A novel approach to the Geissman-Waiss lactone and a key intermediate in the synthesis of pyrrolidine trans-lactones

Article abstract of DOI:10.1016/j.tetasy.2004.09.020

Based on the highly regio- and diastereoselective reductive- ethoxycarbonylmethylation of protected (S)-malimide 4, a new approach to the Geissman-Waiss lactone 1 and a key intermediate 3 for the synthesis of pyrrolidine trans-lactones (e.g., 2) is descri

Full text of DOI:10.1016/j.tetasy.2004.09.020

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3461–3466
A novel approach to the Geissman–Waiss lactone and a
key intermediate in the synthesis of pyrrolidine trans-lactones
Jing-Xing Du, Hui-Ying Huang and Pei-Qiang Huang*
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen,
Fujian 361005, PR China
Received 30 August 2004; accepted 16 September 2004
Abstract—Based on the highly regio- and diastereoselective reductive-ethoxycarbonylmethylation of protected (S)-malimide 4, a
new approach to the Geissman–Waiss lactone 1 and a key intermediate 3 for the synthesis of pyrrolidine trans-lactones (e.g., 2)
is described. The synthesis features a one-step and a two-step chemoselective reduction of an amide carbonyl in the presence of
an ester group as the key steps.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
asymmetric synthesis of pyrrolidine trans-lactone 2 and
swainsonine.
Pyrrolizidine alkaloids consisting of hydroxylated 1-
methylpyrrolizidines (necine bases) and acidic moieties
(necine acids) are widely present in plants.1 Their diverse
structures and interesting bioactivities, such as antitu-
mor activity and carcinogenicity,2 have attracted much
synthetic attention. Particular attention has been paid
to the synthesis of the pyrrolizidine moieties.3
O
O
O
HO
O
Cl-
EtO2C
N
Cl-
N
N
Cbz
H2
H2
1
2
3
Since the pioneering use of lactone 1 by Geissman and
Waiss4 as a key intermediate for the synthesis of (+)-ret-
ronecine,4,5 this lactone (latterly known as Geissman–
Waiss lactone) and its N-protected derivatives have be-
come the standard intermediates for the synthesis of
other necine bases, such as (ꢀ)-turneforcidine,6 (+)-platy-
necine,7 and (+)-croalbinecine.5b As a result, a number
of approaches to enantioenriched Geissman–Waiss lac-
tone have been reported.8 In addition, structurally re-
lated pyrrolidine trans-lactone 2,9 prepared from 3, has
recently been introduced as a scaffold for designing
inhibitors of serine proteases with the aim of developing
therapies for respiratory and cardiovascular diseases
amongst others. In connection with our work on the
development of (S)-malimide-based synthetic methodol-
ogy for the synthesis of bioactive pyrrolidines,10 we
report herein a new approach to (ꢀ)-Geissman–Waiss
lactone 1 and pyrrolidine 3, a key intermediate for the
2. Results and discussion
Central to our plan was the introduction of the side
chain of Geissman–Waiss lactone via reductive alkyl-
ation of the protected (S)-malimide 410c,f in a regio-
and diastereoselective manner. Although it has been
observed that addition of alkyllithium reagents to mali-
mide 4 leads to poor regioselectivity,10f,11 in light of
our recent results,10g we envisioned that ethyl acetate
lithium enolate, being a stabilized organolithium reagent
would behave similarly to Grignard reagents, leading to
high C-2 regioselectivity. This turned out to be correct,
when a THF solution of the known (S)-malimide 410c,f
was added to a solution of lithium enolates, generated
in situ from ethyl acetate at ꢀ78ꢁC, a pair of diastereo-
mers 5 was obtained in 89% yield (based on the
recovered starting material, 4, 13%) (Scheme 1). No
other regioisomers were detected after the subsequent
reductive deoxygenation reaction. The observed high
*
Corresponding author. E-mail: pqhuang@xmu.edu.cn
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.09.020

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J.-X. Du et al. / Tetrahedron: Asymmetry 15 (2004) 3461–3466
difficult task. After several trials, it was observed that
BnO
O
BnO
HO
EtO2C
the chemoselective deoxygenation reduction of 9 could
be achieved by treating 9 with 3mol equiv of borane
dimethylsulfide in THF at rt for 24h. In such a way,
the desired cis-pyrrolidine lactone 10 was obtained in
about 58% yield. Furthermore, fully reduced 11 was iso-
lated as a by-product in 10% yield (Scheme 3). To
complete the synthesis of 1, 10 was subjected to hydro-
genolytic conditions (H2, 10% Pd/C, 6M HCl, MeOH)
to provide Geissman–Waiss lactone 1, which was iso-
LHMDS, AcOEt
O
O
THF, -78 o
76%(89%)
C
N
PMB
4
N
PMB
5
BnO
Et3SiH, F3B-OEt2
CH2Cl2, -78 oC~rt
86%
EtO2C
O
N
PMB
6
lated as the hydrochloride salt {mp 185–189ꢁC (EtOH/
20
Scheme 1.
