A novel dynamic kinetic resolution accompanied by intramolecular transesterification: Asymmetric synthesis of a 4-hydroxymethyl-2-oxazolidinone from serinol derivatives

Article abstract of DOI:10.1016/S0040-4020(03)00477-0

Reaction paths of the one-pot reaction of (R)-2-(α-methylbenzyl)amino-1,3-propanediol (1) and 2-chloroethyl chloroformate with DBU giving (4S,αR)-4-hydroxymethyl-3-(α-methylbenzyl)-2-oxazolidinone [(4S)-2] (94% de) were investigated. Intermediates of this reaction, 2-chloroethyl (2S)- and 2-chloroethyl (2R)-3-hydroxy-2-[(αR)-α-methylbenzyl]aminopropyl carbonates [(2S)-4 and (2R)-4], were synthesized individually. After the addition of DBU to the respective solution of the carbonate (2S)-4 and that of (2R)-4 in dichloromethane, the intramolecular transesterification between (2S)-4 and (2R)-4 and the diastereoselective intramolecular cyclization proceeded to afford (4S)-2 in high diastereomeric excess. Therefore, two monocarbonates (2S)-4 and (2R)-4 were kinetically resolved by this cyclization during the intramolecular transesterification between (2S)-4 and (2R)-4. We found that this process involved dynamic kinetic resolution accompanied by intramolecular transesterification.

Full text of DOI:10.1016/S0040-4020(03)00477-0

Tetrahedron 59 (2003) 3417–3425
A novel dynamic kinetic resolution accompanied
by intramolecular transesterification: asymmetric synthesis
of a 4-hydroxymethyl-2-oxazolidinone from serinol derivatives
Shigeo Sugiyama, Shoko Watanabe, Takayuki Inoue, Rie Kurihara, Takahiro Itou
*
and Keitaro Ishii
Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose, Tokyo 204-8588, Japan
Received 22 February 2003; revised 24 March 2003; accepted 24 March 2003
Abstract—Reaction paths of the one-pot reaction of (R)-2-(a-methylbenzyl)amino-1,3-propanediol (1) and 2-chloroethyl chloroformate
with DBU giving (4S,aR)-4-hydroxymethyl-3-(a-methylbenzyl)-2-oxazolidinone [(4S)-2] (94% de) were investigated. Intermediates of this
reaction, 2-chloroethyl (2S)- and 2-chloroethyl (2R)-3-hydroxy-2-[(aR)-a-methylbenzyl]aminopropyl carbonates [(2S)-4 and (2R)-4], were
synthesized individually. After the addition of DBU to the respective solution of the carbonate (2S)-4 and that of (2R)-4 in dichloromethane,
the intramolecular transesterification between (2S)-4 and (2R)-4 and the diastereoselective intramolecular cyclization proceeded to afford
(4S)-2 in high diastereomeric excess. Therefore, two monocarbonates (2S)-4 and (2R)-4 were kinetically resolved by this cyclization during
the intramolecular transesterification between (2S)-4 and (2R)-4. We found that this process involved dynamic kinetic resolution
accompanied by intramolecular transesterification. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
monoacyl 1,3-propanediols migrate to create an equili-
bration (intramolecular transesterification).3 If the reac-
tivities of two monoesters were different enough to be
resolved, a mixture of the monoesters would be a suitable
substrate for DKR (Scheme 1). However, DKR involving
the intramolecular transesterification has not been well
studied.
Dynamic kinetic resolution (DKR) is a powerful method for
the preparation of optically active compounds,1 and the
reaction mechanisms of some kinds of DKR have been
studied in detail.2 Racemic and epimeric mixtures are
resolved kinetically with racemization and epimerization to
give optically active compounds by DKR. Kinetic resolu-
tion also prepares optically active compounds from the
racemate; however, their maximum yields are limited to
50%, because less reactive substrates remain in the reaction
mixture. DKR includes two reactions. The first is kinetic
resolution, and the other is equilibrium between two
racemic or epimeric intermediates. Because of the rapid
equilibrium, all substrates including less reactive substrates
are consumed, and the theoretical yields are up to 100%.
a-Substituted carbonyl compounds such as ketones, esters,
amides, and hydantoins are frequently used for the
substrates in DKR,1a,b,d,f,h–j and other types of compounds
(cyanohydrins, alkyl lithiums, alkyl zinc chlorides,
Grignard reagents, vinyl esters, etc.) also have been
investigated as substrates for DKR.1b,c,e–j
We are investigating the asymmetric desymmetrization of
2-substituted propane derivatives.4 In the preceding
communication, we disclosed a one-pot reaction of (R)-2-
(a-methylbenzyl)amino-1,3-propanediol (1) and 2-chloro-
ethyl chloroformate with DBU to give optically active
(4S,aR)-4-hydroxymethyl-3-(a-methylbenzyl)-2-oxazolidi-
none [(4S)-2] in high diastereomeric excess (94% de) (Fig.
1).4a In the reaction mixture of 1 and 2-chloroethyl
chloroformate before the addition of DBU, the monocarbo-
nates (2S)-4 and (2R)-4 (1:1, 40%) as intermediates and a
dicarbonate 3 (5%) are obtained after work-up and
On the other hand, migration of functional groups also
creates equilibrium. For example, acyl groups of some
Keywords: dynamic kinetic resolution; transesterification; oxazolidinone;
serinol.
*
Corresponding author. Tel.: þ81-424958791; fax: þ81-42498783;
e-mail: ishiikei@my-pharm.ac.jp
Scheme 1. Possibility of DKR of 1,3-propanediol monoester derivatives.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00477-0

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S. Sugiyama et al. / Tetrahedron 59 (2003) 3417–3425
Scheme 3. Reagents and conditions: (a) (S)-a-methylbenzylamine, Et3N,
CH3CN, rt; (b) NaBH4, MeOH, THF; (c) 2-chloroethyl chloroformate, Py,
CH2Cl2, then DBU, 18C to rt.
Figure 1.
was stirred for 4 h to afford (4R)-2 (94% de, 68% yield).
We have already reported that 2-chloroethyl chloroformate
is the best chloroformate for this reaction among other
chloroformates, including methyl, ethyl, benzyl, phenyl,
2,2,2-trichloroethyl, and 1,2,2,2-tetrachloroethyl chloro-
formates.4a
The absolute configurations of (4S)-2 and (4R)-2 were
determined by comparison with the spectral data of the
samples obtained from (R)-a-methylbenzyl isocyanate and
(S)-glycidol and from the isocyanate and (R)-glycidol,
respectively (Scheme 4).6 The spectrum data of (4S)-2 were
also in agreement with those of the reported data7 of an
antipode of (4S)-2.
Scheme 2. Possible paths to afford (4S)-2.
purification with silica gel column chromatography. The
oxazolidinone (4S)-2 is obtained in 94% de from the
equimolar mixture of (2S)-4 and (2R)-4 quantitatively by
treatment of DBU (Scheme 2).4a We have proposed the
possible paths indicating that (i) monocarbonates (2S)-4 and
(2R)-4 exist as an equimolar mixture before the addition of
DBU, and (ii) at least the monocarbonate (2R)-4 is
converted to (2S)-4 via intramolecular transesterification
after the addition of DBU, after which the cyclization of
(2S)-4 proceeds to give (4S)-2.4a
Scheme 4. Preparation of the oxazolidinones from glycidols.
