A facile approach to trans-4,5-pyrrolidine lactam and application in the synthesis of nemonapride and streptopyrrolidine

Article abstract of DOI:10.1016/j.tet.2011.07.049

An efficient approach to trans-4-hydroxylpyrrolidine lactams 1 starting from amino acid is described. The utility of this method has been demonstrated in the synthesis of antipsychotic nemonapride 3 and antiangiogenic streptopyrrolidine 4. Compared four s

Full text of DOI:10.1016/j.tet.2011.07.049

Tetrahedron 67 (2011) 7829e7837
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Tetrahedron
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A facile approach to trans-4,5-pyrrolidine lactam and application in the synthesis
of nemonapride and streptopyrrolidine
,
,b,
*
Wei Huang a b, Jing-Yi Ma a, Mu Yuan a, Long-Fei Xu a, Bang-Guo Wei a
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
b Institutes of Biomedical Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 June 2011
Received in revised form 6 July 2011
Accepted 19 July 2011
Available online 22 July 2011
An efficient approach to trans-4-hydroxylpyrrolidine lactams 1 starting from amino acid is described. The
utility of this method has been demonstrated in the synthesis of antipsychotic nemonapride 3 and an-
tiangiogenic streptopyrrolidine 4. Compared four synthetic stereoisomers of natural streptopyrrolidine 4
in term of spectroscopic and physical data, the absolute structure of the natural product was proposed as
(4S,5S)-configuration.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloid
Lactam
Asymmetric synthesis
Nemonapride
Streptopyrrolidine
1. Introduction
obtained from pyrrodinone by reductive alkylation6 or nucleophilic
substitution,8 which usually required multiple steps, and led to an
Functionalized 5-substituted pyrrolidine lactams 1 and pyrro-
lidines 2 (see Fig. 1) are common structural motif found in a wide
variety of biologically active natural products and pharmaceuticals.
As a prime instance, the racemic form of nemonapride (formerly
called emonapride) 3 has been used as a dopamine receptor an-
tagonist since 1991.1,2 Because of its high efficacy and intriguing
structure, the synthesis of nemonapride 3 in optically pure form
has attracted lots of attention, and several synthetic approaches
have been reported recently.3 From the practical point of view, the
most straightforward way is the asymmetric construction of opti-
cally active 2-amino or 2-hydroxyl pyrrolidine unit 2. The pyrroli-
dine 2 could be derived from pyrrolidinone 1, however, the
transformation is strongly limited since the control of the desired
stereochemistry of the substituents on the heterocycle is
a challenge.4
unsatisfactory overall yield. Only few direct methods for the
preparation of trans-1 have appeared, which gave moderate to high
enantioselectivities. It is noted that so far either oxidative
O
OMe
HN
OH
N
OH
NHMe
Cl
O
N
H
Ph
X
R
N
Nemonapride 3
Streptopyrrolidine 4
R'O
O
MeO
1 X= O; 2 X=2H
O
H
O
O
O
O
N
O
In past decades, tremendous efforts have been devoted to the
development of stereospecific preparation of trans or cis-4-
hydroxyl-5-substituted pyrrolidine lactams, and a number of
powerful approaches have been reported.3a,e,5,6 A common strategy
for the synthesis of optically pure cis-1 was the stereoselective
reduction of tetramic acid derivatives,5a,b,d,7 while trans-1 was
NH
n-C7H15
O
N
O
OH
Ph
NH
O
O
OH
OH
6 Hapalosin
5 Melleumin A
* Corresponding author. Tel./fax: þ86 21 54237757; e-mail address: bgwei1974@
Fig. 1. The structure of several bioactive molecules.
fudan.edu.cn (B.-G. Wei).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.049

7830
W. Huang et al. / Tetrahedron 67 (2011) 7829e7837
cyclization9d of primary alcohol9aec or the condensation of car-
boxylic acid with amide in the presence of Bop-Cl10 appears to be
convenient way.
Table 1
Highly diastereoselective reduction of
a
-aminoketonesa
O
O
O
In continuation of our interests in pursuing the building blocks
based methods for the synthesis of piperidine alkaloids, dep-
sipeptides, and ceramides,11 we decided to develop a novel ap-
proach for the asymmetric synthesis of 2-substituted 3-hydroxy
piperidine alkaloids and their analogues. Herein we report a facile
method for the preparation of trans-4-hydroxyl-5-substituted
pyrrolidine lactam 1 starting from amino acid, and are used in
the asymmetric synthesis of nemonapride 3 and all isomers of
natural streptopyrrolidine 4. Moreover, the possible configuration
of the natural streptopyrrolidine 4 was proposed by comparing
their spectroscopic and physical data with the natural product 4
(Fig. 2). The advantages of this methodology cover: (1) a facile
method for preparation of building blocks possessing the skeleton
of trans-pyrrolidine lactam, (2) high tolerance of functional groups
in the substrates, (3) the traditional conversion of terminal olefins
to alcohols is replaced by using Ruthenium/NaIO4 oxidative cycli-
zation, (4) all the materials are derived from inexpensive reagents.
[H-]
HN
R2
OR1
HN
R2
OR1
HN
OR1
+
R2
OH
R=H, cis-10a-h
O
9a-h
OR
R=H, trans-10a-h
TBSCl, Imid.
R=TBS, 7a-h
DMF, 12h, 91-95%
Entrya
R1
R2
trans-10
Yb
%
anti/syn c
d
1
2
3
4
5
6
7
8
t-Bu
Bn
Me
Me
Me
Me
10a
10b
10a
10a
10a
10c
10d
10e
10f
82
88
85
93
96
92
95
91
87
94
95
53:47
99:1
98:2
99:1
99:1
99:1
99:1
98:2
97:3
98:2
d
e
e
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
f
g
Me
g
CHMe2
CH2CHMe2
CH2OTBS
Cyclohexyl
Bn
g
g
g
9
g
10
11
10g
10h
d
H
O
a
The reaction was performed with 2.0 mmol of reductive reagents and 1 mmol of
OMe
OTBS
O
OTBS
allyl ketones.
HN
OH-
b
c
d
e
f
Combined yield of cis/trans products.
The diastereoselectivity was examined by HPLC or isolated products.
NaBH4, EtOH, rt, 1 h.
R
R=Me
RO
O
R
N
N
NHBoc
NHMe
NaBH4, EtOH, ꢀ78 ꢁC, 1 h.
Boc
lactams 1
Cl
LiEt3BH, THF, ꢀ78 ꢁC, 0.5 h.
g
Li(t-BuO)3AlH, EtOH, ꢀ78 ꢁC, 2 h.
R=Bn
one-pot
oxidative cyclization
OH
diastereoselectivity of the desired product increased significantly
(Table 1, entries 2e3). When LiEt3BH was used as a reducing
agent,13 trans-10a was obtained in 99:1 dr (Table 1, entry 4). Li(t-
BuO)3AlH was also examined and the result showed that trans-10a
was smoothly generated with excellent diastereoselectivity and in
96% yield (Table 1, entry 5). Accordingly, under the similar condi-
tions, compounds 9ceg were smoothly converted to secondary
alcohols 10ceg with excellent diastereoselectivities and in good
yields (Table 1, entries 6e10). Subsequently, protection (TBSCl,
imidazole) of secondary alcohols 10aeh afforded protected com-
pounds 7aeh in high yields.
To explore an efficient method for the synthesis of trans-4-
hydroxyl-5-substituted pyrrolidine lactam 1, terminal alkene 7a
was treated with NaIO4 in the presence of a catalytic amount of
RuCl3$xH2O. Gratifyingly, the main product 1a was generated in
‘one-pot’ with an excellent yield (Table 2, entry 1).
It is noteworthy that the uncylized free acid was not observed
for the reaction mixture. Encouraged by the ‘one-pot’ oxidative
cyclization, terminal alkenes 7b, 7g, and 7i bearing with phenyl
group were subjected to the oxidative cyclization to generate 1b,
1g, and 1i in moderate yields, indicating that the phenyl group was
unaffected under this oxidation condition (Table 2, entries 2, 7, 8,
and 10). As summarized in Table 2, various substituted terminal
alkenes bearing a range of R substituents were examined in the
oxidative cyclization. In most cases, the ‘one-pot’ reaction pro-
ceeded smoothly with excellent yields (entries 1e11). Reactions of
terminal alkenes 7k and 7l under the same conditions were also
examined. The results indicated that the ‘one-pot’ oxidative cycli-
zation could not occur for the formation of four and six-membered
lactams (Table 2, entries 12 and 13).
OTBS
R
Amino Acid
O
N
H
Ph
NHBoc
7
Fig. 2. Multi-purpose building block.
2. Results and discussion
As shown in Fig. 2, lactam 1 is the key intermediate for the
synthesis of nemonapride 3 and streptopyrrolidine 4. Thus, a reli-
able method for the preparation of protected (R,S)-amino alcohols 7
is pre-required. To develop a general method to prepare protected
alcohols 7, diastereoselective reduction of a-aminoketones was first
examined. A series of commercialized protected amino acids were
converted into Weinreb amides 8aeh in excellent yields according
to known method.12 Amides 8aeh could be used in next step
without further purification. Then, treated with allylmagnesium
bromide, 8aeh was converted to
a
-aminoketones 9aeh in good
yields (Scheme 1).
O
O
O
HN
OR1
OH
HN
OR1
HN
OR1
AllylMgCl
-20oC~rt 6h
Ref.12
N
R
R
R
O
O
O
O
Protective
amino acid
8 a-h
9 a-h
Scheme 1. Preparation of
a-aminoketones 9aeh.
