Studies on two different diastereoselective reaction pathways from a serinol derivative to 4-hydroxymethyl-2-oxazolidinones using 2-chloroethyl chloroformate and N,N′-disuccinimidyl carbonate

Article abstract of DOI:10.1016/j.tetasy.2010.11.022

Two reaction pathways and their diastereoselectivity-determining steps of the asymmetric desymmetrization of (R)-2-(α-methylbenzyl)amino-1,3- propanediol 1 with 2-chloroethyl chloroformate (CCF) and with N,N′-disuccinimidyl carbonate giving (4S,αR)-4-hydr

Full text of DOI:10.1016/j.tetasy.2010.11.022

Tetrahedron: Asymmetry 21 (2010) 2904–2910
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Studies on two different diastereoselective reaction pathways from a
serinol derivative to 4-hydroxymethyl-2-oxazolidinones using 2-chloroethyl
0
chloroformate and N,N -disuccinimidyl carbonate
⇑
⇑
Shigeo Sugiyama , Keitaro Ishii
Department of Life and Pharmaceutical Scieneces, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Two reaction pathways and their diastereoselectivity-determining steps of the asymmetric desymmetri-
Received 13 October 2010
Accepted 19 November 2010
Available online 11 January 2011
zation of (R)-2-(
with N,N -disuccinimidyl carbonate giving (4S,
a
-methylbenzyl)amino-1,3-propanediol 1 with 2-chloroethyl chloroformate (CCF) and
R)-4-hydroxymethyl-3- -methylbenzyl-2-oxazolidinones
R)-diastereomer (4R)-3 were investigated. The reaction of serinol 1 and CCF to give
the corresponding carbonates was not a diastereoselectivity-determining step. The carbonates gave
R)-5-( -methylbenzyl)amino-1,3-dioxan-2-one 4 after addition of DBU, and an intramolecular acyl
0
a
a
(4S)-3 and its (4R,a
(
a
transfer of 4 was found to be a diastereoselectivity-determining step to give (4S)-3. Conversely, the reac-
0
tion of serinol 1 and N,N -disuccinimidyl carbonate afforded directly the opposite diastereomer (4R)-3 but
not via the intermediate 4. Thus, their diastereoselectivities depended on the acylating reagent.
Ó 2010 Elsevier Ltd. All rights reserved.
1
. Introduction
2 2
the monobenzoates of 1 was achieved in CH Cl at room tempera-
ture by treatment with DBU. The intramolecular acyl transfers of
the monoacetates of N-Boc-serinol and 2-O-benzylglycerol6 have
also been reported. Thus, we proposed a reaction mechanism
involving the conversion of (2S)-2 and (2R)-2 into (4S)-3 diastere-
oselectively due to the dynamic kinetic resolution accompanied
4
Asymmetric desymmetrization is one of the most effective strat-
1
egies for the asymmetric synthesis of optically active compounds.
For example, 2-amino-1,3-propanediol (serinol) derivatives A have
been used for prochiral compounds to be converted into optically
2
–9
14
active monosubstituted serinols B by enzymatic
or chemical
with the intramolecular acyl transfers between (2S)-2 and (2R)-2.
1
0–12
methods (Scheme 1). Generally, the enzymatic method for
asymmetric desymmetrization of A gives monoesters B (R = acyl
groups), which are useful intermediates to synthesize aziridines,
On the other hand we have synthesized prochiral cyclic carbon-
2
3
ate 4 and found that the reaction of 4 with DBU in CDCl gives (4S)-
2
,11
19
3 quantitatively in 94% de. The diastereoselectivity was identical
3
,4,11
11
14
2
-oxazolidinones,
and silyl ethers. On the other hand, the
to those of the two reactions from (2S)-2 and (2R)-2 to (4S)-3,
symmetrization of monoesters B gives diesters C, which have also
and 4 might be formed from (2S)-2 and (2R)-2 during the two reac-
tions. Consequently, these facts prompted us to reexamine the
reactions. Herein, the pathways from (2S)-2 and (2R)-2 to (4S)-3
been used as substrates to synthesize optically active monoesters
5
,6,9
B via asymmetric desymmetrizations using enzymatic methods.
