
ethyl 2-(p-chlorophenylsulfinyl)acetate (5) in various solvents. The
result clearly shows the advantage of the 2-BTsulfinyl compound in
addition to cheaper price and odorless character of 2-
mercaptobenzothiazole (2-BTSH).
synthesis, we have to be cautious of handling the starting sulfur
compounds because of their unpleasant smell and expensive price
for practical use. Thus, we thought that 2-mercaptobenzothiazole
(2-BTSH), which is odorless and much cheaper than other arene-
thiols, seems to be useful for the above described sulfinyl-
Knoevenagel reaction.
Fortunately, we found that alkyl 2-(2-benzothiazolyl(2-BT)sul-
finyl)acetates prepared by using 2-BTSH reacted with various al-
dehydes more smoothly to give the desired alkyl 4-hydroxyalk-2-
enoates in better product and optical yields (up to 91% ee) than
those prepared by so far reported reactions using methyl 2-(p-
nitrophenylsulfinyl)acetate (79% ee).11b,e Here, we report our de-
tailed results of the improved sulfinyl-Knoevenagel reaction using
2-BTsulfinyl compounds.
2.2. Asymmetric sulfinyl-Knoevenagel reaction
2.2.1. Preparation of optically active isopropyl, ethyl, and methyl 2-
(2-benzothiazolylsulfinyl)acetates (1, 2, and 3, respectively). To in-
vestigate further the effect of 2-benzothiazolyl(2-BT) group on the
sulfinyl-Knoevenagel reaction including chirality transfer from
chiral sulfinyl group to the hydroxy-carbon of the product, we tried
to prepare optically active sulfoxides (R or S)-1, 2, and 3 of high ee in
good yield using available inexpensive reagents. First, we employed
the enzymatic kinetic resolution of (ꢀ)-1, 2, and 3, according to
Burgess and a co-worker’s pioneering work, in which they obtained
(R)-methyl 2-(arylsulfinyl)acetate [aryl¼p-XC6H4 (X¼H, NO2, CH3O,
Cl)] in >98% ee and in good chemical yield using Pseudomonas sp.
AK (Amano).11b The reported method was, however, ineffective for
our 2-benzothiazolyl derivatives such as 2. Although, Burgess and
co-workers reported very recently the improved method for
2. Results and discussion
2.1. Reactivity of alkyl 2-(2-benzothiazolyl(2-BT)sulfinyl)
acetates 1, 2, and 3
Isopropyl, ethyl, and methyl 2-(2-BTsulfinyl)acetates (1, 2, and 3)
were readily prepared via oxidation (by m-CPBA) of the corre-
sponding sulfides12 derived from the respective reactions of iso-
propyl,
ethyl,
and
methyl
2-chloroacetates
with
2-
mercaptobenzothiazole (2-BTSH) in the presence of K2CO3 in ace-
tone at 20 ꢁC(Eq. 1).
O
N
K2CO3
[O]
S
CO2R
Cl
CO2R
(1)
SH
S
CO2R
+
BT
BT
S
1 R = iPr
2 R = Et
3 R = Me
2-mercaptobenzothiazole
(2-BTSH)
Table 1
Reactions of 2 and 5 with 3-phenylpropanal (4a) in various solvents
CHO
CO2Et
Ar
O
S
Ph
Ph
CO2Et
Ph
4a (1.5 equiv)
S
CO2Et
O
Ar
+
OH
6a
piperidine (2 equiv), rt
2 Ar = BT
7 Ar = BT
5 Ar = p-ClC6H4
8 Ar = p-ClC6H4
Entry
Ar
Solventa
Reaction time (h)
Yieldb (%)
6a
7 or 8c
1
2
3
4
5
6
7
2
2
2
5
5
5
5
BT
BT
BT
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
MeCN
5
8
8
93
82
7
7
7
8
8
8
8
ND
10
ND
5
ND
23
9
Benzene
90% Aq EtOH
MeCN
MeCN
Benzene
90% Aq EtOH
84
5
75d
91
10
20
20
38e
80
a
Commercially available solvents were used without further purification and drying.
ND means ‘not detected’ by TLC and 1H NMR in crude products.
b
c
Though the geometry (E or Z) was not clear, single stereoisomer was detected in both 7 and 8 (see 1H and 13C NMR).13
Compound 5 was recovered (12%).
d
e
Compound 5 was recovered (28%).

Z. Du et al. / Tetrahedron 68 (2012) 2471e2480
2473
enzymatic kinetic resolution of 3 using Amano AK to obtain (R)-3 in
46% yield with 100% ee,11e we independently improved the reaction
conditions and eventually obtained (R)-2 (in >40% yield with >99%
ee) from (ꢀ)-2 using porcine pancreatic lipase (PPL; Sigma Type II)
in toluene and tert-butyl methyl ether under phosphate buffer (pH
7.5) as shown in Table 2. It is noteworthy that the reaction rate is
clearly different depending on the alkyl group of an ester moiety,
observed a difference of the reaction rate in the reactions of opti-
cally pure (>99% ee) (R)-1 (isopropyl ester), (R)-2 (ethyl ester), and
(R)-3 (methyl ester) with 3-phenylpropanal 4a for giving the best
yield of (R)-10a (20 h), (R)-6a (14 h), and (R)-11a (10 h), re-
spectively, as shown in Table 3 (entries 6e8).
The yield of product (R)-6a was decreased when the amount of
aldehyde 4a was decreased from 1.5 equiv to 1.1 equiv (entries 1 and
Table 2
Kinetic resolution of (ꢀ)-1, 2, and 3 to give (R)-1, 2, and 3 via enzymatic hydrolysis by PPLa,b
O
O
PPL (Sigma Type-II)
phosphate buffer (pH 7.5), toluene
S
CO2R
S
CO2R
BT
BT
t-BuOMe, 20 ºC
(
(
(
)-1 R = iPr
)-2 R = Et
)-3 R = Me
(R)-1 R = iPr
(R)-2 R = Et
(R)-3 R = Me
Entry
(ꢀ)-1, 2, 3
PPL (g)
Buffer (mL)
Toluene (mL)
t-BuOMe (mL)
Time (h)
(R)-1, 2, 3
E
R
(mmol)
Yield/%
(% ee)c
1
2
3
(ꢀ)-1
(ꢀ)-1
(ꢀ)-1
(ꢀ)-1
(ꢀ)-2
(ꢀ)-2
(ꢀ)-3
i-Pr
i-Pr
i-Pr
i-Pr
Et
1.0
1.0
1.0
1.0
1.0
0.4
0.4
0.8
0.8
0.8
4.0
0.8
4.0
4.0
8.0
8.0
8.0
1.0
1.0
1.0
1.0
1.0
8.0
1.0
d
48
168
32
38
4
(R)-1
(R)-1
(R)-1
(R)-1
(R)-2
(R)-2
(R)-3
37
29
24
42
41
40
44
(50)
(54)
(94)
(>99)
(>99)
(>99)
(>99)
3
3
6
>30
>27
>27
>41
d
d
4
1.0
1.0
8.0
1.0
5
6d
7
Et
Me
10.0
1.0
50.0
8.0
2
0.5
a
All reactions were performed with(ꢀ)-1, 2, 3 (1 mmol), PPL, and toluene (1 mL) under phosphate buffer (pH 7.5) at 20 ꢁC, unless otherwise noted.
b
c
BT¼2-benzothiazolyl.
Determined by chiral HPLC (Daicel Chiralcel OD and Chiralpak AD-H): >99 shows no peak of the enantiomer by the HPLC analysis.
Reaction was performed with(ꢀ)-2 (10 mmol), PPL, toluene, and t-BuOMe under phosphate buffer at 20 ꢁC.
d
and the reaction rate is in the order of methyl>ethyl>isopropyl as
2; Table 3). Addition of trimethylphosphite, P(OCH3)3, which has
been known to accelerate the MisloweEvans rearrangement,6 was
revealed to be slightlyeffective for increasing the product yield when
1.1 equiv of aldehyde was employed as the starting compound (en-
tries 2 and 3; Table 3). The reason seems to be as follows: P(OCH3)3
reacts with the intermediate I2 in the MisloweEvans rearrangement
to give 2-(methylthio)-2-benzothiazole (12; ca. 40% isolated yield),
and suppresses the formation of N-(2-benzothiazolylthio)piperidine
(13) [byproduct of the reaction in the absence of P(OCH3)3], which
slowly reacts with aldehyde to give the corresponding 2-(2-
benzothiazolylthio)-3-phenylpentanal (14) and subsequently di-
minished the yield of the desired product 6a (Scheme 2).
shown in entries 4, 5, and 7 using PPL (0.8 g)/(ꢀ)-2 (mmol). Since it
was easier to stir the reaction mixture in a larger scale than in
a smaller scale, a larger scale reaction (10 mmol) could be carried
out faster than a small scale one (1 mmol) using even a half amount
of PPL [0.4 g of PPL/(ꢀ)-2 (mmol)] (entries 5 and 6; Table 2).
Unfortunately, the formation of (S)-2-(2-benzothiazolyl)acetic
acid was not observed at all even in acidified and concentrated
aqueous phase, in contrast to the case of the corresponding p-
chlorophenyl analogue where 38% yield of the corresponding acid
(91% ee) was obtained as reported by Burgess.11b At present, al-
though it was impossible for us to obtain the enantiomers (S)-1e3
enzymatically, these compounds were obtained directly from iso-
propyl 2-(2-benzothiazolylthio)acetate employing the method
discovered by Uemura and co-workers,14 in which (S)-1 (86% ee)
was obtained in 35% yield by enantioselective oxidation of the
corresponding sulfide by tert-butyl hydroperoxide (1 equiv) with
titanium(IV) isopropoxide [Ti(Oi-Pr)4; 2.5 mol %] catalysis, using
5 mol % of (R)-binaphthol as a chiral auxiliary.