With lactam 1a in hand, we turned our attention to synthesize
nemonapride 3. Treatment of compound 1a with TFA in DCM at 0 ꢁC
for 6 h and subsequent protection with BnBr gave the amide 11 in
65% overall yield (Scheme 2). Removal of protective group (SOCl2/
MeOH) and subsequent reduction of amide 11 with BH3$SMe2 gave
amine 12 in 84% yield. Treatment of compound 12 with MsCl in the
Next, a survey of diastereoselective reduction of ketones was
carried out. Treatment of -aminoketone 9a with 2.0 equiv of
NaBH4 in EtOH at room temperature gave a mixture of trans-10a
and cis-10a with low diastereoselectivity in 82% combined yield
(Table 1, entry 1). When the reaction was performed at ꢀ78 ꢁC, the
a

W. Huang et al. / Tetrahedron 67 (2011) 7829e7837
7831
Table 2
To elucidate the absolute configuration of 4, it is desirable to
synthesize all the possible isomers and compare them with the
natural product in term of spectroscopic and physical data. Treat-
ment of lactam (2S)-1g with SOCl2 in MeOH at 0 ꢁC afforded
Ruthenium-catalyzed ‘one-pot’ oxidative cyclization of 7ael
O
R3
HN
R2
OR1
n
RuCl3 H2O/NaIO4
n
(4R,5S)-streptopyrrolidine 4 {½a D25
þ16.8 (c 0.05, MeOH)}in 81%
ꢂ
O
R2
OR1
CCl4/CH3CN/H2O
rt, 16h
N
yield (Scheme 3). Similarly, (4S,5R)-streptopyrrolidine 4 {½a D25
ꢂ
R3
O
ꢀ16.6 (c 0.05, MeOH)} was obtained from (2R)-1g. Deprotection of
lactam (2S)-1g with TBAF and subsequent oxidation with DMSO/
(COCl)2 at ꢀ78 ꢁC gave compound 15a in 94% overall yield. Next,
compound 15a was treated with NaBH4 in MeOH to afford 16a in
96% yield. Finally, treatment of compound 16a with SOCl2 in MeOH
7a-l (7a~j, n=1; 7k, n=0; 7l, n=2)
1a-l
a
b
Entry
R1
R2
R3
1ael
Yield
%
1
2
3
4
5
6
7
8
t-Bu
Bn
Me
Me
CHMe2
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
OTBS
H
1a
1b
1c
1d
1e
1f
82
71
78
81
76
69
72
68
75
64
77
0
generated the (4S,5S)-streptopyrrolidine 4 {½a D25
ꢂ
ꢀ44.6 (c 0.05,
MeOH); lit.14
½
a 2D5
ꢂ
ꢀ12 (c 0.05, MeOH); lit.5b,g
½ ꢂ ꢀ44 (c 1.0,
a 2D5
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Bn
CH2CHMe2
CH2OTBS
Cyclohexyl
MeOH)} in 61% yield (three steps). Accordingly, (4R,5R)-strepto-
pyrrolidine 4 {½a D25
þ44.8 (c 0.05, MeOH)} was obtained from (2R)-
ꢂ
Bn
Bn
H
H
H
5S-1g
5R-1g
1h
1g. The data of the specific rotations show that the two pairs of the
synthetic enantiomers are consistent with each other. Then the
spectral and specific rotation of the four synthetic isomers were
compared with the data of natural product, exhibiting that ste-
reochemistry of streptopyrrolidine was cis. As for the absolute
configuration, we think the natural streptopyrrolidine maybe
possess (S,S)-stereochemistry due to having the same negative sign
of rotation and the same physical data of NMR as the synthetic
(4S,5S)-4, although there is a significant difference in specific ro-
tation value between natural 4 and our synthetic sample. Most
possibly, the minute amount of isolated natural streptopyrrolidine
4 prevent a accurate measurement of rotation.
9
10
11
12
13
1i
1j
1k
1l
t-Bu
t-Bu
t-Bu
H
OTBS
OTBS
Me
Me
0
a
Compounds 7ael (2 mmol) were treated with 8.0 mmol NaIO4 and 5% mmol
RuCl3$H2O in CH3CN/CCl4/H2O (v/v/v¼2:2:1) at room temperature for 16 h.
b
Isolated yields.
N3
OH
OTBS
OTBS
a
b
c
O
O
N
N
N
N
OTBS
Bn
OTBS
OH
Bn
12
OH
Boc
1a
Bn
11
a
a
13
O
O
O
O
O
N
N
N
H
N
H
OMe
Boc
Ph
Boc
Ph
NH2
Ph
Ph
(4S,5R)- 4
HN
Ref. 3c
e
(2S)-1g
d
(4R,5S)- 4
(2R)-1g
N
[α]D25 = – 16.6 (c 0.05, MeOH)
[α]D25 = + 16.8 (c 0.05, MeOH)
OH
N
NHMe
Bn
Cl
OTBS
O
OH
14
c
b
d
O
O
O
O
N
N
N
H
Nemonapride 3
N
Boc
16a
Boc
Boc
15a
Ph
Ph
Ph
Ph
Scheme 2. Synthesis of nemonapride 3. Reagents and conditions: a. (i) TFA, DCM, 0 ꢁ
C
(4S,5S)- 4
(2S)-1g
wrt, 4 h; (ii) NaH, DMF, BnBr, 0 ꢁC wrt, 2.5 h, 65%, two steps; b. (i) SOCl2, MeOH, 0 ꢁC
wrt, 2 h; (ii) BH3$SMe2, THF, 0 ꢁC wrt, 20 h, 84%, two steps; c. (i) DMAP, MsCl, TEA,
DCM, 0 ꢁC wrt, 3 h; (ii) NaN3, DMF, 80 ꢁC, 36 h, 68%, two steps; d. Pd on PbCO3/C,
MeOH, H2, 5 h, quantitative yield; e. TEA, ClCOOEt, 5-chloro-2-methoxy-4-(methyl-
amino)benzoic acid, DCM, 0 ꢁC, 2 h, 72%.
[α]D25 = - 44.6 (c 0.05, MeOH)
OH OH
OTBS
b
O
c
d
O
O
O
O
N
N
N
N
H
Boc
Ph
Boc
Boc
Ph
Ph
Ph
presence of triethylamine and followed by substitution with NaN3
in DMF smoothly generated azides 13 in 68% yield, which was
subjected to hydrogenation (Pd on PbCO3/C, H2, MeOH) to afford
cyclic diamine 14 in quantitative yield. Finally, by the known
method3c the condensation of amine 14 with 5-chloro-2-methoxy-
4-(methylamino)benzoic acid in the presence of ClCO2Et afforded
(2R)-1g
(4R,5R)- 4
16b
15b
[α]D25 = + 44.8 (c 0.05, MeOH)
Scheme 3. Synthesis and determination of streptopyrrolidine 4. Reagents and condi-
tions: a. SOCl2, MeOH, 0 ꢁC wrt, 2 h, 81%; b. (i) TBAF, THF, rt, 3 h; (ii) DMSO, (COCl)2,
TEA, DCM, ꢀ78 ꢁC wrt, 94%; c. MeOH, NaBH4, 0 ꢁC wrt, 2 h, 96%; d. SOCl2, MeOH, 0 ꢁ
wrt, 2 h, 87%.
C
nemonapride 3 {½a D25
ꢂ
þ2.5 (c 0.6, CHCl3); lit.3c
½
a 2D5
ꢂ
þ2.3 (c 0.6,
CHCl3); lit.3b
½
a 2D5
ꢂ
þ4 (c 0.6, CHCl3)} in 72% yield. The spectroscopic
3. Conclusions
and physical data of the synthetic nemonapride 3 were identical
with the reported data.3b,c,d
In summary, an efficient ‘one-pot’ approach for the preparation
of trans-4-hydroxylpyrrolidine lactams 1 starting from amino acid
has been developed. Using this method, nemonapride 3 and
streptopyrrolidine 4 have been synthesized. Comparing four syn-
thetic stereoisomers 4 with natural product for the physical data
including specific rotation, the absolute structure of 4 was pro-
posed as (4S,5S). Further exploration and application in the total
synthesis of other bioactive natural products and their analogues
are now in progress in our laboratory.
To extend the utility of the ‘one-pot’ oxidative cyclization, the
synthesis of streptopyrrolidine 4 was also performed. Strepto-
pyrrolidine 4 was isolated from the fermentation broth of a marine
Streptomyces sp. KORDI-3973 from the deep sea sediment,14 which
could significantly block the capillary tube formation of the cells at
the same potency as the known angiogenesis inhibitor SU11248.14
The absolute configuration of streptopyrrolidine 4 was unsolved
due to the significant difference in the specific rotation between
natural product and the synthetic samples.5b,g

7832
W. Huang et al. / Tetrahedron 67 (2011) 7829e7837
4. Experimental section
2981, 2960, 1723, 1681, 1548, 1367, 1283, 1177, 1041 cmꢀ1; 1H NMR
(400 MHz, CDCl3): 5.90e5.80 (m, 1H), 5.13e5.06 (m, 3H),
d
4.1. General
4.31e4.26 (m, 1H), 3.21 (d, J¼6.80 Hz, 2H), 1.68e1.61 (m, 1H),
1.52e1.40 (m, 1H), 1.40 (s, 9H), 1.33e1.25 (m, 1H), 0.89 (d, J¼6.4 Hz,
3H), 0.86 (d, J¼6.8 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):
THF was distilled from sodium/benzophenone. All reactions
were monitored by thin layer chromatography (TLC) on glass plates
coated with silica gel with fluorescent indicator (Huanghai
HSGF254). Flash chromatography was performed on silica gel
(Huanghai 300e400) with petroleum/EtOAc as eluent. Melting
points were recorded on a Mel-Temp apparatus and uncorrected.