Et2O), ½aꢂ ¼ þ45:0 (c 0.4, MeOH); lit.8h mp 185–
20
D
20
D
188ꢁC,
½aꢂ ¼ þ47:9 (c 1.5, MeOH); lit.5b
½aꢂ ¼ þ45:6 (c 0.3, MeOH)} in 95% yield.
D
regioselectivity is in support of our previous argument
that the different regioselective behaviors of Grignard
`
reagents and alkyllithium vis-a-vis the (S)-malimide 4
O
O
O
O
H3B-SMe2
(3 equiv.)
was due to the higher reactivity of organolithium rea-
gents, which precluded a precoordination of the metal
ion (Li+) with the oxygen atom at the C-3 position,
while Grignard reagents did precoordinate, leading reg-
ioselectively to C-2 addition.10f Treatment of the dia-
stereomeric N,O-acetal 5 with F3BÆOEt2/Et3SiH10,12
(ꢀ78ꢁC, then rt) led to the desired lactam 6, as the only
isolable diastereomer, in 86% yield. The stereochemistry
of lactam 6 was assigned as trans according to the ob-
O
+
O
O
N
PMB
N
PMB
N
PMB
10
THF, 24 h
58%
9
11 (10%)
H2,10% Pd/C
MeOH, 6 M HCl
95%
O
N
H2Cl
served small vicinal coupling constants10,13 (J4,5
0Hz), which was further confirmed by converting 6 to
known 1 and 3.
ꢁ
1
Scheme 3.
Debenzylation of 6 under hydrogenolytic conditions
(1atm H2, 10% Pd/C, EtOH, rt) provided hydroxy lac-
tam 7 in 87% yield (Scheme 2). Compound 7 was then
subjected successively to saponification (1.1equiv LiOH,
H2O, rt, 5h) and intramolecular Mitsunobu reaction
conditions (PPh3, DEAD, CH2Cl2, 0ꢁC–rt),14 which
afforded the desired lactone 9 in an overall yield of
96% from 7.
Next, we turned our attention to the synthesis of pro-
tected 3-pyrrolidininol derivative 3, the key intermediate
for the synthesis of pyrrolidine trans-lactone 2.9 For this
purpose, lactam–ester 6 was treated with borane dimeth-
ylsulfide in the same way as described for 9. Unfortu-
nately, the desired 13 was obtained, in the best case, in
only 41% yield. We then decided to explore a two-step
procedure16 (Scheme 4). Thus, 6 was first treated with
2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane
2,4-disulfide (Lawessonꢀs reagent)17 (90ꢁC, 1h), which
led to thioamide 12 in 90% yield. Subsequent desulfuri-
zation of 12 with Raney-nickel deserves comments.
Initially, when 12 was treated with ethanol–washed
Raney nickel (W-2), a large amount of C–N bond
HO
LiOH, H2O
rt, 5 h
H2, 10% Pd/C
EtO2C
6
O
N
EtOH
87%
PMB
7
HO
O
O
PPh3, DEAD
HO2C
BnO
BnO
0 oC-rt
96% from 7
O
N
O
N
PMB
8
Lawesson's
reagent, tol.
90 oC, 1 h
90%
PMB
EtO2C
EtO2C
O
S
N
PMB
6
N
9
PMB
12
Scheme 2.