Amine should play some important roles during the reaction, not
only to accelerate the condensation of the sulfinyl-activated meth-
ylene compound with the corresponding iminium salt of aldehyde
(2/7), but also to accelerate the migration of double bond from
a,b
to
b,g
(7/I1) as exemplified in Scheme 2. In order to clarify this
point, we investigated the effect of the amount and the kind of amine
in this reaction and observed that at least 2 equiv amount of piper-
idine was required to give the best result as shown in entries 7, 9, 10,
and 11 of Table 3. Although piperidine was the only effective amine
in cases of substituted-phenyl sulfinyl reagents, dimethylamine,
pyrrolidine, and 2-methylpiperidine were also revealed to be effec-
tive in 2-BTsulfinyl case (entries 13e15; Table 3).
2.2.2. Sulfinyl-Knoevenagel reaction by using optically active 2-
benzothiazolylsulfinyl reagent. Next, the chirality transfer in
sulfinyl-Knoevenagel reaction of (R)-2 (>99% ee) to the product 6
was examined. Interestingly, we found that the reaction of (R)-2
with 3-phenylpropanal (4a) at 0 ꢁC gave (R)-6a in 88% yield (91%
We assumed that an electron-withdrawing substituent on sul-
finyl group would accelerate the OeS bond cleavage of the in-
ee), which is higher than that from (R)-p-ClC6H4S (O)CH2CO2Et
*
[(R)-5] (80% yield, 75% ee; 20 ꢁC,10 h) as a starting material (entry 7,
Table 3). Here, the absolute configuration of the products was
assigned based on the results previously reported; namely
(þ)-brefeldin A possessing the (4S)-configuration has been pre-
pared enantioselectively via sulfinyl-Knoevenagel reaction by
Corey and co-workers2k and Nokami and co-workers2l utilizing (S)-
termediate I2 and therefore, (R)-p-ClC6H4S
*
(O)CH2CO2Et [(R)-5] and
(O)CH2CO2Me could give significantly higher
chemical and optical yields than (R)-p-CH3C6H4S (O)CH2CO2Et [(R)-
9] and (R)-p-CH3C6H4S (O)CH2CO2Me. It should be considered that
(R)-p-ClC6H4S
*
*
*
racemization of I1 will take place predominantly by reverse Mis-
loweEvans rearrangement of I2 to I1 when SeO bond cleavage is
slow (Scheme 2). In this meaning, BT seems to be the most electron-
withdrawing substituent for giving the products in higher yield
with higher ee without such a racemization.
p-CH3C6H4S (O)CH2CO2Et [(S)-9] and (S)-5, respectively.
*
Although we did not expect that the kind of an ester moiety
might affect the sulfinyl-Knoevenagel reaction, we actually

2474
Z. Du et al. / Tetrahedron 68 (2012) 2471e2480
Table 3
Reactions of (R)-1, 2, 3 with 3-phenylpropanal (4a) under various reaction conditionsa
Entry
Reagent
4a (mmol)
Amine (mmol)
P(OCH3)3 (mmol)
Temp (ꢁC)
Time (h)
Product
R
(mmol)
Yield/%
(% ee)b
1
2
(R)-2
(R)-2
(R)-2
(R)-2
(R)-1
(R)-1
(R)-2
(R)-3
(R)-2
(R)-2
(R)-2
(R)-2
(R)-2
(R)-2
(R)-2
Et
Et
Et
Et
i-Pr
i-Pr
Et
Me
Et
Et
Et
Et
Et
Et
Et
1.0
1.0
1.0
10.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.1
1.0
1.0
1.0
1.5
1.1
1.1
11.0
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.0
1.1
1.1
1.1
Piperidine (2.0)
Piperidine (2.0)
Piperidine (2.0)
Piperidine (20.0)
Piperidine (2.0)
Piperidine (2.0)
Piperidine (2.0)
Piperidine (2.0)
Piperidine (0.5)
Piperidine (1.0)
Piperidine (4.0)
Piperidine (2.0)
Diethyl amine (2.0)
Pyrrolidine (2.0)
2-Methylpiperidine (2.0)
d
20
20
20
20
20
0
0
0
0
0
5
5
5
5
5
20
14
10
24
20
8
12
14
14
14
(R)-6a
(R)-6ac
(R)-6ad
(R)-6a
(R)-10a
(R)-10a
(R)-6a
(R)-11a
(R)-6af
(R)-6a
(R)-6a
(R)-6ag
(R)-6a
(R)-6a
(R)-6a
93
81
89
87
89
86
88
89
70
83
88
92h
84
75
85
(84)
(84)
(85)
(84)
(85)
(88)
(91)
(88)
(77)
(88)
(88)
(90)
(90)
(90)
(85)
d
3
1.0
10.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
4e
5
6
7
8
9
10
11
12
13
14
15
0
0
0
0
0
a
All reactions were performed with(R)-reagent (1 mmol, >99% ee) in acetonitrile (0.1 M) unless otherwise noted.
Determined by chiral HPLC (Daicel Chiralpak AD-H, 5% i-PrOH in hexane).
b
c
N-(2-Benzothiazolylthio)piperidine (13; 33%) and 2-benzothiazolylthio-3-phenylpropanal (14; 11%) were isolated as byproducts.
2-(Methylthio)-2-benzothiazole (12) was isolated as a byproduct in 40% yield.
Reaction was performed with (R)-2 (10 mmol), 4a (11 mmol), and P(OCH3)3 (10 mmol) in 40 mL of acetonitrile (0.25 M).
(R)-2 (13%) was recovered and the intermediate 7 was isolated in 5% yield by column chromatography on silica gel.
(R)-2 of 11% was recovered.
d
e
f
g
h
Yield based on aldehyde 4a.
Scheme 2. Overview of sulfinyl-Knoevenagel reaction.
We propose the reaction pathways, which afford the major
P(OCH3)3 (1.0 equiv) in acetonitrile (0.1 M) at 0 ꢁC for 14 h except
entries 7 and 8 (Table 4). In the reaction of (R)-2 with 4d, the yield
of the desired product (S)-6d was not high enough, but un-
expectedly (S)-ethyl 4-hydroxy-5-(1-piperidino)pent-2-enoate
[(S)-15] was obtained in 40% yield with 91% ee.15 In the reaction
enantiomer (R)-6a and the minor enantiomer (S)-6a as shown in
Fig. 1. MisloweEvans rearrangement (MeE) via allyl sulfenate in-
termediates I2(A) and I2(B) and diastereo-isomerization via
deprotonation are two reversible processes, which enable the in-
terconversion of four diastereomers of allylsulfoxide intermediates
I1 (A, A0, B and B0). Although it is not clear why the stereochemistry
of diastereomer A is a preferable configuration for Mislow-Evans
rearrangement, we observed the high chirality transfer from allyl-
sulfoxide intermediates I1 to allyl alcohol (R)-6a up to 91% ee.
Therefore, it is reasonable to assume that there is a large difference
in the reaction rates of MisloweEvans rearrangement from these
four diastereomers A, A0, B, and B0.
of (R)-2 with (R)-4e and (S)-4e having a chiral center at the b-po-
sition of the carbonyl group,16 we observed the existence of mis-
matching pair [(R)-2 and (S)-4e], which gave (4S,5S)-ethyl 5-tert-
butyldimethylsilyloxy-4-hydroxy-7-phenylhept-2-enoate (4S,5S)-
6e in 64% de, while the reaction of (R)-2 with (R)-4e gave (4S,5R)-6e
in 88% de (entries 4 and 5; Table 4).
Optically active tert-alcohols (6g, 6h) (entries 7 and 8; Table 4)
were also prepared in reasonable yields, although optical yields
were lower than those of secondary alcohols. These tert-alcohols
Finally, we conducted the reaction of (R)-2 with various alde-
hydes (1.1 equiv) in the presence of piperidine (2.0 equiv) and
were obtained via allylsulfoxide intermediates having
a tri-

Z. Du et al. / Tetrahedron 68 (2012) 2471e2480
2475
H
r
Bn
r
CO2Et
R
isomerization
CO2Et
S
Bn
M.-E.
O
S
O
S
H
BT
M.-E.
retro-
R
R
retro-
M.-E.
I1
A
BT
B
r
Bn
CO2Et
M.-E.
S
s
OH
O
BT
Bn
CO2Et
s
O
r
S
Bn
(R)-6a
major product
CO2Et
Bn
CO2Et
(S)-6a
OH
BT
I2(A)
I2(B)
M.-E.
M.-E.
H
BT
R
Bn
retro-M.-E.
retro-M.-E.
BT
S
CO2Et
isomerization
CO2Et
Bn
O
S
O
S
H
s
S
S
r, s : lone pair
Bn = PhCH2
s
B' (enantiomer of B)
A' (enantiomer of A)
Fig. 1. Stereochemistry of MisloweEvans rearrangement.
