Samarium diiodide-mediated reductive couplings of chiral nitrones with aldehydes/ketones and acyl chlorides

Article abstract of DOI:10.1016/j.tet.2010.01.011

The SmI₂-mediated and H₂O-promoted reductive cross-coupling reactions of the l-tartaric acid derived nitrone (3S,4S)-8 with aldehydes/ketones, and the l-malic acid derived nitrone (S)-6 with aliphatic acyl chlorides have been investi

Full text of DOI:10.1016/j.tet.2010.01.011

Tetrahedron 66 (2010) 1653–1660
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Samarium diiodide-mediated reductive couplings of chiral nitrones with
aldehydes/ketones and acyl chlorides
*
Shao-Feng Wu, Yuan-Ping Ruan, Xiao Zheng, Pei-Qiang Huang
Department of Chemistry, Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The SmI2-mediated and H2O-promoted reductive cross-coupling reactions of the L-tartaric acid derived
Received 14 October 2009
Received in revised form 26 December 2009
Accepted 5 January 2010
nitrone (3S,4S)-8 with aldehydes/ketones, and the L-malic acid derived nitrone (S)-6 with aliphatic acyl
chlorides have been investigated, respectively. (2R,3S,4S)-1,3,4-Trihydroxyprolinol derivatives 9a–f were
obtained with high C-2/C-3 trans-selectivities, and 72:28–85:15 diastereoselectivities at the carbinol
center from aromatic ketones/aldehydes, while low diastereoselectivities for aliphatic aldehydes. Con-
ditions have been established for the syntheses of (2R,3S,4S)-3,4-dihydroxyprolinol derivatives such as
18, by N–O bond cleavage of the corresponding N-hydroxyprolinol derivatives 9b–f, or more conveniently
by a one-pot reductive coupling of nitrone 8 and in situ N–O bond cleavage of the resultant coupling
product. The 2-acyl-3-benzyloxy-1-hydroxypyrrolidines 10a–f were formed in 48–82% yields, and in
74:26–78:22 diastereoselectivities. It was revealed that the amount of water required for the reaction is
substrate-depending.
Available online 11 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
R2
OH
OH
HO
OH
H
8
R1
HO
HO
1
HO
HO
8a
N
N
O
A
Nitrones (A, Fig. 1) are well recognized as an important class of
versatile synthetic intermediates, which have gained widespread
application in organic synthesis.1–3 However, as versatile 1,3-di-
poles and electrophiles, they were largely limited to the application
in 1,3-dipolar cycloadditions1 and nucleophilic additions.2 Until
2002, by an ingenious combination of nitrones with samarium
diiodide, a versatile one-electron reducing agent originally de-
N
H
2
(+)-castanospermine
(1)
HO
H
OH
Ph
Ph
Ph
N
OH
N
H
Ph
HO
O
B
N
OP
veloped by Kagan and co-workers,4 Py–Vallee have reported a sa-
´
H
4a. P = H
marium diiodide-induced reductive cross-coupling of nitrones
with aldehydes and ketones.5 This seminal work opened a new
page in the nitrone chemistry, namely, umpoled nitrones.6 Indeed,
in the almost meantime, the SmI2-induced nitrones coupling with
activated olefins have independently been reported by Skrydstrup7
and Py–Valle´e;8a both the application of this method to the total
synthesis of natural products or bioactive compounds,8 and the
extension of this concept to the SmI2-mediated coupling of alicyclic
nitrones with chiral N-tert-butanesulfinyl imines9 have been
reported. However, to the best of our knowledge, investigation of
these reactions with enantiomerically pure nitrones10 has not been
reported.
5
australine (3)
4b. P = TMS
BnO
BnO
HO
R2
N
OH
7
N
O
6
R1
BnO
OBn
BnO
BnO
OBn
O
HO
R2
N
OH
9
N
OH
10
N
O
8
R1
R
(R1 = Alkyl, aryl; R2 = H, Alkyl, aryl)
In view of the presence of b-hydroxyprolinol as the key struc-
tural feature in many aza-sugars11 (e.g., 1–3, Fig. 1), and the
Figure 1.
widespread use of prolinol-based organocatalysts12 (e.g., 4a,b) and
chiral ligands (e.g., 5),13 very recently, we reported a versatile
* Corresponding author. Tel.: þ86 592 2182240; fax: þ86 592 2186400.