BnO
BnO
Raney Ni, THF
The next problem was the selective conversion of 9 to
pyrrolidine cis-lactone 10. Although a three-step proce-
dure (thionation, ethylation with Et3OÆBF4 and selective
reduction with NaBH3CN)5c,8h,i has been developed for
the selective deoxygenative reduction of the carbonyl of
a lactone–lactam, a direct one-pot chemoselective reduc-
tion was desirable. A survey of the literature showed
that the chemoselective reduction of an amide carbonyl
in the presence of an ester group was possible.15 How-
ever, selective reduction of an amide carbonyl without
affecting the more reactive lactone carbonyl was a more
EtO2C
EtO2C
N
PMB
13
N
Et
14
rt, 1 h
84~90%
HO
1. HCO2H, 10% Pd/C
2. H2, 10% Pd/C, EtOH
EtO2C
13
N
Cbz
3
3. CbzCl, NEt3, CH2Cl2
60%
Scheme 4.

J.-X. Du et al. / Tetrahedron: Asymmetry 15 (2004) 3461–3466
3463
cleaved/re-ethylated side product 14 was isolated. Such a
side reaction has previously been observed.18 After sev-
eral trials, we found that when THF–washed Raney
nickel (W-2) was used (rt, 1h) instead, 13 could be ob-
tained in high yields (84–90%).
(0.12mL, 1.22mmol) was added dropwise over 15min
and the stirring continued for another 15min. To the
ethyl lithioacetate was added dropwise a solution of 4
(394mg, 1.22mmol) in tetrahydrofuran (0.6mL) over
15min and the stirring continued at ꢀ78ꢁC for 3h.
The reaction was quenched by the addition of hydro-
chloric acid (2M, 1mL). The cooling bath was removed,
and the solution allowed to warm to room temperature.
The organic layer was separated, and the aqueous layer
extracted with CH2Cl2 (2 · 2mL). The combined ex-
tracts were washed successively with a saturated solu-
tion of NaHCO3 and brine, dried over anhydrous
sodium sulfate, filtered, and concentrated under reduced
pressure. Flash chromatographic purification (eluent:
AcOEt–PE = 1:2) of the crude afforded 5 (white solid,
381mg, diastereomeric mixture, combined yield: 76%)
and the recovered starting material 4 (53mg, 13%).
Carbinol 5 was used in the next step as a diastereomeric
mixture.
Finally, successive N-debenzylation and O-debenzyl-
ation via transfer hydrogenolysis and catalytic hydro-
genolysis led to the desired 3-pyrrolidinol derivative,
which without further purification, was reprotected
20
D
(CbzCl, NEt3, CH2Cl2, rt) to give 319 {½aꢂ ¼ ꢀ33:9}
in 60% overall yield from 13. It should be noted that
transfer hydrogenolysis should be followed by catalytic
hydrogenolysis so as to ensure the complete cleavage
of both N,O-protective groups. Since compound 6 is a
common intermediate in the syntheses of Geissman–
Waiss lactone 1 and 3, and no epimerization has been
observed during the transformation from 6 to 3, the
enantiomeric excess of 3 was estimated to be 98% by
comparing with that of Geissman–Waiss lactone 1.
To a cooled (ꢀ78ꢁC) solution of the diastereomeric mix-
ture 5 (970mg, 2.34mmol) in dichloromethane (14mL)
was added successively Et3SiH (3.73mL, 23.4mmol)
and BF3ÆOEt2 (0.88mL, 7.0mmol) under an N2 atmos-
phere. The resulting mixture was stirred at ꢀ78ꢁC for
6h and at room temperature overnight. The resultant
mixture was quenched by addition of a saturated solu-
tion of NaHCO3 at 0ꢁC. After the mixture was ex-
tracted with CH2Cl2 (3 · 5mL), the combined organic
phases were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pres-
sure. Flash chromatographic purification of the crude
3. Conclusion
In conclusion, we have shown that ethyl acetate lithium
enolates, being a moderate nucleophile, can add regio-
selectively at the C-2 carbonyl of the N,O-di-protected
(S)-malimide 4 in excellent regioselectivity. A one-step
and a two-step chemoselective amide carbonyl reduction
procedure have been used respectively for the conver-
sion of 6 to Geissman–Waiss lactone (+)-1 and (ꢀ)-3.
