A study on the racemization step in the synthesis of pyrrolidinols via cyclic α-hydroxyimides

Article abstract of DOI:10.1016/j.tetasy.2011.01.012

Analytical HPLC methods for the determination of the enantiomeric excess of N-protected malimides 1 as well as the corresponding pyrrolidinol 5 and tartarimides 2 and 3 have been established. On this basis, a study to reveal the racemization step in the synthesis of pyrrolidinols from α-hydroxyacids, via chiral cyclic α-hydroxyimides, has been undertaken. It was confirmed that the known, one-step method for the synthesis of the N-protected chiral cyclic imides from α-hydroxydiacids proceeded with little racemization, and partial racemization has been proven to occur during the reduction of the resultant imide 1a with LAH to yield the corresponding pyrrolidinol 5. Conditions have been defined in order to avoid racemization in the LAH reduction step.

Full text of DOI:10.1016/j.tetasy.2011.01.012

Tetrahedron: Asymmetry 22 (2011) 257–263
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A study on the racemization step in the synthesis of pyrrolidinols via cyclic
a-hydroxyimides
⇑
⇑
Jin-Li Zheng, Hui Liu, Yu-Feng Zhang, Wei Zhao, Jin-Shuan Tong, Yuan-Ping Ruan , Pei-Qiang Huang
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen,
Fujian 361005, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Analytical HPLC methods for the determination of the enantiomeric excess of N-protected malimides 1 as
well as the corresponding pyrrolidinol 5 and tartarimides 2 and 3 have been established. On this basis, a
Received 24 November 2010
Accepted 11 January 2011
Available online 15 March 2011
study to reveal the racemization step in the synthesis of pyrrolidinols from
cyclic -hydroxyimides, has been undertaken. It was confirmed that the known, one-step method for
the synthesis of the N-protected chiral cyclic imides from -hydroxydiacids proceeded with little racemi-
a-hydroxyacids, via chiral
a
a
zation, and partial racemization has been proven to occur during the reduction of the resultant imide 1a
with LAH to yield the corresponding pyrrolidinol 5. Conditions have been defined in order to avoid race-
mization in the LAH reduction step.
Ó 2011 Elsevier Ltd. All rights reserved.
HO
HO
OH
BnO
O
OBn
O
1. Introduction
In the field of asymmetric synthesis, access to enantiopure chiral
building blocks, chiral auxiliaries, and chiral ligands is essential.
Enantiomerically pure cyclic imides derived from a-hydroxydiacids,
such as malimides 1 and tartarimides 2 and 3 (Fig. 1), have been
widely used as chiral building blocks, chiral auxiliaries, and chiral li-
gands in asymmetric synthesis.1 Two methods are generally used for
their synthesis. The first one is the direct thermally induced conden-
O
O
O
O
N
P
1
N
P
2
N
PMB
3
(a. P = Bn; b. P = PMB; c. P = Me)
Figure 1. Structure of malimides 1 and tartarimides 2, 3.
sation between an amine and an a-hydroxydiacid (Scheme 1, Meth-
od A)2–5 and the second one consists of a one-pot activation–
condensation-ring closure, followed by deacetylation (Method B).6,7
The simplicity of the thermic condensation method is quite
attractive. However, an early report by Joullié et al. on the enantio-
selective synthesis of (3S)-pyrrolidinol 5 (by direct condensation of
over, the use of (S)-malimide 1c, prepared from L-malic acid by
the direct thermal condensation with methylamine, as a chiral aux-
iliary in the asymmetric Diels–Alder reaction, has been shown to
give, after cleavage of the chiral auxiliary (S)-malimide 1c,
compound 10 in only 84% ee (Scheme 4).4d However, racemization
has not been noted in previous reports on similar
transformations.4a,b
These apparently contradictory results might account for the
fact that the one-pot multi-step method (Method B) is more fre-
quently adopted for the synthesis of malimides than the more con-
venient thermal condensation method.6 In view of the importance
of both the chiral imides 1 and 2, as well as their reduced products
(hydroxylated pyrrolidines such as 58) in asymmetric synthesis,
and as medicinal agents,9 it was important to clarify these issues
and establish racemization-free methods. In connection with our
longstanding interest in the development of enantiomerically pure
cyclic imide-based synthetic methodologies,1c,10 we undertook an
investigation to quantify the extent of racemization in the synthe-
sis of malimides 1 and tartarimide 2 by Method A (Scheme 1), as
L-malic acid with benzylamine followed by reduction of the result-
ing malimide 1a with lithium aluminum hydride) in only 84% ee
(Scheme 2, Method A) led us to question the occurrence of partial
racemization during the thermic condensation step.2b In this con-
text, on the basis of a comparison of the mp and specific rotation
data, Nagel and Nedden indicated3 that the preparation of malimide
1a by Joullié et al. proceeded with some racemization. Nagel et al.