Optical rotations were measured on a JASCO P-1030 polarimeter
with a sodium lamp. Mass spectra were recorded on an HP-5989
instrument and HRMS (MALDI/DHB) were measured on an LCMS-
IT-TOF (Shimazu Corporation) apparatus. IR spectra were recor-
ded using KBr disks or film, on a Fourier Transform Infrared Spec-
trometer, Type: Avatar 360 E.S.P, manufactured by Thermo Nicolet
Corporation, USA. NMR spectra were recorded on a Varian or
a Bruker spectrometer (300 or 400 MHz), and chemical shifts are
d
¼208.0, 155.6, 130.1, 119.0, 79.6, 57.5, 44.4, 40.4, 28.3, 24.8, 23.2,
21.6 ppm; MS (ESI): 264 (MþNaþ); HRMS (ESI) calcd for
(C14H25NO3þNaþ): 278.1732, found: 278.1720.
4.2.5. (S)-tert-Butyl 1-(tert-butyldimethylsilyloxy)-3-oxohex-5-en-2-
ylcarbamate (9e). Colorless oil; ½a D25
ꢀ57.55 (c 2.8, CHCl3); IR (film):
ꢂ
nmax 3435, 2956, 2930,1713,1494,1473,1367,1255,1172,1112 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
5.96e5.85 (m, 1H), 5.45 (d, J¼6.8 Hz,
1H), 5.18 (dd, J¼0.8, 10.4 Hz, 1H), 5.12 (dd, J¼1.2, 18.4 Hz, 1H),
4.32e4.30 (m, 1H), 4.06 (dd, J¼2.8, 10.4 Hz, 1H), 3.80 (dd, J¼4.0,
10.4 Hz, 1H), 3.36 (dd, J¼6.8, 17.6 Hz, 1H), 3.27 (dd, J¼6.8, 17.2 Hz,
1H), 1.44 (s, 9H), 0.85 (s, 9H), 0.02 (s, 6H) ppm; 13C NMR (100 MHz,
CDCl3):
d
¼205.8, 155.3, 129.9, 119.0, 79.8, 63.3, 60.9, 44.9, 28.3, 25.7,
reported in
d
(ppm) referenced to an internal TMS standard for 1H
18.1, ꢀ5.51, ꢀ5.63 ppm; MS (ESI): 264 (MþNaþ); HRMS (ESI) calcd
for (C17H33NO4SiþNaþ): 366.2076, found: 366.2061.
NMR and CDCl3 (77.0 ppm) for 13C NMR.
4.2. General procedure for the preparation of 9aeh
4.2.6. (S)-tert-Butyl 1-cyclohexyl-2-oxopent-4-enylcarbamate
(9f). White solid, mp 79e80 ꢁC; ½a D25
þ93.63 (c 1, CHCl3); IR
ꢂ
Compound 8aeh (22.1 mmol) in dry THF (90 mL) wastreated with
a solution of allylmagnesium chloride (44.2 mmol, 1.7 mol in THF) at
ꢀ20 ꢁC under argon atmosphere and was stirred for 5 h at ꢀ20 to 0 ꢁC.
The reaction was quenched with saturated NH4Cl aqueous solution
and diluted with EtOAc (150 mL), and the mixture was separated. The
aqueous solution was extracted with EtOAc for two times, and the
combined organic layers were washed with brine for three times.
Dried over anhydrous Na2SO4, filtered, and concentrated, the residue
was purified by chromatography on silica gel to give 9aeh.
(film): nmax 3289, 2976, 2929, 1717, 1659, 1452, 1366, 1251,
1164 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 5.94e5.87 (m, 1H),
5.27e5.25 (m, 1H), 5.21e5.13 (m, 2H), 4.29e4.27 (m, 1H), 3.27e3.24
(m, 2H), 1.82e1.62 (m, 4H), 1.44 (s, 9H) 1.15e0.92 (m, 7H) ppm; 13C
NMR (100 MHz, CDCl3):
d 207.5, 199.7, 155.9, 145.4, 129.9, 125.8,
119.0, 64.0, 45.7, 40.7, 40.0, 30.2, 28.3, 27.2, 26.1 ppm; MS (ESI): 304
(MþNaþ); HRMS (ESI) calcd for (C16H27NO3þNaþ): 304.1889,
found: 304.1892.
4.2.7. (S or R)-tert-Butyl 3-oxo-1-phenylhex-5-en-2-ylcarbamate
4.2.1. (S)-tert-Butyl
3-oxohex-5-en-2-ylcarbamate (9a). White
(9g). White solid, mp 89e90 ꢁC; (S)-9g: ½a D25
þ61.2 (c 1.1, CHCl3);
ꢂ
solid, mp 44e45 ꢁC; (S)-9a: ½a D25
ꢂ
þ54.4 (c 1, CHCl3); (R)-9a: ½a D25
ꢂ
(R)-9g: ½a 2D5
ꢀ60.8 (c 1.05, CHCl3); IR (film): nmax 3358, 2982, 2935,
ꢂ
ꢀ53.8 (c 1, CHCl3); IR (film): nmax 3389, 2975, 1728, 1697, 1520, 1366,
1723, 1688, 1520, 1372, 1313, 1170 cmꢀ1; 1H NMR (400 MHz, CDCl3):
1285, 1177 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
5.97e5.86 (m, 1H),
d
7.30e7.13 (m, 5H), 5.90e5.80 (m, 1H), 5.18e5.03 (m, 3H),
4.58e4.56 (m,1H), 3.21e3.12 (m, 2H), 3.06e3.03 (m,1H), 2.98e2.93
(m, 1H), 1.46 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3):
5.27e5.20 (m, 1H), 5.19e5.14 (dd, J¼1.7, 17.2 Hz, 1H), 4.38e4.35 (m,
1H), 3.34e3.32 (dd, J¼6.80, 17.0 Hz, 1H), 3.24e3.22 (dd, J¼6.4,
17.0 Hz, 1H), 1.44 (s, 9H), 1.33 (d, J¼6.80 Hz, 3H) ppm; 13C NMR
d
¼207.4,
155.1, 136.2, 129.8, 129.3, 128.7, 127.0, 119.2, 79.9, 59.8, 45.5, 37.7,
28.3 ppm; MS (ESI): 236 (MþNaþ); HRMS (ESI) calcd for
(C11H19NO3þNaþ): 236.1263, found: 236.1253.
(100 MHz, CDCl3):
d
¼207.3, 155.1, 129.8, 119.3, 79.8, 54.8, 44.0, 28.3,
17.7 ppm; MS (ESI): 236 (MþNaþ); HRMS (ESI) calcd for
(C11H19NO3þNaþ): 236.1263, found: 236.1253.
4.2.8. tert-Butyl 2-oxopent-4-enylcarbamate (9h). Colorless oil; IR
(film): nmax 3361, 2979, 2934, 1705, 1506, 1368, 1251, 1161,
4.2.2. (S)-Benzyl 3-oxohex-5-en-2-ylcarbamate (9b). Colorless oil;
½
a 2D5
ꢂ
ꢀ59.29 (c 0.61, CHCl3); IR (film): nmax 3334, 2917, 1714, 1525,
1048 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
5.96e5.86 (m, 1H),
1246, 1027 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d
7.40e7.26 (m, 5H),
5.24e5.17 (m, 3H), 4.07e4.06 (m, 2H), 3.22e2.19 (m, 2H), 1.45 (s,
5.95e5.85 (m, 1H), 5.58e5.56 (m, 1H), 5.28e5.06 (m, 2H), 5.10 (s,
2H), 4.47e4.40 (m, 1H), 3.34e3.21 (m, 2H), 1.36 (d, J¼6.8 Hz,
9H) ppm; 13C NMR (100 MHz, CDCl3):
d 203.6, 155.6, 129.3, 119.8,
79.9, 49.9, 45.0, 28.3 ppm; MS (ESI): 222 (MþNaþ); HRMS (ESI)
3H) ppm; 13C NMR (100 MHz, CDCl3):
d¼207.0, 155.8, 136.5, 129.8,
calcd for (C10H17NO3þNaþ): 222.1106, found: 222.1112.
128.5, 128.1, 119.3, 66.8, 55.2, 43.8, 17.4 ppm; MS (ESI): 270
(MþNaþ); HRMS (ESI) calcd for (C14H17NO3þNaþ): 270.1106, found:
270.1097.
4.3. General procedure for the preparation of trans-10aeh
Compound 9aeh (1 mmol) in absolute EtOH (30 mL) was
treated with Li(t-BuO)3AlH (2 mmol) at ꢀ78 ꢁC under argon at-
mosphere for 2 h. The reaction was quenched with 1 M KHSO4
aqueous solution and concentrated to give yellow solid. The crude
solid was dissolved in EtOAc (50 mL) and 1 M HCl aqueous solution.
The mixture was separated, and the aqueous solution was extracted
with EtOAc for two times. The combined organic layers were
washed with brine for three times. Dried over anhydrous Na2SO4,
filtered, and concentrated, the residue was purified by chroma-
tography on silica gel to give 10aeh.