Since racemic 3 has been converted to ( )-2, our
approach to enantioenriched 3 would, a priori, open a
route to optically active 2.
(eluent: EtOAc–PE = 1:2) afforded 6 (822mg, 86%) as
20
D
a pale yellow oil. ½aꢂ ¼ þ24:5 (c 1.0, CHCl3). IR (film)
m
max: 3031, 2931, 1731, 1693, 1513, 1247, 1177,
1
1029cmꢀ1. H NMR (500MHz, CDCl3): d 1.22 (t, 3H,
J = 7.1Hz, CH2CH3), 2.32 (dd, J = 8.7, 15.8Hz, 1H,
CH2COO), 2.52 (d, J = 17.4Hz, 1H, H-3), 2.56 (dd,
J = 3.9, 15.8Hz, 1H, CH2COO), 2.77 (dd, J = 6.2,
17.4Hz, 1H, H-3), 3.79 (s, 3H, OCH3), 3.89 (dd,
J = 3.9, 8.7Hz, 1H, H-5), 3.99 (m, 1H, H-4), 4.00 (d,
J = 15.0Hz, 1H, NCH2Ar), 4.10 (q, J = 7.1Hz, 2H,
CH2CH3), 4.46 (d, J = 11.8Hz, 1H, OCH2Ph), 4.50 (d,
J = 11.8Hz, 1H, OCH2Ph), 4.89 (d, J = 15.0Hz, 1H,
NCH2Ar), 6.80–7.38 (m, 9H, Ar) ppm. 13C NMR
(125MHz, CDCl3) d: 14.1 (CH2CH3), 35.6 (CH2COO),
37.2 (C-3), 43.7 (C-5), 55.3 (NCH2Ar), 59.9, 61.0
(CH2CH3), 70.6, 75.9 (OCH2Ph), 114.1, 127.7, 127.8,
128.1, 128.4, 129.1, 137.6, 159.1 (Ar), 170.2 (C-2),
172.8 (COO) ppm. MS (ESI, m/z): 420 (M+Na+, 40),
398 (M+H+, 100). HRMS calcd for [C23H27NO5+H]+:
398.1962. Found: 398.1961.
4. Experimental
4.1. General
All 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 KBr pellet tech-
1
niques. H NMR spectra were recorded in CDCl3 on a
Varian unity +500 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 injection).
Optical rotations were measured with a Perkin–Elmer
341 automatic polarimeter. Flash column chromatogra-
phy was carried out with silica gel (200–300mesh).
Solvent THF was distilled over sodium, with dichloro-
methane being distilled over P2O5.
4.3. Ethyl (4S,5R)-[4-hydroxy-1-(4-methoxybenzyl)-2-
oxopyrrolidin-5-yl]acetate 7
4.2. Ethyl (4S,5R)-[4-benzyloxy-1-(4-methoxybenzyl)-2-
oxopyrrolidin-5-yl]acetate 6
A mixture of 6 (225mg, 0.57mmol) and 10% Pd/C
(56mg) in EtOH (3mL) was stirred under an atmos-
phere of hydrogen (1atm, balloon technique) at room
temperature for 9days. The catalyst was filtered through
Celite, and the filtrate washed successively with a satu-
rated solution of NaHCO3 and brine, dried over
anhydrous Na2SO4, filtered, and concentrated under
To
a solution of hexamethyldisilazane (0.33mL,
1.34mmol) in THF (1mL) was added dropwise n-butyl-
lithium (0.49mL, 1.22mmol) at ꢀ78ꢁC under N2 atmos-
phere. After being stirred for 0.5h, ethyl acetate

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J.-X. Du et al. / Tetrahedron: Asymmetry 15 (2004) 3461–3466
reduced pressure. Column chromatographic purification
of the crude (eluent: EtOAc–PE = 2.5:1) afforded 7 as
4.6. (1R,5R)-6-(4-Methoxybenzyl)-2-oxa-6-azabicyclo-
[3.3.0]octan-3-one 10
colorless crystals (152mg, 87%). Mp 50–52ꢁC (EtOAc/
20
PE). ½aꢂ ¼ þ1:6 (c 1.1, CHCl3). IR (film) mmax: 3379,
To a solution of 9 (60mg, 0.23mmol) in dry tetra-
hydrofuran (4.6mL) was added dropwise borane
dimethylsulfide complex (0.05mL, 0.58mmol) at 0ꢁC
under N2 atmosphere. The mixture was stirred at 0ꢁC
for 0.5h and then at rt for 19h. Methanol was added
until the evolution of gas had ended. The solvents were
removed under reduced pressure. Methanol (4 · 5mL)
was added and then evaporated (this procedure was re-
peated for four times). Purification of the residue by sil-
ica gel chromatography (AcOEt–PE = 1:2.5) afforded 10
D
2933, 1730, 1670, 1514, 1247, 1177, 1031cmꢀ1
.
