Synthesis of a chiral phosphonium salt for the preparation of α-substituted alaninol derivatives

Article abstract of DOI:10.1016/j.tet.2014.05.086

We herein report the synthesis of a chiral phosphonium salt, {[(4S)-4-methyl-2-oxo-1,3-oxazolidin-4-yl]methyl}(triphenyl)phosphonium iodide 13 to provide a new Wittig reagent for the general method of synthesizing α-substituted alaninol derivatives. Our method described here is widely applicable to reactions with various types of aldehyde to afford olefin products with high E-selectivity, enabling us to provide a new approach to the synthesis of chiral S1P₁agonists including our key intermediates, and of the trace amine-associated receptor 1 (TAAR1) agonist.

Full text of DOI:10.1016/j.tet.2014.05.086

Tetrahedron xxx (2014) 1e8
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Tetrahedron
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Synthesis of a chiral phosphonium salt for the preparation
of a-substituted alaninol derivatives
,
a
a
b
Takashi Tsuji a , Keisuke Suzuki , Tsuyoshi Nakamura , Takahide Nishi
*
a Medicinal Chemistry Research Laboratories, Daiichi Sankyo Co, Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
b Daiichi Sankyo India Pharma Pvt. Ltd, Village Sarhaul, Sector 18, Udyog Vihar Industrial Area, Gurgaon 122015, Haryana, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We herein report the synthesis of a chiral phosphonium salt, {[(4S)-4-methyl-2-oxo-1,3-oxazolidin-4-yl]
methyl}(triphenyl)phosphonium iodide 13 to provide a new Wittig reagent for the general method of
synthesizing a-substituted alaninol derivatives. Our method described here is widely applicable to re-
actions with various types of aldehyde to afford olefin products with high E-selectivity, enabling us to
provide a new approach to the synthesis of chiral S1P1 agonists including our key intermediates, and of
the trace amine-associated receptor 1 (TAAR1) agonist.
Received 6 March 2014
Received in revised form 21 May 2014
Accepted 22 May 2014
Available online xxx
Keywords:
Wittig reaction
Chiral
Ó 2014 Elsevier Ltd. All rights reserved.
a,a-Disubstituted a-amino alcohol
S1P1 receptor agonist
TAAR agonist
1. Introduction
a novel mechanism of action for the treatment of schizophrenia.
Although considerable efforts have already been implemented into
In recent years, a great deal of attention has been paid to the
synthesis of -disubstituted -amino acids or alcohols not only
due to the ubiquitous existence of their structures among natural
products, but also with a view to the design and synthesis of bi-
ologically active compounds. In the area of natural products, myr-
iocin (1),1 sphingofungin E and F (2, 3)2 are known as representative
developing the synthetic method for a,a-disubstituted a-amino
a
,a
a
acids and alcohols,8 the recent emersion of medicinal chemistry
interest toward these classes of compounds still requires estab-
lishing a new efficient method of constructing these structures.
Meanwhile, our group has conducted a series of research pro-
grams to explore efficacious and safer S1P1 agonists that led us to
find a promising clinical candidate CS-0777 (7)5 and its analogues,
compounds possessing a
their structural feature (Fig. 1). On the other hand, for instance in
the area of medicinal chemistry, -disubstituted -amino alcohol
a,a-disubstituted a-amino acid part as
possessing
a chiral 2-methyl-2-aminoethanol structure. Pre-
a
,a
a
liminary studies indicated that the stereochemistry of the quater-
nary carbon center is closely associated with biological activity, and
the (R)-configuration of the amino alcohol moiety was critically
needed to show the S1P1 agonistic activity. Therefore, our research
campaign on S1P1 receptor agonists focused on the synthesis of
or carboxylic acid has been recognized as one of the common
structural motifs of S1P1 agonists, which is a novel mechanism of
action to be able to afford promising medical treatment for various
autoimmune diseases. Indeed, many amphipathic lipid-like mole-
cules containing
a
,a
-disubstituted
a-amino alcohol or carboxylic
a chiral a,a-disubstituted a-amino alcohol structure having various
acid units, such as compound 4e7 have been reported as potent
S1P1 agonists by several groups.3e5 In particular, fingolimod
(FTY720, 4) has been launched in 2010 as an effective therapeutic
agent for multiple sclerosis.6 In addition, a research group of Roche
disclosed a patent concerning the trace amine-associated receptor
1 (TAAR1) agonist7 represented by 8 possessing a chiral 4,5-
dihydro-1,3-oxazol-2-ylamine structure, which is supposed to be
heteroaromatic rings, such as pyrrole, thiophene, or furan rings
adjacent to the chiral center. Our general synthetic approach is
described in Scheme 1 in a retrosynthetic manner. We had con-
sistently set compound 9 as a key intermediate throughout our
derivatization campaign. In the previous method (shown as ‘route
a’ in Scheme 1), compound 9 was synthesized from chiral aldehyde
10, and aryl phosphonium salt 11. Compound 10 was obtained via
either enzymatic desymmetrization or Seebach’s diastereoselective
alkylation methods,9 and aryl phosphonium salt 11 could be pre-
pared from the corresponding arylmethyl halide 12. However, due
to the instability of electron-rich arylmethyl halide 12, at times we
* Corresponding author. Tel.: þ81 3 3492 3131; fax: þ81 3 5436 8563; e-mail
addresses: tsuji.takashi.y3@daiichisankyo.co.jp, t-taka4@i.softbank.jp (T. Tsuji).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.05.086
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2
T. Tsuji et al. / Tetrahedron xxx (2014) 1e8
Fig. 1. Biological active compounds, possessing the a,a-disubstituted a-amino alcohol unit.
reagent to construct a a,a-disubstituted a-amino alcohol structure.
In this manuscript, we report the synthesis of a novel chiral phos-
phonium salt, {[(4S)-4-methyl-2-oxo-1,3-oxazolidin-4-yl]meth-
yl}(triphenyl)phosphonium iodide 13 and the results of the
reactions of 13 with various aldehydes.
2. Results & discussion
The synthetic route of the {[(4S)-4-methyl-2-oxo-1,3-
oxazolidin-4-yl]methyl}(triphenyl)phosphonium iodide 13 from
17 is shown in Scheme 2. Chiral alcohol 17 was synthesized by our
Scheme 1. Retrosynthesis of key intermediates 9 of S1P1 modulator (a; previous route,
b; new route).
previously reported method using commercially available L-serine
as a starting material.9c The protection of the primary alcohol 17
with benzyl bromide proceeded smoothly in the presence of NaH in
DMF to provide 18 in good yield. After the deprotection of the t-
butylmethylidene group of 18, successive treatment with t-BuOK in
THF gave oxazolidinone 20 in good yield. The deprotection of the
benzyl group was achieved by hydrogenation using PdeC in EtOH
to give alcohol 21 in 91% yield (two steps). Alcohol 21 was treated
with p-TsCl in pyridine, and the resulting tosylate was successively
converted to iodide 22 with NaI in acetone under a reflux condition.
A reaction of 22 with triphenylphosphine in DMF provided the
desired phosphonium salt 13 in moderate yield as a stable white
crystalline solid.
had to modify the synthetic route of phosphonium salt to detour
unstable intermediates, such as 2-bromomethyl pyrrole, which
easily decomposed at ambient temperature. In the process of our
effort to improve the synthetic route of 9, we focused on an alter-
native method using novel chiral phosphonium salt 13 (shown as
‘route b’ in Scheme 1). This umpolung strategy allowed us to syn-
thesize a broad structure variation in the part of the aromatic ring
of 9 by directly using commercially available aldehydes 14 without
step-demanding synthesis of each heteroaromatic phosphonium
salt 11.
Regarding the phosphonium salt containing amino alcohol
moiety, Itaya et al.10 and Sibi et al.11 previously reported the Wittig
reaction using 15 and 16, respectively (Fig. 2). They reported the
preparation and the reactions of 15 and 16 with various aldehydes
that provided the coupling products in good yields, and utilized
them as the precursors of unnatural amino acids. However, to the
best of our knowledge, no reports have been published about the
phosphonium salt bearing the quaternary carbon along with 2-
aminoalcohol functional groups, which would be a useful Wittig
Scheme 2. Reagents and conditions: (a) PhCH2Br, NaH, DMF, 88%; (b) p-TsOH mono-
hydrate, MeOH; (c) t-BuOK, THF, 95% (two steps); (d) H 2, PdeC, K2CO3, EtOH (91%); (e)
p-TsCl, pyridine, and then NaI, acetone, 78%; (f) PPh3, DMF, 57%.
Fig. 2. Wittig reagents bearing the tertiary carbon center at a-position of the amino
acid unit.
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T. Tsuji et al. / Tetrahedron xxx (2014) 1e8
3
Table 1
Wittig reactions with phosphonium salt 13 and benzaldehyde
Entry
Conditions
Phosphonium
Base
Yield (%)
E/Za
ee (%)b
salt 13 (equiv)
(equiv)
1
2
3
4
5
6
7
n-BuLi, ꢀ78 ꢁC, 0.5 h, then rt, 2 h
n-BuLi, ꢀ78 ꢁC, 0.5 h, then rt, 2 h
n-BuLi, ꢀ78 ꢁC, 0.5 h, then rt, 2 h
n-BuLi, ꢀ78 ꢁC, 0.5 h, then rt, 2 h
n-BuLi, 0 ꢁC, 0.5 h, then rt, 2 h
1.2
1.2
1.5
2.0e
2.0
2.0
2.0
2.3
1.2
2.9
3.9
3.9
3.9
3.9
46
Trace
83
>99/1
N.T.