also reported that the reduction of malimide 1a with either LAH,
or B2H6/diglyme, or BH3/THF proceeded with partial racemization
that yielded 5 in 92% ee, while the reduction of the corresponding
acetate 4a6h proceeded without racemization (Scheme 3).3 More-
⇑
Corresponding authors. Fax: +86 592 2186400 (P.-Q.H.).
E-mail addresses: ypruan@xmu.edu.cn (Y.-P. Ruan), pqhuang@xmu.edu.cn (P.-Q.
Huang).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.01.012

258
J.-L. Zheng et al. / Tetrahedron: Asymmetry 22 (2011) 257–263
HO
(OH)n
O
HO
HO
HO
(OH)n
BnNH2, xylene
reflux
PNH2, xylene
*
O
O
HOOC
COOH
N
Me
O
HOOC
COOH
reflux
Method A
N
P
55%
L-malic acid
malic acid (n = 0)
tartaric acid (n = 1)
(S)-N-methylmalimide
1. malimide (n = 0)
2. tartarimide (n = 1)
1c
O
O
TiCl4
D
2H4-butadiene
O
N
Me
AcCl, reflux;
OX
D
Method B
O
0 °C
93%
PNH2,
D
EtOH, AcCl, rt
(OAc)n
O
(S)-8
CH2Cl2, reflux;
AcCl, reflux
D
9
Xc
. X =
AcO
LiOH/H2O2
82%
(single diastereomer)
O
10. X = H
(84% e.e.)
O
N
O
Xc
O
O
N
P
4. (P = Bn, PMB, Me)
Me
Scheme 1. Two main methods for the synthesis of malimides 1 and tartarimides 2.
Scheme 4.
of benzylamine and L-malic acid in absolute ethanol was heated at
HO
HO
HOOC
BnNH2, EtOH
reflux for 0.5 h and concentrated under reduced pressure. Benzene
was added to the residue and the resultant mixture was heated at
reflux for 3.5 h with removal of the resulting water by a Dean–
Stark apparatus. The ee of the resulting (S)-malimide 1a was
shown to be >99.1% by HPLC analysis on a chiral stationary phase
(vide infra). This result meant that little racemization occurred
during the synthesis of malimide 1a by the thermal condensation
method (Joullié’s method).
165-170 °C,
C6H6
COOH
O
O
N
Bn
62%
L-malic acid
(S)-N-benzylmalimide
1a
MeO
Ph
CF3
HO
LiAlH4, THF
MTPACl
THF
O
With dual aims both to simplify the procedure and to substitute
benzene by a less toxic solvent, two more frequently used building
blocks (R)- and (S)-N-p-methoxybenzylmalimide 1b1-5 were syn-
O
heat, 3 h
66%
N
Bn
N
Bn
(S)-5
thesized from L- and D-malic acid, respectively, by heating with
6
(84% e.e. determined via
)
6
(3S,3'S)- (84% e.e.)
para-methoxybenzylamine in xylene at reflux for 8 h (Scheme 1).
The yields of (R)- and (S)-1b were improved to 92% and 90%,
respectively, after one recrystallization. As can be seen from Table 1
(entries 2 and 3), the enantiomeric excesses of the products were
still quite high. For the sake of comparison, the O-acetylmalimide
derivative was synthesized by a one-pot three-step procedure
(Method B, Scheme 1). Deacetylation in AcCl-containing absolute
ethanol at rt gave (S)- and (R)-malimide (S)-1b and (R)-1b in 85%
overall yield with 98.6% and 99.5% ee, respectively (Table 1, entries
4 and 5). At this stage, it was clear that both Joullié’s method
(Scheme 2) and its modified version (Method A in Scheme 1) pro-
ceeded with little racemization.
Scheme 2. Joullié’s synthesis of (3S)-N-benzylpyrrolidinol 5.
