Asymmetric synthesis of α,α-disubstituted α-amino alcohol derivatives

Article abstract of DOI:10.1016/j.tetasy.2011.02.006

Herein we report the asymmetric synthesis of α,α-disubstituted α-amino alcohol derivatives 22, 25 and 26, key intermediates of a novel immunomodulator, using Seebach's method. This synthetic method can be applied to the large scale synthesis of chiral sph

Full text of DOI:10.1016/j.tetasy.2011.02.006

Tetrahedron: Asymmetry 22 (2011) 323–328
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of a,a-disubstituted a-amino alcohol derivatives
Yukiko Iio a, Makoto Yamaoka b, Masayoshi Jin b, Yoshitaka Nakamura b, Takahide Nishi a,
⇑
a Lead Discovery and Optimization Research Laboratories I, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
b Process Technology Research Laboratories, Daiichi-Sankyo Co., Ltd, 1-12-1 Shinomiya, Hiratsuka, Kanagawa 254-0014, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we report the asymmetric synthesis of
a
,
a
-disubstituted
a
-amino alcohol derivatives 22, 25 and
Received 28 December 2010
Accepted 3 February 2011
Available online 14 March 2011
26, key intermediates of a novel immunomodulator, using Seebach’s method. This synthetic method can
be applied to the large scale synthesis of chiral sphingosine 1-phosphate-1 (S1P1) receptor agonists, with
significant improvements to the previously reported method with regard to the reaction temperature.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
proceeded in >98% de. This synthetic method gives a 68% chemical
yield; it requires a low temperature and carcinogenic HMPA as an
In recent years, a great deal of attention has been focused on the
synthesis of -disubstituted -amino alcohol derivatives with a
view to the design and synthesis of biologically active compounds.1
In particular, -disubstituted -amino alcohols have been recog-
additive. To accomplish a more practical large scale synthetic
method, we attempted to fine tune this procedure.
a
,
a
a
a
,a
a
2. Results and discussion
nized as significant components of novel immunomodulators, such
as fingolimod (FTY720) and its chiral analogues.2 Accordingly, the
synthetic importance as well as the biological interest for the con-
struction of stereogenic quaternary carbon centres has been recog-
nized, as seen in recent positive reviews.3 In this context and as a
part of our S1P1 receptor agonist research program, we have been
interested in the study and development of a methodology for the
synthesis of intermediate 1. Preliminary studies indicated that the
stereochemistry of the stereogenic quaternary carbon centre is clo-
sely associated with the biological activity, and that the (R)-config-
uration is essential for S1P1 agonistic activity. We have already
reported on a practical synthetic method used for the preparation
of pyrrole, thiophene and furan-based amino alcohol analogues 1
via enzymatic desymmetrization of 2-tert-butoxycarbonylamino-
2-methyl-1,3-propanediol 3.4
Although lipase-catalysed desymmetrization is an efficient and
practical method for the preparation of key intermediates, the ee of
the chiral monoester of 2-tert-butoxycarbonylamino-2-methyl-
1,3-propanediol 2 was about 90% ee. Therefore, in order to increase
the ee of 1 up to 99%, resolution and recrystallization were
required. As a result, we focused our attention on an alternative
synthetic strategy to increase the enantioselectivity of the stereo-
genic quaternary carbon centre by using Seebach’s method. In
1984, Seebach reported a diastereoselective alkylation to construct
a stereogenic quaternary carbon centre, as shown in Scheme 1.5
At first, we evaluated the use of diastereoselective methylation
with known compound 7.6 As already noted, the decomposition of
the enolate is the main reason for the low yield, and some modified
procedures involving the addition of cosolvents5 and reverse addi-
tion7 have already been reported to circumvent this issue. Initial
methylation of 7 was performed following the procedure using
DMPU as an additive. This involves the slow, dropwise addition
of LiHMDS (1.2 equiv) at ꢀ74 to ꢀ65 °C to a mixture of the oxazol-
idine 7 and MeI (2 equiv) in DMPU (1 vol/wt) and THF to provide 8
in high diastereoselectivity and with good chemical yield (>99% de,
98% yield) (run 1). Next, to accomplish a more practical large scale
synthesis of 8, the reaction temperature was increased to ꢀ25 to
ꢀ15 °C, which is a feasible temperature range for the large scale
application by using a normal brine-cooling reactor; however,
the results were disappointing as a low yield was attained (run
2) (Table 1).