E-mail address: pqhuang@xmu.edu.cn (P.-Q. Huang).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.011

1654
S.-F. Wu et al. / Tetrahedron 66 (2010) 1653–1660
Table 1
approach to
b-hydroxyprolinol derivatives 7 via SmI2-mediated
couplings of aldehydes/ketones with nitrone 6.14 As a continuation
of this work, we set to investigate the reductive cross-coupling
reactions not only of the (3S,4S)-tartaric acid derived chiral nitrone
8 with aldehydes/ketones but also of chiral nitrone 6 with aliphatic
acyl chlorides, and the results are reported herein.
The reductive cross-coupling of nitrone 8 with carbonyl compounds
O
BnO
BnO
OBn
OBn
R1
R2
HO
N
N
O
8
SmI2/THF (4.5 equiv.)
H2O (26 equiv)
−78 °C, 1 h
R1
R2
OH
9a ~ 9f
2. Results and discussion
Entry
1
Carbonyl compounds
Product (% yield)a
dr
O
In order to investigate the reductive coupling of the tartaric acid
derived chiral nitrone 8 with carbonyl compounds, the requisite
9a (90)
d
nitrone (3S,4S)-815 was prepared from
L-tartaric acid by the route
shown in Scheme 1. Diethyl O,O-bisbenzyltartarate 11 was con-
verted to the bis-mesylate 13 by successive lithium aluminum hy-
dride reduction (LAH, THF, reflux) and bis-mesylation (MsCl, NEt3,
CH2Cl2, rt). The reaction of the resultant bis-mesylate 13 with hy-
droxylamine hydrochloride salt gave 3,4-bis(benzyloxy)pyrrolidin-
1-ol 14. Although the oxidation of 1-hydroxypyrrolidine 14 to
nitrone (3S,4S)-8 by highly toxic HgO has been repoted,15 the use of
a less toxic oxidant is highly desirable. Thus treatment of 14 with
freshly prepared manganese dioxide16 in dichloromethane gave the
desired nitrone (3S,4S)-8 in 78% overall yield from 13. The nitrone
(3S,4S)-8 exhibited reasonable stability, which can be stored for
several weeks at ꢀ20 ꢁC under an inert atmosphere.
O
2
3
4
5
9b (50)
9c (75)
9d (42)
9e (92)
84:16b
85:15b
72:28b
83:17b
Cl
CHO
CHO
MeO
O
O
CHO
1.LAH,THF
OBn
BnO
OBn
OX
reflux
99%;
BnO
XO
6
9f (90)
43:27:17:13c
O
EtOOC COOEt
11
2. MsCl, Et3N
CH2Cl2
a
Isolated yields based on nitrone 8.
Ratio determined by 1H NMR.
Ratio determined by HPLC.
12. X = H
b
c
13. X = Ms
99%
BnO
OBn
OBn
BnO
MnO2
NH2OH•HCl
CH2Cl2
Et3N, reflux
stereochemistry of the products was determined as 2,3-trans on the
basis of 2D NOESY experiments undertaken on the major di-
astereomer of 9e (Fig. 2). The observed vicinal coupling constant of
this compound (J2,3¼4.5 Hz) is also consistent with the pyrrolidine
derivatives that possess a 2,3-trans stereochemical relationship
(e.g., 15–17 in Fig. 3).17 As can be seen from Figure 2, the vicinal
coupling constants (J2,3) of the 2,3-trans pyrrolidine derivatives 15–
17 range from 3.6 Hz to 4.6 Hz. The 2,3-relative stereochemistries of
the major diastereomers of 9b–d were thus deduced as trans
according to their J2,3 (Table 2). The stereochemistry of the exocyclic
chiral center was no determined. The same diastereoselectivity was
assumed to be retained for benzophenone. For aliphatic aldehydes
(cf. entry 6, Table 1) both the two new stereocenters were formed
with low stereoselectivities.
N
OH
14
N
O
8
78%
(from13)
Scheme 1. Synthesis of the chiral nitrone 8.
With the desired nitrone (3S,4S)-8 in hand, we turned our at-
tention to investigate its reductive coupling with carbonyl com-
pounds. We first attempted the conditions established for nitrone
6,14a namely, in the presence of 78 mol equiv of water, treatment
of 3.0 mol equiv of benzophenone and nitrone 8 with 6.5 mol
equiv of SmI2 produced the desired product 9a in only 41% yield.