4.2.3. (S)-tert-Butyl 2-methyl-4-oxohept-6-en-3-ylcarbamate
(9c). Colorless oil; ½a D25
þ84.21 (c 1, CHCl3); IR (film): nmax 3346,
ꢂ
2968, 2932, 1712, 1504, 1392, 1367, 1245, 1172, 1012 cmꢀ1; 1H NMR
(400 MHz, CDCl3):
d 5.94e5.84 (m, 1H), 5.19e5.10 (m, 3H),
4.30e4.27 (m, 1H), 3.30e3.10 (m, 2H), 2.20e2.10 (m, 1H), 1.40 (s,
9H), 0.98 (d, J¼6.8 Hz, 3H), 0.76 (d, J¼6.8 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3):
d
¼207.3, 155.9, 129.9, 119.0, 79.5, 63.7, 45.3, 28.3,
16.7 ppm; MS (ESI): 264 (MþNaþ); HRMS (ESI) calcd for
(C13H23NO3þNaþ): 264.1576, found: 264.1570.
4.2.4. (S)-tert-Butyl 2-methyl-5-oxooct-7-en-4-ylcarbamate
4.3.1. tert-Butyl (2S,3R)-3-hydroxyhex-5-en-2-ylcarbamate
(9d). Colorless oil; ½a D25
ꢂ
þ27.53 (c 1, CHCl3); IR (film): nmax 3301,
(10a). White solid, mp 54e55 ꢁC; ½a D25
ꢀ22.67 (c 1.07, CHCl3); IR
ꢂ

W. Huang et al. / Tetrahedron 67 (2011) 7829e7837
7833
(film): nmax 3359, 2918, 1682, 1532, 1368, 1327, 1290, 1272, 1177,
1040, 1025 cmꢀ1; 1H NMR (400 MHz, CDCl3):
5.89e5.79 (m, 1H),
(film): nmax 3361, 2979, 2931, 1684, 1527, 1316, 1171 cmꢀ1; 1H NMR
(400 MHz, CDCl3): 7.30e7.19 (m, 5H), 5.94e5.84 (m, 1H), 5.21 (d,
d
d
5.15 (d, J¼10.0 Hz, 1H), 5.12 (s, 1H), 4.78 (br s, 1H), 3.74e3.65 (m,
J¼8.0 Hz, 1H), 5.18 (s, 1H), 4.65 (br s, 1H), 3.86 (br s, 1H), 3.75 (br s,
1H), 2.31e2.12 (m, 3H), 1.45 (s, 9H), 1.11 (d, J¼6.8 Hz, 3H) ppm; 13C
1H), 2.98 (dd, J¼4.4, 14.0 Hz, 1H), 2.85e2.72 (m, 2H), 2.42e2.25 (m,
NMR (100 MHz, CDCl3):
d¼156, 134.7, 118.0, 79.5, 73.3, 50.3, 38.3,
2H), 1.34 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3):
d¼156.0, 138.2,
28.4, 14.6 ppm; MS (ESI): 238 (MþNaþ); HRMS (ESI) calcd for
(C11H21NO3þNaþ): 238.1419, found: 238.1407.
134.7, 129.4, 128.4, 126.3, 118.3, 79.6, 72.7, 55.9, 38.4, 28.3 ppm; MS
(ESI): 314 (MþNaþ); HRMS (ESI) calcd for (C17H25NO3þNaþ):
314.1732, found: 314.1727.
4.3.2. Benzyl (2S,3R)-3-hydroxyhex-5-en-2-ylcarbamate
(10b). White solid, mp 70e71 ꢁC; ½a D25
ꢂ
ꢀ17.00 (c 1.1, CHCl3); IR
4.3.8. tert-Butyl 2-hydroxypent-4-enylcarbamate (10h). Colorless
oil; IR (film): nmax 3361, 2978, 2931, 1694, 1522, 1367, 1252,
(film): nmax 3316, 2973, 2940, 1686, 1541, 1289, 1267, 1237, 1083,
1038 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
7.33e7.25 (m, 5H),
1172 cmꢀ1 1H NMR (400 MHz, CDCl3): 5.87e5.77 (m, 1H), 5.16 (d,
;
5.85e5.75 (m, 1H), 5.20 (br s, 1H), 5.14e5.08 (m, 4H), 3.75e3.71 (m,
2H), 2.41 (br s, 1H), 2.24e2.11 (m, 2H), 1.11 (d, J¼8.0 Hz, 3H) ppm;
J¼6.0 Hz, 1H), 5.12 (s, 1H), 5.00 (br s, 1H), 3.78e3.72 (m, 1H),
3.36e3.31 (m, 1H), 3.08e3.01 (m, 1H), 2.31e2.17 (m, 2H), 1.45 (s,
13C NMR (100 MHz, CDCl3):
d
156.2, 136.5, 134.5, 128.5, 128.1, 118.1,
9H) ppm; 13C NMR (100 MHz, CDCl3):
d¼156.8, 134.1, 118.2, 79.6,
73.1, 66.8, 50.7, 38.4, 14.3 ppm; MS (ESI): 272 (MþNaþ); HRMS (ESI)
70.5, 46.0, 39.3, 28.4 ppm; MS (ESI): 224 (MþNaþ); HRMS (ESI)
calcd for (C10H19NO3þNaþ): 224.1263, found: 224.1254.
calcd for (C14H19NO3þNaþ): 272.1263, found: 272.1269.
4.3.3. tert-Butyl (3S,4R)-4-hydroxy-2-methylhept-6-en-3-
4.4. General procedure for the preparation of 7aeh
ylcarbamate (10c). White solid, mp 81e82 ꢁC; ½a D25
ꢂ
0.47 (c 1.0,
CHCl3); IR (film): nmax 3376, 2979, 2936, 1686, 1522, 1367, 1310,
To a mixture of 10aeh (1 mmol), DMAP (0.1 mmol), and imid-
azole (2 mmol) in dry DMF (10 mL) was dropped a solution of TBSCl
in DMF at 0 ꢁC, then the mixture was allowed to warm to room
temperature and stirred for overnight. The reaction was quenched
with water and diluted with EtOAc, and the mixture was separated.
The aqueous solution was extracted with EtOAc for two times, and
the combined organic layers were washed with brine for three
times. Dried over anhydrous Na2SO4, filtered, and concentrated, the
residue was purified by chromatography on silica gel to give 7aeh.
1253, 1173, 1060 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d 5.92e5.81 (m,
1H), 5.15e5.10 (m, 2H), 4.49e4.47 (m, 1H), 3.60e3.46 (m, 2H),
2.34e2.32 (m, 2H), 2.18e2.10 (m, 1H), 2.03e1.98 (m, 1H), 1.42 (s,
9H), 0.92 (d, J¼6.8 Hz, 3H), 0.87 (d, J¼6.8 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3):
d 156.6, 135.1, 118.1, 79.4, 71.5, 59.5, 38.1, 28.4,
28.1, 20.3, 17.1 ppm; MS (ESI): 266 (MþNaþ); HRMS (ESI) calcd for
(C13H25NO3þNaþ): 266.1732, found: 266.1726.
4.3.4. tert-Butyl (4S,5R)-5-hydroxy-2-methyloct-7-en-4-ylcarbamate
(10d). White solid, mp 85e86 ꢁC; ½a D25
ꢂ
ꢀ43.32 (c 1.1, CHCl3); IR
4.4.1. tert-Butyl (2S,3R)-3-(tert-butyldimethylsilyloxy)hex-5-en-2-
(film): nmax 3359, 2982, 2953, 1682, 1531, 1367, 1349, 1278, 1174,
ylcarbamate (7a). Colorless oil; ½a D25
ꢀ15.30 (c 0.95, CHCl3); IR
ꢂ
1041 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
5.88e5.83 (m, 1H),
(film): nmax 2955, 2930, 2857, 1719, 1496, 1365, 1253, 1173, 1103,
5.15e5.10 (m, 2H), 4.68 (br s, 1H), 3.67 (br s, 2H), 2.70 (br s, 1H),
2.22e2.15 (m, 2H),1.67e1.60 (m,1H),1.44 (s, 9H),1.31e1.22 (m, 2H),
1048 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d 5.82e5.71 (m, 1H), 5,09 (d,
J¼7.6 Hz, 1H), 5.03 (s, 1H), 4.56 (br s, 1H), 3.88e3.79 (m, 1H),
3.75e3.64 (m, 1H), 2.27e2.11 (m, 2H), 1.43 (s, 9H), 1.04 (d,
J¼6.80 Hz, 3H), 0.9 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H) ppm; 13C NMR
0.95e0.79 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3):
d 156.3, 135.0,
117.7, 79.4, 73.9, 53.1, 38.4, 38.0, 28.4, 24.8, 23.7, 21.6 ppm; MS (ESI):
280 (MþNaþ); HRMS (ESI) calcd for (C14H27NO3þNaþ): 280.1889,
found: 280.1876.
(100 MHz, CDCl3):
d 155.0, 134.4, 117.3, 79.0, 73.8, 49.2, 39.4, 28.5,
28.8, 18.1, 13.3, ꢀ4.2, ꢀ4.7 ppm; MS (ESI): 352 (MþNaþ); HRMS
(ESI) calcd for (C17H35NO3SiþNaþ): 352.2284, found: 352.2281.