2.2. Stability of (4S)-2 and (4R)-2 in the basic reaction
conditions
It might be expected that the two oxazolidinones (4S)-2 and
(4R)-2 would epimerize by acyl transfer6,8 in the basic
reaction conditions. Therefore, we studied the stability of
(4S)-2 and (4R)-2 in the reaction mixtures. Respective
solutions of (4S)-2 and (4R)-2 in CDCl3 (0.04 mol/L) were
treated with three equivalents of DBU at room temperature
for 24 h; however, 1H NMR analyses of both reaction
mixtures showed no reactions, and each oxazolidinone
was recovered quantitatively (Scheme 5). Thus, (4S)-2 and
Herein, we report the details of reaction pathways from the
serinol 1 to (4S)-2 including the transesterification between
the monocarbonates (2R)-4 and (2S)-4.
2. Results and discussion
2.1. Preparation of the oxazolidinones (4S)-2 and (4R)-2
The oxazolidinone (4S)-24a was prepared by a three-step
synthesis from diethyl bromomalonate (5). Amination
of 5 with (R)-a-methylbenzylamine (6) gave diethyl
(R)-(a-methyl-benzyl)aminomalonate. The ester groups
were reduced with sodium borohydride by Soai’s method5
to give 1 (Scheme 3). To a mixture of the serinol 1 and
pyridine in dichloromethane was added 2-chloroethyl
chloroformate by one-shot with gentle warming. After the
mixture was stirred for 15 h, it was cooled with an ice bath,
and DBU was added to the mixture. The resulting mixture
Scheme 5. Acyl transfer of the oxazolidinones.

S. Sugiyama et al. / Tetrahedron 59 (2003) 3417–3425
3419
Scheme 6. Reagents and conditions: (a) AcOH, CHCl3, reflux, 6 h; (b) KOH, EtOH, reflux, 30 min; (c) ClCO2CH2CH2Cl, Py, CH2Cl2, rt, 15 h; (d) BF3·OEt2,
Me2S, CH2Cl2, rt, 3 h. Ref. 7.
a
(4R)-2 were stable in the reaction mixture. On the other
hand, (4S)-2 and (4R)-2 converted independently to their
approximate equimolar diastereomixtures by sodium
hydride or potassium tert-butoxide in THF at room
temperature for 24 h.
oxazolidinone (4S)-2, and pyridine-d5 (1 equiv.) with
DBU (3 equiv.) (Scheme 8, Eq. 1). The reaction was carried
out in a spinning NMR tube at 268C, and each process was
1
monitored by H NMR analysis (Fig. 2). The yields were
determined from the integration of the materials compared
to an internal standard (triphenylmethane) in the 400 MHz
1H NMR spectra during the reactions.
2.3. Preparation of (2S)-4 and (2R)-4 and their stabilities
in the presence of DBU
To investigate the intramolecular transesterification
between monocarbonates (2S)-4 and (2R)-4 and their
intramolecular cyclization, we prepared diastereomerically
pure monocarbonates (2S)-4 and (2R)-4 individually. Mono-
O-benzylserinol (2R)-9, which was derived from an
optically active aziridine (R)-7 according to the reported
procedure,7 was treated with 2-chloroethyl chloroformate to
give carbonate (2S)-10 (Scheme 6). Although we tried to
remove the benzyl group of (2S)-10 with catalytic
hydrogenation using Pd/C and Pt2O in an atmosphere of
hydrogen, complex mixtures were obtained. This benzyl
group was removed with a boron trifluoride diethyl ether
complex and dimethylsulfide in dichloromethane9 to afford
monocarbonate (2S)-4. Monocarbonate (2R)-4 was also
prepared from (S)-7 by an analogous procedure.
Scheme 8. Treatment of (2S)-4 and (2R)-4 with DBU ( p : starting
material). Reaction conditions: (a) DBU, Py-d5, CDCl3, room temp. 24 h.
Respective CDCl3 solutions (0.04 mol/L) of the mono-
carbonates (2R)-4 and (2S)-4 were treated with pyridine-d5
(1 equiv.) at room temperature for 12 h. No transesterifica-
tion occurred, and the monocarbonates were recovered in
diastereomerically pure forms in each case (Scheme 7).
Therefore, the intramolecular transesterification between
(2S)-4 and (2R)-4 did not proceed before the addition of
DBU.
2.4. Treatment of (2S)-4 and (2R)-4 with DBU
To confirm the intramolecular transesterification between
the monocarbonates (2S)-4 and (2R)-4 in the presence of
DBU (Scheme 2), we treated a CDCl3 solution (0.04 mol/L)
of (2S)-4, which is a direct precursor of the major
Scheme 7.
Figure 2. Progress of the reaction starting from (2S)-4.

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S. Sugiyama et al. / Tetrahedron 59 (2003) 3417–3425
Figure 3. Progress of the reaction starting from (2R)-4.
As shown in Figure 2, the monocarbonate (2S)-4 began to be
converted to (2R)-4 immediately after the addition of DBU,
and the ratio of (2S)-4 and (2R)-4 became 1:1 within 16 min.
The oxazolidinones 2 also began to form immediately, and
the yield increased according to the decrease in the
equimolar mixture of the monocarbonates (2S)-4 and
(2R)-4. Thus, the intramolecular transesterification from
(2S)-4 to (2R)-4 proceeded in the reaction mixture to afford
the equimolar mixture of the monocarbonates (2S)-4 and
(2R)-4. The NMR analysis continued for 2 h. After the
analysis, the mixture was further allowed to stand for 22 h at
room temperature. After work-up, the oxazolidinone (4S)-2
was obtained quantitatively in 92% de.
Scheme 9. Pathways from 1 to (4S)-4 and (4R)-4.
from (2S)-4 and (2R)-4, (4S)-2 would be given diastereo-
selectively (about 92% de) during the reaction.
3. Conclusions
The one-pot reaction of the serinol 1 with 2-chloroethyl
chloroformate in dichloromethane affords the oxazolidinone
(4S)-2 in excellent diastereoselectivity. This one-pot reac-
tion involves two reactions (Scheme 9); the first reaction is
from the serinol 1 to the monocarbonates (2S)-4 and (2R)-4
with no selectivity (paths A and B), and the second reaction
is the intramolecular cyclization (paths E and F)
accompanied by the intramolecular transesterification of
the monocarbonates (2S)-4 and (2R)-4 (paths C2nd and
D2nd). The monocarbonates (2S)-4 and (2R)-4 are stable
under the first reaction conditions; the intramolecular
transesterification between (2S)-4 and (2R)-4 (paths C1st
and D1st) and the intramolecular cyclization of the
monocarbonates are not observed. After addition of DBU,
intramolecular transesterification of the monocarbonates
(paths C2nd and D2nd) occurred rapidly and reached
equilibrium, and oxazolidinones (4S)-2 and (4R)-2 began
to form (paths E and F). With respect to the intramolecular
cyclization of the monocarbonates to give the oxazolidi-
nones, (2S)-4 is more reactive than (2R)-4, affording (4S)-2
predominantly. Therefore, oxazolidinone (4S)-2 is obtained
diastereoselectively from the mixture of monocarbonates
(2S)-4 and (2R)-4 in excellent yield. This one-pot reaction
is the first example of a dynamic kinetic resolution
accompanied by intramolecular transesterification.