>99/1
>99/1
d
N.T.c
N.T.
N.T.
98.6
N.T.
N.T.
N.T.
99
N.R.d
80
LiHMDS, ꢀ78 ꢁC, 0.5 h, then rt, 2 h
>99/1
>99/1
NaHMDS, ꢀ78 ꢁC, 0.5 h, then rt, 2 h
Established by 1H NMR.
76
a
b
c
Estimated by chiral HPLC compared with the corresponding racemic compound.
N.T.¼not tested.
d
e
Benzaldehyde was 90% recovered (N.R.¼no reaction).
Redundant phosphonium salt 13 was recovered as phosphine oxide 13-o in 99% yield (based on the theoretical amount of non-reacted phosphonium salt 13) after
a regular work-up manipulation.
Having established the preparation method for phosphonium
salt 13, we first conducted the optimization of the reaction condi-
tion toward aldehydes in several parameters, such as the equivalent
of phosphonium salt, a base for deprotonation, and the reaction
temperature by using benzaldehyde as a counter substrate. The
results of the evaluation of those factors are summarized in Table 1.
The reaction between benzaldehyde and 1.2 equiv of ylide pre-
pared from phosphonium salt 13 by treatment with 2.3 equiv of n-
BuLi afforded the desired coupling product in 46% yield along with
high E-selectivity (entry 1). Concerning the deprotonation of phos-
phonium salt 13, 2.0 equiv of the base was essentially needed to
prepare dianionic ylide (entry 1, 2). The product yield was improved
by increasing the amount of phosphonium salt and culminating with
2.0 equiv of phosphonium salt to benzaldehyde (entry 3, 4), and the
enantiomeric excess of product was confirmed to be maintained
(entry 4). The redundant phosphonium salt 13 was recovered not as
itself, but as phosphine oxide 13-o quantitatively instead.12 No other
high E-selectivity. It is noteworthy that ortho-substituted com-
pounds, such as 2,4-Me2 (14b) and 2-CO2Me (14c), which are
thought to be less reactive, nevertheless gave the corresponding
products (9b, 9c) in 72% and 75% yields, respectively (entry 2, 3).
Furthermore, highly electron rich aldehyde, such as 2,4,6-(OMe)3
(14d) and 4-NMe2 (14e), also afforded the corresponding alkenes
9d and 9e in acceptable yields (entry 4, 5). As the instability of
benzyl halide possessing electron donating groups, such as the
alkoxy- or alkylamino group at a para or ortho position generally
complicates the preparation of their phosphonium salt, our
Table 2
The reactions of aromatic and aliphatic aldehydes with Wittig reagent 13
byproducts, such as the one formed via b-elimination of the nitrogen
Entry
1
Aldehyde
(YeCHO, 14ael)
Product Yield (%) E/Za
(9ael)
atom of phosphonium salt 13, were observed as long as the reaction
mixture was kept at ꢀ78 ꢁC, while raising the temperature to 0 ꢁC at
the deprotonation step impaired the reaction (entry 5). We assume
that an anion on the oxazolone ring, formed via deprotonation on
R¼H
14a
9a
99
>99/1
a nitrogen atom, effectively prevented the b-elimination reaction of
2
3
4
5
2,4-Me2
2-CO2Me
2,4,6-(OMe)3 14d 9d
4-NMe2
14b 9b
14c 9c
72
75
89
63
>99/1
>99/1
>99/1
>99/1
a nitrogen atom during the reaction process at low temperatures.
The selection of the base did not affect the reaction drastically, but
using LiHMDS or NaHMDS slightly deteriorated the yield of 9a (entry
6, 7). Throughout Table 1, the geometry of product 9a was consis-
tently regulated to an E isomer completely, which was identical to
the previous results reported by Sibi et al.11a Use of NaHMDS as the
base (lithium-free condition) did not influence the predominant E-
selectivity, although removal of the lithium ionwas generally known
to decrease the E-selectivity in the Wittig reaction. In fact, Sibi et al.
previously reported the drastic deterioration of E-selectivity under
the lithium-free condition, where the E/Z-selectivity deteriorated
from >99:1 to 3.2:1. The difference between Sibi’s and our results
was thought to be due to the bulkiness of our phosphonium salt,
which destabilized the transition state for the cis isomer, resulting in
the high E-selectivity.
14e
14f
14g
9e
6
R¼H
9f
75
>99/1
7
8
3-Me
3-Br
9g
99
66
>99/1
>99/1
14h 9h
9
14i
14j
9i
9j
83
>99/1
10
11
82
62
>99/1
With an optimized condition (Table 1, entry 4) in hand, scope
and limitation regarding the substrate of this reaction was then
explored with various aromatic and aliphatic aldehydes as shown
in Table 2.
14k 9k
71/29
12
14l
9l
62
88/12
The reactions between phosphonium salt 13 and various aro-
matic aldehydes proceeded smoothly to afford each alkene with
a
Established by 1H NMR.
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4
T. Tsuji et al. / Tetrahedron xxx (2014) 1e8
umpolung strategy could provide a complementary method to
synthesize -substituted alaninol derivatives having electron rich
treatment with cyanogen bromide in the presence of potassium
carbonate in THF (69% yield in three steps).
a
aromatic groups. Hetero aromatic aldehydes, such as 2-
formylthiophene (14f), 2-formyl-1-methylpyrrole (14i) or 2-
formylfuran (14j), gave the corresponding olefin compounds in
good yields (entry 6, 9, 10). Substituted heteroaryl aldehydes, such
as 3-Me (14g) and 3-Br (14h), also gave the olefin compounds (9g,
9h), although the yield of 9h was slightly deteriorated (66%) com-
pared to 9g (99%). The geometrical selectivity of the products was
not influenced by the fashion of aromatic rings to solely give E al-
kenes as a major isomer. In terms of the reaction with aliphatic
aldehydes, the yields of the products tended to be inferior to aro-
matic aldehydes, probably because those aldehydes were partly
inactivated by conversion to the corresponding enolates in the basic
condition (entry 11, 12). Furthermore, the E-selectivity was also
deteriorated, which had the same tendency as the results reported
by Sibi et al.11a
As we could obtain basic information regarding the reaction
condition and scope of substrate of the Wittig reaction using
phosphonium salt 13, we then turned our focus to the application
of 13. Several examples using phosphonium salt 13 for the syn-
thesis of biological active compounds are depicted in Scheme 3. As
for the synthesis of our S1P1 agonist intermediates, a wide variety
of heterocyclic key intermediates were able to be synthesized from
the corresponding commercially available aldehydes in only a two-
step manipulation, which allowed us to enhance the efficiency of
synthesizing a broad structural variation (Scheme 3, Eq. 1). Namely,
the Wittig reaction using phosphonium salt 13 with 2-
formylthiophene (14f), 2-formyl-1-methylpyrrole (14i) or 2-
formylfuran (14j) afforded olefin products (9f, 9i, and 9j), re-
spectively in good yields (Table 2), and they were reduced with 10%
PdeC in MeOH under a hydrogen atmosphere to respectively give
key compounds9b 23a, 23b, and 23c in good yields. This new ap-
proach could be applicable to a short step synthesis of the chiral
analogue of FTY720 (25),13 which is an invaluable tool for the elu-
cidation of the mechanism of action of FTY720 (Scheme 3, Eq. 2).
Commercially available aldehyde 24 was reacted with the ylide
prepared from our phosphonium salt 13 to afford an olefin com-
pound in 77% yield. The olefin moiety was reduced by hydroge-
nation with PdeC, and successive alkaline hydrolysis of the
oxazolidinone part gave the chiral analogue of FTY720 (25) in 90%
yield for two steps. The synthesis of another S1P1 agonist (6) was
also achieved by using aldehyde 2614 and the same transformations
as compound 25 (Scheme 3, Eq. 3). Furthermore, TAAR1 agonist 8
was able to be synthesized by this manner (Scheme 3, Eq. 4).
Starting from 9a, the corresponding amino alcohol was obtained by
the same procedure (hydrogenation and hydrolysis), and then the
1-aminooxazoline structure of 8 was successively constructed by
3. Conclusion
In conclusion, we have established the method for preparation
of optically active phosphonium salt 13, bearing the quaternary
carbon along with 2-aminoalcohol functional groups. The ylide
prepared from phosphonium salt 13 was revealed to react with
various aromatic and aliphatic aldehydes in moderate to good
yields, providing not only a practical synthetic method for the S1P1
receptor modulators and their key intermediates represented by
23aec, 25, and 6, but also a short synthetic route for a chiral TAAR1
agonist 8. These results manifest a wide applicability of phospho-
nium salt 13 for the synthesis of biologically active compounds. It is
synthetically noteworthy that the Wittig reaction using 13 with
various aldehydes afforded corresponding alkenes with high E-se-
lectivity, which would be a good flag for stereoselective installation
of further functionalities. Further applications of phosphate 13 will
be reported in due course.