We are currently investigating new synthetic methods toward
via 4 are reported in detail.
1
3–18
0
optically active 2-oxazolidinones,
metric desymmetrization of prochiral materials.1
prochiral materials, (R)-2-( -methylbenzyl)amino-1,3-propanediol
, reacts with 2-chloroethyl chloroformate (CCF) to give a diastereo-
meric mixture (ca. 1:1) of two monocarbonates, (2S)-2 and (2R)-2
Fig. 1). Treatment of a mixture of (2S)-2 and (2R)-2 with DBU gives
-oxazolidinone (4S)-3 in 68% (two steps) with 94% de. Both diaste-
especially, using the asym-
N,N -Disuccinimidyl carbonate is also
a
good reagent to
3–15
11,16,17,20,21
One of these
synthesize oxazolidinones from 2-aminoalkanols.
We
a
also report the diastereoselective reaction from 1 to 3 using
0
1
N,N -disuccinimidyl carbonate. The difference of the reaction path-
0
ways when using CCF or N,N -disuccinimidyl carbonate was also
1
(
2
investigated by H NMR analysis in detail.
reomerically pure (2S)-2 and (2R)-2 were also converted into (4S)-3
with DBU independently and quantitatively in 92–91% de. We have
also reported on the intramolecular acyl transfers of monobenzo-
2. Results and discussion
1
1
ates of serinol 1. The equilibrium between two diastereomers of
2.1. Reaction pathways from (2S)-2 and (2R)-2
At first, we investigated whether cyclic carbonate 4 existed as
an intermediate in the reaction mixture from 2 to 3 according to
our procedure. To a mixture of (2S)-2 and triphenylmethane as
⇑
Tel./fax:+81 42 495 8783.
E-mail addresses: sugiyama@my-pharm.ac.jp (S. Sugiyama), ishiikei@my-pharm.
1
4
ac.jp (K. Ishii).
0
957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.11.022

S. Sugiyama, K. Ishii / Tetrahedron: Asymmetry 21 (2010) 2904–2910
2905
R1
R1
R1
desymmetrization
symmetrization
symmetrization
HN
HN
HN
OR2
R O
2
OR2
HO
OH
HO
desymmetrization
A
B
C
Scheme 1. Desymmetrization and symmetrization of serinol derivatives A, B, and C.
an internal standard in CDCl
spectra (Figs. 2 and 3) and results of the analyses (Figs. 4 and 5) are
shown. Three minutes after the start of the two reactions from
3
in an NMR tube was added DBU. The
(2S)-2 and (2R)-2, transesterification between (2S)-2 and (2R)-2
occurred (3.65–3.75 ppm in Figs. 2 and 3). Ten minutes later,
2-chloroethanol and the 2-oxazolidinones 3 were formed in ca.
5
5% and ca. 22% yields, respectively (Figs. 4 and 5). These
phenomena indicate that at least one intermediate should exist
1
in the reaction mixture. The H NMR signals of cyclic carbonate 4
were found in both of the reaction mixtures (Figs. 2 and 3), and
then as 4 was consumed, the 2-oxazolidinones began to be formed.
This fact showed that the reactions from monocarbonates 2 to
HN
Ph
OR2
1
R O
2
-oxazolidinones 3 proceeded via intermediate 4.