To clarify the cause for the low yield, we carefully checked the
reaction mechanism. It was revealed that decomposition with the
b-elimination of enolate to form 10, and a side reaction to provide
12 are the main reasons for the low yield as shown in Scheme 2.
Therefore, we concluded that one way to reduce the relative
amount of by-product was to enhance the stability of the enolate
even at high temperatures.
We first examined various combinations of bases and additives
in order to increase the stability of enolate 9 at ꢀ25 to ꢀ15 °C (Ta-
ble 2). No drastic effects in terms of yields were observed using
strong bases, such as LDA or NaHMDS (runs 2–3). Amongst all
the bases examined, Cs2CO3 gave poor results (run 4) while t-BuOK
Starting from L-serine methyl ester, methylation to oxazolidine
⇑
Corresponding author.
E-mail address: nishi.takahide.xw@daiichisankyo.co.jp (T. Nishi).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.02.006

324
Y. Iio et al. / Tetrahedron: Asymmetry 22 (2011) 323–328
Lipase-catalyzed
Desymmetrization
O
Me
Me
HO
OH
NHBoc
n-C5H11
O
OH
NHBoc
2
3
Me
PO
X
Me
H
N
NHP
CO2Me
CO2Me
R
CO2Me
HO
H2N
O
O
1: X = N-Me, S, O
P = protecting group
N
H
R
tBu
tBu
H
H
4
5
6
Seebach's Method
Application
Scheme 1.
Table 1
Table 2
MeI (2 eq)
MeI (2 eq)
Base
H
N
Me
N
H
N
Me
N
LiHMDS (1.2 eq)
DMPU (1 vol/wt)
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Additive (1 vol/wt)
O
O
O
O
THF
THF
tBu
tBu
H
tBu
tBu
H
H
H
7
8
7
8
Run
Temp (°C)
Yield (%)
de (%)
>99
Run
Base (equiv)
Additive
Temp (°C)
Yield (%)
de (%)
1
2
LiHMDS (1.2)
LDA (1.2)
DMPU
DMPU
DMPU
DMPU
DMPU
DMF
Tetraglyme
Tetraglyme
Tetraglyme
ꢀ25 to ꢀ15
ꢀ25 to ꢀ15
ꢀ25 to ꢀ15
ꢀ25 to ꢀ15
ꢀ25 to ꢀ15
ꢀ25 to ꢀ15
ꢀ25 to ꢀ15
ꢀ9 to ꢀ3
(56)a
(44)a
(68)a
(ND)a
89
89
94
92
90
1
2
ꢀ74 to ꢀ65
ꢀ25 to ꢀ15
98
(56)a
3
NaHMDS (1.2)
Cs2CO3 (1.2)
t-BuOK (1.2)
t-BuOK (1.2)
t-BuOK (1.5)
t-BuOK (1.5)
t-BuOK (1.5)
a
HPLC area% at 210 nm except for the solvent, additive and MeI.
4b
5
6
7
>99
>99
>99
gave the highest chemical yield (run 5). Next, additives were also
explored. Thus, it was found that using DMPU, DMF and tetraglyme
provided good results (runs 5–7). In particular, combinations of t-
BuOK and tetraglyme gave the best results (run 7). Increasing the
amount of MeI (3 equiv) and the temperature (ꢀ9 to ꢀ3 °C) was
also studied (run 8). This reaction was successfully scaled up to
multi-kilogram scale without diminishing the yield or de (run 9).
The absolute stereochemistry of 8 was confirmed by leading to
known oxazolidinone 168 as shown in Scheme 3, and the ee of 16
was determined by chiral HPLC analysis (column, Daicel CHIRAL-
8c
9cd
ꢀ13 to ꢀ7
a
b
c
HPLC area% at 210 nm except for the solvent, additive and MeI
DMA was used as a reaction solvent
3 equiv of MeI was used.
d
Reaction was performed at 22.0 kg scale of 7.