Table 4
Reactions of (R)-2 with various aldehydes (4) to optically active ethyl 4-hydroxyalk-2-enoates (6)a
Entry
Aldehyde 4
Yield of 6b (%)
(% ee)c
1
2
3
4
4b
4c
4d
(R)-4e
(S)-4e
4f
4g
4h
4i
4j
(R)-4k
(S)-4k
Hexanal
3-Methylbutanal
3-(p-Chlorophenylthio)propanal
(3R)-3-tert-Butyldimethylsilyloxy-5-phenylpentanal
(3S)-3-tert-Butyldimethylsilyloxy-5-phenylpentanal
6-Tetrahydropyranyloxyhexanal
(R)-6b
(R)-6c
(S)-6d
85
86
52d
81
83
86
75
65
50
42
94
89
(88)
(88)
(89)
(88e)
(64e)
(88)
(76)
(57)
(89)
(82)
(91e,j
(90e,j
(4S,5R)-6e
(4S,5S)-6e
(R)-6f
5
6
7f
8f
9
(ꢀ)-2-Phenylpropanal
(S)-6gg
(ꢀ)-2-Methyl-3-phenylpropanal
(R)-6hh
(R)-6i
4-Hydroxybutanal (2-hydroxytetrahydrofuran)i
5-Hydroxypentanal (2-hydroxytetrahydropyran)i
(4R)-6-tert-Butyldimethylsilyloxy-4-methylhexanal
(4S)-6-tert-Butyldimethylsilyloxy-4-methylhexanal
10
11
12
(R)-6j
(4R,6R)-6k
(4R,6S)-6k
)
)
a
All reactions were performed with (R)-2 (1 mmol, >99% ee) and aldehyde (1.1 mmol) in the presence of piperidine (2 mmol) and P(OCH3)3 (1 mmol) at 0 ꢁC in acetonitrile
(0.1 M) for 14 h unless otherwise noted.
b
Isolated yield.
c
Determined by chiral HPLC (Daicel Chiralpak AD-H) unless otherwise noted.
Ethyl 4-hydroxy-5-(1-piperidino)pent-2-enoate (15) was obtained as byproduct in 40% yield (91% ee).
Diastereomer excess (de).
The reaction was performed at 10 ꢁC for 24 h.
d
e
f
g
Absolute configuration was determined by comparison with an authentic sample prepared separately.
h
Absolute configuration was assigned by analogy with (R)-6g.
i
1H NMR spectra showed that the structure was not the aldehyde but the corresponding lactol (cyclic hemiacetal).
j
de was determined by chiral HPLC (Daicel Chiralcel OD-H).
substituted alkene in which both E and Z positions are substituted.
Thus, it is reasonable to propose that the reaction also proceeds via
both E and Z isomers of allylsulfoxide having a di-substituted al-
kene. This is another possible mechanism for the decrease of
enantioselectivity, because the Z isomer of allylsulfoxide may afford
the S-enantiomer as proposed in Eq. 2.
of (R)-6h was assigned by analogy with (S)-6g (steric hindrance of
PhCH2 is larger than CH3).
The high reactivity of BT derivative 2 was also proved by the
reaction with lactols 4i and 4j to give (R)-6i and (R)-6j, which
were scarcely obtained in the reaction with (R)-5. The key
compound for (þ)-neosymbioimine synthesis,17 (4R,6S)-6k was
very easily prepared from (S)-4k in 89% yield with 90% de (entry
12; Table 4).
The authentic sample of (S)-6g was prepared via Sharpless AD
using AD mix
b as shown below (Eq. 3). The absolute configuration
Bn
H
Bn
BT
OH
CO2Et
O
S
CO2Et
O
S
(2)
Bn
CO2Et
BT
(S)-6a
minor product
(Z)-A

2476
Z. Du et al. / Tetrahedron 68 (2012) 2471e2480
3. Conclusion
rt, the reaction mixture was filtrated to remove precipitates and the
filtrate was concentrated in vacuo. The residue was diluted with
ethyl acetate (100 mL) and washed with water (30 mL) and brine
(20 mL). The organic phase was dried over sodium sulfate, filtrated,
and concentrated in vacuo to give ethyl 2-(2-bezothiazolylthio)ace-
tate as a yellow oil (7.46 g, >99%). This crude acetate (7.46 g,
29.5 mmol) was dissolved in dichloromethane (40 mL) and then the
solution was cooled to 0 ꢁC. A solution of m-chloroperbenzoic acid
(4.59 g, 26.6 mmol) in dichloromethane (80 mL) was slowly added
into the solution at 0 ꢁC. The mixture was stirred for 3 h at rt and
then quenched with saturated aqueous Na2S2O3 (10 mL). The organic
phase was washed with saturated aqueous NaHCO3 (10ꢃ2 mL) and
brine (10 mL), dried over sodium sulfate, and concentrated under
reduced pressure. The residue was purified by chromatography
(hexane/EtOAc¼6:1e1:1) to afford ethyl 2-(2-benzothiazolylsulfinyl)
acetate (2, 5.16 g, 96%); pale yellow crystal; mp 60 ꢁC; IR (neat) 2994,
2361, 1732, 1559, 1479, 1429, 1267, 1063, 999, 903, 762, 733 cmꢂ1; 1H
The sulfinyl-Knoevenagel reaction, i.e., oxidative Knoevenagel
reaction utilizing ethyl 2-(2-benzothiazolyl(2-BT)sulfinyl)acetate
(2) with various aldehydes, gave ethyl 4-hydroxyalk-2-enoates 6
directly in good yields. Enzymatic kinetic resolution of (ꢀ)-2 to (R)-
2 (>99% ee) was achieved using inexpensive lipase (PPL; Sigma
Type II) under phosphate buffer (pH 7.5) in toluene and tert-butyl
methyl ether in reasonable yield. Enantiomeric excess of the
product induced by sulfinyl-Knoevenagel reaction of (R)-2 with
aldehydes was much higher (up to 91% ee) than that obtained by
starting from (R)-5 (w75% ee). It is noteworthy that 2-
mercaptobenzothiazole (mp 177e181 ꢁC), used for the prepara-
tion of 1e3, is nonvolatile and much cheaper than any other are-
nethiols, and it is able to handle all of these reagents very easily
without unpleasant smell of common thiols.
At present, we assume that the optical yield of sulfinyl-
Knoevenagel reaction using 2-BTsulfinyl compounds (R)-1e3 would
largely depend on the geometry of allylsulfoxide intermediates I1,
although the reaction using p-chlorophenyl sulfinyl compound (R)-5,
for example, would include some other racemization steps such as
racemization of sulfinyl group by reverse MisloweEvans rearrange-
ment to give racemic sulfoxide and/or MisloweEvans rearrangement
of diastereoisomer of I1. Thus, the fast elimination of 2-BTS group
from the MisloweEvans rearrangement product I2 seems to be an-
other advantage of using 2-BTsulfinyl compounds. Further mecha-
nistic study in order to reveal the origin of high enantioselectivity of
2-BT derivatives is in progress in our laboratory.
NMR (400 MHz, CDCl3)
d
1.26 (t, J¼6.8 Hz, 3H), 4.12 (d, J¼14.4 Hz,
1H), 4.23 (d, J¼14.4 Hz, 1H), 4.25 (q, J¼6.8 Hz, 2H), 7.52 (t, J¼8.0 Hz,
1H), 7.59 (t, J¼8.0 Hz, 1H), 8.02 (d, J¼8.0, Hz, 1H), 8.08 (d, J¼8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d 14.0, 60.5, 62.5, 122.2, 124.0, 126.4,
127.0, 136.0, 153.5, 163.8, 175.7; HRMS (FAB) m/z for C11H12O3NS2
[MþH]þ calcd 270.0259, found 270.0263.
4.2.3. Methyl 2-(2-benzothiazolylsulfinyl)acetate [(ꢀ)-3]. Pale yel-
low crystal; mp 55 ꢁC; IR (neat) 2994, 2361, 1732, 1479, 1427, 1273,
1063, 1001, 903, 845, 762, 733 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
d
3.81 (s, 3H), 4.13 (d, J¼14.4 Hz, 1H), 4.25 (d, J¼14.4 Hz, 1H), 7.53 (t,
J¼7.2 Hz, 1H), 7.58 (t, J¼7.2 Hz, 1H), 8.02 (d, J¼8.0 Hz, 1H), 8.08 (d,
4. Experimental section
4.1. General methods
J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 53.1, 60.4, 122.2, 124.0,
126.4, 127.0, 136.1, 153.5, 164.3, 175.6; HRMS (FAB) m/z for
C10H10O3NS2 [MþH]þ calcd 256.0102, found 256.0117.
Infrared spectra (IR) were recorded on a FT-IR spectrometer and
reported in wave numbers (cmꢂ1). 1H and 13C NMR spectra were
taken on a FT-NMR spectrometer at 400 and 100 MHz, respectively.
CDCl3 was used as solvent. Chemical shifts were reported in parts
4.3. General procedure for sulfinyl-Knoevenagel reaction of
ethyl 2-(2-benzothiazolylsulfinyl)acetate [( )-2] with 3-
phenylpropanal (4a) (Table 1)
per million shift (
d
value) from TMS (
d
0 ppm for 1H) or based on the
77.00 ppm for 13C NMR) as an
4.3.1. Ethyl 4-hydroxy-5-phenylpent-2-enoate (6a) (entry 1; Table
1). To a stirred solution of ethyl 2-(2-benzothiazolylsulfinyl)ace-
tate (2,134.5 mg, 0.5 mmol) in 5 mL of MeCN, 3-phenylpropanal (4a,
middle peak of the solvent (CDCl3) (
d
internal standard. Signal patterns were indicated as br, broad; s,
singlet; d, doublet; t, triplet; q, quartet; or m, multiplet. Coupling
constants (J) were given in hertz. Elemental analyses were obtained
in our laboratory by a CHN analyzer. Optical rotations were ob-
98 mL, 0.75 mmol) and piperidine (100 mL, 1.0 mmol) were added at
rt. After the reaction mixture was stirred for 5 h at rt, saturated
aqueous NH4Cl (5 mL) was added to the mixture and the resultant
mixture was extracted with ethyl acetate (3ꢃ5 mL). The combined
extract was washed with brine, dried over anhydrous MgSO4, and
concentrated in vacuo. The residue was purified by chromatography
on silica gel to give 6a as a colorless oil in 93% yield (102.3 mg).