4. Experimental section
4.1. General
Unless otherwise noted, materials were obtained from com-
mercial suppliers and used without further purification. 1H and 13
C
NMR spectra were recorded on Unity Mercury Plus 400 or 500
spectrometer (Varian) and chemical shifts are given in parts per
million from tetramethylsilane (TMS) as an internal standard. Op-
tical rotations were measured on a JASCO P-1030, HORIBA SEPA-
300 or an Autopol V plus digital polarimeter. IR absorption spec-
tra were recorded on a Jasco FT/IR-610 spectrophotometer. The
mass spectra (Low- or High-resolution mass) spectroscopy was
carried out with a JEOL GCmate or JEOL JMS-AX505H. Elemental
analyses and melting point calculations were performed by the
analytical department of Daiichi Sankyo RD Novare Co., Ltd. Thin-
layer chromatography (TLC) was performed on Merck precoated
TLC glass sheets with silica gel 60F254. Separation of the compounds
by column chromatography was carried out with silica gel 60
(Merck, 230e400 mesh ASTM).
4.2. Synthesis of compounds
4.2.1. Methyl (2R,4R)-4-[(benzyloxy)methyl]-2-tert-butyl-4-methyl-
1,3-oxazolidine-3-carboxylate (18). Sodium hydride (60%, 2.2 g,
58 mmol) was added to a solution of methyl (2R,4R)-2-tert-butyl-4-
(hydroxymethyl)-4-methyl-oxazolidine-3-carboxylate (17) (11 g,
Scheme 3. Reagents and conditions: (a) Aldehyde, n-BuLi, THF, 77e99%; (b) H2, PdeC, MeOH; (c) KOH, MeOH, H2O, 71e90% (two steps); (d) cyanogen bromide, K2CO3, THF, 69%.
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T. Tsuji et al. / Tetrahedron xxx (2014) 1e8
5
48 mmol) in DMF (100 mL) at 0 ꢁC. After stirring for 10 min, ben-
zylbromide (10.7 g, 62 mmol) was added to the reaction mixture at
0 ꢁC. The solution was warmed to ambient temperature and stirred
for 2 h. After quenching with saturated aq NH4Cl (100 mL), the
resulting biphasic mixture was extracted with AcOEt (200 mLꢂ2).
The combined organic layer was washed with water (100 mL) and
brine (100 mL), dried over Na2SO4, filtered, and evaporated. Puri-
fication by silica gel column chromatography (hexane:AcOEt¼5:1
and brine (50 mL), dried over Na2SO4 filtered, and evaporated,
giving a crude tosylate. To a solution of the obtained crude tosylate
in acetone (120 mL) was added NaI (18 g, 117 mmol), and then the
suspension was refluxed for 12 h. The reaction mixture was filtrated
and evaporated in vacuo. The residue was diluted with AcOEt
(150 mL) and the organic layer was washed with saturated
aq Na2SO3 (50 mL) and brine (50 mL), dried over Na2SO4, filtered,
and evaporated. Purification by silica gel column chromatography
(hexane:AcOEt¼2:1 to 1:2) provided 22 (5.8 g, 78% for two steps) as
to 3:1) provided 18 (13.6 g, 88%) as a pale yellow oil. [
1.0, CH3OH); 1H NMR (500 MHz, CDCl3)
a]
20 ꢀ13.6 (c
D
d
ppm; 0.89 (s, 9H), 1.39 (s,
a colorless oil. [
a]
20 ꢀ14.9 (c 1.0, CH3OH); 1H NMR (500 MHz, CDCl3)
D
3H), 3.63 (m, 1H), 3.64 (s, 3H), 3.86 (br s, 1H), 3.72 (d, 1H, J¼8.8 Hz),
d
ppm: 1.58 (s, 3H), 3.31 (d, 2H, J¼4.9 Hz), 4.15 (d,1H, J¼8.8 Hz), 4.28
4.13 (d, 1H, J¼8.8 Hz), 4.51 (q, 2H, J¼11.7 Hz), 5.11 (br s, 1H),
(d, 1H, J¼8.8 Hz), 5.68 (br s, 1H); 13C NMR (126 MHz, CDCl3)
d ppm;
7.24e7.35 (m, 5H); 13C NMR (126 MHz, CDCl3)
d
ppm; 20.6, 26.5,
15.1, 25.4, 57.2, 74.9, 158.5; IR (KBr) cmꢀ1: 3248, 1776, 1401, 1289,
1214, 1140, 1051, 956, 762; MS (FAB) m/z: 242 (MþH)þ; HRMS (ESI):
calcd for C5H9NO2I [MþH]þ 241.9678; found 241.9687.
38.6, 52.0, 63.4, 73.5, 74.7, IR (KBr) cmꢀ1: 2954, 1707, 1441, 1338,
1311, 1174, 1111, 1063, 1028, 958, 737, 698; MS (FAB) m/z: 322
(MþH)þ; HRMS (ESI): calcd for C18H28NO4 [MþH]þ 322.2022;
found 322.2018.
4.2.6. {[(4S)-4-Methyl-2-oxo-1,3-oxazolidin-4-yl]methyl}(triphenyl)
phosphonium iodide (13). To a solution of (4S)-4-(iodomethyl)-4-
methyl-1,3-oxazolidin-2-one (22) (4.2 g, 17 mmol) in DMF
(20 mL) was added PPh3 (46 g, 174 mmol), and then the solution
was stirred for 3 h at 110 ꢁC. The reaction mixture was diluted with
MeOH/AcOEt (20 mL/50 mL), and then left at ambient temperature
for 1 day. After the removal of supernatant liquid by decantation,
the residue was evaporated in vacuo, giving a crude phosphonium
compound (13) (7 g). Recrystallization from MeOH/AcOEt (20 mL/
200 mL) provided 13 (5.0 g, 57%) as a white solid. Mp: 106.0 ꢁC;
4.2.2. Methyl [(2S)-1-(benzyloxy)-3-hydroxy-2-methylpropan-2-yl]
carbamate (19). To a solution of methyl (2R,4R)-4-[(benzyloxy)
methyl]-2-tert-butyl-4-methyl-1,3-oxazolidine-3-carboxylate (18)
(9.9 g, 25 mmol) in MeOH (120 mL) was added p-TsOH mono-
hydrate (1.5 g, 8.5 mmol), and then the solution was refluxed for
1 h. The reaction mixture was evaporated in vacuo, giving the crude
19 (13.6 g) as a pale yellow oil. The crude 19 was carried on to the
next step without further purification. MS (FAB) m/z: 254 (MþH)þ.
[
a
]
20 ꢀ37.3 (c 1.6, CH3OH); 1H NMR (500 MHz, CDCl3)
d ppm: 1.73 (s,
D
4.2.3. (4R)-4-[(Benzyloxy)methyl]-4-methyl-1,3-oxazolidin-2-one
(20). To a solution of the crude methyl [(2S)-1-(benzyloxy)-3-
hydroxy-2-methylpropan-2-yl]carbamate (19) (13.6 g) in THF
(200 mL) was added t-BuOK (7.7 g, 68 mmol) at ambient temper-
ature, and then the solution was stirred for 3 h. After quenching
with aq 1 N HCl (100 mL), the resulting biphasic mixture was
extracted with AcOEt (100 mLꢂ2). The combined organic layer was
washed with water (100 mL) and brine (100 mL), dried over
Na2SO4, filtered, and evaporated. Purification by silica gel column
chromatography (hexane:AcOEt¼3:1 to 1:2) provided 20 (8.8 g,
3H), 3.81e3.87 (m, 2H), 4.40 (dd, 1H, J¼3.2, 12.8 Hz), 4.76 (dd, 1H,
J¼3.2, 12.8 Hz), 6.52 (s, 1H), 7.71e7.75 (m, 6H), 7.80e7.84 (m, 3H),
7.97e8.01 (m, 6H); 13C NMR (126 MHz, CDCl3)
d ppm; 30.3 (d,
J¼8.0 Hz), 32.2 (d, J¼49.1 Hz), 57.0 (d, J¼4.6 Hz), 74.8, 118.0 (d,
J¼85.9 Hz), 130.7 (d, J¼12.7 Hz), 134.0 (d, J¼10.3 Hz), 135.3 (d,
J¼3.0 Hz), 157.2; IR (KBr) cmꢀ1: 3394, 3225, 2854, 1741, 1438, 1108,
1052, 747, 690; HRMS (ESI): calcd for
376.1466; found 376.1461.
C
23H23INO2P [MꢀI]þ
4.2.7. (4R)-4-Methyl-4-[(E)-2-phenylethenyl]-1,3-oxazolidin-2-one
(9a) and (4S)-4-(diphenylphosphorylmethyl)-4-methyl-oxazolidin-2-
one (13eo). Typical procedure of a Wittig reaction: To a suspension
of the phosphonium salt (13) (500 mg, 1.0 mmol, 2.0 equiv) in THF
(5 mL) was added n-butyllithium (1.9 M in hexane, 1.0 mL,
1.95 mmol, 3.9 equiv) at ꢀ78 ꢁC and then the solution was stirred
for 30 min at the same temperature. After the addition of benzal-
dehyde (54 mg, 0.5 mmol,1.0 equiv) at ꢀ78 ꢁC, the reaction mixture
was gradually warmed to ambient temperature and stirred for 2 h.
After quenching with saturated aq NH4Cl (10 mL), the resulting
biphasic mixture was extracted with AcOEt (10 mLꢂ2). The com-
bined organic layer was washed with water (10 mL) and brine
(10 mL), dried over Na2SO4, filtered, and evaporated. Purification by
silica gel column chromatography (hexane:AcOEt¼3:1 to 1:1)
provided 9a (101 mg, 99% yield, 98.6% ee) as a white solid, and 13-o
(156 mg, 99% yield) as a white solid. The enantiomeric excess of 9a
was determined by HPLC analysis by using the following condition.