CEL OD (4.6
u
ꢁ 250 mm); eluent, 70:30 n-hexane/2-propanol mix-
ture; flow rate, 1.0 mL/min; tR of (S)-isomer, 6.2 min: tR of (R)-
Li
O
H
O
O
OMe
OMe
LiHMDS
OMe
O
O
N
N
N
CO2Me
CO2Me
Li
CO2Me
tBu
tBu
H
H
tBuCHO
7
9
10
tBu
OH
tBu
MeO2C
O
MeO2C
O
O
N
N
CO2Me
tBu
tBu
O
H
H
11
12
Scheme 2.

Y. Iio et al. / Tetrahedron: Asymmetry 22 (2011) 323–328
325
Me
N
Me
Me
N
BnBr
CO2Me
CO2Me
LiBH4
NaH
OH
OBn
O
O
O
N
THF
98%
CO2Me
CO2Me
DMF
tBu
tBu
tBu
H
H
H
8
13
14
Me
p-TsOH
t-BuOK
Me
OBn
HO
OBn
NHCO2Me
O
NH
MeOH
THF
94%
O
95%
(2 steps)
15
16
Scheme 3.
Scheme 4. The reaction was carried out in the similar manner to
run 8 in Table 2.
Benzyl bromide (3 eq)
or
H
N
R
CO2Me
CO2Me
CO2Me
CO2Me
Allyl bromide (3 eq)
The synthetic route of the pyrrole key intermediate 22 is shown
in Scheme 5. Chiral ester 8 was treated with KBH4 and LiCl in THF
to give alcohol 13 in 98% yield. The oxidation of the primary alco-
hol with TEMPO gave aldehyde 19 in 87% yield. Wittig condensa-
tion with phosphonium salt 209 was performed in the presence
of t-BuOK in DMF to give olefin 21. Subsequent hydrogenation with
Pd-C in MeOH was completed to give the desired key intermediate
22 in 92% yield over two steps. As a result, 22 was prepared in 72%
overall yield from 7 in five steps.
O
O
N
t-BuOK (1.5 eq)
Tetraglyme (1 vol/wt)
THF
tBu
tBu
H
H
7
17; R = Benzyl (89 %)
18; R = Allyl (82 %)
-10 ºC
Scheme 4.
The encouraging results obtained in the preparation of 22
prompted us to apply this synthetic methodology to the prepara-
tion of thiophene and furan analogues as shown in Scheme 6. In
general, thiophene- or furan-based derivatives also could be
isomer, 9.0 min), thereby providing the pure diastereomers (>99%
ee).
Alkylations of the enolate of 7 with benzyl bromide and allyl
bromide also proceeded in satisfactory yields as shown in
cat. TEMPO
NaClO, NaBr
Me
N
Me
N
Me
N
KBH4
LiCl
CO2Me
CO2Me
CHO
OH
O
O
O
Toluene-H2O
87%
CO2Me
CO2Me
THF-Toluene
98%
tBu
tBu
tBu
H
H
H
8
13
19
>99% de
P+Ph3I-
N
Me
H2
Me
N
Me
20
Pd-C
N
Me
N
Me
O
O
N
MeOH
CO2Me
22
72% overall yield
t-BuOK
CO2Me
tBu
tBu
H
H
DMF
92%
21
(2 steps)
Scheme 5.
Me
N
H2
Pd(OH)2-C
S
O
P+Ph3Br-
CO2Me
25
tBu
X
EtOH
H
H
Me
N
Me
23a X = S
CHO
CO2Me
73%
23b X = O
X
(2 steps)
O
O
N
CO2Me
t-BuOK
DMF
tBu
tBu
H2
H
H
Me
Pd - C
19
24a X = S
24b X = O
O
O
N
AcOEt
CO2Me
tBu
78%
(2 steps)
26
Scheme 6.

326
Y. Iio et al. / Tetrahedron: Asymmetry 22 (2011) 323–328
synthesized along the same procedures described in Scheme 5.
Wittig condensation of aldehyde 19 with phosphonium salt 23a10
or 23b11 was carried out in the presence of t-BuOK in DMF yield
24a, 24b. Then, the reduction of olefin with Pd(OH)2-C in EtOH
or Pd-C in AcOEt under a hydrogen atmosphere provided 25, 26
in good yield. Thus, using common key intermediate 19, a practical
and versatile synthetic method for the preparation of novel pyr-
role, thiophene and furan-based amino alcohol analogues 22, 25
and 26 was achieved.