4.3.5. tert-Butyl (2S,3R)-1-(tert-butyldimethylsilyloxy)-3-
hydroxyhex-5-en-2-ylcarbamate (10e). Colorless oil; ½a D25
ꢂ
ꢀ28.14
4.4.2. Benzyl (2S,3R)-3-(tert-butyldimethylsilyloxy)hex-5-en-2-
(c 1.0, CHCl3); IR (film): nmax 3446, 2955, 2929, 2857, 1698, 1504,
ylcarbamate (7b). Colorless oil; ½a D25
þ6.11 (c 0.89, CHCl3); IR
ꢂ
1391, 1366, 1254, 1173, 1109 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
(film): nmax 3345, 2954, 2929, 2857, 1724, 1504, 1471, 1253,
d
5.89e5.78 (m, 1H), 5.20e5.01 (m, 3H), 3.96e3.93 (m, 1H),
1105 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 7.38e7.26 (m, 5H),
3.78e3.66 (m, 2H), 3.53 (br s, 1H), 3.03e3.01 (m, 1H), 2.34e2.30 (m,
5.82e5.71 (m,1H), 5.11e5.06 (m, 4H), 4.84e4.82 (m,1H), 3.84e3.56
(m, 2H), 2.31e2.14 (m, 2H), 1.08 (d, J¼6.4 Hz, 3H), 0.90 (s, 9H), 0.06
2H), 1.42 (s, 9H), 0.88 (s, 9H), 0.06 (s, 6H) ppm; 13C NMR (100 MHz,
CDCl3):
d
155.9, 134.6, 117.7, 79.4, 72.7, 63.2, 53.8, 39.3, 28.4, 25.8,
(s, 3H), 0.04 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d 155.6, 136.8,
18.1, ꢀ5.6 ppm; MS (ESI): 368 (MþNaþ); HRMS (ESI) calcd for
134.2, 128.5, 128.2, 128.1, 117.8, 73.8, 66.6, 49.9, 39.3, 25.9, 18.1, 13.3,
ꢀ4.2, ꢀ4.7 ppm; MS (ESI): 352 (MþNaþ); HRMS (ESI) calcd for
(C20H33NO3SiþNaþ): 386.2127, found: 386.2130.
(C17H35NO4SiþNaþ): 368.2233, found: 368.2226.
4.3.6. tert-Butyl (1S,2R)-1-cyclohexyl-2-hydroxypent-4-
enylcarbamate (10f). Colorless oil; ½a D25
ꢂ
ꢀ2.45 (c 1.0, CHCl3); IR
4.4.3. tert-Butyl (3S,4R)-4-(tert-butyldimethylsilyloxy)-2-
(film): nmax 3368, 2981, 2926, 2853, 1685, 1527, 1447, 1367, 1302,
methylhept-6-en-3-ylcarbamate (7c). Colorless oil; ½a D25
ꢀ17.68 (c
ꢂ
1245, 1173, 1050 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
5.95e5.84 (m,
1.14, CHCl3); IR (film): nmax 3367, 2959, 2930, 2857,1703,1498,1390,
1H), 5.17e5.13 (m, 2H), 4.53e4.51 (m, 1H), 3.68e3.66 (m, 1H),
3.52e3.47 (m, 1H), 2.44e2.43 (m, 1H), 2.32e2.30 (m, 1H), 2.17e2.11
(m, 1H), 1.80e1.62 (m, 6H), 1.45 (s, 9H), 1.29e0.90 (m, 5H) ppm; 13C
1365, 1255, 1174, 1079, 1004 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
5.86e5.76 (m, 1H), 5.09e5.03 (m, 2H), 4.56e4.52 (m, 1H),
3.80e3.76 (m, 1H), 3.51e3.47 (m, 1H), 2.28e2.25 (m, 2H), 2.01e1.94
(m, 1H), 1.42 (s, 9H), 0.91e0.87 (m, 6H), 0.89 (s, 9H), 0.05 (s, 3H),
NMR (100 MHz, CDCl3):
d 156.6, 135.3, 117.7, 79.3, 71.1, 59.3, 38.3,
37.8, 30.5, 28.4, 27.4, 26.3, 26.2, 26.1 ppm; MS (ESI): 306 (MþNaþ);
HRMS (ESI) calcd for (C16H29NO3þNaþ): 306.2045, found:
306.2038.
0.02 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d 155.8, 134.6, 117.3,
78.7, 73.6, 57.6, 38.8, 28.4, 27.4, 25.8, 20.9, 18.0, 17.4, ꢀ4.3,
ꢀ4.8 ppm; MS (ESI): 352 (MþNaþ); HRMS (ESI) calcd for
(C19H39NO3SiþNaþ): 380.2597, found: 380.2607.
4.3.7. tert-Butyl (2S,3R) and (2R,3S)-3-hydroxy-1-phenylhex-5-en-2-
ylcarbamate (10g). White solid, mp 99e100 ꢁC; (2S,3R)-10g ½a 2D5
ꢂ
4.4.4. tert-Butyl (4S,5R)-5-(tert-butyldimethylsilyloxy)-2-methyloct-
ꢀ19.86 (c 1.04, CHCl3); (2R,3S)-10g ½a D25
ꢂ
þ22.39 (c 1.02, CHCl3); IR
7-en-4-ylcarbamate (7d). Colorless oil; ½a D25
ꢀ30.36 (c 1.0, CHCl3);
ꢂ

7834
W. Huang et al. / Tetrahedron 67 (2011) 7829e7837
IR (film): nmax 3271, 2956, 2857, 1705, 1498, 1390, 1365, 1254, 1175,
1095, 1064 cmꢀ1; 1H NMR (400 MHz, CDCl3):
5.83e5.73 (m, 1H),
5.09e5.04 (m, 2H), 4.43e4.41 (m, 1H), 3.82 (br s,1H), 3.63 (br s,1H),
2.28e2.15 (m, 2H), 1.67e1.59 (m, 1H), 1.44 (s, 9H), 1.26 (m, 2H),
0.95e0.85 (m, 6H), 0.89 (s, 9H), 0.06e0.0 (m, 6H) ppm; 13C NMR
with brine for three tomes. Dried over anhydrous Na2SO4, filtered,
and concentrated, the residue was purified by chromatography on
silica gel to give 1ael.
d
4.5.1. (2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-methyl-5-
(100 MHz, CDCl3):
d
155.4, 134.4, 117.2, 78.8, 74.3, 52.0, 39.1, 36.8,
oxopyrrolidine-1-carboxylate (1a). Colorless oil; ½a D25
þ17.2 (c 1.09,
ꢂ
28.4, 25.9, 24.6, 24.0, 21.6, 18.1, ꢀ4.3, ꢀ4.7 ppm; MS (ESI): 394
(MþNaþ); HRMS (ESI) calcd for (C20H41NO3SiþNaþ): 394.2753,
found: 394.2761.
CHCl3); IR (film): nmax 3010, 2956, 2937, 1777, 1377, 1359, 1292,
1160 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
4.02 (dd, J¼6.4, 13.2 Hz,
1H), 3.95 (d, J¼5.2 Hz, 1H), 2.77 (dd, J¼5.6, 17.6 Hz, 1H), 2.33 (d,
J¼17.6 Hz, 1H), 1.54 (s, 9H), 1.25 (d, J¼6.8 Hz, 3H), 0.88 (s, 9H), 0.08
4.4.5. tert-Butyl (2S,3R)-1,3-bis(tert-butyldimethylsilyloxy)hex-5-en-
(s, 3H), 0.07 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d
¼172.3,
2-ylcarbamate (7e). Colorless oil; ½a D25
ꢂ
þ4.08 (c 1.60, CHCl3); IR
150.0, 82.8, 70.4, 63.7, 41.3, 28.1, 25.7, 18.0, 17.8, ꢀ4.8 ppm; MS (ESI):
352 (MþNaþ); HRMS (ESI) calcd for (C16H31NO4SiþNaþ): 352.1920,
found: 352.1904.
(film): nmax 3455, 2956, 2929, 2857, 1722, 1496, 1472, 1390, 1365,
;
1255, 1174, 1097, 1056 cmꢀ1 1H NMR (400 MHz, CDCl3):
d
5.93e5.83 (m, 1H), 5.11e5.07 (m, 2H), 4.67e4.65 (m, 1H),
3.91e3.90 (m, 1H), 3.77e3.67 (m, 3H), 2.38e2.25 (m, 2H), 1.45 (s,
4.5.2. (2S,3R)-Benzyl 3-(tert-butyldimethylsilyloxy)-2-methyl-5-
9H), 0.92 (s, 9H), 0.91 (s, 9H), 0.08e0.07 (m, 12H) ppm; 13C NMR
oxopyrrolidine-1-carboxylate (1b). Colorless oil; ½a D25
þ17.2 (c 1,
ꢂ
(100 MHz, CDCl3):
d
155.5, 134.6, 117.3, 78.9, 71.4, 61.3, 55.3, 38.5,
CHCl3); IR (film): nmax 2955, 2928, 1747, 1909, 1379, 1359, 1296,
28.4, 25.9, 18.3, ꢀ4.3, ꢀ5.3 ppm; MS (ESI): 482 (MþNaþ); HRMS
1205, 1104 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 7.44e7.32 (m, 5H),
(ESI) calcd for (C23H49NO4Si2þNaþ): 482.3099, found: 482.3104.