Since we observed the formation of cyclic carbonate 4 with the
1
1
; R = R2 = H
2
(
(
2S)-2; R1 = CO2(CH2)2Cl, R = H
release of 2-chloroethanol, the reaction of monocarbonates 2 to
-oxazolidinone (4S)-3 should proceed predominantly via
1
2
2R)-2; R = H, R = CO2(CH2)2Cl
2
4
1
2
5
; R = R = CO2(CH2)2Cl
following intramolecular acyl transfer to give (4S)-3 rather than
via a direct formation of (4S)-3 from (2S)-2. The reaction pathways
are shown in Scheme 2. After the addition of DBU to the mixture
HN
Ph
of (2S)-2 in CDCl
-chloroethanol, and (4S)-3 was then transformed from 4 with
high diastereoselectivity similar to the reported reaction of 4 to
3
, 4 began to form with the release of
O
O
2
Ph
Ph
O
O
N
N
O
O
19
(
4S)-3. In the case of the reaction from (2R)-2, identical pathways
OH
OH
O
(R)
(S)
would be given. Therefore, the diastereoselectivity-determining
step would be the intramolecular acyl transfer of 4 to give (4S)-3,
and the ratio of (2S)-2 and (2R)-2 did not reflect that of (4S)-3
and (4R)-3 at all.
4
(4S)-3
(4R)-3
Figure 1.
Figure 2. 1H NMR spectra (400 MHz) of the reaction of monocarbonate (2S)-2 to oxazolidinones (4S)-3 and (4R)-3 by treatment with DBU (3 equiv) in CDCl
5 °C: (a) monocarbonate (2S)-2 as a starting material before the addition of DBU, (b) monocarbonate (2R)-2, (c) 4 min; 2-chloroethanol (s), the sum of oxazolidinones (2S)-2
and (2R)-2 (d), and cyclic carbonate 4 (h), (d) 6 min, (e) 8 min, (f) 10 min, (g) 30 min, (h) 90 min, (i) cyclic carbonate 4, (j) a mixture of (4S)-3 (the major product) and DBU
3 equiv) in CDCl , and (k) a mixture of (4R)-3 (the minor product) and DBU (3 equiv) in CDCl
(0.04 mol/L) at
3
2
(
3
3
.

2
906
S. Sugiyama, K. Ishii / Tetrahedron: Asymmetry 21 (2010) 2904–2910
Figure 3. 1H NMR spectra (400 MHz) of the reaction of monocarbonate (2R)-2 to oxazolidinones (4S)-3 and (4R)-3 by treatment with DBU (3 equiv) in CDCl
5 °C: (a) monocarbonate (2S)-2, (b) monocarbonate (2R)-2 as a starting material before the addition of DBU, (c) 3 min; 2-chloroethanol (s), the sum of oxazolidinones (2S)-2
and (2R)-2 (d), and cyclic carbonate 4 (h), (d) 6 min, (e) 8 min, (f) 10 min, (g) 30 min, (h) 90 min, (i) cyclic carbonate 4, (j) a mixture of (4S)-3 (the major product) and DBU
3 equiv) in CDCl , and (k) a mixture of (4R)-3 (the minor product) and DBU (3 equiv) in CDCl
(0.04 mol/L) at
3
2
(
3
3
.
Figure 5. Time course of the reaction from (2R)-2 [the sum of (2S)-2 and (2R)-2; d]
to 2-oxazolidinones (4S)-3 and (4R)-3 (N, 97:3) via cyclic carbonate 4 (h) with the
release of 2-chloroethanol (s).
Figure 4. Time course of the reaction from (2S)-2 [the sum of (2S)-2 and (2R)-2; d]
to 2-oxazolidinones (4S)-3 and (4R)-3 (N, 97:3) via cyclic carbonate 4 (h) with the
release of 2-chloroethanol (s).
0
2
.2. Reaction of serinol 1 and N,N -disuccinimidyl carbonate
OH
Cl
(
2S)-2
DBU
2R)-2
0
Next we investigated the reaction of serinol 1 and N,N -disucc-
inimidyl carbonate (Table 1). The reaction using 1 equiv of N,N -
disuccinimidyl carbonate gave (4S)-3 and (4R)-3 in 91% yield but
(4S)-3
0
(major)
DBU
4
DBU
0
in poor selectivity (entry 1). Using 2 equiv of N,N -disuccinimidyl
(4R)-3
(
(
minor)
carbonate, 3 was obtained quantitatively (entry 2). A reaction in
the presence of DBU gave the products in similar diastereoselectiv-
ity (entry 3). It is worthy to note that the major product was (4R)-3,
which is a minor product of the reaction using CCF.