1141, 1115, 1059, 1034 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 0.97
.
(s, 9H), 1.62 (s, 3H), 3.69 (s, 3H), 3.77 (s, 3H), 3.82 (d, 1H,
J = 8.3 Hz), 4.28 (d, 1H, J = 8.3 Hz), 5.15 (s, 1H). 13C NMR (CDCl3,
100 MHz): d 21.2, 26.3, 39.0, 52.4, 52.6, 66.5, 76.9, 97.6, 155.1,
172.2. MS (FAB) m/z: 260 (M+H)+.
4.2. Synthesis of dimethyl (2R,4S)-4-benzyl-2-tert-butyl-1,3-
oxazolidine-3,4-dicarboxylate 17
The reaction was carried out in a manner similar to 4.1. using
benzyl bromide to obtain the title compound (89% yield). IR (Liquid
Film): 2955, 2908, 1740, 1711, 1443, 1358, 1312, 1269, 1247, 1225,
3. Conclusion
1196, 1138, 1124, 1093, 1063, 1035, 961, 782, 759, 703 cmꢀ1 1H
.
In conclusion, asymmetric synthesis of
a,a-disubstituted a-
NMR (CDCl3, 400 MHz): d 0.91 (s, 9H), 3.28 (d, 1H, J = 14.1 Hz),
3.58–3.67 (m, 1H), 3.75 (s, 3H), 3.82 (s, 3H), 4.18 (d, 1H,
J = 9.0 Hz), 4.20 (d, 1H, J = 9.0 Hz), 4.64 (s, 1H), 7.12–7.16 (m, 2H),
7.23–7.33 (m, 3H). MS (FAB) m/z: 336 (M+H)+.
amino alcohol derivatives 22, 25 and 26, key intermediates of
S1P1 receptor agonist, using the application of Seebach’s method
was accomplished. Diastereoselective methylation under con-
trolled reaction conditions achieved by the inverse addition of t-
BuOK to the mixture of oxazolidine 7 and MeI in tetraglyme and
THF, cleanly provided the desired diastereomer 8 in good yield.
This method makes it possible to apply to the large scale synthesis
and to be carried out with a significant improvement to the previ-
ously reported method corresponding to the reaction temperature.
Further work in this area is now in progress.
4.3. Synthesis of dimethyl (2R,4S)-4-allyl-2-tert-butyl-1,3-
oxazolidine-3,4-dicarboxylate 18
The reaction was carried out in a manner similar to 4.1. using
allyl bromide to obtain the title compound (82% yield). IR (Liquid
Film): 2956, 2909, 1715, 1442, 1352, 1312, 1248, 1197, 1128,
1045, 958, 785 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 0.98 (s, 9H),
.
4. Experimental
2.72 (dd, 1H, J = 14.5, 6.3 Hz), 3.10 (brs, 1H), 3.69 (s, 3H), 3.78 (s,
3H), 4.10 (d, 1H, J = 8.6 Hz), 4.28 (dd, 1H, J = 8.6, 1.8 Hz), 5.08–
5.17 (m, 3H), 5.74–5.85 (m, 1H). MS (FAB) m/z: 286 (M+H)+.
Optical rotations were measured with a HORIBA SEPA-300 dig-
ital polarimeter. The IR spectra were measured on a JASCO VELOR-
III or FT/IR 610 spectrophotometer as KBr pellet or liquid film on
4.4. Synthesis of methyl (2R,4R)-2-tert-butyl-4-hydroxymethyl-
4-methyl-1,3-oxazolidine-3-carboxylate 13
KBr plate, and peaks are recorded in cmꢀ1 1H NMR and 13C NMR
.
spectra were recorded on a JEOL JNM-LA 400 in CDCl3, and 1H
NMR chemical shifts are reported in ppm downfield of internal tet-
ramethylsilane. Mass spectra were recorded using a JEOL JMS-BU
30, JMS-700 or JMS-700V spectrometer. An analytical HPLC was
performed using a SHIMADZU LC-10A system or AGILENT 1100
system. Thin layer chromatography (TLC) was used routinely to
monitor the progress and purity of compounds and performed on
Merck Kieselgel 60 F254 plates. For flash column chromatography,
silica gel (Kieselgel 60, 230–400 mesh) was employed.