95% for two steps) as a colorless oil. [
(500 MHz, CDCl3)
ppm; 1.35 (s, 3H), 3.35 (d, 2H, J¼4.4 Hz), 4.00 (d,
1H, J¼8.8 Hz), 4.19 (d, 1H, J¼8.8 Hz), 4.53 (d, 2H, J¼2.4 Hz), 5.26 (s,
1H), 7.27e7.36 (m, 5H); 13C NMR (126 MHz, CDCl3)
ppm; 23.0,
57.3, 73.4, 73.6, 75.1, 127.7, 128.0, 128.5, 137.5, 159.2; IR (KBr) cmꢀ1
a]
20 7.3 (c 1.0, CH3OH); 1H NMR
D
d
d
:
3271, 1738, 1383, 1254, 1194, 1097, 1039, 933, 737, 698; MS (FAB) m/
z: 222 (MþH)þ; HRMS (ESI): calcd for C12H16NO3 [MþH]þ 222.1130;
found 222.1121.
4.2.4. (4R)-4-(Hydroxymethyl)-4-methyl-1,3-oxazolidin-2-one
(21). To a solution of (4R)-4-[(benzyloxy)methyl]-4-methyl-1,3-
oxazolidin-2-one (20) (2.6 g, 11.8 mmol) in EtOH (150 mL) was
added potassium carbonate (6.0 g, 43 mmol) and 10% PdeC (50%
wet, 4.0 g), and then the suspension was stirred for 3 h under
a hydrogen atmosphere. The reaction mixture was filtered through
a Celite pad and evaporated in vacuo, giving 21 (2.6 g, 91%) as
a white solid. The crude 21 was of high purity and carried on to the
next step without further purification. 1H NMR (500 MHz, CD3OD)
DAICEL CHIRALCEL IA column (4.6
f
ꢂ150 mm), hexane:EtOH¼95:5
(0 min)d50:50 (8.0 min), flow rate: 2.0 ml/min, temperature:
d
ppm: 1.22 (s, 3H), 3.37 (d, 1H, J¼11.2 Hz), 3.43 (d, 1H, J¼11.2 Hz),
25.0 ꢁC. The retention times of (S)-9a and (R)-9a were 4.6 min and
20
3.98 (d, 1H, J¼8.6 Hz), 4.29 (d, 1H, J¼8.6 Hz); MS (FAB) m/z: 132
5.3 min, respectively. (Compound 9a) mp: 155.6 ꢁC; [
a]
ꢀ61.0 (c
D
(MþH)þ.
0.27, CH3OH); 1H NMR (500 MHz, CDCl3)
d ppm: 1.53 (s, 3H), 4.17 (d,
1H, J¼8.3 Hz), 4.23 (d, 1H, J¼8.3 Hz), 5.09 (s, 1H), 6.21 (d, 1H,
4.2.5. (4S)-4-(Iodomethyl)-4-methyl-1,3-oxazolidin-2-one (22). To
a solution of (4R)-4-(hydroxymethyl)-4-methyl-1,3-oxazolidin-2-
one (21) (4.2 g, 31 mmol) in pyridine (40 mL) was added p-TsCl
(8.9 g, 46 mmol), and then the solution was stirred for 3 h at am-
bient temperature. After an addition of aq 1 N HCl (100 mL), the
resulting biphasic mixture was extracted with CH2Cl2 (100 mLꢂ2).
The combined organic layers were washed with aq 2 N HCl (50 mL)
J¼16.1 Hz), 6.59 (d, 1H, J¼16.1 Hz), 7.26e7.36 (m, 5H); 13C NMR
(126 MHz, CDCl3)
d ppm; 25.6, 58.5, 76.5, 126.7, 128.3, 128.7, 130.1,
131.2, 135.7, 159.0; IR (KBr) cmꢀ1: 3293, 1756, 1710, 1393, 1288, 1171,
1042, 967, 751, 659; MS (ESI) m/z: 203 (M)þ; Anal. Calcd for
C
12H13NO2: C, 70.92; H, 6.45; N, 6.89. Found: C, 70.80; H, 6.49; N,
6.83. (Compound 13-o) mp: 181.4 ꢁC; [
NMR (500 MHz, CDCl3)
a]
20 þ9.1 (c 0.41, CH3OH); 1H
D
d
ppm: 1.34 (s, 3H), 4.09 (d, 1H, J¼8.8 Hz),
Please cite this article in press as: Tsuji, T.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.086

6
T. Tsuji et al. / Tetrahedron xxx (2014) 1e8
2.60e2.78 (m, 2H), 4.21 (d, 1H, J¼8.8 Hz), 6.44 (br s, 1H), 7.46e7.57
(m, 5H), 7.67e7.71 (m, 2H), 7.78e7.82 (m, 2H); 13C NMR (126 MHz,
1H, J¼8.3 Hz), 4.22 (d, 1H, J¼8.3 Hz), 5.01 (br s, 1H), 5.97 (d, 1H,
J¼15.6 Hz), 6.72 (d,1H, J¼15.6 Hz), 6.78 (d,1H, J¼4.9 Hz), 7.07 (d,1H,
CDCl3)
d
ppm; 26.7, 39.9 (d, J¼69.1 Hz), 57.3 (d, J¼4.8 Hz), 77.4 (d,
J¼4.9 Hz); 13C NMR (126 MHz, CDCl3)
d ppm; 50.7, 58.7, 76.6, 121.8,
J¼12.5 Hz), 128.9 (d, J¼3.6 Hz), 129.0 (d, J¼3.6 Hz), 130.3 (d,
J¼9.5 Hz), 130.6 (d, J¼9.5 Hz), 132.2, 132.3, 132.8 (d, J¼90.6 Hz),
133.6 (d, J¼93.0 Hz), 157.7; IR (KBr) cmꢀ1: 3308, 1758, 1439, 1255,
1175, 1034, 930, 752, 699; HRMS (ESI): calcd for C17H19NO3P
[MþH]þ 316.1103; found 316.1105.
123.6, 129.8, 130.8, 134.2, 136.4, 159.1; IR (KBr) cmꢀ1: 3218, 1730,
1401, 1286, 1173, 1036, 957, 724; HRMS (ESI): calcd for C11H14NO2S
[MþH]þ 224.0745; found 224.0746.
4.2.14. (4R)-4-[(E)-2-(3-Bromothiophen-2-yl)ethenyl]-4-methyl-1,3-
oxazolidin-2-one (9h). Pale yellow oil. [
NMR (500 MHz, CDCl3)
a
]
20 ꢀ41.2 (c 1.0, CH3OH); 1H
D
4.2.8. (4R)-4-[(E)-2-(2,4-Dimethylphenyl)ethenyl]-4-methyl-1,3-
d
ppm: 1.57 (s, 3H), 4.17 (d, 1H, J¼8.3 Hz),
20
oxazolidin-2-one (9b). Pale yellow solid. Mp: 115.5 ꢁC;
[a
]
4.23 (d, 1H, J¼8.3 Hz), 5.08 (br s, 1H), 6.12 (d, 1H, J¼16.1 Hz), 6.77 (d,
D
ꢀ42.5 (c 0.19, CH3OH); 1H NMR (500 MHz, CDCl3)
d ppm: 1.56 (s,
1H, J¼16.1 Hz), 6.93 (d,1H, J¼5.9 Hz), 7.17 (d,1H, J¼5.9 Hz); 13C NMR
3H), 2.28 (s, 6H), 4.17 (d, 1H, J¼8.3 Hz), 4.23 (d, 1H, J¼8.3 Hz), 5.03
(br s, 1H), 6.05 (d, 1H, J¼15.6 Hz), 6.77 (d, 1H, J¼15.6 Hz), 6.96 (s,
1H), 6.97 (d, 1H, J¼8.3 Hz), 7.27 (d, 1H, J¼8.3 Hz); 13C NMR
(126 MHz, CDCl3) d ppm; 25.4, 58.5, 76.2, 111.73, 122.0, 124.9, 130.9,
132.6, 135.0, 158.7; IR (KBr) cmꢀ1: 3220, 3107, 1744, 1727, 1402,
1295, 1036, 961, 870, 727; HRMS (ESI): calcd for C10H11NO2SBr
[MþH]þ 287.9694; found 287.9691.
(126 MHz, CDCl3)
d ppm; 19.7, 21.1, 25.7, 58.7, 76.6, 125.6, 127.0,
127.8, 131.2, 131.6, 132.0, 135.6, 138.0, 158.9; IR (KBr) cmꢀ1: 3206,
3112, 2970, 2871, 1782, 1736, 1403, 1291, 1037, 984; HRMS (ESI):
calcd for C14H18NO2 [MþH]þ 232.1338; found 232.1337.