RO
HO
BnNH2, xylene
1a
reflux (to );
O
O
HOOC
COOH
N
4a
ref. 6h (to
)
L-malic acid
Bn
(S)-1a. R = H
(S)-4a. R = Ac
LAH or
B2H6/diglyme
or BH3/THF
We next investigated the reduction of malimide 1a to reveal the
origin of the low ee of the reducing product 5. Treatment of a THF
F3COCO
HO
Table 1
N
N
Bn
Conditions for the synthesis of malimide 1
92%e.e. from 1a;
COCF3
without racemization
Entry Starting
material
Method Amine
Product Yieldd
(%)
eee
(%)
from 4a
7
(S)-5
(92% e.e. by GC)
1
Aa
Ab
Ab
Bc
Bc
Bc
BnNH2
1a
62
92
90
85
85
96
99.1
99.2
98.5
98.6
99.5
L
L
-Malic acid
-Malic acid
-Malic acid
-Malic acid
-Malic acid
-Malic acid
Scheme 3.
2
3
4
5
6
PMBNH2 1b
PMBNH2 1b
PMBNH2 1b
PMBNH2 1b
D
L
well as in the reduction of malimide with LAH and the results are
reported herein.
D
f
BnNH2
1a
ꢀ
L
a
2. Results and discussion
2.1. Synthesis
Joullié’s method was used (EtOH; then reflux in benzene for 3.5 h, cf. Scheme 2).
Modified Joullié’s method was used (reflux in xylene for 8 h, cf. Scheme 1,
b
Method A).
c
Four-step method was used (cf. Scheme 1, Method B).
Isolated yield.
Determined by chiral HPLC, relative error 0.4% (cf.SI).
Not determined.
d
e
f
(S)-N-Benzylmalimide 1a was synthesized from
L-malic acid in
62% yield by Joullié’s method, as shown in Scheme 2.2b A solution

J.-L. Zheng et al. / Tetrahedron: Asymmetry 22 (2011) 257–263
259
solution of (S)-malimide 1a with LiAlH4 at reflux for 3 h produced
(3S)-pyrrolidinol 5 in 55% yield. HPLC analysis showed that the ee
of the resultant (S)-pyrrolidinol 5 was 89.8%, which is comparable
to that observed by Joullié (84% ee).2b This result indicated that the
observed lower ee of 5 was the result of partial racemization,
which occurred in the LAH reduction step. It was envisioned that
the racemization could be avoided by running the reaction under
milder conditions. Indeed, by the slow addition of malimide 1a
to a suspension of LAH in THF at ꢀ15 °C and stirring the resultant
mixture at rt for 4 h, (3S)-pyrrolidinol 5 was obtained in 53% yield
with an ee of 98.5% (Table 2, entry 2). Similarly, the reduction of
(S)-malimide 1a with NaBH4-I24g in THF at reflux afforded pyrrolid-
inol 5 in 84.9% ee, which was improved to 93.9% ee by running the
reaction at rt.
HO
OH
BnO
OBn
NaH, BnBr, DMF
−20 ~ 0 °C
80-88%
ROOC
COOR
ROOC
COOR
D-tartaric acid
(11, R = H)
12. R = Et
EtOH
LiOH aq.
EtOH
13. R = Et
14
SOCl2, rt
quantitative
0 - 5 oC
. R = H
quantitative
HO
OH
BnO
OBn
AcCl, reflux
PMBNH2, CH2Cl2
O
O
O
O
N
PMB
N
AcCl, reflux
90%
PMB
3
2b
Scheme 5.