A mixture of lithium chloride (132 g, 3.13 mol), potassium boro-
hydride (168 g, 3.13 mol) and tetrahydrofuran (3800 mL) was stir-
red at room temperature under a nitrogen atmosphere for 1 h.
Subsequently, to the mixture was added a solution of 8 (373 g,
1.44 mol) in toluene (1150 mL) under a nitrogen atmosphere with
stirring, and the resulting mixture was warmed to about 45 °C and
furthermore stirred at the same temperature for 3 h. After stirring,
the reaction mixture was cooled in an ice-bath, and to the reaction
mixture was added slowly a 10% aqueous ammonium chloride
solution with stirring to quench the reaction. The reaction mixture
was extracted with toluene, and the extract was washed with
water and evaporated in vacuo to afford the crude product of the
title compound (327 g (determined by HPLC), 98% yield). The crude
product thus obtained was used for the following reaction step
without further purification. Additionally, it could be possible to
obtain the pure title compound by purifying the crude product
by chromatography on a silica gel column (eluent: a mixed solvent
4.1. Synthesis of dimethyl (2R,4S)-2-tert-butyl-4-methyl-1,3-
oxazolidine-3,4-dicarboxylate 8
To a solution of dimethyl (2R,4S)-2-tert-butyl-1,3-oxazolidine-
3,4-dicarboxylate 76 (384 g, 1.57 mol) in tetrahydrofuran
(2300 mL) were added successively tetraethylene glycol dimethyl
ether (380 mL) and methyl iodide (290 mL, 4.70 mol) under a
nitrogen atmosphere with stirring, and the resulting mixture was
cooled to about ꢀ20 °C. Subsequently, to the resulting mixture
was added dropwise slowly a solution of potassium t-butoxide
(263 g, 2.35 mol) in tetrahydrofuran (1900 mL) below ꢀ5 °C under
a nitrogen atmosphere with stirring, and the resulting mixture was
stirred at about ꢀ10 °C for 1 h. After stirring, a 10% aqueous ammo-
nium chloride solution was added to the reaction mixture with
stirring to quench the reaction, and the resulting mixture was ex-
tracted with toluene. The extract separated was washed twice with
a 5% aqueous sodium chloride solution and evaporated in vacuo to
afford the crude product of the title compound (373 g (determined
by HPLC), 92% yield). The crude product thus obtained was used for
the following reaction step without further purification. Addition-
ally, it could be possible to obtain the pure title compound by puri-
fying the crude product by chromatography on a silica gel column
of ethyl acetate and hexane). ½a D27
¼ þ12:7 (c 1.009, MeOH). IR (Li-
ꢂ
quid Film): 3440, 2959, 2909, 2875, 1709, 1686, 1479, 1447, 1399,
1358, 1317, 1281, 1196, 1172, 1134, 1112, 1069, 1047, 960,
805,759 cmꢀ1 1H NMR (CDCl3, 400 MHz): d 0.93 (s, 9H), 1.43 (s,
.
3H), 3.55 (br d, 1H, J = 11.3 Hz), 3.71 (s, 3H), 3.74 (d, 1H,
J = 8.6 Hz), 3.83 (d, 1H, J = 11.3 Hz), 3.87 (br d, 1H, J = 8.6 Hz),
5.13 (s, 1H). 13C NMR (CDCl3, 100 MHz): d 19.5, 26.4, 38.6, 52.5,
65.2, 67.1, 75.8, 97.3, 156.8. MS (FAB) m/z: 232 (M+H)+.
4.5. Synthesis of methyl (2R,4S)-2-tert-butyl-4-formyl-4-
methyl-1,3-oxazolidine-3-carboxylate 19
To a solution of 13 (260 g, 1.12 mol) in toluene (6000 mL) were
added successively water (3000 mL), sodium bromide (128 g) and
sodium hydrogencarbonate (260 g) with stirring, and the resulting
mixture was cooled to about 0 °C. Subsequently, to the resulting
mixture was added 2,2,6,6-tetramethylpiperidinooxy, free radical
(eluent:
¼ ꢀ9:74 (c 1.001, MeOH). IR (Liquid Film): 2958, 2909,
1737, 1719, 1478, 1443, 1345, 1313, 1282, 1249, 1218, 1195,
a
mixed solvent of ethyl acetate and hexane).