1H
NMR (500MHz, CDCl3): d 1.24 (t, J = 7.1Hz, 3H,
CH2CH3), 2.31 (dd, J = 9.6, 16.5Hz, 1H, CH2COO),
2.44 (dd, J = 3.5, 17.6Hz, 1H, H-3), 2.67 (dd, J = 3.9,
16.5Hz, 1H, CH2COO), 2.81 (dd, J = 7.1, 17.6Hz, 1H,
H-3), 3.63 (ddd, J = 2.6, 3.9, 9.6Hz, 1H, H-5), 3.79 (s,
3H, OCH3), 3.98 (d, J = 15.2Hz, 1H, NCH2Ar), 4.11
(q, J = 7.1Hz, 2H, CH2CH3), 4.24 (m, 1H, H-4), 4.85
(d, J = 15.2Hz, 1H, NH2Ar), 6.80–7.30 (m, 4H, Ar)
ppm. 13C NMR (125MHz, CDCl3): d 14.0 (CH2CH3),
36.1 (CH2COO), 39.00 (C-3), 43.6 (C-5), 55.2
(NCH2Ar), 61.3 (C-4), 62.5 (CH2CH3), 70.1 (OCH3),
114.1, 127.84, 129.1, 159.1 (Ar), 171.2 (C-2), 172.6
(COO) ppm. MS (ESI, m/z): 330 (M+Na+, 20), 308
(M+H+, 100). HRMS calcd for [C16H21NO5+H]+:
308.1492. Found: 308.1491. Anal. Calcd for
C16H21NO5: C, 62.53; H, 6.89; N, 4.56. Found: C,
62.33; H, 6.89; N, 4.65.
(32mg, 58%) as colorless crystals. Mp 59–61ꢁC (EtOAc/
20
PE). ½aꢂ ¼ ꢀ3:65 (c 1.0, CHCl3). IR (film) mmax: 2929,
D
2836, 1774, 1611, 1512, 1248, 1163, 1093, 1034cmꢀ1
.
1H NMR (500MHz, CDCl3):
d 2.04 (m, 1H,
NCH2CH2), 2.24 (m, 1H, NCH2CH2), 2.31 (m, 1H,
NCH2), 2.48 (d, J = 17.9Hz, 1H, CH2COO), 2.55 (dd,
J = 6.5, 17.9Hz, 1H, CH2COO), 3.02 (t, J = 8.0Hz,
1H, NCH2), 3.22 (s, 1H, CH N), 3.42 (d, J = 12.7Hz,
1H, NCH2Ar), 3.75 (d, J = 12.7Hz, 1H, NCH2Ar),
4.98 (m, 1H, CHO), 6.82–7.30 (m, 4H, Ar) ppm. 13C
NMR (125MHz, CDCl3): d 31.1 (NCH2CH2), 34.7
(CH2COO), 52.3 (NCH2), 55.2 (CHN), 57.1 (OCH3),
63.3 (NCH2Ar), 83.9 (CHO), 113.8, 129.9, 159.9 (Ar),
176.5 (COO) ppm. MS (ESI, m/z): 270 (M+Na+, 10),
248 (M+H+, 100). HRMS calcd for [C14H17NO3+H]+:
248.1281. Found: 248.1283.
4.4. (4S,5R)-2-[4-Hydroxy-1-(4-methoxybenzyl)-2-oxo-
pyrrolidin-5-yl]acetic acid 8
To a stirred solution of 7 (110mg, 0.36mmol) in EtOH
(2.1mL) was added 1M aqueous LiOH (0.4mL) at 0ꢁC.