After extensive investigations, it was found that the yields of the
reductive coupling of nitrone (3S,4S)-8 with benzophenone can be
significantly improved by justicious selection of the ratio of SmI2–
H2O–carbonyl compounds–nitrone. In the presence of 26 mol
equiv of water, treatment of 3.0 mol equiv of benzophenone and 8
with 4.5 mol equiv of SmI2 produced the N-hydroxyprolinol de-
rivative 9a in 90% yield (Table 1). Under these optimized condi-
tions, the coupling reaction of nitrone (3S,4S)-8 with other
carbonyl compounds were investigated, and the results are sum-
marized in Table 1.
OBn
BnO
3.96
3.66
H
W
J5a,4 = 5.36 Hz
J4,5a = 5.16 Hz
J5a,5b = 11.54 Hz
J3,2 = 4.46 Hz
J2,3 = 4.58 Hz
HS
4
3
3.23H
O
4.72
6
2
1
5b
N
H 3.47
H
O
HO
5a
3.28 OH
As can be seen from Table 1, the reductive hydroxyalkylation of
(3S,4S)-8 with symmetric ketone (benzophenone) gave only one
diastereomer 9a (Table 1, entry 1); and when unsymmetrical ke-
tones or aromatic aldehydes were used, only two diastereomers
were produced in each case (Table 1, entries 2–5); the coupling
with n-butyraldehyde produced a total of four diastereomers (Table
1, entry 6) with low diastereoselectivities at the two newly formed
steric centers. These results indicate that the reductive cross-cou-
pling reactions of nitrone 8 with ketones and aromatic aldehydes
were highly diastereoselective in establishing the C-2 stereocenter
of the pyrrolidine ring, and the diastereo-isomerism arose from the
newly formed exocyclic chiral carbinol center. The cis/trans
Figure 2. NOE correlations on the major diastereomer of 9e.
BnO
BnO
OBn
OBn
PMBO
OPMB
3
3
4
3
4
4
O
2
2
2
5
BnO
5
5
N
N
N
H
H
H
17
HO
HO
PMBO
15
J2,3 = 3.6 Hz
16
J2,3 = 3.9 Hz
J2,3 = 4.6 Hz
Figure 3. The vicinal coupling constants (J2,3) of some known 2,3-trans-substituted
pyrrolidines.

S.-F. Wu et al. / Tetrahedron 66 (2010) 1653–1660
1655
Table 2
Table 3
The 1H NMR spectroscopic data (in part) of the major diastereomers of N-hydrox-
yprolinol derivatives 9a–e
The reductive coupling of nitrone 6 with aliphatic acyl chlorides
O
BnO
BnO
Compound
dH-2, multiplicity
dH-3
,
dH-6
,
J2,3
J2,6
R
Cl
O
multiplicity
multiplicity
N
N
O
6
9a
9b
9c
9d
9e
4.25, d
3.42, d
3.29, dd
3.32, dd
3.28, dd
3.93–3.89, m
4.18, d
3.70, d
3.66, d
3.66, d
d
2.7
3.7
4.6
4.5
4.5
d
SmI2/THF (3.5 equiv.)
H2O (26 equiv)
−78 °C, 1 h
R
OH
d
d
10a ~ 10f
4.77, d
4.75, d
4.72, d
7.3
8.3
8.3
(R = Alkyl)
Entry
1
Acyl chlorides
Product (% yield)a
d.r.b
O
10a (80)
78:22
77:23
75:25
74:26
To demonstrate the possibility for the use of N-hydrox-
ypyrrolidines 9a–f as ready precursors of the corresponding proline
derivatives, a SmI2-mediated cleavage of the N–O bond8c,14a,18 of 9a
was undertaken (Scheme 2). In the event, the N-hydroxypyrrolidine
9a was treated with 4.0 equiv of SmI2 in THF at ꢀ78 ꢁC for 1 h. After
warming up and stirring at rt overnight, the desired pyrrolidine
derivative 18 was obtained in 70% yield.
Cl
O
2
3
4
10b (73)
10c (79)
10d (56)
Cl
O
Cl
O
OBn
BnO
HO
Ph
OBn
BnO
HO
Ph
SmI2/THF
Cl
O
(0.1 M, 4 equiv.)
N
OH
N
H
18
−78 °C ~ r.t.