OH
Cl
Scheme 2. Pathways from monocarbonates (2S)-2 and (2R)-2 to 2-oxazolidinones
(4S)-3 and (4R)-3.

S. Sugiyama, K. Ishii / Tetrahedron: Asymmetry 21 (2010) 2904–2910
2907
Table 1
assigned as methyl group of serinol 1. The shift values of 1 in the
reaction mixture were different from that of pure 1 in CD CN
0
Reaction of serinol 1 and N,N -disuccinimidyl carbonate
3
DSC, DBU
[d 1.29 (3H, d, J = 6.6 Hz, Me)] (Fig. 6a). We confirmed that this
difference of the shift values was due to the effect of N-hydroxy-
CH CN or CD CN
3
3
0
(
4S)-3
+
(4R)-3
succinimide (Fig. 6b), which was given from N,N -disuccinimidyl
1
1
carbonate according to the reaction proceeding. H NMR shift
room temp, 5 h
values of the methyl group of serinol 1 in CD
succinimide (NHS) were as follows: 1 equiv of NHS, d 1.32
J = 6.6 Hz); 2 equiv of NHS, d 1.37 (J = 6.6 Hz); 3 equiv of NHS, d
3
CN with N-hydroxy-
0
Yielda
(%)
(4S)-3:(4R)-3b
(% de)
Entry Equiv of N,N -disuccinimidyl
Equiv of
DBU
carbonate
(
1
2
3
1
2
1
—
—
1
91
Quant.
71
33:67 (34)
32:68 (32)
36:64 (28)
1
.42 (J = 6.6 Hz).
All of these signals were useful to measure the yields of (4S)-3
and (4R)-3 by comparison with an integral value of triphenylmeth-
ane as an internal standard and allowed us to analyze the yields.
The results are shown in Figure 7. Oxazolidinones (4S)-3 and
a
Yields were calibrated with an internal standard (triphenylmethane) by 1
H
NMR integration except for entry 1 (isolated yield).
b
The ratio was obtained by the comparison of their 1H NMR integration.
(
4R)-3 were formed while keeping their ratio, and the reaction
2
.3. Reaction pathways from serinol 1 to oxazolidinones 3 using
was proceeded to give a mixture of (4S)-3 and (4R)-3 in 99% yield
within 20 min.
0
N,N -disuccinimidyl carbonate
During the reaction, we did not observe reaction intermediates
such as monocarbonates (2S)-6 and (2R)-6, dicarbonate 7 (Fig. 8),
To investigate the reaction pathways from serinol 1 to oxazolid-
0
1
inones (4S)-3 and (4R)-3 using N,N -disuccinimidyl carbonate
and cyclic carbonate 4 in the H NMR spectra (Fig. 6). When using
1
0
(
2 equiv), we observed the reaction by following H NMR spectra.
more than 2 equiv CCF and 1,1 -carbonyl diimidazole (CDI), the
The experiments were conducted in CD
3
CN (0.04 mol/L) at a probe
corresponding dicarbonates of 1 are formed and remained in the
14,19
temperature of 25 °C. Four minutes after the start of the reaction of
reaction mixture without forming oxazolidinone rings.