The solution was stirred at room temperature for 5h,
and then acidified with 6M HCl to pH2–3. After the
mixture was extracted with CH2Cl2 (3 · 3mL), the
combined organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure to give crude 8, which was used
in the next step without further purification.
4.7. (1R,5R)-2-Oxa-6-azabicyclo[3.3.0]octan-3-one
hydrochloride 1
To a mixture of 10 (20mg, 0.08mmol) and 10% Pd–C
(8mg) were added successively methanol (0.5mL) and
6M hydrochloric acid (0.1mL) at 0ꢁC. The mixture
was stirred at room temperature under an atmosphere
of H2 overnight. The mixture was filtered through a Cel-
ite pad and then evaporated to give a yellow solid, which
was triturated with ethanol and recrystallized to provide
lactone 1 as a white solid (11mg, 95%). Mp 185–189ꢁC
4.5. (1R,5R)-6-(4-Methoxybenzyl)-2-oxa-6-azabicyclo-
[3.3.0]octan-3,7-dione 9
To a mixture of crude 8 and PPh3 (113mg, 0.43mmol)
in THF (3.6mL) was added dropwise DEAD
(0.07mL, 0.43mmol) at 0ꢁC. After being stirred at rt
for 0.5h, the mixture was concentrated under reduced
pressure. Flash chromatographic purification of the
crude (AcOEt–PE = 1:1.5–2:1) afforded 9 (90mg, 96%)
(EtOH/Et2O) (lit.5b,8n mp 182–184ꢁC; lit.8g mp
20
185–186ꢁC). ½aꢂ ¼ þ45:0 (c 0.4, MeOH) {lit.5b,8n
D
20
D
20
D
½aꢂ ¼ þ45:6 (c 0.3, MeOH); lit.8g ½aꢂ ¼ þ45:8 (c
0.56, MeOH)}. IR (film) mmax: 3388, 2924, 1777, 1719,
1
as
a
white solid. Mp 109–111ꢁC (EtOAc/PE).
1442cmꢀ1. H NMR (500MHz, D2O): d 2.34–2.44 (m,
20
½aꢂ ¼ þ48:2 (c 1.0, CHCl3). IR (film) mmax: 2998,
1H, NCH2CH2), 2.47–2.54 (m, 1H, NCH2CH2), 3.03
(dd, J = 1.6, 19.7Hz, 1H, CH2COO), 3.32 (dd, J = 8.8,
19.7Hz, 1H, CH2COO), 3.48 (ddd, J = 6.6, 11.1,
12.0Hz, 1H, NCH2), 3.59 (ddd, J = 3.4, 7.8, 12.0Hz,
1H, NCH2), 4.71 (ddd, J = 1.6, 5.7, 8.8Hz, 1H, CHN),
5.45 (ddd, J = 0.9, 5.4, 5.7Hz, 1H, CHO) ppm. 13C
NMR (125MHz, D2O): d 33.3 (NCH2CH2), 35.6
(NCH2), 47.0 (CH2COO), 61.8 (NCH), 86.5 (CHO),
179.9 (COO) ppm.
D
2935, 2839, 1784, 1695, 1514, 1404, 1245, 1173,
1030cmꢀ1 1H NMR (500MHz, CDCl3): d 2.63 (dd,
.
J = 6.6, 18.3Hz, 1H, NCOCH2), 2.70 (dd, J = 1.2,
18.3Hz, 1H, NCOCH2), 2.82 (m, 2H, CH2COO), 3.80
(s, 3H, OCH3), 3.96 (d, J = 15.0Hz, 1H, NCH2Ar),
4.18 (ddd, J = 1.2, 5.2, 6.6Hz, 1H, CHN), 4.93 (d,
J = 15.0Hz, 1H, NCH2Ar), 5.04 (ddd, J = 2.9, 5.2,
8.0Hz, 1H, CHO), 6.82–7.30 (m, 4H, Ar) ppm. 13C
NMR (125MHz, CDCl3):
d
32.6 (CHN), 37.1
(NCOCH2), 44.0 (CH2COO), 55.3 (NCH2Ar), 57.2
(OMe), 75.5 (CHO), 114.4, 127.0, 129.5, 159.5 (Ar),
171.2 (NCO), 173.8 (COO) ppm. MS (ESI, m/z): 284
(M+Na+, 60), 262 (M+H+, 100). HRMS calcd for
[C14H15NO4+H]+: 262.1074. Found: 262.1072. Anal.