5.33 (d, J¼12.4 Hz, 1H), 5.28 (d, J¼12.4 Hz, 1H), 4.11 (dd, J¼6.8,
13.6 Hz,1H), 3.98 (d, J¼5.2 Hz,1H), 2.81 (dd, J¼5.2,17.6 Hz,1H), 2.38
(d, J¼17.6 Hz, 1H), 1.45 (d, J¼6.8 Hz, 3H), 0.86 (s, 9H), 0.07 (s,
4.4.6. tert-Butyl (1S,2R)-2-(tert-butyldimethylsilyloxy)-1-
cyclohexylpent-4-enylcarbamate (7f). Colorless oil; ½a D25
ꢂ
ꢀ21.82 (c
6H) ppm; 13C NMR (100 MHz, CDCl3):
128.3, 128.0, 70.5, 67.9, 63.8, 41.2, 30.3, 25.7, 18.0, 17.7, ꢀ4.8 ppm;
MS (ESI): 386 (MþNaþ); HRMS (ESI) calcd for (C19H29NO4SiþNaþ):
386.1764, found: 386.1745.
d
¼172.1, 151.5, 135.4, 128.6,
1.0, CHCl3); IR (film): nmax 3350, 2928, 2854, 1701, 1498, 1450, 1390,
1365, 1251, 1174, 1057 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
5.84e5.79 (m, 1H), 5.10e5.04 (m, 2H), 4.44e4.41 (m, 1H),
4.13e4.08 (m,1H), 3.80e3.78 (m,1H), 3.48e3.40 (m,1H), 2.58e2.36
(m, 1H), 1.86e1.56 (m, 6H), 1.43 (s, 9H), 1.31e1.09 (m, 4H), 0.88 (s,
4.5.3. (2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-isopropyl-
9H), 0.06e0.06 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3):
d
155.7,
5-oxopyrrolidine-1-carboxylate (1c). Colorless oil; ½a D25
þ45.17 (c 1,
ꢂ
134.8, 131.3, 127.3, 117.3, 78.7, 74.1, 73.1, 59.3, 57.8, 31.0, 28.5, 27.6,
26.5, 26.4, 26.3, 25.8, 18.1, 17.7, ꢀ4.79, ꢀ5.07 ppm; MS (ESI): 420
(MþNaþ); HRMS (ESI) calcd for (C22H43NO3SiþNaþ): 420.2910,
found: 420.2922.
CHCl3); IR (film): nmax 2958, 2931, 2857, 1786, 1754, 1716, 1471, 1367,
1304, 1156 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
4.14 (d, J¼5.6 Hz,1H),
3.89 (d, J¼5.6 Hz, 1H), 2.72 (dd, J¼5.2, 17.6 Hz, 1H), 2.33 (d,
J¼18.0 Hz, 1H), 2.01 (ddd, J¼6.8, 13.6, 26.8 Hz, 1H), 1.53 (s, 9H), 1.01
(d, J¼7.2 Hz, 3H), 0.88 (d, J¼7.2 Hz, 3H), 0.87 (s, 9H), 0.09 (s, 3H),
4.4.7. tert-Butyl (2S,3R) or (2R,3S)-3-(tert-butyldimethylsilyloxy)-1-
0.08 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d
¼173.1, 150.3, 82.8,
phenylhex-5-en-2-ylcarbamate (7g) (2S,3R)-7g. Colorless oil; ½a D25
ꢂ
72.9, 65.9, 43.0, 29.8, 28.0, 25.6, 19.3, 17.7, 17.6, ꢀ4.6, ꢀ4.7 ppm; MS
(ESI): 380 (MþNaþ); HRMS (ESI) calcd for (C18H35NO4SiþNaþ):
380.2233, found: 380.2215.
ꢀ19.64 (c 0.87, CHCl3); (2R,3S)-7g ½a D25
þ22.27 (c 1.03, CHCl3); IR
ꢂ
(film): nmax 2956, 2928, 2857, 1704, 1496, 1365, 1253, 1172 cmꢀ1; 1H
NMR (400 MHz, CDCl3): d 7.28e7.16 (m, 5H), 5.88e5.78 (m,1H), 5.15
(d, J¼9.6 Hz, 1H), 5.07 (s, 1H), 4.46 (br s, 1H), 3.93 (br s, 1H), 3.87 (br
s, 1H), 2.96 (dd, J¼4.4, 14.4 Hz, 1H), 2.63e2.57 (m, 1H), 2.37e2.26
(m, 2H), 1.31 (s, 9H), 0.93 (s, 9H), 0.07 (s, 6H) ppm; 13C NMR
4.5.4. (2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-isobutyl-5-
oxopyrrolidine-1-carboxylate (1d). Colorless oil; ½a D25
þ36.06 (c
ꢂ
1.02, CHCl3); IR (film): nmax 2959, 2934, 2856, 1742, 1717, 1473, 1384,
(100 MHz, CDCl3):
d¼155.2, 138.9, 134.3, 130.9, 129.2, 128.9, 128.3,
1368, 1310, 1257, 1161 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 4.29 (d,
126.1, 117.5, 78.9, 65.5, 54.9, 39.2, 34.4, 29.7, 28.3, 18.1, ꢀ4.6,
ꢀ4.9 ppm; MS (ESI): 406 (MþHþ); HRMS (ESI) calcd for
(C23H39NO3SiþHþ): 406.2777, found: 406.2789.
J¼4.8 Hz, 1H), 4.01 (dd, J¼3.2, 10.4 Hz, 1H), 2.77 (dd, J¼4.8, 17.6 Hz,
1H), 2.33 (d, J¼17.6 Hz,1H),1.72e1.63 (m,1H),1.54 (s, 9H),1.57e1.43
(m, 1H), 1.30e1.23 (m, 1H), 1.06 (d, J¼6.4 Hz, 3H), 0.97 (d, J¼6.4 Hz,
3H), 0.88 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H) ppm; 13C NMR (100 MHz,
4.4.8. tert-Butyl 2-(tert-butyldimethylsilyloxy)pent-4-enylcarbamate
CDCl3):
d
¼172.7, 149.9, 82.8, 68.6, 66.4, 41.5, 41.2, 28.1, 25.6, 25.3,
(7h). Colorless oil; IR (film): nmax 3358, 2979, 2934, 1705, 1506,
23.7, 21.7,17.9, ꢀ4.7 ppm; MS (ESI): 394 (MþNaþ); HRMS (ESI) calcd
for (C19H37NO4SiþNaþ): 394.2390, found: 394.2371.
1456, 1368, 1250, 1154, 1050 cmꢀ1 1H NMR (400 MHz, CDCl3):
;
d
5.84e5.74 (m, 1H), 5.08e5.04 (m, 2H), 4.73 (br s, 1H), 3.79e3.78
(m, 1H), 3.26e3.23 (m, 1H), 3.04e2.98 (m, 1H), 2.23e2.20 (m, 2H),
4.5.5. (2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-((tert-bu-
tyldimethylsilyloxy)methyl)-5-oxopyrrolidine-1-carboxylate
1.43 (s, 9H), 0.90 (s, 9H), 0.06 (s, 6H) ppm; 13C NMR (100 MHz,
CDCl3):
d
155.9, 134.2, 117.5, 79.1, 71.0, 45.8, 39.8, 28.4, 25.8, 18.1,
(1e). Colorless oil; ½a D25
ꢂ
þ29.9 (c 1.03, CHCl3); IR (film): nmax 2956,
ꢀ4.5, ꢀ4.7 ppm; MS (ESI): 338 (MþNaþ); HRMS (ESI) calcd for
2930, 2858, 1778, 1473, 1366, 1318, 1254, 1097 cmꢀ1 1H NMR
;
(C16H33NO3SiþNaþ): 338.2127, found: 338.2126.
(400 MHz, CDCl3):
d
4.29 (d, J¼6.0 Hz, 1H), 3.96 (dd, J¼1.6, 4.8 Hz,
1H), 3.80 (dd, J¼4.4, 11.0 Hz, 1H), 3.78 (dd, J¼3.2, 11.0 Hz, 1H), 2.85
(dd, J¼5.6, 17.4 Hz, 1H), 2.31 (d, J¼17.4 Hz, 1H), 1.54 (s, 9H), 0.87 (s,
18H), 0.08 (m, 6H), 0.04 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3):
4.5. General procedure for the preparation of 1ael
To a solution of 7ael (2 mmol) was stirred in CH3CN/CCl4/H2O
(v/v¼2:2:1) at room temperature, the NaIO4 (8 mmol) was added in
one portion and stirred for 10 min. The RuCl3$H2O (catalytic
amount, 5%) was added in portion. After being stirred for overnight,
the reaction was diluted with Et2O and stirred for 1 h. The mixture
was filtered and separated. The aqueous layer was extracted with
DCM for three times and the combined organic layers were washed
d
¼173.2, 150.1, 82.9, 68.8, 67.7, 62.1, 42.9, 28.1, 25.8, 25.7, 18.2, 18.0,
ꢀ4.7, ꢀ5.6 ppm; MS (ESI): 482 (MþNaþ); HRMS (ESI) calcd for
(C22H45NO5Si2þNaþ): 482.2734, found: 482.2726.