Ph
Ph
70%
5
6
10e (50)
10f (82)
75:25
78:22
9a
Cl
Scheme 2. Cleavage of the N–O bond of 9a.
O
Cl
A one-pot reductive coupling-in situ N–O bond cleavage8c was
also investigated. Treatment of a water-containing THF solution of
1.0 equiv of nitrone 8 and 3.0 equiv of benzophenone with 4.5 equiv
of SmI2 at ꢀ78 ꢁC for 1 h, followed by addition of another 6.0 equiv
of SmI2 and reacted at rt for 4 h, produced directly pyrrolidine
derivative 18 in 64% yield (Scheme 3).
O
7
10a (48)
77:23
Cl
Cl
a
Isolated yields, based on nitrone 6.
Ratio determined by 1H NMR.
b
1) Ph2CO, THF;
2) H2O;
OBn
BnO
OBn
BnO
HO
Ph
similar diastereoselectivities, lower yields were obtained with
more hindered acyl chlorides such as pivalyl chloride and phenyl-
acetyl chloride. Noteworthy is that the coupling with chloroacetyl
chloride yielded the concomitantly dechlorinated product 10a
(Table 3, entry 7).
3) SmI2, −78 oC, 1 h;
N
O
8
N
H
4) SmI2, −78 oC, 5 min
r.t., 4 h
64%
Ph
18
To further confirm the structure of the products, 10a was acet-
ylated to give the O-acetyl product 19 in 46% yield as a mixture of
two diastereomers in 67:33 ratio (Scheme 4). This result confirmed
that the coupling products are indeed the desired C-acyl products
10 instead of O-acyl products. The IR spectra of compounds 10a and
Scheme 3. One-pot reductive coupling-in situ N–O bond cleavage of nitrone 8.
We next investigated the reductive cross-coupling reaction of
the chiral nitrone 6 with aliphatic acyl chlorides. To perform the
reductive coupling of the enantiopure nitrone 6 with acyl chlorides
(Table 3), the O-acylation of nitrone 6 with acyl chlorides should be
avoided. Keeping this in mind, a protocol was established, which
consisted in successive addition of 3.0 equiv of acyl chlorides and
a 0.1 M THF solution of SmI2 (3.5 equiv) to a pre-cooled H2O
19 showed carbonyl absorptions at
n ,
1629 cmꢀ1 and 1671 cmꢀ1
respectively, which indicated that an intramolecular hydrogen
bond exists in 10a (Scheme 4). It is to be noted that a partial epi-
merization occurred during the O-acetylation as indicated by the
change of diastereomeric ratio from 77:23 to 67:33.
(26.0 equiv)dcontaining THF solution (ꢀ78 ꢁC) of nitrone
6
BnO
O
(1.0 equiv). Under these conditions, the reductive coupling of
nitrone 6 with acetyl chloride gave 10a (mono-spot on TLC) in 80%
yield, which was a mixture of two isomers as shown by 1H NMR
analysis. To determine the nature of the two isomers (di-
astereomeric or tautomeric), the isolated product 10a was sub-
jected to variant temperature 1H NMR analysis. The fact that the 1H
NMR spectra recorded, respectively, at 25 ꢁC and at 85 ꢁC showed
no notable difference allowed concluding that the product con-
tained two diastereomers. Namely, the reductive coupling of
nitrone 6 with acetyl chloride gave two diastereomers of 10a in
a ratio of 78:22. The reductive coupling reactions of nitrone 6 with
other acyl chlorides were studied, and the results are summarized
in Table 3. As can be seen from Table 3, while all acyl chlorides gave
BnO
O
Cl
N
O
N
O
Et3N, CH2Cl2
0 °C ~ r.t.
46%
O
O
H
10a
19
(dr = 77:23)
(dr = 67:33)
Scheme 4.