Calcd for C14H15NO4: C, 64.36; H, 5.79; N, 5.36.
Found: C, 64.68; H, 5.91; N, 5.31.
4.8. Ethyl (4S,5R)-[4-(benzyloxy)-1-(4-methoxybenzyl)-2-
thioxopyrrolidin-5-yl]acetate 12
To a stirred solution of 282mg (0.710mmol) of 6 in dry
toluene (28mL) was added Lawessonꢀs reagent (185mg,
0.46mmol) in one portion under N2 atmosphere. The
mixture was heated at 90ꢁC for 1h. The resultant

J.-X. Du et al. / Tetrahedron: Asymmetry 15 (2004) 3461–3466
3465
mixture was cooled and concentrated under reduced
pressure. The residue was chromatographed on silica
gel (eluent: ether–PE = 0.8:1) to give 12 (268mg, 90%)
edly with ethanol. The filtrates were concentrated under
reduced pressure. The residue was re-subjected to hydro-
genolysis conditions to afford the 3-pyrrolidinol deriva-
tive, which without further purification, was used in the
following reaction.
as
a
white solid. Mp 88–90ꢁC (ether–PE).
20
½aꢂ ¼ þ99:5 (c 1.0, CHCl3). IR (film) mmax: 3029,
D
2978, 2930, 1731, 1612, 1585, 1513, 1482, 1248, 1178,
1028cmꢀ1; H NMR (500MHz, CDCl3): d 1.14 (t, 3H,
To an ice-bath cooled stirred solution of the crude
(2R,3S)-3-pyrrolidinol derivative in CH2Cl2 were added
successively triethylamine (0.06mL) and benzyl chloro-
formate (0.05mL). After being stirred at room tempera-
ture for 4h, the reaction was quenched by water (2mL).
The organic layer was separated, and the aqueous layer
extracted with CH2Cl2 (3 · 2mL). The combined organ-
ic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. The
resulting residue was chromatographed on silica gel
1
J = 7.2Hz, CH2CH3), 2.28 (dd, J = 9.5, 16.2Hz, 1H,
CH2COO), 2.51 (dd, J = 3.9, 16.2Hz, 1H, CH2COO),
3.12 (d, J = 18.5Hz, 1H, H-3), 3.19 (dd, J = 5.4,
18.5Hz, 1H, H-3), 3.70 (s, 3H, OCH3), 3.90 (d,
J = 5.4Hz, 1H, H-4), 4.02 (q, J = 7.2Hz, 2H, CH2CH3),
4.12 (dd, J = 3.9, 9.5Hz, 1H, H-5), 4.22 (d, J = 14.9Hz,
1H, NCH2Ar), 4.34 (d, J = 12.4Hz, 1H, OCH2Ph), 4.36
(d, J = 12.4Hz, 1H, OCH2Ph), 5.56 (d, J = 14.9Hz, 1H,
NCH2Ar), 6.70–7.28 (m, 9H, Ar) ppm. 13C NMR
(125MHz, CDCl3): d 14.0 (CH2CH3), 34.6 (CH2COO),
48.6 (C-3), 49.8 (C-4), 55.2 (NCH2Ar), 61.2 (CH2CH3),
66.6 (OCH3), 70.4 (CH2Ph), 114.2, 126.6, 127.6, 127.7,
128.3, 129.1, 137.3, 159.3 (Ar), 169.7 (COO), 200.4 (C-
2) ppm. MS (ESI, m/z): 436 (M+Na+, 6), 414 (M+H+,
100). HRESIMS calcd for [C23H27NO4S+H]+:
414.1733. Found 414.1727.
(eluent: EtOAc–PE = 0.8:1) to give 319 as a pale yellow
20
D
oil (43mg, yield: 60%). ½aꢂ ¼ ꢀ33:9 (c 1.0, CHCl3).