Table 2
Reduction of malimide 1a
With regard to the synthesis of tartarimide 3 and its analogues,
the four-step method shown in Scheme 5 was generally adopte-
d.7a,c,f–h,10c,12 Although high yields of the tartarimides 2a and 2b
were obtained by Method A, the dibenzylation of tartarimide 2b
produced the O,O-dibenzylated product 3 in only 45–50% yields,
which made this method less efficient than that of the multi-step
method (80% overall yield).10c
HO
HO
reduction
O
O
N
Bn
N
Bn
(S)-N-benzylmalimide 1a
(S)-5
Entry
Reducing reagent
Conditions
Yielde (%)
eef (%)
2.2. Chromatographic enantioseparation
1
2
3
4
LiAlH4
LiAlH4
NaBH4-I2
NaBH4-I2
Aa
Bb
Cc
Dd
55
53
50
52
89.8
98.5
84.9
93.9
A type of polysaccharide chiral columns13 were selected to
determine the enantiomeric excesses of N-protected malimides 1
and tartarimides 2 and 3. The results of the enantioseparation of
five pairs of N-protected cyclic imides 1–3 and 3-pyrrolidinol 5
using Chiralpak AD-H, Chiralcel OD-H, and Chiralcel OB-H columns
with n-hexane/ethanol (or n-hexane/2-propanol) as the mobile
phase are summarized in Table 4. The elution order of the enanti-
omers was determined by comparing the corresponding enantio-
merically enriched samples. It was evident that an increase in
the concentration of ethanol from 30% to 40% resulted in a de-
creased retention, but the resolution decreased for most of the cyc-
lic imides.
a
Conditions A: slow addition of malimide to LAH at 0 °C followed by reaction in
THF at reflux for 3 h.
b
Conditions B: slow addition of malimide to LAH at ꢀ15 °C followed by reaction
at rt for 4 h.
c
Conditions C: slow addition of malimide to NaBH4-I2 at 0 °C followed by reac-
tion in THF at reflux for 8 h.
Conditions D: slow addition of malimide to NaBH4-I2 at 0 °C followed by
reaction at rt for 8 h.
d
e
Isolated yield.
Determined by chiral HPLC, relative error 0.4% (cf.SI).
f
Chromatograms of the enantioseparations of malimide 1a and
1b and tartarimides 2b and 3 on the Chiralpak AD-H column using
n-hexane/ethanol (60:40 v/v) are shown in Figure 2. N-Benzylmal-
imide 1a and N-p-methoxybenzylmalimide 1b were well resolved.
A longer retention time and higher resolution of malimide 1b than
those of malimide 1a were observed. The enantioseparation factors
(a) for 1a and 1b were 1.36 and 1.51, respectively. The elution or-
der for 1a and 1b are the same; that is, the (R)-malimides eluted
first.
We next investigated the synthesis of tartarimides 2. As in the
case of malimides 1, both one-step5 and multi-step methods7 have
been used for the synthesis of tartarimides 2. The direct thermal
condensation method afforded the corresponding tartarimides 2
in 45–90% yields,5e,11 along with a small amount of epimerized
meso by-product.5e To compare the two methods, we synthesized
(R)- and (S)-N-(p-methoxybenzyl)tartarimides 2a and 2b by
Method A (Scheme 1). As shown in Table 3, both 2a and 2b were
formed in 90–92% yields with excellent ee (P99%). These results
also confirmed that little racemization occurred by Method A.
N-p-Methoxybenzyltartarimide 2b and N-p-methoxybenzy-3,4-
dibenyltartarimide 3 were also resolved on the Chiralpak AD-H
Table 3
Conditions used for the synthesis of tartarimides 2
Entry
Starting material
Method
Amine
Conditions
Product
Yield (%)
eea (%)
1
2
3
4
5
6
7
8
A
A
A
A
A
A
B
B
BnNH2
Reflux in xylene, 8 h
Reflux in xylene, 1 h
Reflux in xylene, 2 h
Reflux in xylene, 4 h
Reflux in xylene, 8 h
Reflux in xylene, 15 h
Four-step method
2a
2b
2b
2b
2b
2b
3
91
12
36
72
91
93
80
81
99.0
99.1
99.0
99.1
99.0
99.0
99.1
99.0
L
L
L
L
L
L
-Tartaric acid
-Tartaric acid
-Tartaric acid
-Tartaric acid
-Tartaric acid
-Tartaric acid
PMBNH2
PMBNH2
PMBNH2
PMBNH2
PMBNH2
PMBNH2
PMBNH2
D
-Tartaric acid
Four-step method
3
L-Tartaric acid
a
Determined (on the products obtained after one recrystallization from water) by chiral HPLC, relative error 0.4% (cf.SI).