½ ꢂ
a 2D7

Y. Iio et al. / Tetrahedron: Asymmetry 22 (2011) 323–328
327
(1.94 g, 0.0125 mol) with stirring, and furthermore, to the resulting
mixture was added dropwise slowly a 12.7% aqueous sodium
hypochlorite solution (748 mL, 1.34 mol) below 5 °C with stirring,
and the resulting mixture was furthermore stirred at about 0 °C
for 30 min. After stirring, ethanol was added to the reaction mix-
ture with stirring, and the resulting mixture was stirred for about
1 h, and then the reaction was quenched. After partitioning the
reaction mixture, the organic layer separated was washed succes-
sively with an aqueous sodium thiosulfate solution and water, and
evaporated in vacuo to afford the crude product of the title com-
pound (225 g, 87% yield). The crude product thus obtained was
used for the following reaction step without further purification.
Additionally, it could be possible to obtain the pure title compound
by recrystallization of the crude product from hexane.
in N,N-dimethylformamide (5 mL) with stirring under ice-cooling,
and the resulting mixture was stirred under ice-cooling for
45 min. After stirring, saturated aqueous NH4Cl was added to the
reaction mixture to quench the reaction, and the reaction mixture
was extracted with diethyl ether. The extract was washed with
brine and dried over MgSO4. After filtration, the solvent was evap-
orated in vacuo, and the residue was purified by chromatography
on a silica gel column (eluent, hexane–ethyl acetate = 97:3–93:7)
to afford the Wittig reaction product. Subsequently, to a solution
of the Wittig reaction product obtained above in ethanol (12 mL)
was added 20% palladium hydroxide on carbon (280 mg) with
stirring, and the resulting mixture was stirring at room tempera-
ture under a hydrogen atmosphere for 20 h. After stirring, the reac-
tion mixture was filtered through a Celite, and the filtrate was
evaporated in vacuo. The residue was purified by chromatography
on a silica gel column (eluent, hexane–ethyl acetate = 98:2–92:8)
½
a 2D7
ꢂ
¼ ꢀ7:09 (c 1.002, acetonitrile). IR (KBr pellet): 2982, 2967,
2958, 2938, 2897, 2887, 1737, 1711, 1476, 1443, 1357, 1340,
1307, 1216, 1198, 1181, 1115, 1051, 995, 950, 937 cmꢀ1 1H NMR
.
to afford the title compound (494 mg, 73% yield). ½a D25
¼ ꢀ13:6 (c
ꢂ
(CDCl3, 400 MHz): d 0.98 (s, 9H), 1.48 (s, 3H), 3.67 (d, 1H,
J = 8.8 Hz), 3.70 (s, 3H), 4.17 (d, 1H, J = 8.8 Hz), 5.20 (s, 1H), 9.72
(s, 1H). 13C NMR (CDCl3, 100 MHz): d 18.1, 26.3, 38.9, 52.7, 70.0,
73.1, 97.3, 155.6, 199.2. MS (FAB) m/z: 230 (M+H)+.
2.31, MeOH). IR (Liquid Film): 2956, 2906, 2872, 1710, 1441,
1340, 1310, 1195, 1164, 1064, 694 cmꢀ1
.
1H NMR (CDCl3,
400 MHz): d 0.97 (s, 9H), 1.41 (s, 3H), 2.02–2.10 (m, 1H), 2.41–
2.51 (m, 1H), 2.77–2.97 (m, 2H), 3.67 (d, 1H, J = 8.6 Hz), 3.70 (s,
3H), 3.98 (d, 1H, J = 8.6 Hz), 5.14 (s, 1H), 6.80–6.82 (m, 1H), 6.92
(dd, 1H, J = 5.1, 3.5 Hz), 7.12 (dd, 1H, J = 5.1, 1.2 Hz). MS (FAB) m/
z: 312 (M+H)+.