We
0
0
1
and N,N -disuccinimidyl carbonate, new signals began to appear
considered that the reaction of serinol 1 and N,N -disuccinimidyl
carbonate gave (2S)-6 and (2R)-6, which converted into oxazolidi-
nones (4S)-3 and (4R)-3, respectively, by a rapid intramolecular
cyclization. By analogy with CCF and CDI, we considered that
(Fig. 6). The signals which appeared at d 4.92 (1H, q, J = 7.1 Hz,
PhCH) and 4.98 (1H, q, J = 7.1 Hz, PhCH) were the benzylic protons
of (4S)-3 and (4R)-3, respectively. The signals at d 1.67 (3H, d,
J = 7.1 Hz, Me) and d 1.61 (3H, d, J = 7.1 Hz, Me) were the methyl
0
N,N -disuccinimidyl carbonate does not react with the amino group
0
protons of
a-methylbenzyl groups of (4S)-3 and (4R)-3, respec-
of serinol 1 in CD CN at 25 °C. For instance N,N -disuccinimidyl car-
3
tively. Another doublet signal at d 1.41 (3H, d, J = 6.6 Hz, Me) was
bonate almost did not react with N-benzyl-a-methylbenzylamine
Figure 6. Two regions of the 1H NMR spectra (400 MHz) of the reaction of serinol 1 to oxazolidinones (4S)-3 and (4R)-3 by treatment of N,N -disuccinimidyl carbonate
0
(
2 equiv) in CD
3
CN (0.02 mol/L) at 25 °C: (a) serinol 1, (b) a mixture of serinol 1 and N-hydroxysuccinimide (NHS) (3 equiv), (c) 4 min, (d) 6 min, (e) 8 min, (f) 10 min, (g)
1
2 min, (h) 14 min, (i) (4S)-3, (j) (4R)-3, (k) cyclic carbonate 4.

2
908
S. Sugiyama, K. Ishii / Tetrahedron: Asymmetry 21 (2010) 2904–2910
O
OH
N
O
no
4
reaction
(4S)-3:(4R)-3
quant.
CD3CN room
temp.
DBU
6.5 h
84:16
1
8 h
Scheme 3.
O
O
N,N'-disuccinimidyl carbonate
X
Ph
N
O
O
(
4S)-3
O
O
CD3CN, room temp., 24 h
N
N
O
O
(
4R)-8
O
Figure 7. Time course of the formation of (4S)-3 (N) and (4R)-3 (4) from serinol 1
O
0
(
}) and N,N -disuccinimidyl carbonate in CD
3
CN.
N,N'-disuccinimidyl carbonate
Ph
O
N
O
(
4R)-3
X
O
CD3CN, room temp., 24 h
O
(
4S)-8
O
HN
Ph
OH HO
HN
Ph
O
O
O
O
O
Scheme 4.
N
N
O
O
O
O
(2S)-6
(2R)-6
0
could be explained by the fact that N,N -disuccinimidyl carbonate
was more reactive to the hydroxyl groups of serinol 1 and less
reactive to those of the products (4S)-3 and (4R)-3, and that the
rapid cyclization of the intermediates (2S)-6 and (2R)-6 would pre-
vent the formation of dicarbonate 7.
O
HN
Ph
O
O
O
O
O
N
N
O
O
O
O
The diastereomeric ratio of (4R)-3/(4S)-3 (ca. 2:1) was influ-
enced by the reaction of one of the two hydroxyl groups of 1 with
7
0
N,N -disuccinimidyl carbonate, giving (2S)-6 and (2R)-6, because
Figure 8. Proposed intermediates (2S)-6 and (2R)-6 and imaginary product 7 for
the reaction of serinol 1 with N,N -disuccinimidyl carbonate.
0
the direct cyclization of (2S)-6 and (2R)-6 would proceed immedi-
ately and cyclic carbonate 4 did not exist in the reaction mixture
as an intermediate. Monocarbonates (2S)-6 and (2R)-6 were con-
verted into (4R)-3 and (4S)-3 without DBU. For the reaction of
1
in CD
3
CN at 25 °C within 20 min (checked by H NMR analysis).
1
Therefore, (2S)-6 and (2R)-6 were not observed by H NMR analy-
sis, and dicarbonate 7 did not form because the intramolecular
cyclization would be faster than the reaction of the monocarbon-
ates and N,N -disuccinimidyl carbonate.
To confirm the possibility of the existence of cyclic carbonate 4
in the reaction mixture of 1 and N,N -disuccinimidyl carbonate, we
(
2S)-2 and (2R)-2, DBU activated their hydroxyl groups to proceed
via interamolecular transesterifications and intramolecular acyl
transfer to give cyclic carbonate 4. Thus, the main product (4R)-3
was formed via (2R)-6 directly.