Rf¼0.30 (hexane/EtOAc¼3:1); IR (neat) 3443, 2949, 2359,1717,1653,
tained on a digital polarimeter with sodium lamp, and reported as
T ꢀC
follows: [
a
]
D
(c¼g/100 mL, solvent). The ee was determined by
HPLC analysis using Chiralcel OR and OD-H and Chiralpac AD and
AD-H columns (0.46 cm 4ꢃ25 cm L). All chemical reagents and
solvents were used as supplied without further purification.
1437, 1279, 1171, 1103, 1044, 700 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
4.2. Preparation of sulfinyl-activated methylene compounds
1, 2, and 3
d
1.22 (t, J¼7.2 Hz, 3H), 2.72 (dd, J¼13.6, 8.4 Hz,1H), 2.89 (dd, J¼13.6,
4.8 Hz, 1H), 4.14 (q, J¼7.2 Hz, 2H), 4.45e4.48 (m, 1H), 5.99 (dd,
J¼15.6, 1.6 Hz, 1H), 6.94 (dd, J¼15.6, 4.8 Hz, 1H), 7.17e7.22 (m, 3H),
4.2.1. Isopropyl 2-(2-benzothiazolylsulfinyl)acetate [(ꢀ)-1]. Pale yel-
7.25e7.28 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 14.3. 43.3, 60.5, 71.8,
low crystal; mp 84 ꢁC; IR (neat) 2926, 2854,1716,1186,1070, 761 cmꢂ1
;
120.6, 126.9, 128.6, 129.4, 136.7, 148.7, 166.3; HRMS (FAB) m/z for
1H NMR (CDCl3)
d
1.25 (d, J¼6.2 Hz, 3H), 1.25 (d, J¼6.2 Hz, 3H), 4.10 (d,
C13H17O3 [MþH]þ calcd 221.1178, found 221.1199.
J¼14.4 Hz, 1H), 4.21 (d, J¼14.4 Hz, 1H), 5.11 (septet, J¼6.2 Hz, 1H), 7.51
(t, J¼7.6 Hz, 1H), 7.58 (t, J¼7.6 Hz, 1H), 8.01 (d, J¼7.6 Hz, 1H), 8.08 (d,
4.3.2. Ethyl 2-(2-benzothiazolylsulfinyl)-5-phenylpent-2-enoate (7)
(entry 2; Table 1). Pale yellow oil; 11% yield. Rf¼0.38 (hexane/
EtOAc¼3:1); IR (neat) 3026, 2982, 1724, 1456, 1369, 1213, 1071,
J¼7.6 Hz, 1H); 13C NMR (CDCl3)
d 21.6. 21.7, 60.7, 70.5, 122.3, 124.0,
126.4,127.0,136.1,153.6,163.5,175.9; HRMS (FAB) m/z for C12H14O3NS2
[MþH]þ calcd 284.0415, found 284.0411. Anal. Calcd for C12H13O3NS2:
C, 50.86; H, 4.62; N, 4.94. Found: C, 51.10; H, 4.62; N, 4.93.
1022, 762, 700 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
1.23 (t, J¼7.6 Hz,
3H), 2.90 (t, J¼7.6 Hz, 2H), 3.12e3.19 (m, 2H), 4.22e4.25 (m, 2H),
7.20e7.30 (m, 6H), 7.48 (t, J¼6.8 Hz, 1H), 7.53 (t, J¼6.8 Hz, 1H), 7.92
(d, J¼7.2 Hz, 1H), 8.08 (d, J¼7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
4.2.2. Ethyl 2-(2-benzothiazolylsulfinyl)acetate [(ꢀ)-2]. To a stirred
suspension of 2-mercaptobenzothiazole (3.34 g, 20 mmol) and po-
tassium carbonate (5.53 g, 40 mmol) in acetone (30 mL) was added
ethyl chloroacetate (2.43 mL, 20 mmol). After being stirred for 3 h at
d
14.0, 31.1, 34.6, 61.7, 122.0, 122.1, 124.3, 124.5, 126.2, 126.6, 128.3,
135.3, 136.1, 140.0, 149.1, 153.0, 161.5, 174.8; HRMS (EI) m/z for
C20H19O3NS2 [M]þ calcd 385.0806, found 386.0809.

Z. Du et al. / Tetrahedron 68 (2012) 2471e2480
2477
4.3.3. Ethyl 4-chlorobenzenesulfinyl-5-phenylpent-2-enoate (8) (en-
tries 4, 6, and 7; Table 1). Colorless oil; 5, 23, and 9% yields, re-
spectively. Rf¼0.35 (hexane/EtOAc¼3:1); IR (neat) 3026, 2982,
mixture was stirred for 5 h at 20 ꢁC. To the mixture was added
saturated aqueous NH4Cl (30 mL) and then the mixture was
extracted with ethyl acetate (3ꢃ25 mL). The combined extract was
washed with brine, dried over anhydrous MgSO4, filtrated, and
concentrated in vacuo. The residue was purified by chromatogra-
1722, 1699, 1476, 1211, 1051, 1013, 824, 741, 700 cmꢂ1 1H NMR
;
(400 MHz, CDCl3)
d
1.18 (t, J¼7.2 Hz, 3H), 2.89e2.92 (m, 2H),
3.02e3.06 (m, 1H), 3.15e3.17 (m, 1H), 4.10 (q, J¼7.2 Hz, 2H),
phy on silica gel to give (R)-6a as a colorless oil in 87% yield (1.91 g,
25
7.15e7.29 (m, 6H), 7.37 (d, J¼8.4 Hz, 2H), 7.47 (d, J¼8.4 Hz, 2H); 13C
84% ee). Rf¼0.30 (hexane/EtOAc¼3:1); [
(Entry 7; Table 3). To
benzothiazolylsulfinyl)acetate [(R)-2, 134.5 mg, 0.5 mmol] in 5 mL
of MeCN, 3-phenylpropanal (4a, 72 L, 0.55 mmol), P(OCH3)3 (58 L,
0.5 mmol), and piperidine (100
L,1.0 mmol) were added at 0 ꢁC, and
a
]
þ0.2 (c 1.00, CHCl3).
D
NMR (100 MHz, CDCl3)
d
14.1, 30.8, 34.7, 61.3, 126.6, 127.3, 128.4,
a
solution of (R)-ethyl 2-(2-
129.2, 136.7, 137.5, 140.2, 142.2, 147.0, 147.1, 162.0; HRMS (FAB) m/z
for C19H19O3ClS2 [M]þ calcd 362.0743, found 362.0721.
m
m
m
4.4. Preparation of optically active sulfinyl-activated
methylene compounds by enzymatic kinetic resolution of the
corresponding racemic mixture (Table 2)
then the reaction mixture was stirred for 14 h at 0 ꢁC. To the mixture
was added saturated aqueous NH4Cl (5 mL) and then the mixture was
extracted with ethyl acetate (3ꢃ5 mL). The combined extract was
washed with brine, dried over anhydrous MgSO4, filtrated, and con-
centrated in vacuo. The residue was purified by chromatography on
4.4.1. Isopropyl 2-(2-benzothiazolylsulfinyl)acetate [(R)-1] (entry 4;
Table 2). A mixture of isopropyl 2-(2-benzothiazolylsulfinyl)acetate
(1, 283 mg, 1 mmol) and PPL (porcine pancreatic lipase, Sigma Type
II) (0.8 g) in a mixed solvent of toluene (1 mL), 2-methyl-2-
methoxypropane (1 mL), and phosphate buffer (pH 7.5, 8 mL) was
stirred at rt for 38 h. The reaction mixture was extracted with ethyl
acetate, and the extract was dried and concentrated in vacuo to give
crude crystals, which were recrystallized from ether/hexane to give
pure crystals (42% yield, pale yellow crystal, mp 106 ꢁC; 99% ee de-
silica gel to give (R)-6a as a colorless oil in 88% yield (96.8 mg, 91% ee).
25
Rf¼0.30 (hexane/EtOAc¼3:1); [
a
]
þ0.2 (c 0.86, CHCl3); IR (neat)
D
3445, 3030, 2330,1716,1437,1308,1171,1103, 985, 700 cmꢂ1; 1H NMR
(400 MHz, CDCl3)
d
1.22 (t, J¼7.2 Hz, 3H), 2.72 (dd, J¼13.6, 8.4 Hz,1H),
2.89 (dd, J¼13.6, 4.8 Hz, 1H), 4.14 (q, J¼7.2 Hz, 2H), 4.45e4.48 (m,1H),
5.99 (dd, J¼15.6, 1.6 Hz, 1H), 6.94 (dd, J¼15.6, 4.8 Hz, 1H), 7.17e7.22
(m, 3H), 7.25e7.28 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 14.3. 43.3,
60.5, 71.8,120.6,126.9,128.6,129.4,136.7,148.7,166.3; HRMS (FAB) m/
termined by HPLC using Chiralpac AD); [
a
]
25 þ68.6 (c 1.00, CHCl3).
z for C13H17O3 [MþH]þ calcd 221.1178, found 221.1196.