4.2.15. (4R)-4-Methyl-4-[(E)-2-(1-methyl-1H-pyrrol-2-yl)ethenyl]-
20
1,3-oxazolidin-2-one (9i). Pale yellow oil. [
a
]
D
ꢀ30.8 (c 0.23,
CH3OH); 1H NMR (500 MHz, CDCl3)
d
ppm: 1.52 (s, 3H), 3.60 (s, 3H),
4.2.9. Methyl
ethenyl}benzoate (9c). Pale yellow solid. Mp: 90.5 ꢁC; [
0.17, CH3OH); 1H NMR (500 MHz, CDCl3)
2-{(E)-2-[(4R)-4-methyl-2-oxo-1,3-oxazolidin-4-yl]
4.15 (d, 1H, J¼8.3 Hz), 4.19 (d, 1H, J¼8.3 Hz), 5.00 (s, 1H), 5.95 (d, 1H,
J¼15.6 Hz), 6.08 (d, 1H, J¼3.2 Hz), 6.33 (dd, 1H, J¼2.0, 3.2 Hz), 6.46
(d, 1H, J¼15.6 Hz), 6.59 (d, 1H, J¼2.0 Hz); 13C NMR (100 MHz, CDCl3)
a]
20 ꢀ18.0 (c
D
d
ppm: 1.59 (s, 3H), 3.88 (s,
3H), 4.18 (d,1H, J¼8.3 Hz), 4.26 (d,1H, J¼8.3 Hz), 5.20 (br s,1H), 6.06
d ppm; 25.8, 34.1, 58.6, 76.8, 107.0, 108.2, 118.7, 123.8, 127.9, 129.8,
(d, 1H, J¼16.1 Hz), 7.34 (m, 1H), 7.42 (d, 1H, J¼16.1 Hz), 7.45e7.50
158.9; IR (KBr) cmꢀ1: 3278, 1734, 1478, 1375, 1033, 957, 712;
MS(FAB) m/z: 207 (MþH)þ; HRMS (ESI): calcd for C11H14N2O2
[MþH]þ 207.1134; found 207.1127.
(m, 2H), 7.92 (m, 1H); 13C NMR (126 MHz, CDCl3)
d ppm; 25.3, 52.2,
58.7, 76.3, 127.6, 127.8, 128.6, 129.8, 130.7, 132.3, 133.7, 138.0, 158.9,
167.5; IR (KBr) cmꢀ1: 3206, 3112, 2970, 2871, 1782, 1736, 1403, 1291,
1037, 984; HRMS (ESI): calcd for C14H16NO4 [MþH]þ 262.1079;
found 262.1077.
4.2.16. (4R)-4-[(E)-2-(Furan-2-yl)ethenyl]-4-methyl-1,3-oxazolidin-
20
2-one (9j). Pale yellow oil. [
(500 MHz, CDCl3)
a
]
D
ꢀ44.1 (c 0.20, CH3OH); 1H NMR
d
ppm: 1.52 (s, 3H), 4.12 (d, 1H, J¼8.3 Hz), 4.24 (d,
4.2.10. (4R)-4-[(E)-2-(2,4,6-Trimethoxylphenyl)ethenyl]-4-methyl-
1,3-oxazolidin-2-one (9d). Off-white solid. Mp: 119.7 ꢁC; [
1H, J¼8.3 Hz), 4.96 (s, 1H), 6.16 (d, 1H, J¼16.1 Hz), 6.28 (d, 1H,
J¼3.4 Hz), 6.37 (dd,1H, J¼1.7, 3.4 Hz), 6.40 (d,1H, J¼16.1 Hz), 7.34 (d,
20
a]
D
ꢀ27.1 (c 0.22, CH3OH); 1H NMR (500 MHz, CDCl3)
d
ppm: 1.59 (s,
1H, J¼1.7 Hz); 13C NMR (126 MHz, CDCl3)
d ppm; 25.5, 58.5, 76.6,
3H), 3.85 (s, 3H), 3.86 (s, 6H), 4.20 (d, 1H, J¼10.5 Hz), 4.28 (d, 1H,
109.6, 111.6, 118.5, 129.4, 142.6, 151.4, 159.0; IR (KBr) cmꢀ1: 3276,
1749, 1391, 1039, 739; HRMS (ESI): calcd for C10H11NO3 [MþH]þ
194.0817; found 194.0813.
J¼10.5 Hz), 5.26 (br s, 1H), 6.16 (s, 2H), 6.60 (d, 1H, J¼20.5 Hz), 6.86
(d, 1H, J¼20.5 Hz); 13C NMR (100 MHz, CDCl3)
d ppm; 25.7, 55.3,
55.7, 59.3, 77.1, 90.5, 106.0, 120.3, 131.7, 158.8, 159.4, 160.6; IR (KBr)
cmꢀ1: 3313, 2941, 1764, 1732, 1605, 1460, 1230, 1124, 1039, 817;
4.2.17. (4R)-4-Methyl-4-(oct-1-en-1-yl)-1,3-oxazolidin-2-one
HRMS (ESI): calcd for
294.1358.
C
15H20NO5 [MþH]þ 294.1341; found
(9k). Colorless oil. [
CDCl3)
a
]
20 ꢀ30.4 (c 0.98, CH3OH); 1H NMR (500 MHz,
D
d
ppm: 0.86 (t, 3H, J¼7.6 Hz),1.19e1.38 (m, 8H),1.41 (s, 2.1H),
1.46 (s, 0.9H), 1.99e2.07 (m, 2H), 4.06 (d, 0.7H, J¼8.3 Hz), 4.10 (d,
0.7H, J¼8.3 Hz), 4.21 (d, 0.3H, J¼8.3 Hz), 4.28 (d, 0.3H, J¼8.3 Hz),
5.00 (s, 0.7H), 5.15 (s, 0.3H), 5.41e5.50 (m, 1.4H), 5.64e5.70 (m,
4.2.11. (4R)-4-[(E)-2-(4-Dimethylaminophenyl)ethenyl]-4-methyl-
1,3-oxazolidin-2-one (9e). White solid. Mp: 137.5 ꢁC; [
a
]
20 ꢀ76.5 (c
D
0.090, CH3OH); 1H NMR (500 MHz, CDCl3)
d
ppm: 1.56 (s, 3H), 2.97
0.6H); 13C NMR (126 MHz, CDCl3)
d
ppm; 14.1, 22.6, 25.5, 28.8, 29.0,
(s, 6H), 4.16 (d, 1H, J¼8.5 Hz), 4.23 (d, 1H, J¼8.5 Hz), 5.25 (br s, 1H),
31.6, 32.1, 58.2, 76.7, 131.6, 131.9, 132.0, 133.8, 159.1; IR (KBr) cmꢀ1
:
6.02 (d, 1H, J¼15.9 Hz), 6.51 (d, 1H, J¼15.9 Hz), 6.69 (d, 2H,
3261, 2925, 1746, 1387, 1281, 1038, 969, 770; HRMS (ESI): calcd for
J¼8.0 Hz), 7.26 (d, 2H, J¼8.0 Hz); 13C NMR (125 MHz, CDCl3)
d
ppm;
C
12H21NO2 [MþH]þ 212.1651; found 212.1654.
25.5, 40.5, 58.5, 76.8, 112.5, 126.5, 127.6, 130.1, 150.1, 158.7; IR (KBr)
cmꢀ1: 3372, 3253, 2904, 1768, 1720, 1608, 1522, 1355, 1188, 1035,
966, 806, 770; HRMS (ESI): calcd for C14H19N2O2 [MþH]þ 247.1447;
found 247.1439.
4.2.18. (4R)-4-(2-Cyclohexylethenyl)-4-methyl-1,3-oxazolidin-2-one
(9l). Colorless oil. [
CDCl3)
a
]
20 ꢀ23.6 (c 0.44, CH3OH); 1H NMR (500 MHz,
D
d
ppm: 0.99e1.33 (m, 6H), 1.41 (s, 2.7H), 1.41 (s, 0.3H),
1.62e1.74 (m, 4H), 1.92e1.98 (m, 0.9H), 2.07e2.17 (s, 0.1H), 4.07 (d,
1H, J¼8.3 Hz), 4.10 (d, 1H, J¼8.3 Hz), 4.90 (br s, 0.9H), 5.10 (br s,
0.1H), 5.36e5.25 (m, 0.2H), 5.44 (d, 0.9H, J¼15.6 Hz), 5.62 (dd, 0.9H,
4.2.12. (4R)-4-Methyl-4-[(E)-2-(thiophen-2-yl)ethenyl]-1,3-
20
oxazolidin-2-one (9f). Yellow oil. [
NMR (500 MHz, CDCl3)
a
]
ꢀ62.7 (c 0.38, CH3OH); 1H
D
d
ppm: 1.49 (s, 3H), 4.16 (d, 1H, J¼8.5 Hz),
J¼6.8, 15.6 Hz); 13C NMR (126 MHz, CDCl3)
d ppm; 25.6, 25.9, 26.1,
4.22 (d, 1H, J¼8.5 Hz), 5.03 (s, 1H), 6.04 (d, 1H, J¼16.1 Hz), 6.71 (d,
32.7, 40.2, 58.2, 76.7, 129.6, 137.1, 159.0; IR (KBr) cmꢀ1: 3210, 2922,
2849, 1742, 1397, 1286, 1038, 968, 771, 701; HRMS (ESI): calcd for
1H, J¼16.1 Hz), 6.94e6.98 (m, 2H), 7.18 (d, 1H, J¼5.4 Hz); 13C NMR
(126 MHz, CDCl3)
d
ppm; 25.2, 58.5, 76.5, 123.5, 125.1, 127.0, 127.6,
C
12H19NO2 [MþH]þ 210.1494; found 210.1496.
130.5, 140.7, 159.1; IR (KBr) cmꢀ1: 3264, 1735, 1388, 1280, 1034, 956,
697; HRMS (ESI): calcd for C10H11NO2S [MþH]þ 210.0589; found
210.0594.