0
0
3
. Conclusion
investigated the reactivity of 4 in CD
NHS) should be obtained from the reaction of 1 and N,N -disuccin-
3
CN. N-Hydroxysuccinimide
0
(
The reaction pathways from monocarbonates (2S)-2 and (2R)-2
imidyl carbonate. Therefore, a mixture of 4 and NHS (1 equiv) in
CD CN was allowed to stand for 18 h at room temperature; how-
ever, 4 remained stable under these conditions (Scheme 3). After
the addition of DBU (3 equiv) to this ‘no reaction’ mixture, and
being left to stand for 6.5 h at room temperature, oxazolidinones
4S)-3 and (4R)-3 (84:16) were obtained quantitatively. In this
reaction the major product was (4S)-3, which was the minor
product of the reaction of 1 and N,N -disuccinimidyl carbonate
Table 1). These results indicated that cyclic carbonate 4 did
to 2-oxazolidinones (4R)-3 and (4S)-3 were investigated. Both (2S)-
and (2R)-2 were found to convert into cyclic carbonate 4 with the
3
2
release of 2-chloroethanol, after which 4 was converted into (4S)-3
in high diastereoselectivity via intramolecular acyl transfer.
Therefore, with regards to the reaction of serinol 1 to (4S)-3 and
(
13,14
(
4R)-3,
serinol 1 reacts with 2-chloroethyl chloroformate to
afford monocarbonates (2S)-2 and (2R)-2 (pathways A and B,
desymmetrization, Scheme 5). The overall reaction of serinol 1
0
(
0
not exist in the reaction mixture of 1 and N,N -disuccinimidyl
The diastereoselectivity of the reaction of serinol 1 and N,N’-disuccinimidyl
carbonate would be due to the nature of N,N’-disuccinimidyl carbonate more than the
conformation of 1 in CH CN. In fact, N,N’-disuccinimidyl carbonate reacted with the
3
pro-R hydroxymethyl group of 1 to give oxazolidinone (4R)-3, while, CCF reacted with
the pro-R and pro-S hydroxymethyl groups identically to give a ca. 1:1 mixture of
monocarbonates (2S)-2 and (2R)-2.14 For the reactions of 1 with benzoic anhydride
carbonate in CD
3
CN.
0
In addition, N,N -disuccinimidyl carbonate selected the hydro-
xyl groups as the reaction proceeded. First, N,N -disuccinimidyl
carbonate was added to two solutions of oxazolidinones (4S)-3
CN and allowed to stand for 24 h at room temper-
ature; however, N,N -disuccinimidyl carbonate did not react at all
Scheme 4). The quantitative yield of (4S)-3 and (4R)-3 from serinol
using 2 equiv of N,N -disuccinimidyl carbonate (Table 1, entry 2)
0
and (4R)-3 in CD
3
2 2
and 4-nitrobenzoic anhydride in CH Cl , the major products were the (2S)-
0
11
monobenzoate of 1 and the (2R)-mono-4-nitrobenzoate of 1, respectively. Thus,
the differences in the reactivities of the pro-R and pro-S hydroxyl groups of 1 mainly
depend on the acylating reagents.
(
1
0

S. Sugiyama, K. Ishii / Tetrahedron: Asymmetry 21 (2010) 2904–2910
2909
Diastereoselectivity-determining step
Asymmetric desymmetrization
Desymmetrization
Symmetrization
CCF
(
2S)-2
pathway C
pathway E
(
4S)-3
pathway A
(
major, 94 % de)
fast
*
*
*
1
4
*
*
*
slow
pathway F
CCF
(
4R)-3
minor)
pathway D
(2R)-2
(
pathway B
Scheme 5. Pathways from serinol 1 to 2-oxazolidinones (4S)-3 and (4R)-3 via monocarbonates (2S)-2 and (2R)-2 and cyclic carbonate 4 (*: DBU-mediated reaction14).
with 2-chloroethyl chloroformate gives diester 5 (5%), and no
N-acyl product of 1. Serinol 1 was also recovered in 27%. After
the addition of DBU both (2S)-2 and (2R)-2 were converted into 4
This report shows clearly that there are two possible reaction path-
ways from serinol 1 to oxazolidinones (4S)-3 and (4R)-3.