Next, we examined the reactions from (2R)-4 (Scheme 8,
Eq. 2). The starting material, monocarbonate (2R)-4, is a
direct precursor of the minor oxazolidinone (4R)-2. As
shown in Figure 3, the monocarbonate (2R)-4 was also
converted to (2S)-4 immediately after the addition of DBU,
and (2R)-4 became a 1:1 mixture of (2R)-4 and (2S)-4 within
4 min. This period giving the 1:1 mixture of monocarbo-
nates from (2R)-4 was shorter than that from (2S)-4 (within
16 min). The yields of oxazolidinones (4S)-2 and (4R)-2
increased according to the decrease in the equimolar
mixture of (2S)-4 and (2R)-4. After the 1H NMR was
analyzed for 2 h, the mixture was further allowed to stand
for 22 h at room temperature, and the oxazolidinone (4S)-2
was obtained quantitatively in 91% de.
In the presence of DBU, the ratio of the oxazolidinones
1
(4S)-2/(4R)-2 could not be estimated by H NMR analysis
because of an overlap of the signals of (4S)-2, (4R)-2, and
DBU in CDCl3. Therefore, we treated the 1:1 mixture of
monocarbonates (2S)-4 and (2R)-4 with DBU (3 equiv.) in
dichloromethane (0.04 mol/L) at room temperature. After
the reaction mixture was stirred for 4, 8, 16, 32, 48, and
64 min, a small amount of the reaction mixture was
analyzed with HPLC after work-up. The ratio of the
oxazolidinones (4S)-2/(4R)-2 (96:4) was kept constant
during the reaction. The diastereomeric excess (92% de)
of (4S)-2 from the 1:1 mixture of the monocarbonates (2S)-4
and (2R)-44a was identical to the diastereomeric excess of
(4S)-2 from the two pure starting materials, (2S)-4 and
(2R)-4 (Figs. 2 and 3). Therefore, in the case of the reactions
4. Experimental
4.1. General
Melting porints were measured with Yanaco MP-3 appara-
tus and are uncorrected. Optical rotations were determined
on a JASCO DIP-140 polarimeter. IR spectra were recorded

S. Sugiyama et al. / Tetrahedron 59 (2003) 3417–3425
3421
on a Hitachi 215 spectrophotometer. NMR spectra were
obtained with a JEOL JNM-LA500 (1H NMR: 500 MHz), a
JEOL JNM-GSX400 (1H NMR: 400 MHz and 13C NMR:
100 MHz), and a JEOL JNM-AL300 (1H NMR: 300 MHz)
spectrometers using tetramethylsilane as an internal stan-
dard. MS and high-resolution MS (HR-MS) were taken on a
JEOL JMS-DX302 spectrometer. Column chromatography
was performed with Merck silica gel 60 (230–400 mesh).
Analytical TLC was performed on plates pre-coated with
0.25 mm layer of silica gel 60 F254 (Merck).
also recrystallized to afford a pure 1 (2.6 g, total 22.0 g,
64%). Colorless plates, mp 117–1188C (ethyl acetate/
1
methanol, 40:1). [a]D21¼þ57.18 (c 1.0, MeOH). H NMR
(500 MHz, CDCl3) d: 7.30–7.35 (5H, m, Ar), 7.23–7.25
(1H, m, Ar), 3.91 (1H, q, J¼6.6 Hz, PhCH), 3.73 (1H, dd,
J¼11.0, 4.6 Hz, OCHH), 3.53 (1H, dd, J¼11.0, 4.0 Hz,
OCHH), 3.52 (2H, d, J¼5.2 Hz, OCH2), 2.64 (1H, quintet-
like m, NCHCH2O), 1.39 (3H, d, J¼6.6 Hz, Me). 13C NMR
(100 MHz, CDCl3) d: 145.2, 128.5 (£2), 127.0, 126.3 (£2),
63.6, 61.9, 56.9, 55.7, 24.9. IR (KBr) cm21: 3320, 3220,
1050, 955. MS (positive FAB) m/z: 196 [(Mþ1)þ]. Anal.
Calcd for C11H17NO2: C, 67.66; H, 8.78; N, 7.17. Found: C,
67.49; H, 8.75; N, 7.08.
4.2. Synthesis of the oxazolidinones (4S)-2 and (4R)-2
4.2.1. Diethyl (R)-(a-methylbenzyl)aminomalonate (6).
A mixture of triethylamine (23.9 g, 236 mmol) and (R)-a-
methylbenzylamine (28.5 g, 235 mmol) was added to a
mixture of diethyl bromomalonate (5) (92% purity, Aldrich,
61.1 g, 321 mmol as 92% purity) in acetonitrile (235 mL) at
room temperature and the resulting mixture was stirred for
9 h at room temperature. After the reaction mixture was
concentrated in vacuo, the residue was diluted with diethyl
ether (100 mL) and extracted with 10% hydrochloric acid
(100 mL£2). The extracts were combined, washed with
diethyl ether (100 mL£2), alkalified (pH; ca. 10) with 20%
sodium hydroxide aqueous solution (ca. 100 mL), and
extracted with diethyl ether (150 mL£3 and 50 mL£1). The
extracts were combined, washed with water (100 mL, three
times), dried with magnesium sulfate, and concentrated in
vacuo to give 6 (65.8 g, 79%) as a brown liquid. This
material was used at the next reaction without any other
purification. A small amount of 6 was distilled (Kugelrohr,
,1658C/0.18 Torr) for analysis. Colorless liquid. [a]2D2¼
þ61.68 (c 1.1, CHCl3). 1H NMR (400 MHz, CDCl3) d:
7.22–7.32 (5H, m, Ar), 4.24 (2H, q, J¼7.1 Hz, CH2Me),
4.15 (1H, dq, J¼10.7, 7.1 Hz, CHHMe), 4.13 (1H, dq, J¼
10.7, 7.1 Hz, CHHMe), 3.89 (1H, s, CHN), 3.80 (1H, q,
J¼6.6 Hz, PhCHMe), 1.39 (3H, d, J¼6.6 Hz, PhCHMe),
1.27 (3H, t, J¼7.1 Hz, CH2Me), 1.22 (3H, t, J¼7.1 Hz,
CH2Me). 13C NMR (100 MHz, CDCl3) d: 168.9, 168.1,
143.7, 128.4 (£2), 127.2, 126.8 (£2), 63.0, 61.7 (£2), 56.5,
24.6, 14.3, 14.1. IR (film) cm21: 1730, 1750. MS (EI) m/z:
279 (Mþ, 0.25%), 264 (6.7), 206 (27), 120 (20), 105 (100),
77 (0.1). Anal. Calcd for C15H21NO4: C, 64.50; H, 7.58; N,
5.01. Found: C, 64.31; H, 7.68; N, 4.95.
4.2.3. (4S)-2 from the serinol 1 (Scheme 3). The serinol 1
(5.00 g, 25.6 mmol) was dissolved in methylene chloride
(640 mL, 0.04 mol/L) at 408C (bath temperature). Pyridine
(2.16 g, 25.6 mmol) was added, and then 2-chloroethyl
chloroformate (3.66 g, 25.6 mmol) was added by one-shot
to the mixture at room temperature. After being stirred for
24 h at room temperature, the mixture was cooled to 18C
(internal temperature) using an ice bath and treated with
DBU (11.9 g, 76.8 mmol). The resulting mixture was stirred
for 4 h with warming to room temperature. The reaction
mixture was washed twice with 5% hydrochloric acid
(60 mL) and once with water (60 mL). The mixture was
then dried, filtered and concentrated in vacuo to give a
yellow oil (5.92 g) which was chromatographed on silica
gel (hexane/ethyl acetate, 1:2, column 7 cm f£22 cm) to
afford the dicarbonate 3 (503 mg, 5%) as a colorless oil
and a mixture of oxazolidinones (4S)-2 and (4R)-2 (3.85 g,
68% yield, 97:3, 94% de) as colorless crystals. The
crystals (3.84 g) were recrystallized from tert-butyl methyl
ether (30 mL) to give pure (4S)-2 as colorless plates
(2.19 g).