4.6. Synthesis of methyl (2R,4R)-2-tert-butyl-4-methyl-4-[2-(1-
methyl-1H-pyrrol-2-yl)ethyl]-1,3-oxazolidine-3-carboxylate 22
To a solution of 19 (225 g, 0.981 mol) in N,N-dimethylformam-
ide (1125 mL) was added [(1-methyl-1H-pyrrol-2-yl)methyl]tri-
phenylphosphonium iodide 209 (522 g, 1.08 mol) with stirring,
and the resulting mixture was cooled to about ꢀ10 °C. Subse-
quently, to the reaction mixture was added dropwise a solution
of potassium t-butoxide (132 g, 1.18 mol) in N,N-dimethylformam-
ide (125 mL) below 5 °C with stirring, and the resulting mixture
was stirred at about 0 °C for about 1 h. After stirring, water was
added to the reaction mixture to quench the reaction, and the reac-
tion mixture was extracted with heptane. The extract was evapo-
rated in vacuo to afford the Wittig reaction product.
Subsequently, to a solution of the Wittig reaction product obtained
above in methanol (2250 mL) was added 5% palladium-charcoal
(45 g) with shaking, and the resulting mixture was shaken at room
temperature under a hydrogen atmosphere for about 1.5 h. After
shaking, the reaction mixture was filtered through a membrane fil-
4.8. Synthesis of methyl (2R,4R)-2-tert-butyl-4-methyl-4-[2-
(furan-2-yl)ethyl]-1,3-oxazolidine-3-carboxylate 26
To a suspension of (furan-2-yl)methyl triphenylphosphonium
bromide 23b11 (1.27 g, 3.00 mmol) in N,N-dimethylformamide
(6 mL) was added potassium t-butoxide (348 mg, 3.10 mmol) with
stirring under ice-cooling, and the resulting mixture was stirred
under ice-cooling for 15 min. Subsequently, to the reaction mix-
ture was added dropwise a solution of 19 (229 mg, 1.00 mmol) in
N,N-dimethylformamide (2 mL) with stirring under ice-cooling,
and the resulting mixture was stirred under ice-cooling for
45 min. After stirring, saturated aqueous NH4Cl was added to the
reaction mixture to quench the reaction, and the reaction mixture
was extracted with diethyl ether. The extract was washed with
brine and dried over MgSO4. After filtration, the solvent was
evaporated in vacuo, and the residue was purified by chromatogra-
phy on a silica gel column (eluent, hexane–ethyl acetate = 97:3–
93:7) to afford the Wittig reaction product. Subsequently, to a solu-
tion of the Wittig reaction product obtained above in ethyl acetate
(6 mL) was added 10% palladium-charcoal (30 mg) with stirring,
and the resulting mixture was stirred at room temperature under
a hydrogen atmosphere for 4 min. After stirring, the reaction mix-
ture was filtered through a Celite, and the filtrate was evaporated
in vacuo. The residue was purified by chromatography on a silica
gel column (eluent, hexane–ethyl acetate = 97:3–93:7) to afford
ter (pore diameter: 0.2 lm), and the filtrate was evaporated in va-
cuo. The residue obtained was recrystallized from a mixed solvent
of methanol and water (1:1, v/v) to afford the almost pure title
compound (278 g, 92% yield). ½a D27
¼ ꢀ12:6 (c 1.001, MeOH). IR
ꢂ
(KBr pellet): 2979, 2954, 2921, 2891, 1698, 1493, 1466, 1447,
1351, 1318, 1304, 1168, 1098, 1063, 958, 725 cmꢀ1 1H NMR
.
(CDCl3, 400 MHz): d 0.97 (s, 9H), 1.43 (s, 3H), 2.05 (apparent dt,
1H, J = 4.3, 12.8 Hz), 2.39 (apparent dt, 1H, J = 4.1, 12.7 Hz), 2.51
(ddd, 1H, J = 4.4, 12.4, 14.6 Hz), 2.61 (ddd, 1H, J = 4.6, 12.6,
14.5 Hz), 3.55 (s, 3H), 3.69 (s, 3H), 3.70 (d, 1H, J = 8.3 Hz), 4.00 (d,
1H, J = 8.3 Hz), 5.15 (s, 1H), 5.90 (br s, 1H), 6.05 (s, 1H), 6.53 (br
s, 1H). 13C NMR (DMSO-d6, 100 MHz): d 21.6, 22.1, 26.6, 33.2,
37.2, 38.3, 52.1, 63.7, 77.1, 96.5, 105.1, 106.3, 121.4, 132.3, 156.2.