4.5.6. (2S,3R)-tert-Butyl 3-(tert-butyldimethylsilyloxy)-2-cyclohexyl-
5-oxopyrrolidine-1-carboxylate (1f). Colorless oil; ½a D25
þ40.73 (c
ꢂ
0.88, CHCl3); IR (film): nmax 2931, 2856, 1739, 1719, 1367, 1305, 1255,

W. Huang et al. / Tetrahedron 67 (2011) 7829e7837
7835
1153 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
4.54 (d, J¼4.8 Hz, 1H), 3.91
purified by flash chromatography on silica gel to give 11 (1266 mg,
(d, J¼5.6 Hz, 1H), 2.74 (dd, J¼5.6, 18.0 Hz, 1H), 2.34 (d, J¼18.0 Hz,
65%) as a colorless foam. ½a D25
ꢀ60.6 (c 1.09, CHCl3); IR (film): nmax
ꢂ
1H), 1.92e1.58 (m, 6H), 1.57 (s, 9H), 1.46e1.10 (m, 5H), 0.87 (s, 9H),
2953, 2931, 1697, 1463, 1441, 1419, 1413, 1254, 1063 cmꢀ1; 1H NMR
0.08 (s, 3H), 0.07 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d
¼173.1,
(400 MHz, CDCl3):
d
7.33e7.24 (m, 5H), 5.06 (d, J¼15.6 Hz, 1H), 3.97
150.4, 82.7, 82.3, 72.5, 66.6, 42.9, 40.3, 29.8, 29.0, 28.7, 28.0, 26.3,
26.2, 25.8, 25.7, 25.3, 17.9, ꢀ4.6 ppm; MS (ESI): 420 (MþNaþ);
HRMS (ESI) calcd for (C21H39NO4SiþNaþ): 420.2546, found:
420.2545.
(dd, J¼2.8, 5.6 Hz, 1H), 3.93 (d, J¼15.6 Hz, 1H), 3.33 (ddd, J¼2.4, 6.4,
13.2 Hz, 1H), 2.72 (dd, J¼6.4, 16.8 Hz, 1H), 2.35 (dd, J¼3.2, 16.8 Hz,
1H), 1.1 (d, J¼6.4 Hz, 3H), 0.85 (s, 9H), 0.04 (s, 3H), ꢀ0.01 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3):
d¼172.4, 136.4, 128.6, 127.7,
127.3, 72.4, 61.8, 43.5, 40.1, 25.6, 17.9, 16.4, ꢀ4.8, ꢀ4.9 ppm; MS
(ESI): 320 (MþHþ); HRMS (ESI) calcd for (C18H29NO2SiþHþ):
320.2046, found: 320.2034.
4.5.7. (2S,3R) or (2R,3S)-tert-Butyl 2-benzyl-3-(tert-butyldimethyls-
ilyloxy)-5-oxopyrrolidine-1-carboxylate (1g) (2S,3R)-1g. Colorless-
oil; ½a 2D5
ꢂ
þ8.67 (c 1.07, CHCl3); (2R,3S)-1g ½a D25
ꢀ8.54 (c 1.19, CHCl3);
ꢂ
IR (film): nmax 2954, 2929, 2957, 1786, 1755, 1713, 1368, 1312, 1257,
4.5.12. (2S,3R)-1-Benzyl-2-methylpyrrolidin-3-ol (12). To a solution
of 11 (143 mg, 0.45 mmol) in MeOH (5 mL) was slowly dropped
SOCl2 (0.3 mL) at 0 ꢁC. After being stirred for 2 h at room temper-
ature, the mixture was concentrated in vacuo and the residue was
stirred in dry THF (5 mL) at 0 ꢁC. A solution of BH3$SMe2 was slowly
dropped and stirred for 20 h at 0 ꢁC to room temperature. The re-
action was carefully quenched with EtOH (4 mL) and refluxed for
6 h. The resulting mixture was concentrated and the residue was
purified by flash chromatography on silica gel to give 12 (72 mg,
1156, 1087 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 7.34e7.18 (m, 5H),
4.16 (dd, J¼3.6, 10.4 Hz, 1H), 4.06 (d, J¼5.2 Hz, 1H), 3.17 (dd, J¼3.2,
13.2 Hz, 1H), 2.62 (dd, J¼5.2, 17.6 Hz, 1H), 2.51 (dd, J¼10.4, 13.2 Hz,
1H), 2.29 (d, J¼17.6 Hz, 1H), 1.60 (s, 9H), 0.74 (s, 9H), ꢀ0.22 (s, 3H),
ꢀ0.24 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3):
¼172.7, 150.0,
d
136.7, 129.3, 128.9, 127.1, 83.0, 69.1, 66.9, 41.3, 38.0, 28.1, 25.6, 17.8,
ꢀ5.2, ꢀ5.3 ppm; MS (ESI): 428 (MþNaþ); HRMS (ESI) calcd for
(C22H35NO4SiþNaþ): 428.2233, found: 428.2224.
a 25
84%) as colorless oil. ½ ꢂD þ80.31 (c 0.67 CHCl3); IR (film): nmax
4.5.8. tert-Butyl 4-(tert-butyldimethylsilyloxy)-2-oxopyrrolidine-1-
3315, 2975, 2926, 2783, 2701, 2641, 1452, 1419, 1101, 1057 cmꢀ1; 1H
carboxylate (1h). Colorless oil; IR (film): nmax 2956, 2934, 1766,
NMR (400 MHz, CDCl3):
d
7.32e7.23 (m, 5H), 3.95 (d, J¼12.8 Hz,1H),
1366, 1310, 1254, 1159 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
3.92e3.89 (m, 1H), 3.35 (d, J¼12.8 Hz, 1H), 2.83 (ddd, J¼2.4, 8.8,
10.4 Hz, 1H), 2.50e2.40 (m, 2H), 2.17e2.07 (m, 2H), 1.64e1.57 (m,
1H), 1.19 (d, J¼6.4 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d
4.41e4.36 (m, 1H), 3.86 (dd, J¼5.20, 11.2 Hz, 1H), 3.62 (dd, J¼2.80,
11.6 Hz, 1H), 2.71 (dd, J¼6.0, 17.6 Hz, 1H), 2.46 (dd, J¼3.2, 17.2 Hz,
1H), 1.53 (s, 9H), 0.88 (s, 9H), 0.08 (s, 6H) ppm; 13C NMR (100 MHz,
d
¼130.7, 129.5, 129.1, 69.3, 58.1, 52.3, 31.6, 15.4 ppm; MS (ESI): 192
CDCl3):
d
¼172.1, 150.1, 83.0, 63.9, 55.4, 43.2, 28.0, 25.7, 25.6, 18.0,
(MþHþ); HRMS (ESI) calcd for (C18H29NO2SiþHþ): 192.1383, found:
ꢀ4.8 ppm; MS (ESI): 338 (MþNaþ); HRMS (ESI) calcd for
(C15H29NO3SiþNaþ): 338.1764, found: 338.1755.
192.1380.
4.5.13. (2S,3S)-3-Azido-1-benzyl-2-methylpyrrolidine (13). To a so-
lution of 12 (179 mg, 0.94 mmol) and DMAP (12 mg, 0.095 mmol) in
dry CH2Cl2 (10 mL) were simultaneously treated with TEA (0.39 mL,
2.82 mmol) and MsCl (214 mg, 1.88 mmol) at 0 ꢁC. After being
stirred for 3 h at 0 ꢁC wroom temperature, the reaction was
quenched with saturated NaHCO3 aqueous solution and extracted
with CHCl3 for three times. The combined organic layers were
washed with brine, dried over NaSO4, and concentrated in vacuo.
The residue was purified by flash chromatography on silica gel to
give yellow oil (239 mg, 95%). The above oil was dissolved in DMF
(10 mL) and treated with NaN3 (183 mg, 2.8 mmol) at room tem-
perature. The reaction was stirred at 80 ꢁC for 36 h and diluted with
water. The mixture was extracted with EtOAc for three times and
the combined organic layers were washed with brine for three
times. Dried and concentrated, the residue was purified by flash
chromatography on silica gel to give 13 (137 mg, 68%) as a colorless
4.5.9. Benzyl 2-oxopyrrolidine-1-carboxylate (1i). Colorless oil; IR
(film): nmax 3033, 2963, 1786, 1751, 1718, 1456, 1383, 1299,
1175 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
7.44e7.26 (m, 5H), 5.28 (s,
2H), 3.81 (t, J¼6.8 Hz, 2H), 2.53 (t, J¼8.0 Hz, 2H), 2.06e1.99 (m,
2H) ppm; 13C NMR (100 MHz, CDCl3):
d
¼174.0, 151.5, 135.4, 128.6,
128.4, 128.2, 68.0, 46.4, 32.8, 17.6 ppm; MS (ESI): 242 (MþNaþ);
HRMS (ESI) calcd for (C12H13NO3þNaþ): 242.0793, found:
242.0788.