To recover the starting material 1, the 5% hydrochloric acid
layers to be given after washing the reaction mixture were
combined, alkalified (pH; ca. 11) with sodium hydroxide,
and extracted with ethyl acetate (200 mL£1 and
100 mL£7). The extracts were combined, washed with
water, dried with magnesium sulfate, filtered, and concen-
trated in vacuo. The residue was filtered through a short
silica gel column and filtrate was concentrated in vacuo to
give a crude 1 (1.94 g), which was recrystallized with ethyl
acetate (30 mL) to give a pure 1 (1.36 g, 27% recovery).
4.2.2. (R)-2-(a-Methylbenzyl)amino-1,3-propanediol (1).
Methanol (142 mL) was added dropwise5 for 2 h to a
mixture of 6 (49.4 g, 177 mmol) and sodium borohydride
(16.7 g, 441 mmol) in THF (354 mL) with stirring without
cooling. This reaction was exothermic reaction, and the
maximum internal temperature was 568C. After being
stirred for 15 h with allowing cooling to room temperature,
the reaction mixture was concentrated in vacuo. The residue
was diluted with ethyl acetate (100 mL) and extracted with
10% hydrochloric acid (250 mL). The extract was washed
with ethyl acetate (200 mL£2 and 100 mL£1), alkalified
(ca. pH 11) with 20% aqueous sodium hydroxide (180 mL),
and extracted with ethyl acetate (100 mL£2 and 50 mL£5).
The extracts were combined, washed with water (100 mL),
dried with magnesium sulfate, filtered, and concentrated
in vacuo to give a crude 1. This crude material was
recrystallized with ethyl acetate/methanol (40:1, 974 mL) to
give a pure 1 (19.4 g). A solid given from the filtrate was
4.2.4. (4S)-2 from (S)-(2)-glycidol (Scheme 4). (R)-(þ)-a-
Methylbenzyl isocyanate (2.48 g, 16.9 mmol) was added to
a mixture of (S)-(2)-glycidol (1.25 g, 16.9 mmol) and
triethylamine (3.5 mL) in dichloromethane (12 mL) at room
temperature, and this mixture was refluxed for 36 h.6 After
being cooled to room temperature, the reaction mixture was
poured into saturated aqueous ammonium chloride and
extracted with dichloromethane. The extracts were com-
bined, dried with magnesium sulfate, filtered, and concen-
trated in vacuo to give brown viscous oil. The oil was
chromatographed on silica gel (hexane/ethyl acetate, 1:4)
to give a mixture of (4S)-2 and (4R)-2 (94:6) as a white
solid (1.59 g, 42% yield). The solid was recrystallized from
(tert-butyl methyl ether/THF 7:1, 11.4 mL) to give pure
(4S)-2 as colorless plates (1.16 g, 31% yield from the
glycidol).

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S. Sugiyama et al. / Tetrahedron 59 (2003) 3417–3425
4.2.5. (4R)-2 from (R)-(1)-glycidol (Scheme 4). Accord-
ing to the procedure described for the preparation of (4S)-2
from (R)-(þ)-glycidol, a mixture of (4R)-2 and (4S)-2 (94:6)
was obtained from (R)-(þ)-glycidol (1.25 g, 16.9 mol) and
(R)-(þ)-a-methylbenzyl isocyanate (2.48 g, 16.9 mmol) as
a white solid (1.46 g, 39% yield). This mixture was
recrystallized from hexane/ethyl acetate (1:1, 10 mL) to
give colorless plates (1.08 g, 29% yield from the glycidol).
4.3. Treatment of the oxazolidinones (4S)-2 and (4R)-2
with bases (Scheme 5)
4.3.1. With DBU. A mixture of (4S)-2 (4.3 mg, 19 mmol)
and DBU (8.9 mg, 58 mmol) in CDCl3 (0.49 mL) in a NMR
tube was allowed to stand for 48 h at room temperature.
Another oxazolidinone (4R)-2 (4.3 mg) was also examined
by this method; however, no reaction occurred in each case
1
(checked with H NMR).
4.2.6. (4S, aR)-4-Hydroxymethyl-3-(a-methylbenzyl)-2-
oxazolidinone [(4S)-2]. Colorless plates, mp 88–898C
(tert-butyl methyl ether/THF 7:1). [a]2D0¼þ102.18 (c 1.0,
CHCl3) [for (4R, aS)-enantiomer, ref.,7 [a]D27¼293.08 (c
4.3.2. With sodium hydride. A mixture of (4S)-2 (15 mg,
69 mmol) and sodium hydride (ca. 60% oil suspension,
2.8 mg) in THF was stirred for 17 h at room temperature.
The reaction was quenched with saturated aqueous
ammonium chloride, and the mixture was extracted with
ethyl acetate. The organic extracts were combined, dried
with magnesium sulfate, filtered, and concentrated in vacuo
to give a mixture of the oxazolidinones (4S)-2 and (4R)-2
(49:51 mixture, 10.4 mg, 69% yield). Another oxazolidi-
none (4R)-2 (15 mg) was also examined by this method, and
the mixture of (4S)-2 and (4R)-2 (43:57 mixture, 11.1 mg,
74% yield) was given.
1
1.0, CHCl3)]. H NMR (400 MHz, CDCl3) d: 7.31–7.49
(5H, m, Ar), 5.31 (1H, q, J¼7.1 Hz, PhCH), 4.32 (1H, dd,
J¼9.3, 8.5 Hz, CO2CHH), 4.21 (1H, dd, J¼8.5, 6.3 Hz,
CO2CHH), 3.95 (1H, m, NCHCH2), 3.22 (1H, dt, J¼12.2,
4.8 Hz, HOCHH), 3.13 (1H, ddd, J¼12.2, 8.4, 2.8 Hz,
HOCHH), 1.69 (3H, d, J¼7.1 Hz, Me), 0.93 (1H, dd, J¼8.4,
4.8 Hz, OH); (400 MHz, CDCl3 and D2O) d: 7.37–7.53
(5H, m, Ar), 5.30 (1H, q, J¼7.3 Hz, PhCH), 4.32 (1H, t,
J¼8.5 Hz, CO2CHH), 4.21 (1H, dd, J¼8.5, 6.3 Hz,
CO2CHH), 3.95 (1H, m, NCHCH2), 3.21 (1H, dt, J¼12.2,
4.8 Hz, HOCHH), 3.13 (1H, dd, J¼12.2, 2.7 Hz, HOCHH),
1.69 (3H, d, J¼7.3, Me). 13C NMR (100 MHz, CDCl3) d:
158.6, 141.2, 128.8 (£2), 128.0, 126.6 (£2), 64.6, 61.2, 54.8,
51.0, 15.6. IR (CHCl3) cm21: 1715. MS (EI) m/z: 221 (Mþ,
16%), 190 (24), 105 (100), 77 (8). Anal. Calcd for
C12H15NO3: C, 65.14; H, 6.83; N, 6.33. Found: C, 65.21;
H, 6.80; N, 6.52.