260
J.-L. Zheng et al. / Tetrahedron: Asymmetry 22 (2011) 257–263
Table 4
Optimal enantioseparation for cyclic imides and 3-pyrrolidinol conditions on different CSPs and chromatographic parameters: retention factors (k01), enantioseparation factor (
and resolution (Rs)a
a)
k10
Solute
Column
Mobile phase (v/v)
a
Rs
6.18
1a
AD-H
AD-H
n-Hexane/ethanol 70:30
n-Hexane/ethanol 60:40
2.438 (R)
1.506 (R)
1.36
1.36
5.04
1b
2a
AD-H
AD-H
n-Hexane/ethanol 70:30
n-Hexane/ethanol 60:40
6.630 (R)
4.965 (R)
1.48
1.51
8.48
8.16
AD-H
AD-H
AD-H
n-Hexane/ethanol 70:30
n-Hexane/2-propanol 90:10
n-Hexane/2-propanol/ethanol 80:5:15
2.575 (S,S)
3.565 (S,S)
4.369 (R,R)
1.07
1.09
1.31
1.00
1.23
4.84
2b
3
AD-H
AD-H
n-hexane/ethanol 70:30
n-hexane/ethanol 60:40
5.403 (S,S)
3.251 (S,S)
2.85
2.80
10.0
5.92
AD-H
AD-H
n-Hexane/ethanol 70:30
n-Hexane/ethanol 60:40
5.308 (R,R)
4.510 (R,R)
1.36
1.32
5.94
5.11
5
OD-H
OB-H
n-Hexane/2-propanol 97:3
n-Hexane/ethanol 98:2
3.060
1.977 (R)
1.10
1.16
1.05
2.03
a) were calculated as a
¼ k02=k01, where k10 and k02 are retention factors for the
a
The retention factors (k0) were determined as k0 = (tR ꢀ t0)/t0. The enantioseparation factors (
first and second eluting enantiomers, respectively. The resolutions (Rs) were calculated by the following formula: Rs = 2(tR,2 ꢀ tR,1)/(w1 + w2), where w1 and w2 are baseline
peak widths for the first and second eluting enantiomers, respectively.
a
b
(S)-1a
(R)-1a
(R)-1b
(S)-1b
6
7
8
9
10
11
12
10
12
14
16
18
20
22
t (min)
t (min)
c
d
(R,R)-3
(S,S)-2b
(R,R)-2b
(S,S)-3
6
8
10
12
14
16
12
13
14
15
16
17
18
19
Time (min)
Time (min)
Figure 2. Chromatograms of artificially mixed enantiomers (ca. 1:1 ratio) of malimides and tartarimides on Chiralpak AD-H column. (a) 1a, (b) 1b, (c) 2b, (d) 3. Eluent: n-
hexane/ethanol 60:40 v/v for (a, b) and 40:60 v/v for (c, d); Detection: UV 250 nm; t = 30 °C; flow: 1 mL/min.
column. The best enantioseparation (
a
= 2.80) was obtained for
ethanol (80:5:15 v/v) as the mobile phase. This reversal of the elu-
tion order of the enantiomers on the Chiralpak AD-H column is an
impressive chromatographic phenomenon. It may result from an
alteration of the steric environment of the chiral cavities when
the alcohol modifier was changed.13b
Joullié et al. described the determination of the enantiomeric
purity of (S)-3-pyrrolidinol via Mosher’s ester 6 by 19F NMR2b
(Scheme 2). Tomori et al. described the determination of the enan-
tiomeric purity of (S)-3-pyrrolidinol using HPLC on a Chiralcel OJ-H
column.13b To develop a chiral HPLC method to monitor the enan-
tiomeric purity of (S)-3-pyrrolidinol, we first attempted enantio-
separation of 3-pyrrolidinol with the Chiralpak AD-H column.
However, no enantioseparation was observed using n-hexane/eth-
tartarimide 3. The elution order of 2b was opposite to that of 3.