4.2.19. (4R)-4-Methyl-4-[2-(thiophen-2-yl)ethyl]-1,3-oxazolidin-2-
one (23a). To a solution of (4R)-4-methyl-4-[(E)-2-(thiophen-2-yl)
ethenyl]-1,3-oxazolidin-2-one (9f) (200 mg, 0.95 mmol) in meth-
anol (10 mL) was added 10% PdeC (50% wet, 20 mg), and then the
suspension was stirred for 2 h under a hydrogen atmosphere at
ambient temperature. The reaction mixture was filtered through
4.2.13. (4R)-4-Methyl-4-[(E)-2-(3-methylthiophen-2-yl)ethenyl]-1,3-
oxazolidin-2-one (9g). Pale yellow oil. [
a
]
20 ꢀ36.4 (c 0.62, CH3OH);
D
1H NMR (500 MHz, CDCl3)
d
ppm: 1.54 (s, 3H), 2.22 (s, 3H), 4.16 (d,
Please cite this article in press as: Tsuji, T.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.086

T. Tsuji et al. / Tetrahedron xxx (2014) 1e8
7
20
a Celite pad and evaporated in vacuo. Purification by silica gel
a pale yellow solid. Mp: 70.7 ꢁC; [
NMR (500 MHz, CDCl3)
a
]
ꢀ44.5 (c 0.14, CH3OH); 1H
D
column chromatography (hexane:AcOEt¼3:1 to 1:2) provided 23a
(184 mg, 92% yield, 99% ee) as a pale yellow solid. The enantiomeric
excess of (4R)-methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one
(23a) was determined by HPLC analysis by using the following
d
ppm: 0.87 (t, 3H, J¼7.8 Hz), 1.23e1.36 (m,
6H), 1.39e1.45 (m, 2H), 1.54 (s, 3H), 1.72e1.79 (m, 2H), 3.93 (t, 2H,
J¼6.6 Hz), 4.15 (d, 1H, J¼8.8 Hz), 4.21 (d, 1H, J¼8.8 Hz), 5.02 (br s,
1H), 6.06 (d, 1H, J¼16.1 Hz), 6.52 (d, 1H, J¼16.1 Hz), 6.83 (d, 2H,
condition. DAICEL CHIRALCEL OD-H (4.6
f
ꢂ250 mm), hexane:2-
J¼6.8 Hz), 7.27 (d, 2H, J¼6.8 Hz); 13C NMR (126 MHz, CDCl3)
d ppm;
propanol¼60:40, flow rate: 0.5 ml/min, temperature: 25.0 ꢁC. The
14.1, 22.6, 25.6, 26.0, 29.1, 29.3, 31.8, 58.6, 68.1, 76.7, 114.7, 127.9,
128.2, 128.7, 129.7, 159.1, 159.4; IR (KBr) cmꢀ1: 3268, 2929, 2857,
1776, 1607, 1513, 1252, 1175, 1044; HRMS (ESI): calcd for C19H28NO3
[MþH]þ 318.2069; found 318.2068.
retention times of (S)-23a and (R)-23a were 16.8 min and 17.6 min,
20
respectively. Mp: 83.5 ꢁC; [
a
]
D
þ7.8 (c 2.0, CHCl3), þ1.9 (c 0.10,
CH3OH); 1H NMR (400 MHz, CDCl3)
d : 1.42 (s, 3H), 2.08e1.92 (m,
2H), 3.00e2.84 (m, 2H), 4.08 (d, 1H, J¼8.4 Hz), 4.19 (d, 1H, J¼8.4 Hz),
5.39 (br s, 1H), 6.81 (d, 1H, J¼3.6 Hz), 6.93 (dd, 1H, J¼5.2, 3.6 Hz),
4.2.23. (2R)-2-Amino-4-[4-(heptyloxy)phenyl]-2-methylbutan-1-ol
(25). To a solution of (4R)-4-{(E)-2-[4-(heptyloxy)phenyl]vinyl}-4-
methyl-1,3-oxazolidin-2-one (25a) (30 mg, 0.1 mmol) in methanol
(5 mL) was added 10% PdeC (50% wet, 10 mg), and then the sus-
pension was stirred for 2 h under a hydrogen atmosphere at am-
bient temperature. The reaction mixture was filtered through
a Celite pad and evaporated in vacuo. The residue was diluted with
THF (2 mL) and methanol (1 mL). Aq 5 N potassium hydroxide
(1 mL) was added to the solution, which was then refluxed for 18 h.
After cooling to room temperature, water (10 mL) was added to the
reaction mixture and the resulting biphasic mixture was extracted
with CH2Cl2 (10 mLꢂ2). The combined organic layer was washed
7.15 (d, 1H, J¼5.2 Hz); 13C NMR (100 MHz, CDCl3)
d ppm; 24.6, 25.9,
42.3, 57.5, 75.5, 123.6, 124.6,127.0, 147.6, 159.5; IR (KBr) cmꢀ1: 3283,
1770, 1399, 1244, 1043, 941, 846, 775, 706, 691; HRMS (ESI): calcd
for C10H14NO2S [MþH]þ 212.0275; found 212.0741.
4.2.20. (4R)-4-Methyl-4-[2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,3-
oxazolidin-2-one (23b). Compound 23b was obtained as a yellow
oil from 9i by using the procedure described for 23a in 88% yield
(99% ee). The enantiomeric excess of (4R)-4-methyl-4-[2-(1-
methylpyrrol-2-yl)ethyl]oxazolidin-2-one (23b) was determined
by HPLC analysis by using the following condition. DAICEL CHIR-
ALCEL OJ (4.6
f
ꢂ250 mm), hexane:2-propanol¼70:30, flow rate:
with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered,
20
1.0 ml/min, temperature: 25.0 ꢁC. The retention times of (S)-23b
and evaporated, providing 25 (25 mg, 90%) as a colorless oil. [a]
D
and (R)-23b were 12.5 min and 15.5 min, respectively. [
a
]
20 þ1.2 (c
ꢀ2.4 (c 0.92, CH3OH); 1H NMR (500 MHz, CDCl3)
d ppm: 0.86 (t, 3H,
D
0.30, CH3OH); 1H NMR (400 MHz, CDCl3)
d
: 1.42 (s, 3H), 2.00e1.87
J¼6.8 Hz), 1.10 (s, 3H), 1.22e1.77 (m, 12H), 2.56 (t, 2H, J¼8.5 Hz),
3.29 (d,1H, J¼10.3 Hz), 3.34 (d,1H, J¼10.3 Hz), 3.90 (t, 2H, J¼6.6 Hz),
6.80 (d, 2H, J¼6.6 Hz), 7.07 (d, 1H, J¼6.6 Hz); 13C NMR (126 MHz,
(m, 2H), 2.70e2.58 (m, 2H), 4.07 (d, 1H, J¼8.3 Hz), 4.14 (d, 1H,
J¼8.3 Hz), 5.15 (br s, 1H), 5.88 (d, 1H, J¼3.2 Hz), 6.05 (dd, 1H,
J¼3.2 Hz, 2.4 Hz), 6.58 (t, 1H, J¼2.4 Hz); 13C NMR (100 MHz, CDCl3)
CDCl3) d ppm; 14.1, 22.6, 24.5, 26.0, 29.1, 29.3, 29.4, 31.8, 42.2, 53.0,
d
ppm; 20.8, 25.8, 33.6, 38.9, 57.5, 75.7, 105.7, 106.8, 121.9, 131.0,
68.1, 70.3, 114.6, 129.1, 134.1, 157.4; IR (KBr) cmꢀ1: 3147, 2923, 2855,
2737, 1740, 1613, 1513, 1276, 1244, 1060, 825; MS(ESI) m/z: 294
(MþH)þ; Anal. Calcd for C18H31NO2: C, 73.67; H, 10.65; N, 4.77.
Found: C, 73.37; H, 10.60; N, 4.64.
158.8; IR (KBr) cmꢀ1: 3289, 3103, 2977, 2938, 1759, 1713, 1495, 1397,
1381, 1309, 1281, 1231, 1032, 945, 928, 776, 718, 706, 656; HRMS
(ESI): calcd for C11H17N2O2 [MþH]þ 209.1290; found 209.1291.
4.2.21. (4R)-4-[2-(Furan-2-yl)ethyl]-4-methyl-1,3-oxazolidin-2-one
(23c). Compound 23c was obtained as a pale yellow oil from 9j by
using the procedure described for 23a in 78% yield (99% ee). The
enantiomeric excess of (4R)-methyl-4-[2-(furan-2-yl)ethyl]-1,3-
oxazolidin-2-one (23c) was determined by HPLC analysis by us-
ing the following condition. DAICEL CHIRALCEL AD
4.2.24. 2-Chloro-4-[(3-methoxyphenyl)sulfanyl]benzaldehyde
(26). To a solution of 3-methoxybenzenethiol (1.4 g, 10 mmol) and
2-chloro-4-fluorobenzaldehyde (1.6 g, 10 mmol) in DMF (10 mL)
was added potassium carbonate (2.1 g, 15 mmol) at ambient tem-
perature, and then the suspension was stirred for 30 min at 45 ꢁC.
After cooling at 0 ꢁC, water (25 mL) was added to the reaction
mixture. The resulting biphasic mixture was extracted with AcOEt
(30 mLꢂ2). The combined organic layer was washed with water
(30 mL) and brine (30 mL), dried over Na2SO4, filtered, and evap-
orated. Purification by silica gel column chromatography
(hexane:AcOEt¼5:1 to 1:1) provided 26 (2.5 g, 91%) as a white solid.