4.3.3. With potassium tert-butoxide. A mixture of (4S)-2
(9.8 mg, 44 mmol) and potassium tert-butoxide (4.1 mg) in
THF (0.44 mL) was stirred for 24 h at room temperature.
The reaction was quenched with saturated aqueous
ammonium chloride, and the mixture was extracted with
ethyl acetate. The organic extracts were combined, dried
with magnesium sulfate, filtered, and concentrated in vacuo
to give a mixture of the oxazolidinones (4S)-2 and (4R)-2
(1:1 mixture, 9.2 mg, 94% yield). Another oxazolidinone
(4R)-2 (9.8 mg) was also examined by this method, and the
mixture of (4S)-2 and (4R)-2 (1:1 mixture, 9.3 mg, 95%
yield) was given.
4.2.7. (4R,aR)-4-Hydroxymethyl-3-(a-methylbenzyl)-2-
oxazolidinone [(4R)-2]. Colorless plates, mp 85–868C
(hexane/ethyl acetate, 1:1). [a]2D0¼þ40.78 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3) d: 7.38 (4H, m, Ar), 7.33 (1H,
m, Ar), 5.15 (1H, q, J¼7.3 Hz, PhCH), 4.22 (2H, d, J¼
7.3 Hz, CO2CH2), 3.66 (1H, dt, J¼6.3, 4.9 Hz, HOCHH),
3.58 (1H, m, HOCHH), 3.54 (1H, m, NCHCH2), 1.69 (3H,
d, J¼7.3 Hz, Me), 1.65 (1H, dd, J¼6.8, 4.6 Hz, OH);
(400 MHz, CDCl3 and D2O) d: 7.38 (4H, m, Ar), 7.33 (1H,
m, Ar), 5.15 (1H, q, J¼7.1 Hz, PhCH), 4.22 (2H, d, J¼
7.6 Hz, CO2CH2), 3.65 (1H, dd, J¼11.2, 5.1 Hz, HOCHH),
3.56 (1H, m, HOCHH), 3.52 (1H, m, NCHCH2), 1.69
(3H, d, J¼7.1 Hz, Me). 13C NMR (100 MHz, CDCl3) d:
158.4, 139.1, 128.7 (£2), 127.9, 127.1 (£2), 65.0, 62.6, 55.6,
53.0, 18.7. IR (CHCl3) cm21: 1715. MS (EI) m/z: 221
(Mþ, 17%), 190 (25), 105 (100), 77 (8). Anal. Calcd for
C12H15NO3: C, 65.14; H, 6.83; N, 6.33. Found: C, 65.17; H,
6.84; N, 6.35.
4.4. Asymmetric synthesis of monocarbonates (2S)-4 and
(2R)-4 (Scheme 6)
4.4.1. (2R,aR)-1-[(a-Methylbenzyl)aziridin-2-yl]methyl
benzyl ether [(2R)-7]. According to the reported pro-
cedure,7 we prepared (2R)-7. A colorless oil. [a]2D6¼þ56.28
(c 1.0, CHCl3) [for (2S,aS)-enantiomer, ref.,7 [a]D26¼258.48
(c 1.0, CHCl3)]. 1H NMR (400 MHz, CDCl3) d: 7.23–7.38
(10H, m, Ar), 4.66 (1H, d, J¼12.0 Hz, PhCHHO), 4.57 (1H,
d, J¼12.0 Hz, PhCHHO), 3.55 (1H, dd, J¼10.5, 5.4 Hz,
BnOCHH), 3.51 (1H, dd, J¼10.5, 6.6 Hz, BnOCHH), 2.48
(1H, q, J¼6.6 Hz, PhCHN), 1.58 (1H, d, J¼3.4 Hz, NCHH),
1.83 (1H, m, NCHCH2O), 1.48 (3H, d, J¼6.6 Hz, Me), 1.34
(1H, d, J¼6.3 Hz, NCHH). 13C NMR (100 MHz, CDCl3) d:
144.2, 138.3, 128.4 (£4), 127.3 (£3), 126.7, 126.6 (£2),
72.9, 72.6, 69.6, 39.1, 31.2, 23.3. IR (film) cm21: 2975,
2860, 1505, 1465. MS (EI) m/z: 267 (Mþ, 0.4%), 146 (100),
105 (31), 91 (53). HRMS-EI m/z: (Mþ) calcd for C18H21NO,
267.1624; found, 267.1619.
4.2.8. (R)-2-(a-Methylbenzyl)amino-1,3-propanediol
di(2-chloroethyl)carbonate (3). A colorless oil. [a]2D1¼
þ1.98 (c 1.1, CHCl3). 1H NMR (400 MHz, CDCl3) d: 7.21–
7.36 (5H, m, Ar), 4.38 (2H, t, J¼5.7 Hz, ClCH2CH2), 4.34
(2H, t, J¼5.7 Hz, ClCH2CH2), 4.25 (1H, dd, J¼11.1,
5.5 Hz, CO2CHH), 4.20 (1H, dd, J¼11.1, 4.3 Hz,
CO2CHH), 4.11 (1H, dd, J¼10.9, 5.5 Hz, CO2CHH), 4.08
(1H, dd, J¼10.9, 5.7 Hz, CO2CHH), 3.96 (1H, q, J¼6.6 Hz,
PhCH), 3.71 (2H, t, J¼5.7 Hz, ClCH2), 3.68 (2H, t, J¼
5.7 Hz, ClCH2), 2.95 (1H, m NCHCH2O), 1.33 (3H, d, J¼
6.6 Hz, Me). IR (film) cm21: 1750. MS (positive FAB) m/z:
408 [(Mþ1)þ]. HRMS-FAB m/z: [(Mþ1)þ] calcd for
C17H24NO6Cl2, 408.0982; found, 408.0982.