For 2b, (S,S)-2b eluted first, while (R,R)-3 eluted first for 3. On
the Chiralpak AD-H column, baseline separation could not be
achieved for N-benzyltartarimide 2a with either n-hexane/ethanol
or n-hexane/2-propanol as the mobile phase. Nevertheless, N-ben-
zyltartarimide 2a was well resolved on the Chiralpak AD-H column
when using n-hexane/2-propanol/ethanol (80:5:15 v/v) as the mo-
bile phase (Fig. 3). It is noteworthy that there were remarkable
changes in the enantioselectivity and the elution order. For 2a on
the Chiralpak AD-H column, (S,S)-2a eluted first with n-hexane/
ethanol (70:30 v/v) or n-hexane/2-propanol (90:10 v/v) as the mo-
bile phase, while (R,R)-2a eluted first with n-hexane/2-propanol/

J.-L. Zheng et al. / Tetrahedron: Asymmetry 22 (2011) 257–263
261
a
b
(S,S)-2a
(R,R)-2a
(R,R)-2a
(S,S)-2a
8
9
10
11
12
13
14
10
12
14
16
Time (min)
18
20
Time (min)
c
(S,S)-2a
(R,R)-2a
10
12
14
16
18
20
22
24
Time (min)
Figure 3. Chromatograms of artificially mixed enantiomers (ca. 1:1 ratio) of the tartarimide 2a on a Chiralpak AD-H column, using mobile phases: (a) n-hexane/ethanol 60:40
v/v, (b) n-hexane/2-propanol 90:10, (c) n-hexane/2-propanol/ ethanol 80:5:15. Detection: UV 250 nm; t = 30 °C; flow: 1 mL/min.
a
b
(R)-5
(S)-5
10
12
14
16
18
8
10
12
14
Time (min)
Time (min)
Figure 4. Chromatograms of artificially mixed enantiomers (ca. 1:1 ratio) of 3-pyrrolidinol 5. (a) Chiralcel OD-H, n-hexane/2- propanol 97:3 v/v, (b) Chiracel OB-H, n-hexane/
ethanol 98:2 v/v. Detection: UV 210 nm; t = 30 °C; flow: 1 mL/min.
anol as the mobile phase (retention factor >2) on the Chiralpak
AD-H. When HPLC separation of 3-pyrrolidinol 5 was performed
on a Chiralcel OD-H column using n-hexane/2-propanol (97:3 v/
v) as the mobile phase, enantioseparation was partially achieved,
but did not reach a baseline enantioseparation (Fig. 4a). 3-Pyrrolid-
inol 5 was well resolved on a Chiralcel OB-H column with n-hex-
ane/ethanol (98:2 v/v) as a mobile phase, as shown in Figure 4b
of malimides 1 and tartarimides 2 proceeded with little racemiza-
tion; (2) the reduction of malimide 1a by LAH or by NaBH4-I2 to
the corresponding 3-pyrrolidinol 5 in THF at reflux led to significant
racemization, which was largely avoided by running the reaction at
rt or lower temperature; (3) the direct thermic condensation meth-
od (Method A) is less efficient for the synthesis of fully protected
tartarimide derivative 3 than the multi-step method (Method B).
It is believed that the conclusions gained from this study are of va-
(cf. Table 2). The enantioseparation factor (a) was 1.16, and the
(R)-enantiomer eluted first.
lue in the field of asymmetric synthesis using a-hydroxyimide-de-
rived chiral building blocks, chiral auxiliaries, and chiral ligands.
3. Conclusion
4. Experimental
In conclusion, we have undertaken a detailed study on the one-
step synthesis of chiral non-racemic cyclic imides from -hydrox-
a
4.1. General methods
ydiacids, and the reduction of the resulting malimide 1a to give
3-pyrrolidinol 5. Through the establishment of a chiral HPLC enan-
tioseparation method, we were able to reveal that: (1) the direct
thermal condensation method (Method A) used for the synthesis
Melting points were determined on a Yanaco MP-500 micro
melting point apparatus and are uncorrected. Infrared spectra were
measured with a Nicolet Avatar 360 FT-IR spectrometer using film

262
J.-L. Zheng et al. / Tetrahedron: Asymmetry 22 (2011) 257–263
KBr pellet techniques. 1H NMR spectra were recorded in CDCl3 on a
Bruker 400 spectrometer with tetramethylsilane as an internal
standard. Chemical shifts are expressed in d (ppm) units downfield
from TMS. Mass spectra were recorded by a Bruker Dalton ESquire
3000 plus liquid chromatography-mass spectrum (direct injec-
tion). Optical rotations were measured with a Perkin–Elmer 341
automatic polarimeter. Flash column chromatography was carried
out with silica gel (300–400 mesh). THF was distilled over sodium
benzophenone ketyl under N2.
(ddd, J = 8.8, 5.4, 3.2 Hz, 1H, H-5), 3.62 (br s, 3H, PhCH2 and OH),
4.30 (dddd, J = 10.0, 7.8, 5.4, 2.4 Hz, 1H, H-3), 7.21–7.35 (m, 5H,
PhH) ppm; 13C NMR (100 MHz, CDCl3): d 34.6, 52.6, 60.0, 62.8,
69.6, 126.9, 128.3, 128.7, 139.4 ppm. HRMS calcd for
[C11H16NO+H+]: 178.1232; found: 178.1233.