D
4.4.2. Ethyl 2-(2-benzothiazolylsulfinyl)acetate [(R)-2] (entry 5;
Table 2). A mixture of ethyl 2-(2-benzothiazolylsulfinyl)acetate (2,
269 mg, 1 mmol) and PPL (porcine pancreatic lipase, Sigma Type II)
4.5.2. (R)-Isopropyl 4-hydroxy-5-phenylpent-2-enoate [(R)-10a]
25
(entry 6; Table 3). Colorless oil. Rf¼0.33 (hexane/EtOAc¼3:1); [
a]
D
þ2.2 (c 1.00, CHCl3); IR (neat) 3447, 2980, 2876, 1717, 1645, 1456,
(0.8 g) in
a
mixed solvent of toluene (1 mL), 2-methyl-2-
1279, 1179, 1109, 984, 748, 700 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
methoxypropane (1 mL) and phosphate buffer (pH 7.5, 8 mL) was
stirred at rt for 4 h. The reaction mixture was extracted with ethyl
acetate, and the extract was dried, filtrated, and concentrated in vacuo
to give crude crystals, which were recrystallized from ether/hexane to
give pure crystals (41% yield, pale yellow crystal, mp 88 ꢁC; >99% ee
d
1.20 (d, J¼6.0 Hz, 6H), 2.71 (dd, J¼13.6, 8.8 Hz, 1H), 2.89 (dd, J¼13.6,
4.8 Hz, 1H), 4.45e4.47 (m, 1H), 5.07 (heptet, J¼6.4 Hz, 1H), 5.98 (dd,
J¼15.6, 2.0 Hz, 1H), 6.92 (dd, J¼15.6, 4.4 Hz, 1H), 7.7.17e7.21 (m, 3H),
7.25e7.29 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 21.9, 43.3, 67.8, 71.8,
121.1, 126.9, 128.6, 129.4, 136.8, 148.3, 165.8; HRMS (FAB) m/z for
C14H19O3 [MþH]þ calcd 235.1334, found 235.1310. Anal. Calcd for
C14H18O3: C, 71.79; H, 7.74. Found: C, 71.54; H, 7.88.
determined by HPLC using Chiralpac AD); [
a
]
25 þ73.2 (c 1.00, CHCl3).
D
(Entry 6, Table 2). A mixture of ethyl 2-(2-benzothiazolylsulfinyl)
acetate (2, 2.69 g, 10 mmol) and PPL (porcine pancreatic lipase,
Sigma Type II) (4.0 g) in a mixed solvent of toluene (8 mL), 2-methyl-
2-methoxypropane (8 mL), and phosphate buffer (pH 7.5, 50 mL)
was stirred at 20 ꢁC for 2 h. The reaction mixture was extracted with
ethyl acetate, and the extract was dried, filtrated, and concentrated
in vacuo to give crude crystals, which were recrystallized from ether/
4.5.3. (R)-Methyl 4-hydroxy-5-phenylpent-2-enoate [(R)-11a] (entry
8; Table 3). Colorless oil. Rf¼0.29 (hexane/EtOAc¼3:1); [
a
]
25 ꢂ0.6 (c
D
1.00, CHCl3); IR (neat) 3437, 2984, 2361, 1717, 1655, 1456, 1308,
1275, 1175, 1042, 990, 700, 669 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
d
1.77 (d, J¼4.4 Hz, 1H), 2.79 (dd, J¼13.6, 8.8 Hz, 1H), 2.96 (dd,
hexane to give pure crystals (1.07 g, 40% yield, pale yellow crystal,
J¼13.6, 4.8 Hz, 1H), 3.75 (s, 3H), 4.53e4.56 (m, 1H), 6.08 (dd, J¼15.6,
25
mp 88 ꢁC; >99% ee determined by HPLC using Chiralpac AD); [
þ73.6 (c 1.00, CHCl3).
a]
1.6 Hz, 1H), 7.02 (dd, J¼15.6, 4.4 Hz, 1H), 7.24e7.36 (m, 5H); 13C
D
NMR (100 MHz, CDCl3)
d 43.2, 51.7, 71.7, 120.3, 126.9, 128.6, 129.4,
136.6, 149.1, 166.8; HRMS (FAB) m/z for C12H15O3 [MþH]þ calcd
4.4.3. Methyl 2-(2-benzothiazolylsulfinyl)acetate [(R)-3] (entry 7;
Table 2). A mixture of methyl 2-(2-benzothiazolylsulfinyl)acetate (3,
254 mg, 1 mmol) and PPL (0.8 g) in a mixed solvent of toluene
(1 mL), 2-methyl-2-methoxypropane (1 mL), and phosphate buffer
(pH 7.5, 8 mL) was stirred at rt for 0.5 h. The reaction mixture was
extracted with ethyl acetate, and the extract was dried, filtrated, and
concentrated in vacuo to give crude crystals, which were recrystal-
lized from ether/hexane to give pure crystals (44% yield, pale yellow
crystal, mp 79 ꢁC; 99% ee determined by HPLC using Chiralpac AD);
207.1021, found 207.0994.
4.5.4. 2-(Methylthio)-2-benzothiazole (12). White solid; mp 42 ꢁC.
Rf¼0.45 (hexane/EtOAc¼20:1); IR (neat) 2359, 1458, 1427, 1308,
1234, 1074, 1007, 961, 756, 721, 704, 677 cmꢂ1 1H NMR (400 MHz,
;
CDCl3)
d
2.80 (s, 3H), 7.29 (td, J¼8.0,1.6 Hz,1H), 7.40 (td, J¼7.2, 1.2 Hz,
1H), 7.76 (d, J¼8.0 Hz,1H), 7.87 (d, J¼8.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d 15.9, 120.8, 121.2, 123.9, 125.8, 135.0, 153.1, 167.8; HRMS (EI)
m/z for C8H8NS2 [MþH]þ calcd 182.0098, found 182.0091.
[a]
25 þ77.9 (c 1.00, CHCl3) (lit.11f
[a]
22 þ33 (c 1.04, CHCl3)).
D
D
4.5.5. N-(2-Benzothiazolylthio)piperidine (13). Pale yellow solid;
mp 52 ꢁC. Rf¼0.35 (hexane/EtOAc¼20:1); IR (neat) 2939, 2839,
2359, 1717, 1558, 1456, 1348, 1309, 1271, 1151, 1080, 924, 765,
4.5. Asymmetric sulfinyl-Knoevenagel reaction using (R)-1,
(R)-2, (R)-3 (Table 3)
667 cmꢂ1 1H NMR (400 MHz, CDCl3)
; d 1.50e1.56 (m, 2H), 1.75 (q,
4.5.1. (R)-Ethyl 4-hydroxy-5-phenylpent-2-enoate [(R)-6a] (entry 4;
Table 3). To a solution of (R)-ethyl 2-(2-benzothiazolylsulfinyl)ac-
etate [(R)-2, 2.69 g, 10 mmol] in 40 mL of MeCN, 3-phenylpropanal
(4a, 1.44 mL, 11 mmol), P(OCH3)3 (1.16 mL, 10 mmol), and piperi-
dine (2 mL, 10 mmol) were added at 20 ꢁC, and then the reaction
J¼5.6 Hz, 4H), 3.23 (t, J¼5.6 Hz, 4H), 7.26 (td, J¼5.6, 0.8 Hz, 1H), 7.39
(td, J¼7.2, 1.2 Hz, 1H), 7.80 (dd, J¼8.4, 1.6 Hz, 1H), 7.82 (dd, J¼8.0,
0.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 23.0, 27.3, 58.0, 120.8,
121.4, 123.4, 125.6, 128.3, 128.5, 137.9, 177.3; HRMS (EI) m/z for
C12H15N2S2 [MþH]þ calcd 251.0677, found 251.0658.

2478
Z. Du et al. / Tetrahedron 68 (2012) 2471e2480
4.5.6. 2-(2-Benzothiazolylthio)-3-phenylpentanal (14). Pale yellow
oil. Rf¼0.35 (hexane/EtOAc¼10:1); IR (neat) 3603, 3028, 2924, 2841,
2360, 1728, 1497, 1427, 1309, 1238, 1076, 1018, 997, 854, 756, 727,
EtOAc¼1:10); IR (neat) 2937, 2856, 1715, 1655, 1468, 1370, 1304,
1267, 1173, 1040, 984, 887, 714 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
d
1.28 (t, J¼7.2 Hz, 3H), 1.45e1.47 (m, 2H), 1.56e1.60 (m, 4H),
700 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
3.17 (dd, J¼14.4, 8.0 Hz, 1H),
2.24e2.30 (m, 1H), 2.34 (m, 2H), 2.44 (dd, J¼12.0, 4.0 Hz, 1H), 2.61
(m, 2H), 4.19 (q, J¼7.2 Hz, 2H), 4.31e4.33 (m, 1H), 6.14 (dd, J¼15.6,
1.6 Hz, 1H), 6.87 (dd, J¼15.6, 4.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
3.48 (dd, J¼14.4, 7.2 Hz, 1H), 4.76 (d, J¼8.0 Hz, 1H), 7.26e7.34 (m,
6H), 7.43 (t, J¼8.4 Hz, 1H), 7.75 (d, J¼8.0 Hz, 1H), 7.86 (d, J¼8.0 Hz,
1H), 9.79 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
34.0, 56.6, 121.0, 121.7,
d 14.3, 24.2, 26.1, 54.4, 60.3, 63.3, 66.0, 120.7, 147.7, 166.3; HRMS (EI)
124.6, 127.0, 128.5, 129.2, 135.4, 136.8, 152.5, 163.0, 195.8;HRMS (EI)
m/z for C16H14ONS2 [MþH]þ calcd 300.0517, found 300.0521.