4.4.2. (2S,aR)-1-[(a-Methylbenzyl)aziridin-2-yl]methyl
benzyl ether [(2S)-7]. According to the reported pro-
cedure,7 we prepared (2S)-7. A colorless oil. [a]2D6¼þ17.08
1
(c 1.3, CHCl3). H NMR (400 MHz, CDCl3) d: 7.38–7.40
(2H, m, Ar), 7.21–7.33 (6H, m, Ar), 7.16–7.18 (2H, m, Ar),
4.34 (1H, d, J¼12.2 Hz, PhCHHO), 4.31 (1H, d, J¼12.2 Hz,
PhCHHO), 3.43 (1H, dd, J¼10.7, 5.9 Hz, BnOCHH), 3.40

S. Sugiyama et al. / Tetrahedron 59 (2003) 3417–3425
3423
(1H, dd, J¼10.7, 5.5 Hz, BnOCHH), 2.49 (1H, q, J¼6.6 Hz,
PhCHN), 1.82 (1H, d, J¼3.4 Hz, NCHH), 1.74 (1H, ddd,
J¼12.0, 5.7, 3.4 Hz, NCHCH2O), 1.49 (1H, d, J¼6.6 Hz,
NCHH), 1.43 (3H, d, J¼6.6 Hz, Me). 13C NMR (100 MHz,
CDCl3) d: 143.8, 137.7, 127.6 (£2), 127.5 (£2), 126.8 (£2),
126.7 (£2), 126.3, 126.2 (£2), 72.0, 71.7, 69.1, 37.4, 31.3,
22.8. IR (film) cm21: 2980, 2870, 1503, 1465. MS (EI) m/z:
267 (Mþ, 0.4%), 146 (100), 105 (31), 91 (53). HRMS-EI
m/z: (Mþ) calcd for C18H21NO, 267.1624; found, 267.1626.
we prepared (2S)-9 from (2R)-8. A colorless oil. [a]2D8¼
22.18 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) d: 7.22–
7.36 (10H, m. Ar), 4.43 (1H, d, J¼12.7 Hz, PhCHHO), 4.39
(1H, d, J¼12.7 Hz, PhCHHO), 3.88 (1H, q, J¼6.6 Hz,
PhCH), 3.67 (1H, dd, J¼11.0, 4.4 Hz, BnOCHH), 3.47 (1H,
dd, J¼9.5, 6.1 Hz, HOCHH), 3.43 (1H, dd, J¼11.0, 3.9 Hz,
BnOCHH), 3.42 (1H, dd, J¼9.5, 4.9 Hz, HOCHH), 2.78
(1H, m, NCHCH2), 1.36 (3H, d, J¼6.6 Hz, Me). 13C NMR
(100 MHz, CDCl3) d: 145.3, 137.9, 128.3 (£2), 128.1 (£2),
127.4, 127.3 (£2), 126.8, 126.3, 126.2, 73.0, 71.1, 61.1,
55.2, 55.1, 24.7. IR (film) cm21: 3400, 2960, 1455, 1105.
MS (EI) m/z: 285 (Mþ, 1.2%), 254 (34), 164 (76), 105 (100),
91 (43). HRMS-EI m/z: (Mþ) calcd for C18H23NO2,
285.1730; found, 285.1733.
4.4.3. (2S,aR)-3-Benzyloxy-2-(a-methylbenzyl)amino-
propyl acetate [(2S)-8]. According to the reported pro-
cedure,7 we prepared (2S)-8 from (2R)-7. A colorless oil.
[a]2D5¼þ47.28 (c 1.0, CHCl3) [for (2R,aS)-enantiomer,
1
ref.,7 [a]D25¼249.08 (c 1.0, CHCl3)]. H NMR (400 MHz,
CDCl3) d: 7.37–7.21 (10H, m, Ar), 4.53 (1H, d, J¼12.2 Hz,
PhCHH), 4.49 (1H, d, J¼12.2 Hz, PhCHH), 4.02 (2H, d,
J¼5.9 Hz, AcOCH2), 3.88 (1H, q, J¼6.3 Hz, PhCHMe),
3.52 (1H, dd, J¼9.5, 5.4 Hz, BnOCHH), 3.44 (1H, dd, J¼
9.5, 4.3 Hz, BnOCHH), 2.82 (1H, m, NCHCH2O), 1.97 (3H,
s, Ac), 1.31 (3H, d, J¼6.3 Hz, PhCHMe). 13C NMR
(100 MHz, CDCl3) d: 170.4, 145.4, 137.9, 128.2 (£4),
127.43, 127.40 (£2), 126.7, 126.4 (£2), 73.1, 68.5, 65.0,
58.1, 55.6, 25.0, 20.9. IR (film) cm21: 1740 (CvO). MS
(EI) m/z: 327 (Mþ, 1.0%), 206 (65), 146 (23), 105 (100), 102
(22), 91 (39). HRMS-EI m/z: calcd for C20H25NO3,
327.1830; found, 327.1836.
4.4.7. (2S,aR)-3-Benzyloxy-2-(a-methylbenzyl)amino-
propyl 2-chloroethyl carbonate [(2S)-10]. To a mixture
of (2S)-9 (738 mg, 2.58 mmol) and pyridine (0.44 g,
5.2 mmol) in dichloromethane (6.5 mL) was added 2-chloro-
ethyl chloroformate (0.74 g, 5.2 mmol) at room tempera-
ture. After being stirred for 15 h, the reaction mixture was
poured into water and extracted with dichloromethane. The
extracts were combined, dried with magnesium sulfate,
filtered, and concentrated in vacuo. The residue was
chromatographed on silica gel (hexane/dichloromethane/
ethyl acetate, 5:2:1) to afford (2S)-10 as a colorless oil
1
(972 mg, 83%). [a]D25¼þ37.28 (c 1.0, CHCl3). H NMR
(400 MHz, CDCl3) d: 7.37–7.20 (10H, m, Ar), 4.53 (1H, d,
J¼12.2 Hz, PhCHHO), 4.49 (1H, d, J¼12.2 Hz, PhCHHO),
4.31 (2H, t, J¼5.9 Hz, ClCH2CH2O), 4.10 (2H, dd, J¼5.9,
2.0 Hz, OCO2CH2CHN), 3.87 (1H, q, J¼6.6 Hz, PhCH),
3.66 (2H, t, J¼5.9 Hz, ClCH2), 3.55 (1H, dd, J¼9.5, 5.1 Hz,
BnOCHH), 3.46 (1H, dd, J¼9.5, 4.2 Hz, BnOCHH), 2.86
(1H, m, NCHCH2O), 1.31 (3H, d, J¼6.6 Hz, Me). 13C NMR
(100 MHz, CDCl3) d: 154.3, 145.2, 137.8, 128.14 (£2),
128.09 (£2), 127.4, 127.3 (£2), 126.7, 126.4 (£2), 73.0,
68.5, 68.1, 67.0, 55.5, 53.5, 25.0. IR (film) cm21: 1755. MS
(EI) m/z: 391 (Mþ, 1.2%), 272 (19), 270 (58), 166 (19), 146
(29), 105 (100), 91 (40). HRMS-EI m/z: (Mþ) calcd for
C21H26NO4Cl, 391.1558; found, 391.1549.
4.4.4. (2R,aR)-3-Benzyloxy-2-(a-methylbenzyl)amino-
propyl acetate [(2R)-8]. According to the reported
procedure,7 we prepared (2R)-8 from (2S)-7. A colorless
oil. [a]2D9¼þ27.98 (c 1.0, CHCl3). 1H NMR (400 MHz,
CDCl3) d: 7.35–7.21 (10H, m, Ar), 4.42 (s, 2H, PhCH2),
4.13 (2H, d, J¼5.1 Hz, AcOCH2), 3.94 (1H, q, J¼6.6 Hz,
PhCHMe), 3.40 (2H, d, J¼5.6 Hz, BnCH2O), 2.86 (1H, m,
NCHCH2O), 2.02 (3H, s, Ac), 1.32 (3H, d, J¼6.6 Hz,
PhCHMe). 13C NMR (100 MHz, CDCl3) d: 170.5, 145.2,
137.9, 128.2 (£2), 128.0 (£2), 127.35, 127.29 (£2), 126.7,
126.4, 72.9, 70.3, 63.5, 55.4, 53.4, 53.2, 24.9, 20.9. IR
(film) cm21: 1740 (CvO). MS (EI) m/z: 327 (Mþ, 1.2%),
206 (67), 146 (9), 105 (100), 102 (24), 91 (36). HRMS-EI
m/z: (Mþ) calcd for C20H25NO3, 327.1832; found,
327.1836.