IR (film) mmax: 3435, 3032, 2980, 2963, 2898, 1732,
1701, 1586, 1498, 1417cmꢀ1 1H NMR (500MHz,
.
CDCl3, rotamers): d 1.26 (t, 3H, J = 7.2Hz, CH2CH3),
1.85–1.94 (m, 1H, H-4), 2.02–2.10 (m, 1H, H-4), 2.20–
2.28 (m, 1H, CH2COO), 2.85 (m, 0.87H, CH2COO),
3.00 (s, 0.53H, OH), 3.12 (dd, J = 3.3, 16.4Hz, 0.53H,
CH2COO), 3.40–3.51 (m, 1H, H-5), 3.62–3.78 (m, 1H,
H-5), 4.00–4.20 (m, 2H, OCH2CH3), 4.26 (br s, 1H,
H-2), 5.10–5.18 (m, 2H, PhCH2), 7.24–7.40 (m, 5H,
Ph) ppm. 13C NMR (125MHz, CDCl3): d 14.1
(CH2CH3), 30.9 (CH2COO), 36.8 (C-4), 44.3 (C-5),
60.8 (C-2), 62.3 (CH2CH3), 66.8 (CH2Ph), 75.2 (C-3),
127.8, 128.4, 127.9, 136.7 (Ph), 154.8 (OCOCH2Ph),
171.5 (OCOEt) ppm. MS (ESI, m/z): 308 (M+H+,
100), 330 (M+Na+, 60).
4.9. Ethyl (2R,3S)-[3-(benzyloxy)-1-(4-methoxybenzyl)-
pyrrolidin-2-yl]acetate 13
To a stirred suspension of Raney nickel (4mL in dry
THF) was added a solution of 12 (122mg, 0.295mmol)
in dry THF (15mL). The reaction mixture was stirred
at room temperature for 1h, and then filtered through
Celite and washed repeatedly with methanol. The fil-
trates were concentrated under reduced pressure. The
residue was chromatographed on silica gel (eluent:
EtOAc–PE = 1:3) to give 13 as a pale yellow oil
20
D
(95mg, yield: 84%). ½aꢂ ¼ ꢀ19:4 (c 1.0, CHCl3). IR
Acknowledgements
(film) mmax: 3030, 2977, 2934, 2834, 1732, 1612, 1585,
1512, 1454, 1246, 1173, 1098, 1067cmꢀ1 1H NMR
.
The authors are grateful to the National Science Fund
for Distinguished Young Investigators, the NNSF of
China (20272048; 203900505), the Ministry of Educa-
tion (Key Project 104201), and the Specialized Research
Fund for the Doctoral Program of Higher Education
(20020384004) for financial support.
(500MHz, CDCl3): d 1.14 (t, J = 7.2Hz, 3H, CH2CH3),
1.69–1.84 (m, 2H, H-4), 2.35 (dd, J = 7.9, 14.5Hz, 1H,
CH2COO), 2.38–2.42 (m, 1H, H-5), 2.45 (dd, J = 4.6,
14.5Hz, 1H, CH2COO), 2.72–2.78 (m, 1H, H-5), 2.92–
2.97 (m, 1H, H-2), 3.29 (d, J = 12.8Hz, 1H, NCH2Ar),
3.70 (s, 3H, OCH3), 3.84 (d, J = 12.8Hz, 1H, NCH2Ar),
3.86–3.89 (m, 1H, H-3), 3.99–4.05 (m, 2H, OCH2CH3),
4.41, (dd, J = 12.2Hz, 1H, OCH2Ph), 4.43 (dd, J =
12.2Hz, 1H, OCH2Ph), 6.75–7.30 (m, 9H, Ar) ppm.
13C NMR (125MHz, CDCl3): d 14.2 (CH2CH3), 29.8
(CH2COO), 38.5 (C-4), 51.7 (C-5), 55.2 (OCH3), 58.2
(NCH2Ar), 60.3 (CH2CH3), 66.9 (C-2), 70.8 (CH2Ph),
83.6 (C-3) ppm. MS (ESI, m/z): 384 (M+H+, 100).
HRESIMS calcd for [C23H29NO4+H]+: 384.2169.
Found 384.2173.
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