Reaction of 13 with 3-phenylpropanal to give 14: To a solution of
N-(2-benzothiazolylthio)piperidine (13, 62.4 mg, 0.25 mmol) in
m/z for C12H22NO3 [MþH]þ calcd 228.1600, found 228.1627.
4.6.5. (4S,5R)-Ethyl 5-(tert-butyldimethylsilyloxy)-4-hydroxy-7-
phenylhept-2-enoate [(4S,5R)-6e] (entry 4; Table 4). A di-
2.5 mL of MeCN, 3-phenylpropanal (4a, 33
m
L, 0.25 mmol) and pi-
astereoisomeric mixture (94:6) of 6e was obtained in 81% yield
25
peridine (25
m
L, 0.25 mmol) were added at 20 ꢁC. The reaction mix-
(153.5 mg) as a colorless oil. Rf¼0.33 (hexane/EtOAc¼3:1); [
a]
D
ture was stirred for 2 h at 20 ꢁC, and then saturated aqueous NH4Cl
(3 mL) was added to the mixture and extracted with ethyl acetate
(3ꢃ5 mL). The combined extract was washed with brine, dried over
anhydrous MgSO4, and concentrated in vacuo. The residue was pu-
rifiedbychromatographyonsilicageltogive14 in56%yield(41.8 mg).
ꢂ9.8 (c 1.00, CHCl3); IR (neat) 3462, 2957, 2932, 2855, 1719, 1661,
1472, 1368, 1310, 1175, 1101, 1040, 984, 835, 775, 750, 698,
667 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
ꢂ0.01 (s, 3H), ꢂ0.03 (s, 3H),
0.78 (s, 0.54H), 0.80 (s, 8.46H), 1.17 (t, J¼7.2 Hz, 3H), 1.57e1.60 (m,
1H), 1.71e1.74 (m, 1H), 2.41e2.44 (m, 1H), 2.61e2.64 (m, 1H),
3.71e3.73 (m, 1H), 4.07 (q, J¼7.2 Hz, 2H), 4.24 (m, 1H), 5.99 (dd,
J¼15.6, 1.6 Hz, 1H), 6.79 (dd, J¼15.6, 4.4 Hz, 1H), 7.03e7.08 (m, 3H),
4.6. Asymmetric sulfinyl-Knoevenagel reaction of (R)-2 with
various aldehydes (Table 4)
7.16e7.18 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
ꢂ4.4, 14.3, 18.1, 25.9,
31.7, 33.8, 60.4, 72.3, 74.0, 121.6, 125.8, 128.3, 141.8, 145.4, 148.1,
166.2; HRMS (FAB) m/z for C21H35O4Si [MþH]þ calcd 379.2305,
found 379.2321.
4.6.1. (R)-Ethyl 4-hydroxyoct-2-enoate [(R)-6b] (entry 1; Table 4). To
a solution of (R)-ethyl 2-(2-benzothiazolylsulfinyl)acetate [(R)-2,
134.5 mg, 0.5 mmol] in 5 mL of MeCN were added hexanal (4b,
68
(100
m
L, 0.55 mmol), P(OCH3)3 (58
m
m
L, 0.5 mmol), and piperidine
4.6.6. (4S,5S)-Ethyl 5-(tert-butyldimethylsilyloxy)-4-hydroxy-7-
phenylhept-2-enoate [(4S,5S)-6e] (entry 5; Table 4). A di-
L, 1.0 mmol) at 0 ꢁC, and then the reaction mixture was stir-
red for 14 h at 0 ꢁC. The mixture was quenched with saturated
aqueous NH4Cl (5 mL) and extracted with ethyl acetate (3ꢃ5 mL).
The combined extract was washed with brine, dried over anhy-
drous MgSO4, filtrated, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel to give (R)-6b as
a colorless oil in 85% yield (80.1 mg, 88% ee). Rf¼0.30 (hexane/
astereoisomeric mixture (82:18) of 6e was obtained in 83% yield
25
(156.8 mg) as a colorless oil. Rf¼0.33 (hexane/EtOAc¼3:1); [
a]
D
þ6.0 (c 1.00, CHCl3); IR (neat) 3484, 2955, 2932, 2859, 1722, 1705,
1653, 1497, 1464, 1368, 1258, 1177, 1098, 1065, 1042, 984, 835, 775,
750, 698 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d 0.05 (s, 2.46H), 0.07 (s,
2.46H), 0.08 (s, 0.54H), 0.10 (s, 0.54H), 0.89 (s, 7.38H), 0.92 (s,
1.62H), 1.26 (t, J¼6.4 Hz, 3H), 1.76e1.81 (m, 1H), 1.96e1.99 (m, 1H),
2.39 (d, J¼7.2 Hz, 1H), 2.64e2.67 (m, 1H), 3.70e3.72 (m, 0.82H),
3.82 (m, 0.18H), 4.20 (q, J¼6.4 Hz, 2H), 4.26e4.27 (m, 0.82H),
4.36e4.37 (m, 0.18H), 6.09 (dd, J¼15.6, 2.0 Hz, 1H), 6.90 (dd, J¼15.6,
4.4 Hz, 1H), 7.13e7.20 (m, 3H), 7.26e7.29 (m, 2H); 13C NMR
EtOAc¼3:1); [
a]
25 ꢂ18.1 (c 0.54, CHCl3); IR (neat) 3451, 2934, 2862,
D
1705, 1659, 1466, 1370, 1306, 1179, 1042, 986 cmꢂ1
;
1H NMR
(400 MHz, CDCl3)
d
0.91e0.93 (m, 3H), 1.30 (t, J¼7.2 Hz, 3H), 1.35
(m, 4H), 1.59 (m, 2H), 4.20 (q, J¼7.2 Hz, 2H), 6.03 (d, J¼15.6 Hz, 1H),
6.94 (dd, J¼15.6, 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 14.0, 14.3,
22.6, 27.4, 36.4, 60.5, 71.2, 120.1, 150.1, 166.4; HRMS (FAB) m/z for
(100 MHz, CDCl3)
121.6, 125.9, 128.4, 141.8, 145.4, 148.1, 166.2; HRMS (FAB) m/z for
C21H35O4Si [MþH]þ calcd 379.2305, found 379.2311.
d
ꢂ4.4, 14.3, 18.1, 25.8, 31.9, 35.5, 60.4, 72.3, 74.1,
C10H19O3 [MþH]þ calcd 187.1334, found 187.1321.
4.6.2. (R)-Ethyl 4-hydroxy-5-methylhex-2-enoate [(R)-6c] (entry 2;
Table 4). Colorless oil. Rf¼0.35 (hexane/EtOAc¼3:1); [
a
]
25 ꢂ30.5 (c
4.6.7. (R)-Ethyl 4-hydroxy-8-(tetrahydropyranyloxy)oct-2-enoate
D
0.40, CHCl3); IR (neat) 3462, 2965, 2874, 2359, 1717, 1705, 1653,
[(R)-6f] (entry 6; Table 4). Colorless oil. Rf¼0.18 (hexane/
1472, 1370, 1312, 1277, 1175, 1038, 986, 874 cmꢂ1
(400 MHz, CDCl3)
;
1H NMR
EtOAc¼2:1); [
a
]
25 ꢂ12.2 (c 0.77, CHCl3); IR (neat) 3437, 2943, 2866,
D
d
0.87 (d, J¼3.2 Hz, 3H), 0.89 (d, J¼3.2 Hz, 3H),
2361, 1717, 1655, 1465, 1456, 1368, 1304, 1275, 1175, 1036, 984, 905,
1.23 (t, J¼7.2 Hz, 3H), 1.75e1.80 (m, 1H), 4.02e4.06 (m, H), 4.14 (q,
868, 808 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d
1.30 (t, J¼7.2 Hz, 3H),
J¼7.2 Hz, 2H), 5.98 (dd, J¼15.6, 1.2 Hz, 1H), 6.89 (dd, J¼15.6, 4.8 Hz,
1.55e1.79 (m,12H), 3.38e3.43 (m,1H), 3.49e3.52 (m, 1H), 3.74e3.77
(m, 1H), 3.84e3.86 (m, 1H), 4.20 (q, J¼7.2 Hz, 2H), 4.33 (m, 1H),
4.56e4.57 (m, 1H), 6.06 (dd, J¼15.6, 1.6 Hz, 1H), 6.96 (dd, J¼15.6,
1H); 13C NMR (100 MHz, CDCl3)
d 14.3, 17.5, 18.3, 33.7, 60.4, 75.9,
121.1, 148.7, 166.4; HRMS (EI) m/z for C9H17O3 [MþH]þ calcd
173.1178, found 173.1161.
4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 14.3, 19.7, 22.0, 25.4, 29.4,
30.7, 36.3, 60.4, 62.5, 67.3, 70.9, 98.8, 120.0, 150.1, 166.4; HRMS (FAB)
4.6.3. (S)-Ethyl 5-(p-chlorophenylthio)-4-hydroxypent-2-enoate
m/z for C15H27O5 [MþH]þ calcd 287.1859, found 287.1854.