MS (FAB) m/z: 309 (M+H)+.
the title compound (229 mg, 78% yield). ½a D25
¼ ꢀ7:7 (c 2.33,
ꢂ
MeOH). IR (Liquid Film): 2957, 2909, 2873, 1711, 1442, 1342,
1312, 1195, 1166, 1147, 1075, 1061, 962, 730 cmꢀ1 1H NMR
.
(CDCl3, 400 MHz): d 0.96 (s, 9H), 1.39 (s, 3H), 2.00–2.08 (m, 1H),
2.38–2.47 (m, 1H), 2.57–2.76 (m, 2H), 3.64 (d, 1H, J = 8.6 Hz),
3.69 (s, 3H), 3.93 (d, 1H, J = 8.6 Hz), 5.14 (s, 1H), 5.99–6.01 (m,
1H), 6.28 (dd, 1H, J = 3.1, 2.0 Hz), 7.30 (dd, 1H, J = 2.0, 0.8 Hz). MS
(FAB) m/z: 296 (M+H)+.
4.7. Synthesis of methyl (2R,4R)-2-tert-butyl-4-methyl-4-[2-
(thiophen-2-yl)ethyl]-1,3-oxazolidine-3-carboxylate 25
To a suspension of (thiophene-2-yl)methyl triphenylphospho-
nium bromide 23a10 (1.05 g, 2.40 mmol) in N,N-dimethylformam-
ide (5 mL) was added potassium t-butoxide (294 mg, 2.62 mmol)
with stirring under ice-cooling, and the resulting mixture was stir-
red under ice-cooling for 30 min. Subsequently, to the reaction
mixture was added dropwise a solution of 19 (500 mg, 2.18 mmol)
References
1. For example: (a) Fujita, T.; Inoue, K.; Yamamoto, S.; Ikumoto, T.; Sasaki, S.;
Toyama, R.; Chiba, K.; Hoshino, Y.; Okumoto, T. J. Antibiot. 1994, 47, 208–215;
(b) Miyake, Y.; Kozutsumi, Y.; Nakamura, S.; Fujita, T.; Kawasaki, T. Biochem.
Biophys. Res. Commun. 1995, 211, 396–403.
2. (a) Hinterding, K.; Albert, R.; Cottens, S. Tetrahedron Lett. 2002, 43, 8095–8097;

328
Y. Iio et al. / Tetrahedron: Asymmetry 22 (2011) 323–328
(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, 1667–1670.
5. Seebach, D.; Aebi, J. D. Tetrahedron Lett. 1984, 25, 2545–2548.
6. Seebach, D.; Stucky, G.; Renaud, P. Chimia 1988, 42, 176–178.
7. Giacomo, M. D.; Vinci, V.; Serra, M.; Colombo, L. Tetrahedron: Asymmetry 2008,
19, 247–257.
8. Yakura, T.; Yoshimoto, Y.; Ishida, C. Chem. Pharm. Bull. 2007, 55, 1385–1389.
9. Rawal, V. H.; Jones, R. J.; Cava, M. P. J. Org. Chem. 1987, 52, 19–28.
10. Aitken, R. A.; Drysdale, M. J.; Hill, L.; Lumbard, K. W.; MacCallum, J. R.; Seth, S.
Tetrahedron 1999, 55, 11039–11050.
3. For recent reviews, see: (a) Fuji, K. Chem. Rev. 1993, 93, 2037–2066; (b) Ohfune,
Y.; Horikawa, M. J. Synth. Org. Chem. 1997, 55, 982–993; (c) Cativiela, C.; Díaz-
de-Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517–3599; (d) Cativiela, C.;
Díaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645–732.
4. (a) Tsuji, T.; Iio, Y.; Takemoto, T.; Nishi, T. Tetrahedron: Asymmetry 2005, 16,
3139–3142; (b) Nakamura, T.; Tsuji, T.; Iio, Y.; Miyazaki, S.; Takemoto, T.; Nishi,
T. Tetrahedron: Asymmetry 2006, 17, 2781–2792.
11. Schweizer, E. E.; Creasy, W. S.; Light, K. K.; Shaffer, E. T. J. Org. Chem. 1969, 34,
212–218.