Acknowledgments
The authors are grateful to the NSF of China (20832005),
NFFTBS (No. J1030415) and the National Basic Research Program
(973 Program) of China (Grant No. 2010CB833200) for financial
support.
4.2. Typical procedure for the one-pot synthesis of cyclic imides
from a-hydroxydiacids: synthesis of (S)-3-hydroxy-N-(4-
methoxybenzyl) pyrrolidine-2,5-dione (S)-1b
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To a two-necked round bottom flask equipped with a Dean–
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leum ether and subjected to flash chromatography on silica gel
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½
a 2D0
ꢁ
¼ ꢀ67:5 (c 0.9, CHCl3) {lit.10a,b
½
a 2D0
ꢁ
¼ ꢀ65:4 (c 0.52, CHCl3)}. The spectroscopic data are in agree-
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dione (S,S)-2b
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Following the typical procedure, reaction of D-tartaric acid gave
(S,S)-2b as white crystals in 91% yield after recrystallization from
water. The ee of this product was determined to be 99.0% (vide su-
pra). Mp 185–187 °C (H2O). ½a D20
¼ ꢀ97:4 (c 0.5, MeOH); IR (neat)
ꢁ
3286, 2962, 1710, 1692, 1612, 1515, 1432, 1384, 1352, 1289,
1260, 1161, 1094, 1026 cmꢀ1 1H NMR (400 MHz, DMSO-d6) d
;
3.72 (s, 3H, OMe), 4.31–4.37 (m, 2H, OCH), 4.46 (d, J = 14.6 Hz,
1H, NCH2), 4.52 (d, J = 14.6 Hz, 1H, NCH2), 6.22–6.32 (m, 2H, OH),
6.88 (d, J = 8.6 Hz, 2H, Ar-H), 7.19 (d, J = 8.6 Hz, 2H, ArH) ppm;
13C NMR (400 MHz, DMSO-d6): d 41.15, 55.56, 74.96, 114.38,
128.50, 129.65, 159.16, 174.96 ppm; HRESIMS calcd for
[C12H13NO5+H+]: 252.0866; found: 252.0868.
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4.4. (S)-N-Benzylpyrrolidin-3-ol 5
To a cooled (ꢀ15 °C) suspension of lithium aluminum hydride
(152 mg, 4 mmol) in THF (5 mL) was added dropwise a solution
of N-benzyl-3-hydroxysuccinimide (205 mg, 1 mmol) in dry THF
(5 mL). The mixture was allowed to warm to rt and stirred for
4 h. The reaction was quenched by the successive addition of
0.2 mL of H2O, 0.2 mL of 4 M aqueous NaOH, and 0.6 mL of H2O
at 0 °C. The solid was filtered and washed with CH2Cl2
(5 ꢂ 5 mL). The combined organic layers were dried over anhy-
drous MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel
(eluent: CH2Cl2/MeOH 10: 1) to afford compound 5 (94 mg, yield:
53%) as a pale yellow oil. The ee of this product was determined to
be 98.5% (vide supra).
½
a 2D5
ꢁ
¼ ꢀ5:3 (c 1.0, CHCl3)] {lit.14
½
a 2D5
ꢁ
¼ ꢀ3:145 (c 1.2, CHCl3) for 5 with ca. 100% ee); lit.2b
½
a 2D5
ꢁ
¼ ꢀ2:47 (c 1.175, CHCl3) for 5 with 84% ee)}; IR (neat):
3373, 3067, 3028, 2955, 2925, 2848, 1665, 1453, 1378, 1261,
1211, 1083, 1028 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.71 (dddd,
.
J = 8.5, 7.8, 6.4, 3.2 Hz, 1H, H-4), 2.17 (dddd, J = 8.5, 10.0, 5.4,
2.5 Hz, 1H, H-4), 2.35 (ddd, J = 8.8, 6.4, 2.5 Hz, 1H, H-5), 2.58 (dd,
J = 10.2, 5.4 Hz, 1H, H-2), 2.64 (dd, J = 10.2, 2.4 Hz, 1H, H-2), 2.83
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