4.4.8. (2R,aR)-3-Benzyloxy-2-(a-methylbenzyl)amino-
propyl 2-chloroethyl carbonate [(2S)-10]. According to
the synthetic procedure for (2S)-10, we prepared (2R)-10
(771 mg, 70%) from (2S)-9 (800 mg). A colorless oil.
4.4.5. (2R,aR)-3-Benzyloxy-2-(a-methylbenzyl)amino-
propanol [(2R)-9]. According to the reported procedure,7
we prepared (2R)-9 from (2S)-8. A colorless oil. [a]2D4¼
þ80.38 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) d:
7.38–7.20 (10H, m, Ar), 4.54 (1H, d, J¼12.1 Hz,
PhCHHO), 4.50 (1H, d, J¼12.1 Hz, PhCHHO), 3.87 (1H,
q, J¼6.4 Hz, PhCH), 3.58 (1H, dd, J¼9.5, 4.9 Hz,
BnOCHH), 3.43 (1 h, dd, J¼9.5, 4.6 Hz, BnOCHH), 3.42
(2H, d, J¼5.4 Hz, HOCH2), 2.72 (1H, m, NCHCH2), 1.34
(3H, d, J¼6.4 Hz, Me). 13C NMR (100 MHz, CDCl3) d:
145.2, 137.8, 128.3 (£2), 128.2 (£2), 127.5, 127.4 (£2),
126.8, 126.4, 73.2, 69.4, 62.8, 55.9, 55.4, 25.0. IR
(film) cm21: 3400, 2850, 1455, 1110. MS (EI) m/z: 285
(Mþ, 1.1%), 254 (27), 164 (65), 105 (100), 91 (45). HRMS-
EI m/z: (Mþ) calcd for C18H23NO2, 285.1730; found,
285.1732.
1
[a]2D6¼þ29.0 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3)
d: 7.34–7.21 (10H, m, Ar), 4.41 (2H, s, PhCH2O), 4.35 (2H,
t, J¼5.9 Hz, ClCH2CH2O), 4.22 (2H, d, J¼5.1 Hz, OCO2-
CH2CHN), 3.94 (1H, q, J¼6.6 Hz, PhCH), 3.69 (2H, t, J¼
5.9 Hz, ClCH2), 3.42 (2H, d, J¼5.4 Hz, BnOCH2), 2.90
(1H, m, NCHCH2O), 1.33 (3H, d, J¼6.4 Hz, Me). 13C
(100 MHz, CDCl3) d: 154.5, 145.1, 137.8, 128.4 (£2), 128.2
(£2), 127.3, 127.2 (£2), 126.7, 126.3 (£2), 72.9, 70.0, 67.2,
67.0, 55.4, 53.2, 41.1, 24.9. IR (film) cm21: 1740. MS (EI)
m/z: 391 (Mþ, 1.4%), 272 (17), 270 (49), 166 (15), 146 (69),
105 (100), 91 (64). HRMS-EI m/z: (Mþ) calcd for
C21H26NO4Cl, 391.1558; found, 391.1551.
4.4.9. 2-Chloroethyl (2S,aR)-3-hydroxy-2-(a-methyl-
benzyl)aminopropyl carbonate [(2S)-4]. Dimethyl sulfide
(0.10 mL) was added to the mixture of (2S)-10 (20 mg,
51 mmol) and boron trifluoride etherate (72 mg, 0.51 mmol)
in dichloromethane (0.3 mL) at 08C.9 After being stirred for
4.4.6. (2S,aR)-3-Benzyloxy-2-(a-methylbenzyl)amino-
propanol [(2S)-9]. According to the reported procedure,7

3424
S. Sugiyama et al. / Tetrahedron 59 (2003) 3417–3425
3.5 h with allowing warming to room temperature, the
reaction mixture was poured into 5% aqueous sodium
hydrogen carbonate, and extracted with ethyl acetate. The
extracts were combined, washed with water twice, dried
with magnesium sulfate, filtered, and concentrated in vacuo
to afford (2S)-7 as an yellowish oil (9.0 mg, 58%). [a]2D7¼
þ5.98 (c 0.6, CHCl3). 1H NMR (400 MHz, CDCl3) d: 7.16–
7.28 (5H, m, Ar), 4.28 (2H, t, J¼5.7 Hz, ClCH2CH2O), 4.06
(1H, dd, J¼10.5, 5.6 Hz, OCO2CHHCHN), 4.00 (1H, dd,
J¼11.0, 6.1 Hz, OCO2CHHCHN), 3.83 (1H, q, J¼6.6 Hz,
PhCH), 3.62 (3H, m, ClCH2 and HOCHH), 3.38 (1H, dd,
J¼11.1, 4.3 Hz, HOCHH), 2.78 (1H, m, NCHCH2O), 1.30
(3H, d, J¼6.6 Hz, Me). IR (film) cm21: 1760. MS (positive
FAB) m/z: 302 [(Mþ1)þ]. HRMS-FAB m/z: [(Mþ1)þ]
calcd for C14H21NO4Cl, 302.1160; found, 302.1165.
added to a mixture of (2S)-4 and (2R)-4 (1:1, 7.7 mg,
26 mmol) and triphenylmethane (1.3 mg, 5.3 mmol) as an
internal standard in dichloromethane (0.5 mL) at room
temperature. After being stirred for 15 h, the reaction
mixture was poured into saturated aqueous ammonium
chloride and extracted with dichloromethane. The extracts
were combined, dried with magnesium sulfate, filtered, and
concentrated in vacuo to give (4S)-2 (97% yield, 94% de, 1H
NMR analysis).4a
4.5.4. Analysis of the ratio of the products (4S)-2 and
(4R)-2 from the 1:1 mixture of the carbonates (2S)-4 and
(2R)-4. To a mixture of 1 (100 mg, 0.512 mmol) and
pyridine (61 mL, 0.77 mmol) in dichloromethane (13 mL)
was added 2-chloroethyl chloroformate (95 mg, 0.67 mmol)
at room temperature. After the resulting mixture was stirred
for 24 h at room temperature, triphenylmethane (32.3 mg,
0.13 mmol) and DBU (234 mg, 1.54 mmol) was added. In
the each experimental time, 500 mL of the reaction mixture
was collected and poured into 10% hydrochloric acid
(0.5 mL). The mixture was shaken, and the organic layer
was used for the HPLC analysis. The yield and the ratio of
the products (4S)-2 and (4R)-2 were obtained by the
comparison of their HPLC area. HPLC conditions, column;
LiChroCART/LiChrospher Si 60 (5 mm, Merck), solvent;
hexane/ethyl acetate, 3:7, flow rate; 0.5 mL/min, detection;
UV (254 nm), Retention time, (4S)-2; 35.0 min, (4R)-2;
33.0 min. The ratio of the HPLC area for (4S)-2 and (4R)-2
was in good agreement with that of the 1H NMR integration.