1
4
14
(
pathways C and D, symmetrization) with transesterification
4
4
4
. Experimental
between (2S)-2 and (2R)-2. 2-Oxazolidinone (4S)-3 was then ob-
tained from 4 via diastereoselective asymmetric desymmetrization
.1. Procedure for the time course studies
(
pathway E). Thus, this one-pot reaction includes the diastereose-
lective process of a novel desymmetrization-symmetrization-
desymmetrization, and the diastereoselectivity-determining steps
were determined to be pathways E and F.
.1.1. The reactions of serinol 1, CCF, and DBU (Figs. 2 and 3)
The time course studies of the reactions of serinol 1, CCF, and
DBU were carried out according to the procedure described in a
previous report. The NMR spectra were obtained with JEOL
JNM-GSX400 spectrometer using tetramethylsilane as an internal
standard. At first, DBU (10 mg, 65
of monocarbonate (2S)-2 (6.9 mg 23
1
4
The reaction pathways from serinol 1 to 2-oxazolidinones
0
(
4R)-3 and (4S)-3 using N,N -disuccinimidyl carbonate were also
0
investigated (Scheme 6). The reaction of 1 and N,N -disuccinimidyl
carbonate gave the 2-oxazolidinones and did not require DBU. The
proposed intermediates (2S)-6 and (2R)-6 and their transesterifica-
tion were not observed in 1H NMR spectra because of their fast
transformation to 3. Even though DBU was added to the reaction
mixture, the diastereoselectivity did not significantly change
l
mol) was added to a mixture
mol), pyridine-d (1.8 mL,
mol), and triphenylmethane (as the internal standard,
.7 mg, 7 mol) in CDCl (0.57 mL) in an NMR tube. After the tube
l
5
2
1
3 l
l
3
was shaken vigorously for a few seconds, the reaction was carried
out with spinning at a probe temperature at 25 °C, and the H NMR
spectra of the mixture were then measured immediately. Transe-
sterification was observed by the H NMR signals due to a mixture
1
(Table 1, entry 3). The formation of cyclic carbonate 4 was not
1
confirmed during the reaction. Even if 4 was formed, acyl transfer
giving the 2-oxazolidinones (4R)-3 and (4S)-3 did not proceed
without DBU (Scheme 3). Thus, the reaction of serinol 1 and
N,N -disuccinimidyl carbonate should be a diastereoselectivity-
determining step.
It is worthy of note that the two reaction pathways of serinol 1
to oxazolidinones (4S)-3 and (4R)-3 (Figs. 5 and 6) were completely
different. The reaction pathways with CCF were via cyclic carbon-
ate 4, while the reaction pathways with N,N -disuccinimidyl
carbonate did not proceed via 4. The diastereoselectivities of the
of (2S)-2 and (2R)-2 at d 3.65–3.75 ppm. We analyzed the yields of
the compounds in the reaction mixture using the following 1
H
0
NMR signals; the sum of 2-oxazolidinones (4S)-3 and (4R)-3, d
.16 (1H, q, J = 7.1 Hz) and d 5.18 (1H, q, J = 7.3 Hz) (these two sig-
nals partially overlap in CDCl in the presence of DBU); 2-chloro-
ethanol, d 3.81 (2H, t, J = 5.9 Hz); the sum of monocarbonates
2S)-2 and (2R)-2, d 2.85 [1H, m, for (2S)-2 and 1H, m, for (2R)-
5
3
(
0
2]; and cyclic carbonate 4, d 3.01 (1H, m). After observation for
1
20 min, the tube was allowed to stand for an additional 24 h at
0
reactions of serinol 1 with CCF and N,N -disuccinimidyl carbonate
depended on the different diastereoselectivity-determining steps.
room temperature. The reaction mixture was poured into satd
NH Cl aq and extracted with CH Cl . The extracts were combined,
dried, filtered, and concentrated in vacuo to give (4S)-3 (97%,
NMR analysis, and 94% de, HPLC analysis ). The reaction of mono-
carbonate (2S)-2 was also examined by this method.