(4.6
f
ꢂ250 mm), hexane:2-propanol¼85:15, flow rate: 1.0 ml/min,
temperature: 25.0 ꢁC. The retention times of (S)-23c and (R)-23c
were 13.1 min and 15.4 min, respectively. [
a
]
20 þ2.2 (c 0.11, CHCl3);
D
1H NMR (400 MHz, CDCl3)
d
: 1.38 (s, 3H), 1.68e1.61 (m, 2H),
1.98e1.94 (m, 2H), 2.72 (t, 2H, J¼8.0 Hz), 4.04 (d, 1H, J¼8.4 Hz), 4.11
(d, 1H, J¼8.4 Hz), 5.92 (br s, 1H), 6.03 (d, 1H, J¼2.6 Hz), 6.29 (d, 1H,
Mp: 84.3 ꢁC; 1H NMR (500 MHz, CDCl3)
d
ppm: 3.80 (s, 3H), 6.97 (m,
1H), 7.10e7.02 (m, 4H), 7.34 (t, 1H, J¼8.1 Hz), 7.74 (d, 1H, J¼8.1 Hz),
10.33 (s, 1H); 13C NMR (126 MHz, CDCl3)
ppm; 55.5, 115.7, 119.7,
J¼2.6 Hz), 7.31 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d ppm; 22.8,
25.6, 38.4, 57.4, 75.5, 105.5, 110.4, 141.3, 154.0, 159.0; IR (KBr) cmꢀ1
:
d
3450, 2975, 2928, 2250, 1755, 1599, 1508, 1400, 1381, 1147, 1045,
1010; HRMS (ESI): calcd for C10H14NO3 [MþH]þ 196.0974; found
196.0967.
125.3, 126.8, 127.6, 129.4, 129.6, 130.8, 131.1, 138.5, 148.6, 160.5,
188.8; IR (KBr) cmꢀ1: 3076, 2874, 1677, 1579, 1481, 1381, 1250, 1212,
1043, 853, 797, 691; HRMS (ESI): calcd for C14H12O2SCl [MþH]þ
279.0247; found 279.0251; Anal. Calcd for C14H11ClO2S: C, 60.32; H,
3.98; Cl, 12.72; S, 11.50. Found: C, 60.19; H, 4.12; Cl, 12.55; S, 11.54.
4.2.22. (4R)-4-{(E)-2-[4-(Heptyloxy)phenyl]vinyl}-4-methyl-1,3-
oxazolidin-2-one (25a). To a suspension of the phosphonium salt
(13) (200 mg, 0.4 mmol) in THF (5 mL) was added n-butyllithium
(2.7 M in hexane, 0.29 mL, 0.77 mmol) at ꢀ78 ꢁC and then the
solution was stirred for 30 min at the same temperature. After the
addition of 4-heptoxybenzaldehyde (24) (44 mg, 0.2 mmol) at
ꢀ78 ꢁC, the reaction mixture was gradually warmed to ambient
temperature and then stirred for 2 h. After quenching with a satu-
rated aq NH4Cl (10 mL), the resulting biphasic mixture was
extracted with AcOEt (10 mLꢂ2). The combined organic layer was
washed with water (10 mL) and brine (10 mL), dried over Na2SO4,
filtered, and evaporated. Purification by silica gel column chroma-
tography (hexane:AcOEt¼3:1 to 1:2) provided 25a (49 mg, 77%) as
4.2.25. (4R)-4-[(E)-2-{2-Chloro-4-[(3-methoxyphenyl)sulfanyl]phe-
nyl}ethenyl]-4-methyl-1,3-oxazolidin-2-one (6a). To a suspension of
the phosphonium salt (13) (500 mg, 1.0 mmol) in THF (5 mL) was
added n-butyllithium (1.9 M in hexane, 1.0 mL, 1.95 mmol) at
ꢀ78 ꢁC, and then the solution was stirred for 30 min at the same
temperature. After the addition of 2-chloro-4-[(3-methoxyphenyl)
sulfanyl]benzaldehyde (26) (139 mg, 0.5 mmol) at ꢀ78 ꢁC, the re-
action mixture was gradually warmed to ambient temperature and
stirred for 2 h. After quenching with a saturated aq NH4Cl (10 mL),
the resulting biphasic mixture was extracted with AcOEt
(10 mLꢂ2). The combined organic layer was washed with water
Please cite this article in press as: Tsuji, T.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.086

8
T. Tsuji et al. / Tetrahedron xxx (2014) 1e8
(10 mL) and brine (10 mL), dried over Na2SO4, filtered, and evap-
orated. Purification by silica gel column chromatography
(hexane:AcOEt¼4:1 to 1:2) provided 6a (300 mg, 80%) as a pale
(10 mL) and brine (10 mL), dried over Na2SO4, filtered, and evap-
orated, providing pale yellow oil. To a solution of the obtained
residue in THF (8 mL) was added potassium carbonate (62 mg,
0.46 mmol) and cyanogen bromide (54 mg, 0.51 mmol) at 0 ꢁC
under a N2 atmosphere. After stirring for 6 h at ambient tempera-
ture, water (10 mL) was added to the reaction mixture and the
resulting biphasic mixture was extracted with AcOEt (10 mLꢂ2).
The combined organic layer was washed with water (10 mL) and
brine (10 mL), dried over Na2SO4, filtered, and evaporated. Purifi-
cation by silica gel column chromatography (AcOEt:MeOH¼1:0 to
5:1) provided 8 (69 mg, 69%) as a pale yellow solid. Mp: 103.8 ꢁC;
yellow oil. [
a
]
20 ꢀ39.1 (c 0.45, CH3OH); 1H NMR (500 MHz, CDCl3)
D
d
ppm: 1.58 (s, 3H), 3.37 (s, 3H), 4.18 (d, 1H, J¼8.3 Hz), 4.23 (d, 1H,
J¼8.3 Hz), 5.03 (s, 1H), 6.17 (d, 1H, J¼16.1 Hz), 6.85 (m, 1H),
6.92e6.90 (m, 2H), 6.92 (d, 1H, J¼16.1 Hz), 7.11 (m, 1H), 7.236e7.23
(m, 2H), 7.37 (d, 1H, J¼7.8 Hz); 13C NMR (126 MHz, CDCl3)
d ppm;
25.4, 55.4, 58.7, 76.3, 114.0, 117.4, 124.5, 126.1, 127.3, 128.3, 130.3,
130.4, 132.2, 133.9, 134.0, 134.8, 138.3, 158.8, 160.3; IR (KBr) cmꢀ1
:
3258, 1744, 1586, 1471, 1376, 1282, 1246, 1037, 969, 858, 770, 688;
HRMS (ESI): calcd for C19H19NO3SCl [MþH]þ 376.0774; found
376.0769.
[a
]
20 þ6.5 (c 0.74, CHCl3); 1H NMR (500 MHz, CDCl3)
d ppm: 1.30 (s,
D
3H), 1.90e1.75 (m, 2H), 2.69e2.58 (m, 2H), 3.28 (br s, 2H), 3.94 (d,
1H, J¼8.3 Hz), 4.09 (d, 1H, J¼8.3 Hz), 7.28e7.25 (m, 5H); 13C NMR
4.2.26. (4R)-4-(2-{2-Chloro-4-[(3-methoxyphenyl)sulfanyl]phenyl}
ethyl)-4-methyl-1,3-oxazolidin-2-one (6b). To a solution of (4R)-4-
[(E)-2-{2-chloro-4-[(3-methoxyphenyl)sulfanyl]phenyl}ethenyl]-
4-methyl-1,3-oxazolidin-2-one (6a) (100 mg, 0.26 mmol) in AcOEt
(10 mL) was added 10% PdeC (50% wet, 100 mg), and then the
suspension was stirred for 6 h under a hydrogen atmosphere at
ambient temperature. The reaction mixture was filtered through
a Celite pad and evaporated in vacuo. Purification by silica gel
(126 MHz, CDCl3) d ppm; 27.3, 30.7, 43.6, 67.8, 78.1, 125.8, 128.3,
128.4, 142.4, 159.3; IR (KBr) cmꢀ1: 3432, 2968, 2211, 1702, 1671,
1410, 1218, 1006, 756, 705, 501; HRMS (ESI): calcd for C12H17N2O
[MþH]þ 205.1341; found 205.1348.
References and notes
1. (a) Bagli, J. F.; Kluepfel, D.; St-Jacques, M. J. Org. Chem. 1973, 38, 1253; (b)
Miyake, Y.; Kozutsumi, Y.; Nakamura, S.; Fujita, T.; Kawasaki, T. Biochem. Bio-
phys. Res. Commun. 1995, 211, 396; (c) Chen, J. K.; Lane, W. S.; Schreiber, S. L.
Chem. Biol. 1999, 6, 221.
2. (a) Horn, W. S.; Smith, J. L.; Bills, G. F.; Raghoobar, S. L.; Helmes, G. L.; Kurta, M.
B.; Marrina, J. A.; Frommer, B. R.; Thornton, R. A.; Mandala, S. M. J. Antibiot.
1992, 45, 1692; (b) Ikeuchi, K.; Hayashi, M.; Yamamoto, T.; Inai, M.; Asakawa, T.;
Hamashima, Y.; Kan, T. Eur. J. Org. Chem. 2013, 30, 6789.
3. For compound 5, see: Kiuchi, M.; Tashiro, K.; Hamada, M.; Sugahara, K. EP
Patent 2,168,944, 2010.