[(S)-6d] (entry 3; Table 4). Colorless oil. Rf¼0.26 (hexane/
EtOAC¼3:1); [
a
]
25 ꢂ29.6 (c 0.56, CHCl3); IR (neat) 3391, 2986, 2367,
4.6.8. (S)-Ethyl 4-hydroxy-4-phenylpent-2-enoate [(S)-6g] (entry 7;
D
25
1717, 1661, 1478, 1366, 1317, 1277, 1196, 1098, 1009, 937, 808,
Table 4). Colorless oil. Rf¼0.30 (hexane/EtOAc¼3:1) [
a
]
14.6 (c
D
708 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
1.28 (t, J¼7.2 Hz, 3H), 2.60 (d,
0.82, CHCl3); IR (neat) 3464, 2984, 2363, 1699, 1653, 1446, 1279,
J¼4.0 Hz, 1H), 2.95 (dd, J¼13.6, 8.4 Hz, 1H), 3.18 (dd, J¼13.6, 3.6 Hz,
1H), 4.20 (q, J¼7.2 Hz, 2H), 4.34e4.36 (m, 1H), 6.11 (dd, J¼15.6,
2.0 Hz, 1H), 6.87 (dd, J¼15.6, 4.8 Hz, 1H), 7.29 (d, J¼8.0 Hz, 2H), 7.34
1188, 1030, 984, 764, 700 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
1.29 (t,
J¼7.2 Hz, 3H), 1.73 (s, 3H), 1.97 (s, 1H), 4.19 (q, J¼7.2 Hz, 2H), 6.11 (d,
J¼15.6 Hz, 1H), 7.16 (d, J¼15.6 Hz, 1H), 7.29e7.31 (m, 1H), 7.35e7.39
(d, J¼8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d
14.2, 41.4, 60.6, 68.6,
(m, 2H), 7.45e7.47 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 14.2, 29.0,
121.6, 129.2, 129.2, 131.8, 132.8, 133.1, 146.7, 166.0; HRMS (FAB) m/z
60.5, 74.1, 118.4, 125.0, 127.4, 128.4, 144.6, 153.1, 166.7; HRMS (FAB)
for C13H15O3ClS [MþH]þ calcd 286.0431, found: 286.0456.
m/z for C13H17O3 [MþH]þ calcd 221.1178, found 221.1199.
4.6.4. (S)-Ethyl 4-hydroxy-5-(1-piperidino)pent-2-enoate (15) (by-
product of entry 3; Table 4). Colorless oil. Rf¼0.20 (MeOH/
4.6.9. (R)-Ethyl 4-hydroxy-4-methyl-5-phenylpent-2-enoate [(R)-6h]
(entry 8; Table 4). Colorless oil. Rf¼0.36 (hexane/EtOAc¼3:1);

Z. Du et al. / Tetrahedron 68 (2012) 2471e2480
2479
25
[
a
]
þ35.2 (c 1.00, CHCl3); IR (neat) 3474, 2980, 1715, 1653,
1454, 1368, 1308, 1281, 1182, 1034, 988, 702 cmꢂ1 1H NMR
(400 MHz, CDCl3)
combined extract was washed with brine, dried over anhydrous
MgSO4, filtrated, and concentrated in vacuo. The residue was pu-
rified by chromatography on silica gel to give (S)-15 as a colorless oil
D
;
d
1.28 (t, J¼6.4 Hz, 3H), 1.34 (s, 3H), 1.62 (s,
25
1H), 2.84 (d, J¼13.6 Hz, 1H), 2.93 (d, J¼13.6 Hz, 1H), 4.20 (q,
J¼6.4 Hz, 2H), 5.93 (d, J¼15.6 Hz, 1H), 7.05 (d, J¼15.6 Hz, 1H),
7.17e7.19 (m, 2H), 7.29e7.33 (m, 3H); 13C NMR (100 MHz, CDCl3)
in 67% yield (76.1 mg, 84% ee). Rf¼0.20 (MeOH/EtOAc¼1:10); [
a]
D
þ27.8 (c 1.00, CHCl3); IR (neat) 2937, 2856, 1715, 1655, 1468, 1370,
1304, 1267, 1173, 1040, 984, 887, 714 cmꢂ1 1H NMR (400 MHz,
CDCl3)
;
d
14.2, 27.3, 48.2, 60.4, 72.9, 119.0, 126.9, 128.3, 130.4, 135.6,
d
1.28 (t, J¼7.2 Hz, 3H), 1.45e1.47 (m, 2H), 1.56e1.60 (m, 4H),
153.5, 166.5; HRMS ( FAB) m/z for C14H19O3 [MþH]þ calcd
2.24e2.30 (m, 1H), 2.34 (m, 2H), 2.44 (dd, J¼12.0, 4.0 Hz, 1H), 2.61
(m, 2H), 4.19 (q, J¼7.2 Hz, 2H), 4.31e4.33 (m, 1H), 6.14 (dd, J¼15.6,
1.6 Hz, 1H), 6.87 (dd, J¼15.6, 4.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
235.1334, found 235.1330.
4.6.10. (R)-Ethyl 4,6-dihydroxyhex-2-enoate [(R)-6i] (entry 9; Table
d 14.3, 24.2, 26.1, 54.4, 60.3, 63.3, 66.0, 120.7, 147.7, 166.3; HRMS (EI)
25
4). Colorless oil. Rf¼0.19 (hexane/EtOAc¼1:2); [
a]
þ2.2 (c 0.36,
m/z for C12H22 O3N [MþH]þ calcd 228.1600, found 228.1627.
D
CHCl3); IR (neat) 3376, 2943, 1717, 1701, 1659, 1370, 1306, 1279, 1182,
1115, 1047, 982, 901, 866 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
1.30 (t,
4.7.2. (R)-2-Phenylpropane-1,2-diol (17). To a solution of 1.4 g of
J¼7.2 Hz, 3H), 1.76e1.82 (m,1H),1.91e1.95 (m,1H), 2.04e2.09 (m,1H),
2.93 (m, 1H), 3.88e3.94 (m, 2H), 4.21 (q, J¼7.2 Hz, 2H), 4.61 (m, 1H),
6.11 (dd, J¼15.6, 1.2 Hz, 1H), 6.96 (dd, J¼15.6, 4.4 Hz, 1H); 13C NMR
AD-Mix-b in 10 mL of 50% aqueous t-BuOH was added a-methyl-
styrene (16, 118.2 mg, 1.0 mmol) at 0 ꢁC and the mixture was stirred
at 0 ꢁC for 10 h. After the addition of Na2SO3 (1.5 g), the mixture was
then stirred for additional 30 min at rt. EtOAc (10 mL) was added to
the reaction mixture, and after separation of the layers the aqueous
phase was further extracted with EtOAc (3ꢃ5 mL), then the com-
bined extract was dried over anhydrous MgSO4 and concentrated in
vacuo. The residue was purified by chromatography on silica gel to
(100 MHz, CDCl3)
d 14.1, 37.5, 59.9, 60.6, 69.6, 119.9, 150.0, 166.8;
HRMS(FAB) m/z for C8H15O4 [MþH]þ calcd 175.0970, found 175.0966.
4.6.11. (R)-Ethyl 4,7-dihydroxyhept-2-enoate [(R)-6j] (entry 10; Table
25
4). Colorless oil. Rf¼0.17 (hexane/EtOAc¼1:2); [
a
]
3.8 (c 0.52,
D
CHCl3); IR (neat) 3389, 2942, 2361, 1717, 1699, 1653, 1370, 1306,
give (R)-2-phenylpropane-1,2-diol (17) as a colorless oil in 93%
25
1277, 1184, 1115, 1040, 984, 874 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
yield (141.5 mg). Rf¼0.15 (hexane/EtOAc¼1:1); [
a]
ꢂ10.9 (c 1.00,
D
d
1.30 (t, J¼7.2 Hz, 3H), 1.65e1.74 (m, 3H),1.80e1.83 (m, 1H), 3.72
CHCl3); IR (neat) 3412, 1495, 1447, 1377, 1040, 864, 766, 700,
(t, J¼5.6 Hz, 2H), 4.20 (q, J¼7.2 Hz, 2H), 4.39 (m, 1H), 6.07 (dd,
675 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
1.58 (s, 3H), 1.77 (dd, J¼8.4,
J¼15.6, 2.0 Hz, 1H), 6.95 (dd, J¼15.6, 4.4 Hz, 1H); 13C NMR
4.4 Hz, 1H), 2.56 (s, 1H), 3.64 (dd, J¼11.2, 8.0 Hz, 1H), 3.81 (dd,
J¼11.2, 4.8 Hz, 1H), 7.28e7.30 (m, 1H), 7.35e7.39 (m, 2H), 7.45e7.48
(100 MHz, CDCl3)
d 14.3, 28.4, 33.8, 60.5, 62.5, 70.6, 120.1, 150.1,
166.7; HRMS (FAB) m/z for C9H17O4 [MþH]þ calcd 189.1127,
(m, 2H); 13C NMR (100 MHz, CDCl3)
d 25.9, 70.8, 74.8, 124.9, 126.9,
found 189.1121.
128.2, 144.9; HRMS (EI) m/z for C9H12O2 [M]þ calcd 152.0837, found
152.0866.
4.6.12. (4R,6R)-Ethyl 8-(tert-butyldimethylsilyloxy)-4-hydroxy-6-
methyloct-2-enoate [(4R,6R)-6k] (entry 11; Table 4). Colorless oil.