4.4.10. 2-Chloroethyl (2R,aR)-3-hydroxy-2-(a-methyl-
benzyl)aminopropyl carbonate [(2R)-4]. According to
the synthetic procedure of (2S)-4, we prepared (2R)-4
(138 mg, 52%) from (2R)-10 (347 mg). An yellowish oil
[a]2D6¼þ71.98 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3)
d: 7.32–7.33 (4H, m, Ar), 7.26 (1H, m, Ar), 4.40 (2H, t, J¼
5.6 Hz, ClCH2CH2O), 4.28 (1H, dd, J¼11.2, 5.4 Hz,
OCO2CHHCHN), 4.16 (1H, dd, J¼11.2, 4.4 Hz, OCO2
CHHCHN), 3.97 (1H, q, J¼6.6 Hz, PhCH), 3.72 (2H, t,
J¼5.6 Hz, ClCH2), 3.46 (1H, dd, J¼11.0, 4.9 Hz, HOCHH),
3.40 (1H, dd, J¼11.0, 6.3 Hz, HOCHH), 2.80 (1H, m,
NCHCH2O), 1.37 (3H, d, J¼6.6 Hz, Me). IR (film) cm21
:
1750. MS (positive FAB) m/z: 302 [(Mþ1)þ]. HRMS-FAB
m/z: [(Mþ1)þ] calcd for C14H21NO4Cl, 302.1160; found,
302.1165.
Acknowledgements
4.5. The studies of the DKR of the monocarbonates in the
presence of DBU
The authors wish to thank the staff of the Analysis Center
of Meiji Pharmaceutical University for performing the
elemental analysis (Miss Ayako Ohmae) and mass spectra
(Miss Tamami Koseki). This work was partially supported
by The Science Research Promotion Fund from The
Promotion and Mutual Aid Corporation for Private School
of Japan.
1
4.5.1. The study using H NMR (Figs. 2 and 3). DBU
(10 mg, 65 mmol), was added to a mixture of (2S)-4
(6.9 mg, 23 mmol), pyridine-d5 (1.8 mL, 23 mmol), and
triphenylmethane (1.7 mg, 7 mmol) in CDCl3 (0.57 mL) in a
NMR tube. After being shaken vigorously for a few
seconds, the H NMR spectra of the mixture were begun
to measure immediately at 268C. The other carbonate (2S)-4
was also examined by this method.
1
References
4.5.2. Diastereomixture of monocarbonates (2S)-4 and
(2R)-4. To a mixture of 1 (100 mg, 0.51 mmol) and pyridine
(0.51 mmol) in dichloromethane (13 mL) was added
2-chloroethyl chloroformate (53 mL, 0.51 mmol) at room
temperature. After being stirred for 24 h at this temperature,
the reaction mixture was poured into saturated aqueous
ammonium chloride and extracted with dichloromethane.
The extracts were combined, dried with magnesium sulfate,
filtered, and concentrated in vacuo. The residue was
chromatographed on a silica gel column (hexane/ethyl
acetate; 1:4) to give the dicarbonate 3 (9%) and a mixture of
(2S)-4 and (2R)-4 (1:1 mixture, 40%). The aqueous layer
was alkalified with 10% aqueous sodium hydroxide and
extracted with ethyl acetate. The extracts were combined,
dried with magnesium sulfate, filtered, and concentrated in
vacuo to recover 1 as white crystals (44%).
1. For reviews of DKR, see (a) Noyori, R.; Ohkuma, T. Angew.
Chem., Int. Ed. Engl. 2001, 40, 40–73. (b) Huerta, F. F.;
Minidis, A. B. E.; Baeckvall, J.-E. Chem. Soc. Rev. 2001, 30,
321–331. (c) Bringmann, G.; Menche, D. Acc. Chem. Res.
2001, 34, 615–624. (d) Ratovelomanana-Vidal, V.; Genet,
J.-P. Can. J. Chem. 2000, 78, 846–851. (e) Beak, P.;
Anderson, D. R.; Curtis, M. D.; Laumer, J. M.; Pippel, D. J.;
Weisenburger, G. A. Acc. Chem. Res. 2000, 33, 715–727.
(f) Stecher, H.; Faber, K. Synthesis 1997, 1–16. (g) Sturmer, R.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1173–1174.
(h) Caddick, S.; Jenkins, K. Chem. Soc. Rev. 1996, 25,
447–456. (i) Ward, R. S. Tetrahedron: Asymmetry 1995, 6,
1475–1490. (j) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull.
Chem. Soc. Jpn 1995, 68, 36–56.
2. Recent mechanistic studies for DKR, see (a) Santos, A. G.;
Candeias, S. X.; Afonso, C. A. M.; Jenkins, K.; Caddick, S.;
Treweeke, N. R.; Pardoe, D. Tetrahedron 2001, 57,
6607–6614. (b) Ben, R. N.; Durst, T. J. Org. Chem. 1999, 64,
4.5.3. Treatment of the 1:1 mixture of monocarbonates
(2S)-4 and (2R)-4 with DBU. DBU (11 mg, 74 mmol) was

S. Sugiyama et al. / Tetrahedron 59 (2003) 3417–3425
3425
7700–7706. (c) Weisenburger, G. A.; Faibish, N. C.; Pippel,
D. J.; Beak, P. J. Am. Chem. Soc. 1999, 121, 9522–9530.
(d) Tunge, J. A.; Gately, D. A.; Norton, J. R. J. Am. Chem. Soc.
1999, 121, 4520–4521.
1984, 57, 2327–2328. (b) Soai, K. J. Synth. Org. Chem., Jpn,
(Yuki Gosei Kagaku Kyokaishi) 1987, 45, 1148–1156.
6. Katsumura, S.; Kondo, A.; Han, Q.; Kondo, A. Chem. Lett.
1991, 1245–1248.
3. (a) Fadel, A.; Arzel, P. Tetrahedron: Asymmetry 1997, 8,
283–291. (b) Akai, S.; Naka, T.; Fujita, T.; Takebe, Y.; Kita, Y.
Chem. Commun. 2000, 1461–1462. (c) Neri, C.; Williams, J. M.
J. Tetrahedron: Asymmetry 2002, 13, 2197–2199.
7. Choi, S.-K.; Lee, W.-K. Heterocycles 1998, 48, 1917–1921.
8. (a) Roush, W. R.; Adam, M. A. J. Org. Chem. 1985, 50,
3752–3757. (b) Sibi, M. P.; Rutherford, D.; Renhowe, P. A.; Li,
B. J. Am. Chem. Soc. 1999, 121, 7509–7516. (c) Bew, S. P.;
Bull, S. D.; Davies, S. G. Tetrahedron Lett. 2000, 41,
7577–7581.
4. (a) Sugiyama, S.; Watanabe, S.; Ishii, K. Tetrahedron Lett.
1999, 40, 7489–7492. (b) Sugiyama, S.; Morishita, K.; Ishii, K.
Heterocycles 2001, 55, 353–364.
9. Fuji, K.; Kawabata, T.; Fujita, E. Chem. Pharm. Bull. 1980, 28,
3662–3664.
5. (a) Soai, K.; Oyamada, H.; Takase, M. Bull. Chem. Soc. Jpn