4. For compound 6, see: Yamamuro, N.; Nakamaru, K.; Yasue, T. U.S. Patent
324,057, 2010.
column chromatography (hexane:AcOEt¼3:1 to 1:2) provided 6b
20
(79 mg, 80%) as a pale yellow oil. [
NMR (500 MHz, CDCl3)
a
]
þ1.5 (c 0.76, CH3OH); 1H
D
d ppm: 1.40 (s, 3H), 1.86e1.80 (m, 2H),
2.77e2.65 (m, 2H), 3.76 (s, 3H), 4.09 (d, 1H, J¼7.1 Hz), 4.25 (d, 1H,
J¼7.1 Hz), 5.05 (s, 1H), 6.80 (m, 1H), 6.86 (m, 1H), 6.91 (m, 1H),
7.13e7.09 (m, 2H), 7.21 (m, 1H), 7.28 (m, 1H); 13C NMR (126 MHz,
CDCl3)
d ppm; 26.0, 28.1, 40.4, 55.4, 57.7, 75.4, 113.4, 116.8, 124.0,
129.4, 130.2, 130.8, 131.3, 134.3, 135.7, 135.8, 137.1, 159.0, 160.2; IR
(KBr) cmꢀ1: 3262, 1747, 1589, 1475, 1283, 1230, 1040, 772; HRMS
(ESI): calcd for C19H21NO3SCl [MþH]þ 378.0931; found 378.0926.
5. For compound 7, see: Nishi, T.; Miyazaki, S.; Takemoto, T.; Suzuki, K.; Iio, Y.;
Nakajima, K.; Ohnuki, T.; Kawase, Y.; Nara, F.; Inaba, S.; Izumi, T.; Yuita, H.;
Ohshima, K.; Doi, H.; Inoue, R.; Tomisato, W.; Kagari, T.; Shimozato, T. ACS Med.
Chem. Lett. 2011, 2, 368.
4.2.27. (2R)-2-Amino-4-{2-chloro-4-[(3-methoxyphenyl)sulfanyl]
phenyl}-2-methyl-butan-1-ol (6). To a solution of (4R)-4-(2-{2-
chloro-4-[(3-methoxyphenyl)sulfanyl]phenyl}ethyl)-4-methyl-1,3-
oxazolidin-2-one (6b) (20 mg, 0.06 mmol) in THF (1 mL) and
methanol (1 mL) was added aq 5 N potassium hydroxide (0.5 mL),
and then the solution was refluxed for 12 h. After cooling to room
temperature, water (10 mL) was added to the reaction mixture and
the resulting biphasic mixture was extracted with CH2Cl2
(10 mLꢂ2). The combined organic layer was washed with water
(10 mL) and brine (10 mL), dried over Na2SO4, filtered, and evap-
6. (a) Forrest, M.; Sun, S.-Y.; Hajdu, R.; Bergstrom, J.; Card, D.; Doherty, G.; Hale, J.;
Keohane, C.; Meyers, C.; Milligan, J.; Mills, S.; Nomura, N.; Rosen, H.; Rosenbach,
M.; Shei, G.-J.; Singer, I. I.; Tian, M.; West, S.; White, V.; Xie, J.; Proia, R. L.;
Mandala, S. J. Pharmacol. Exp. Ther. 2004, 309, 758; (b) Sanna, M. G.; Liao, J.; Jo,
E.; Alfonso, C.; Ahn, M.-Y.; Peterson, M. S.; Webb, B.; Lefebvre, S.; Chun, J.; Gray,
N.; Rosen, H. J. Biol. Chem. 2004, 279, 13839; (c) Adachi, K.; Kohara, T.; Nakao, N.;
Arita, M.; Chiba, K.; Mishina, T.; Sasaki, S.; Fujita, T. Bioorg. Med. Chem. Lett.
1995, 5, 853.
7. (a) Galley, G.; Groebke, Z. K.; Norcross, R.; Atalder, H. WO Patent 2008/092785
A1, 2008. (b) Sotnikova, D. T.; Caron, G. M.; Gainetdinov, R. R. Mol. Pharmacol.
2009, 76, 229.
8. For reviews, see, e.g.: (a) Ohfune, Y.; Shinada, T. Eur. J. Org. Chem. 2005, 5127; (b)
€
Tanaka, M. Chem. Pharm. Bull. 2007, 55, 349; (c) Vogt, H.; Brase, S. Org. Biomol.
orated, providing 6 (16 mg, 91%) as a colorless oil. [a]
20 ꢀ2.0 (c 0.53,
ꢀ
ꢀ
ꢀ
Chem. 2007, 5, 406; (d) Soengas, R. G.; Estevez, A. M.; Estevez, J. C.; Estevez, R. J.
Tetrahedron: Asymmetry 2012, 23, 1238; (e) Buyck, T.; Wang, Q.; Zhu, J. Angew.
Chem., Int. Ed. 2013, 52, 12714.
D
CHCl3), ꢀ3.5 (c 0.19, CH3OH); 1H NMR (500 MHz, CDCl3)
d ppm: 1.12
(s, 3H), 1.67e1.54 (m, 2H), 2.76e2.66 (m, 2H), 3.32 (d, 1H,
J¼10.3 Hz), 3.37 (d, 1H, J¼10.3 Hz), 3.75 (s, 3H), 6.78 (d, 1H,
J¼8.3 Hz), 6.85 (m, 1H), 6.88 (m, 1H), 7.15e7.13 (m, 2H), 7.20 (t, 1H,
9. (a) Tsuji, T.; Iio, Y.; Takemoto, T.; Nishi, T. Tetrahedron: Asymmetry 2005, 16,
3139; (b) Nakamura, T.; Tsuji, T.; Iio, Y.; Miyazaki, S.; Takemoto, T.; Nishi, T.
Tetrahedron: Asymmetry 2006, 17, 2781; (c) Iio, Y.; Yamaoka, M.; Jin, M.; Na-
kamura, Y.; Nishi, T. Tetrahedron: Asymmetry 2011, 22, 323.
10. (a) Itaya, T.; Shimomichi, M.; Ozawa, M. Tetrahedron Lett. 1988, 29, 4129; (b)
Itaya, T.; Iida, T.; Shimizu, S.; Mizutani, A.; Morisue, M.; Sugimoto, Y.; Tachinaka,
M. Chem. Pharm. Bull. Jpn. 1993, 41, 252; (c) Itaya, T.; Kanai, T.; Iida, T. Tetra-
hedron Lett. 1997, 38, 1979.
11. (a) Sibi, M. P.; Rutherford, D.; Renhowe, P. A.; Li, B. J. Am. Chem. Soc. 1999, 121,
7509; (b) Sibi, M. P.; Christensen, J. W. J. Org. Chem. 1999, 64, 6434.
12. We tried to reuse 13-o for the Wittig reaction by using the following procedure.
To a solution of 13-o (10 mg, 1 equiv) and LiBr (3 mg, 1 equiv) in THF (3 mL) was
J¼8.3 Hz), 7.30 (s, 1H); 13C NMR (126 MHz, CDCl3)
d ppm; 24.3, 27.9,
40.1, 53.0, 55.3, 70.3, 113.2, 116.4, 123.4, 129.7, 130.8, 131.6, 134.4,
134.7,136.3,139.0,160.1; IR (KBr) cmꢀ1: 2931,1747,1587,1473,1246,
1229, 1039, 853, 772, 686; HRMS (ESI): calcd for C18H23NO2SCl
[MþH]þ 352.1138; found 352.1148.
4.2.28. (4R)-4-Methyl-4-(2-phenylethyl)-4,5-dihydro-1,3-oxazol-2-
amine (8). To a solution of (4R)-4-methyl-4-[(E)-2-phenylethenyl]-
1,3-oxazolidin-2-one (9a) (100 mg, 0.26 mmol) in AcOEt (10 mL)
was added 10% PdeC (50% wet, 100 mg), and then the suspension
was stirred for 6 h under a hydrogen atmosphere at ambient
temperature. The reaction mixture was filtered through a Celite pad
and evaporated in vacuo. The residue was diluted by THF (1 mL) and
methanol (1 mL). Aq 5 N potassium hydroxide (0.5 mL) was added
to the solution, which was then refluxed for 12 h. After cooling to
room temperature, water (10 mL) was added to the reaction mix-
ture and the resulting biphasic mixture was extracted with CH2Cl2
(10 mLꢂ2). The combined organic layer was washed with water
added n-butyllithium (1.9 M in hexane, 35
m
L, 2 equiv) at ꢀ30 ꢁC, and then the
solution was stirred for 30 min. After cooling to ꢀ78 ꢁC, aldehyde 26 (9 mg,
1 equiv) was added. The solution was gradually warmed to ambient temper-
ature and stirred for 2 h. The reaction mixture was analyzed by LCeMS to
detect no desired alkenes or coupling product but intact phosphine oxide 13-o.
For the reference, see: (a) Cavalla, D.; Cruse, W. B.; Warren, S. J. Chem. Soc.,
Perkin Trans. 1 1987, 1883; (b) Cavalla, D.; Warren, S. Tetrahedron Lett. 1983, 24,
295.
13. (a) Hinterding, K.; Albert, R.; Cottens, S. Tetrahedron Lett. 2002, 43, 8095; (b)
Hinterding, K.; Cottens, S.; Albert, R.; Zecri, F.; Buehlmayer, P.; Spanka, C.;
Brinkmann, V.; Nussbaumer, P.; Ettmayer, P.; Hoegenauer, K.; Gray, N.; Pan, S.
Synthesis 2003, 1667.
14. Aldehyde 26 was synthesized from commercially available reagents by fol-
lowing a procedure described in Ref. 4. The details are also shown in our
Experimental section.
Please cite this article in press as: Tsuji, T.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.086