4.7.3. (R)-2-Hydroxy-2-phenylpropanal (18). To a solution of (R)-2-
phenylpropane-1,2-diol (17, 134.5 mg, 0.88 mmol) in 5 mL of
CH2Cl2 was added IBX (739.3 mg, 2.64 mmol). After stirring at 40 ꢁC
for 8 h, the reaction mixture was filtered off under reduced pres-
sure and the filtrate was concentrated in vacuo. The residue was
purified by chromatography on silica gel to give (R)-2-hydroxy-2-
phenylpropanal (18) as a colorless oil in 58% yield (75.3 mg).
25
Rf¼0.34 (hexane/EtOAc¼3:1); [
a
]
ꢂ6.8 (c 1.00, CHCl3); IR (neat)
D
3449, 2930, 1722, 1705, 1655, 1464, 1369, 1258, 1175, 1096, 984, 835,
777 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
d
0.02 (s, 6H), 0.83 (s, 9H),
0.90 (d, J¼6.8 Hz, 3H), 1.23 (t, J¼7.2 Hz, 3H), 1.31e1.37 (m, 1H),
1.45e1.59 (m, 3H), 1.74e1.76 (m, 1H), 2.32 (m, 1H), 3.57e3.67 (m,
2H), 4.13 (q, J¼7.2 Hz, 2H), 4.37 (m, 1H), 6.00 (dd, J¼15.6, 2.0 Hz,
1H), 6.87 (dd, J¼15.6, 4.8 Hz,1H); 13C NMR (100 MHz, CDCl3)
d
ꢂ5.3,
Rf¼0.45 (hexane/EtOAc¼5:1); [
a
]
25 ꢂ167.3 (c 0.52, CHCl3); IR (neat)
D
14.3, 18.4, 20.8, 26.0, 26.5, 38.8, 43.6, 60.4, 61.4, 69.0, 119.9, 150.3,
166.5; HRMS (EI) m/z for C17H35O4Si [MþH]þ calcd 331.2305, found
331.2300.
3451, 2982, 1732, 1493, 1449, 1223, 1071, 1028, 858, 760, 700 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
1H), 7.39e7.43 (m, 2H), 7.46e7.49 (m, 2H), 9.56 (d, J¼1.2 Hz, 1H);
d 1.71 (s, 3H), 3.83 (s, 1H), 7.33e7.35 (m,
13C NMR (100 MHz, CDCl3)
d 23.6, 79.1, 125.7, 128.1, 128.8, 139.1,
4.6.13. (4R,6S)-Ethyl 8-(tert-butyldimethylsilyloxy)-4-hydroxy-6-
199.7; HRMS (FAB) m/z for C9H10O2 [M]þ calcd 150.0681, found
methyloct-2-enoate [(4R,6S)-6k] (entry 12; Table 4). Colorless oil.
150.0677.
25
Rf¼0.34 (hexane/EtOAc¼3:1); [
a
]
þ3.4 (c 1.00, CHCl3); IR (neat)
D
3462, 2930, 2861, 1723, 1709, 1649, 1472, 1389, 1258, 1096, 835,
4.7.4. (S)-Ethyl
4-hydroxy-4-phenylpent-2-enoate
[(S)-6g]. To
778 cmꢂ1 1H NMR (400 MHz, CDCl3)
;
d
0.02 (s, 6H), 0.84 (s, 9H),
a stirred suspension of NaH (30.1 mg, 0.75 mmol) in 5 mL of THF
was added triethyl phosphonoacetate (168.1 mg, 0.75 mmol) at
0 ꢁC. To the mixture was added a solution of (R)-2-hydroxy-2-
phenylpropanal (18, 75.3 mg, 0.5 mmol) in 5 mL of THF at
ꢂ40 ꢁC. After the mixture was stirred for 10 min at ꢂ40 ꢁC, it was
allowed to warm to 0 ꢁC and stirred for further 60 min. Then the
mixture was quenched with saturated aqueous NH4Cl (5 mL)
and extracted with EtOAc (3ꢃ5 mL). The combined extract was
washed with brine, dried over anhydrous MgSO4, and concen-
trated in vacuo. The residue was purified by chromatography to
give (2E,4S)-ethyl 4-hydroxy-4-phenylpent-2-enoate [(S)-6g] as
0.92 (d, J¼6.8 Hz, 3H), 1.25 (t, J¼7.2 Hz, 3H), 1.30e1.39 (m, 1H),
1.40e1.56 (m, 3H), 1.78e1.81 (m, 1H), 2.03 (m, 1H), 3.57e3.67 (m,
2H), 4.14 (q, J¼7.2 Hz, 2H), 4.33 (m,1H), 6.00 (dd, J¼15.6,1.6 Hz,1H),
6.89 (dd, J¼15.6, 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
ꢂ5.3,
14.3, 18.4, 19.8, 26.0, 26.7, 39.8, 43.8, 60.4, 61.1, 69.4, 119.7, 150.7,
166.5; HRMS (FAB) m/z for C17H35O4Si [MþH]þ calcd 331.2305,
found 331.2302.
4.7. Preparation of authentic samples [(S)-15 and (S)-6g]
4.7.1. (S)-Ethyl
4-hydroxy-5-(1-piperidino)pent-2-enoate
[(S)-
a colorless oil in 76% yield (82.5 mg, 95% ee). Rf¼0.30 (hexane/
25
15]. To a solution of (R)-ethyl 2-(2-benzothiazolylsulfinyl)acetate
[(R)-2, 134.5 mg, 0.5 mmol] in 5 mL of MeCN, acrolein (31 mg,
0.55 mmol), P(OCH3)3 (58
1.0 mmol) were added at rt, and then the reaction mixture was
stirred for 5 h at rt. The mixture was poured into saturated aqueous
NH4Cl (5 mL) and extracted with ethyl acetate (3ꢃ5 mL). The
EtOAc¼3/1); [
a
]
22.4 (c 1.00, CHCl3); IR (neat) 3460, 2369,
D
1699, 1495, 1307, 1279, 1030, 984, 700 cmꢂ1
CDCl3)
;
1H NMR (400 MHz,
1.29 (t, J¼7.2 Hz, 3H), 1.73 (s, 3H), 1.97 (s, 1H), 4.19 (q,
mL, 0.5 mmol), and piperidine (100
mL,
d
J¼7.2 Hz, 2H), 6.11 (d, J¼15.6 Hz, 1H), 7.16 (d, J¼15.6 Hz, 1H),
7.29e7.31 (m, 1H), 7.35e7.39 (m, 2H), 7.45e7.47 (m, 2H); 13C
NMR (100 MHz, CDCl3)
d 14.2, 29.0, 60.5, 74.1, 118.4, 125.0, 127.4,

2480
Z. Du et al. / Tetrahedron 68 (2012) 2471e2480
128.4, 144.6, 153.1, 166.7; HRMS (FAB) m/z for C13H17O3 [MþH]þ
M. B. J. Org. Chem. 1993, 58, 6177e6179; (g) Nokami, J.; Taniguchi, T.; Gomyo, S.;
Kakihara, T. Chem. Lett. 1994, 1103e1106.
calcd 221.1178, found 221.1189.
5. Knoevenagel reaction, see: (a) House, H. O. Modern Synthetic Reactions, 2nd
ed;; Benjamin: California, CA, 1972; p 646; (b) Johnson, C. R. Org. React. 1942,
1, 210e265; (c) Jones, G. Org. React. 1967, 15, 204e599; (d) Patterson, J. M.
Organic Syntheses; 1960 Collect. Vol.3, John Wiley & Sons: New York, NY,
pp 783e784.
Acknowledgements
This study was financially supported by the Sasakawa Scien-
tific Research Grant from The Japan Science Society (for Z.D.) and
the Grant from Okayama Foundation for Science and Technology
(for J.N.).
6. (a) Bickart, P.; Carson, F. W.; Miller, E. G.; Mislow, K. J. Am. Chem. Soc. 1968, 90,
4869e4
876; (b) Evans, D. A.; Sims, C. L.; Andrews, G. C. J. Am. Chem. Soc. 1977,
99, 5453e5461; (c) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1979, 18,
563e572; (d) Miller, J. G.; Kurz, W.; Untch, K. G.; Stork, G. J. Am. Chem. Soc. 1974,
96, 6774e6775; (e) St-Denis, Y.; Chan, T.-H. J. Org. Chem. 1992, 57, 3078e3085.
7. EWG¼COR (R¼alkyl, aryl): (a) Nokami, J.; Nishimura, A.; Sunami, M.; Waka-
bayashi, S. Tetrahedron Lett. 1987, 28, 649e650; (b) Nokami, J.; Taniguchi, T.;
Ogawa, Y. Chem. Lett. 1995, 43e44; (c) Nokami, J.; Osafune, M.; Shiraishi, K.;
Sumida, S.; Imai, N. J. Chem. Soc., Perkin Trans. 11997, 2947e2948; (d) Nokami, J.;
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66, 1228e1232.
Supplementary data
Copies of 1H NMR and 13C NMR spectra for all new compounds.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.01.057.
8. EWG¼SO2Ph: (a) Dominguez, E.; Carretero, J. C. Tetrahedron Lett. 1990, 31,
2487e2490; (b) Alcaraz, C.; Carretero, J. C.; Dominguez, E. Tetrahedron Lett.
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1596e1600.
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(15) was produced by the reaction of (R)-2 with acrolein (2-propenenal) in
the presence of piperidine (2 equiv) in acetonitrile at rt for 5 h in 67% yield (84%
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