4
2
2
1
H
1
4
Diastereoselectivity-determining step
Desymmetrization
0
4
.1.2. The reaction of serinol 1 and N,N -disuccinimidyl
carbonate (Fig. 6)
N,N'-disuccinimidyl
NMR spectra were obtained with JEOL JNM-GSX400 spectrome-
carbonate
(2S)-6
(4S)-3
minor)
ter using CD
N,N -disuccinimidyl carbonate in CD
3
CN residual peak as an internal standard. A solution of
CN was poured into an NMR
0
(
3
tube in which serinol 1 was present, and the mixture was shaken
1
4
vigorously for one minute. The reaction was carried out with spin-
ning at a probe temperature at 25 °C, and the H NMR spectra of
1
the mixture were then measured immediately. We analyzed the
(
2R)-6
(4R)-3
major)
yields of the compounds in the reaction mixture using the follow-
ing H NMR signals; 2-oxazolidinones (4S)-3, d 1.67 (3H, d,
J = 7.1 Hz). (4R)-3, d 1.61 (3H, d, J = 7.1 Hz). Serinol 1, d 1.41 (3H,
d, J = 6.6 Hz) at 4 min. As shown in Figure 6, this signal shifted
somewhat during the reaction.
N,N'-disuccinimidyl
(
1
carbonate
Scheme 6. Pathways from serinol 1 to 2-oxazolidinones (4S)-3 and (4R)-3 via
monocarbonates (2S)-6 and (2R)-6.

2
910
S. Sugiyama, K. Ishii / Tetrahedron: Asymmetry 21 (2010) 2904–2910
1
4
4
.1.3. H NMR spectra in CD
3
CN (400 MHz)
-methylbenzyl-2-oxazo-
. d: 7.42 (2H, d, J = 7.6 Hz, Ar), 7.34 (2H, t,
J = 7.6 Hz, Ar), 7.28 (1H, t-like m, Ar), 4.92 (1H, q, J = 7.1 Hz, PhCH),
.27 (1H, t, J = 8.8 Hz, CO CHH), 4.11 (1H, dd, J = 8.5, 5.1 Hz,
CO CHH), 3.88 (1H, m, NCH), 3.21 (2H, t-like m, CH OH), 2.62
1H, t-like m, OH), 1.67 (3H, d, J = 7.1 Hz, Me).
concentrated in vacuo, the residue was diluted with AcOEt, poured
into satd NH Cl aq, and extracted with AcOEt. The extracts were
combined, dried over MgSO , filtered, and concentrated in vacuo.
The residue was chromatographed on silica gel (hexane/AcOEt,
1:4) to give a mixture of (4S)-3 and (4R)-3 (33:67 mixture,
1.03 g, 91% yield).
.1.3.1. (4S, R)-4-Hydroxymethyl-3-
a
a
4
1
3,14,22
lidinones (4S)-3
4
4
2
2
2
(
Acknowledgment
4
.1.3.2. (4R,
lidinones (4R)-3
J = 7.1 Hz, PhCH), 4.19 (1H, t, J = 8.5 Hz, CO
J = 8.5, 4.6 Hz, CO CHH), 3.47–3.57 (3H, m, NCH, CH
1H, t-like m, OH), 1.61 (3H, d, J = 7.1 Hz, Me).
a
R)-4-Hydroxymethyl-3-
a
-methylbenzyl-2-oxazo-
. d: 7.27–7.40 (5H, m, Ar), 4.98 (1H, q,
CHH), 4.10 (1H, d,
OH), 2.93
1
3,14
This work was supported by a grant from the High-Tech Re-
search Center Project, the Ministry of Education, Culture, Sports,
Science and Technology (MEXT), Japan.
2
2
2
(
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.1.3.3. (R)-2-(
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.2. Reaction of serinol 1 and N,N -disuccinimidyl carbonate
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0
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nitrile (200 mL) at room temperature, and the mixture was stirred
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2
2
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