4.5.10. tert-Butyl 2-oxopyrrolidine-1-carboxylate (1l). Colorless oil;
IR (film): nmax 2980, 1785, 1712, 1367, 1313, 1153 cmꢀ1 1H NMR
;
(400 MHz, CDCl3):
d
3.75 (t, J¼6.7 Hz, 2H), 2.50 (t, J¼8.0 Hz, 2H),
2.03e1.95 (m, 2H), 1.53 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3):
d
¼174.2, 150.3, 82.7, 46.5, 33.0, 28.0, 17.4 ppm; MS (ESI): 208
(MþNaþ); HRMS (ESI) calcd for (C9H15NO3þNaþ): 208.0950, found:
208.0942.
oil. ½a 2D5
ꢂ
þ158.7 (c 1.26, CHCl3); IR (film): nmax 2970, 2932, 2792,
2098, 1453, 1256, 739, 698 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
4.5.11. (4R,5S)-1-Benzyl-4-(tert-butyldimethylsilyloxy)-5-
methylpyrrolidin-2-one (11). To a solution of 1a (2.008g, 6.1 mmol)
in CH2Cl2 (20 mL) was dropped TFA (3 mL) at 0 ꢁC and stirred for 4 h
at 0 ꢁC wroom temperature. The reaction was slowly quenched
with saturated NaHCO3 aqueous solution at 0 ꢁC until no bubbles
appeared. Then, the organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 for three times. The combined
organic layers were washed with brine, dried over NaSO4, and
concentrated in vacuo to give yellow crude product without further
purification. The above crude compound was dissolved in cooled
(0 ꢁC) DMF (40 mL) and NaH (242 mg, 12 mmol) was carefully
added in several portions, and then BnBr (2.03 g, 12 mmol) was
dropped. After being stirred for 2.5 h at 0 ꢁC to room temperature,
the reaction was cooled to 0 ꢁC and carefully quenched with water.
The resulting mixture was extracted with EtOAc for four times and
the combined organic layers were washed with brine for three
times. Dried over NaSO4 and concentrated in vacuo, the residue was
d
7.31e7.21 (m, 5H), 4.02 (d, J¼13.2 Hz, 1H), 3.67e3.64 (m, 1H), 3.15
(d, J¼13.2 Hz, 1H), 3.00e2.96 (m, 1H), 2.54 (ddd, J¼5.2, 6.0, 12.6 Hz,
1H), 2.18e2.05 (m, 2H), 1.93e1.85 (m, 1H), 1.24 (d, J¼6.4 Hz,
3H) ppm; 13C NMR (100 MHz, CDCl3):
d¼138.9, 128.7, 128.2, 126.9,
64.3, 63.3, 57.2, 51.6, 28.9, 13.9 ppm; MS (ESI): 217 (MþHþ); HRMS
(ESI) calcd for (C12H16N4þHþ): 217.1448, found: 217.1442.
4.5.14. N-((2S,3S)-1-Benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-
methoxy-4-(methylamino)benzamide (nemonapride) (3). The mix-
ture of 14 (56 mg, 0.26 mmol) and palladium on calcium carbonate
(7 mg, 5% Pd, 3.5%Pb) was stirred in MeOH (10 mL) for 5 h under H2
atmosphere at room temperature. The reaction mixture was fil-
trated and concentrated in vacuo to give crude (2S,3S)-1-benzyl-2-
methylpyrrolidin-3-amine (49 mg, quantitative yield) as a colorless
oil without purification. 5-Chloro-2-methoxy-4-(methylamino)
benzoic acid (84 mg, 0.39 mmol) was dissolved in dry DCM (6 mL)
and cooled to 0 ꢁC, then TEA (0.15 mL, 1.04 mmol) and ClCO2Et

7836
W. Huang et al. / Tetrahedron 67 (2011) 7829e7837
(0.04 mL, 0.39 mmol) were simultaneously dropped. After being
stirred for 45 min at the same conditions, the mixture was treated
with a solution of above crude amine in dry DCM (2 mL) and stirred
for 2 h at 0 ꢁC. The resulting mixture was quenched with water and
extracted with DCM for three times. The combined organic layers
were washed with brine, dried over NaSO4, and concentrated in
vacuo. The residue was purified by flash chromatography on silica
as a white solid. Mp 98e99 ꢁC; (2S,3S)-16a ½a 2D5
þ27.7 (c 1.12,
ꢂ
CHCl3); (2R,3R)-16b ½a D25
ꢀ28.4 (c 0.8, CHCl3); IR (film): nmax 3403,
ꢂ
2975, 1770, 1676, 1366, 1287, 1167 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
7.30e7.19 (m, 5H), 4.51e4.42 (m, 2H), 3.19e3.09 (m, 2H), 2.60 (dd,
J¼7.2, 17.0 Hz, 1H), 2.40 (dd, J¼7.6, 17.0 Hz, 1H), 1.48 (s, 9H) ppm; 13C
NMR (100 MHz, CDCl3):
d
¼171.8, 149.8, 137.8, 129.9, 129.7, 128.6,
126.7, 83.3, 65.6, 62.7, 40.1, 33.9, 28.0 ppm; MS (ESI): 314 (MþNaþ);
HRMS (ESI) calcd for (C16H21NO4þNaþ): 314.1368, found: 314.1372.
gel to give nemonapride 3 (110 mg, 72%) as a colorless solid. ½a D25
ꢂ
þ2.50 (c 0.76, CHCl3), lit.3c
½
a 2D5
ꢂ
þ2.3 (c 0.6, CHCl3); lit.3b
½
a 2D5
ꢂ
þ4.0
(c 0.6, CHCl3); IR (film): nmax 3387, 2967, 2930, 1635, 1601, 1517,
4.5.17. (4S,5S) or (4R,5R)-5-Benzyl-4-hydroxypyrrolidin-2-one (cis-
4). To a solution of 16a or 16b (298 mg, 1.02 mmol) in MeOH
(20 mL) was treated with SOCl2 (1 mL) at 0 ꢁC. After being stirred for
2 h, the reaction was concentrated and the residue was purified by
chromatography on silica gel to give cis-4 (170 mg, yield 87%) as
1455, 1281, 1245, 1213 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 8.10 (s,
1H), 8.01 (d, J¼8.6 Hz,1H), 7.36e7.23 (m, 5H), 6.12 (s,1H), 4.71e4.65
(m, 2H), 4.04 (d, J¼12.6 Hz, 1H), 3.98 (s, 3H), 3.20 (d, J¼12.6 Hz, 1H),
3.00 (m, 1H), 2.97e2.93 (m, 3H), 2.65e2.62 (m, 1H), 2.25e2.12 (m,
2H), 1.67e1.63 (m, 1H), 1.13 (d, J¼6.0 Hz, 3H) ppm; 13C NMR
a white solid. Mp 132e134 ꢁC, lit.5g 133e135; (4S,5S)-4 ½a 2D5
ꢀ44.6
ꢂ
(100 MHz, CDCl3):
d
164.2, 158.1, 148.1, 132.4, 128.7, 128.2, 126.9,
(c 0.05, MeOH); (4R,5R)-4 ½a D25
þ43.87 (c 1.07, MeOH); IR (film):
ꢂ
111.5, 93.3, 61.8, 57.6, 56.1, 52.4, 51.7, 31.4, 30.2, 29.7, 14.0 ppm; MS
(ESI): 388 (MþHþ); HRMS (ESI) calcd for (C21H26ClN3O2þHþ):
388.1792, found: 388.1806.
nmax 3455, 3229, 1693, 1346, 1044 cmꢀ1 1H NMR (400 MHz,
;
CD3OD): d 7.54 (br s, 1H), 7.31e7.21 (m, 5H), 5.12 (s, 1H), 4.13 (s, 1H),
3.71 (dd, J¼6.4, 12.8 Hz, 1H), 2.99 (ddd, J¼3.2, 8.0, 14.0 Hz, 1H), 2.69
(ddd, J¼3.2, 5.6, 9.2 Hz, 1H), 2.40 (dd, J¼5.6, 16.4 Hz, 1H), 2.04e1.99
4.5.15. (4R,5S) or (4S,5R)-5-Benzyl-4-hydroxypyrrolidin-2-one
(4). To a solution of (2R,3S) or (2S,3R)-1g (210 mg, 0.518 mmol)
in MeOH (5 mL) was slowly dropped SOCl2 (0.3 mL) at 0 ꢁC. The
mixture was stirred at room temperature for 2 h and concentrated
in vacuo. The dark residue was purified by flash chromatography on
silica gel to give 4 as white, slightly red solid (80 mg, 81%). Com-
(m, 1H) ppm; 13C NMR (100 MHz, CD3OD):
d
¼175.4, 139.2, 129.4,
128.7, 126.5, 67.4, 60.6, 43.3, 35.05 ppm; MS (ESI): 192 (MþHþ);
HRMS (ESI) calcd for (C11H13NO2þHþ): 192.1025, found: 192.1019.
Acknowledgements
pound (4R,5S)-4 ½a D25
ꢂ
þ16.81 (c 0.05, MeOH); (4S,5R)-4 ½a D25
ꢀ16.56
ꢂ
We thank the National Natural Science Foundation of China
(21072034, 20832005, and 20702007), and the National Basic Re-
search Program (973 program) of China (grant no. 2010CB912600)
for financial support. The authors also thank Dr. X.-S., Lei for helpful
suggestions.
(c 0.05, MeOH); IR (film): nmax 3454, 3227, 1694, 1347, 1045 cmꢀ1
;
1H NMR (400 MHz, MD3OD):
d 7.68 (br s, 1H), 7.32e7.20 (m, 5H),
5.10 (d, J¼4.0 Hz,1H), 3.97e3.95 (m,1H), 3.51 (dd, J¼6.0, 6.8 Hz,1H),
2.74e2.64 (m, 2H), 2.28 (dd, J¼6.4, 16.8 Hz, 1H), 1.83 (dd, J¼2.8,
16.8 Hz, 1H) ppm; 13C NMR (100 MHz, MD3OD):
129.9, 128.7, 126.7, 69.8, 63.9, 40.6, 39.8 ppm; MS (ESI): 192
(MþHþ); HRMS (ESI) calcd for (C11H13NO2þHþ): 192.1025, found:
192.1017.
d
¼175.2, 138.2,
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