3. Conclusions
The SmI2-mediated reductive coupling of enantiopure pyrroli-
dine nitrone (3S,4S)-8 with aldehydes/ketones gave (2R,3S,4S)-

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S.-F. Wu et al. / Tetrahedron 66 (2010) 1653–1660
1,3,4-trihydroxyprolinol derivatives 9a–f in 42–92% yields with
excellent 2,3-trans-diastereoselectivity for ketones and aromatic
aldehydes. Through the syntheses of prolinol derivative 18, we
demonstrated that (2R,3S,4S)-3,4-dihydroxyprolinol derivatives
could be obtained by N–O bond cleavage of the corresponding N-
hydroxyprolinol derivatives 9a–f, or more conveniently by a one-
pot reductive coupling of nitrone 8-in situ N–O bond cleavage of the
resultant coupling product. The SmI2-mediated chemoselective
reductive cross-coupling reactions of chiral nitrone 6 with aliphatic
acyl chlorides gave 2-acyl-3-benzyloxy-1-hydroxypyrrolidines
10a–f in 48–82% yields with diastereoselectivities ranged from
74:26 to 78:22. To the best of our knowledge, this is the first re-
ductive coupling of nitrones with acyl chlorides. Conditions have
been defined to achieve the required chemoselectivity. The cou-
pling products provide the possibility to construct aza-quaternary
chiral center, which is found in many natural products. The
methods may also found applications in the synthesis of organo-
catalysts and aza-sugars.
(4C), 128.0 (2C), 127.9 (4C), 78.9 (2C), 72.6 (2C), 60.9 (2C); MS (ESI,
m/z): 325 (MþNaþ, 100), 341 (MþKþ, 26). Anal. Calcd for C18H22O4:
C, 71.50; H, 7.33. Found: C, 71.54; H, 7.25.
4.2.2. (2S,3S)-2,3-Bis(benzyloxy)butane-1,4-bis(methanesulfonylox-
y)butane (13). To a cooled (0 ꢁC) CH2Cl2 (6 mL) solution of com-
pound 12 (1.27 g, 4.2 mmol) and TEA (3.5 mL, 25.1 mmol) was
added dropwise methanesulfonyl chloride (1.4 mL, 18.0 mmol)
under a N2 atmosphere. The mixture was stirred at rt for 2 h, then
cooled to 0 ꢁC and treated with a saturated aqueous NH4Cl solution
(10 mL). The two phases were separated and the aqueous phase
extracted with CH2Cl2 (80 mL). The combined organic phases were
washed with brine (5 mL), dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel (eluent:EtOAc–PE, 1:2) to
give compound 13 (1.90 g, 99%) as a colorless oil. Rf 0.40 (EtOAc–
20
20
PE¼1:1); [
a
]
D
þ16.6 (c 0.53, CHCl3) {lit.20
[
a]
þ17.9 (c 0.5,
D
CHCl3)}; IR (film): 3444, 2934, 2870, 1584, 1454, 1408, 1353, 1173,
1084 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 7.39–7.28 (m, 10H, Ph-H),
4. Experimental
4.1. General
4.69 (d, 2H, J¼11.7 Hz, PhCH2), 4.58 (d, 2H, J¼11.7 Hz, PhCH2), 4.41
(dd, 2H, J¼4.6, 11.0 Hz, –CH2OMs), 4.29 (dd, 2H, J¼4.6, 11.0 Hz,
–CH2OMs), 3.88–3.81 (m, 2H, J¼4.6, –CHOBn), 2.94 (s, 6H, –CH3);
13C NMR (100 MHz, CDCl3)
d 137.1 (2C), 128.6 (4C), 128.2 (4C), 128.2
Melting points were determined on a Yanaco MP-500 micro
melting point apparatus and were uncorrected. Infrared spectra
were measured with a Nicolet Avatar 360 FT-IR spectrometer using
film KBr pellet techniques. 1H NMR spectra were recorded in CDCl3
on a Bruker 400 spectrometer with tetramethylsilane as an internal
(2C), 75.8 (2C), 73.4 (2C), 68.0 (2C), 37.5 (2C); MS (ESI, m/z): 481
(MþNaþ, 100), 497 (MþKþ, 49). Anal. Calcd for C20H26O8S2: C,
52.39; H, 5.72. Found: C, 52.51; H, 5.83.
4.2.3. (3S,4S)-3,4-Bis(benzyloxy)-1-pyrroline-N-oxide (8). A sus-
pension of compound 13 (1.79 g, 3.9 mmol) and hydroxylamine
hydrochloride salt (1.20 g, 17.2 mmol) in Et3N (19.5 mL) was heated
at reflux for 6 h under N2 atmosphere. The solvent was then
evaporated and the resulting yellow solid was washed thoroughly
with diethyl ether. Ethereal extracts were concentrated to give the
crude N-hydroxypyrrolidine 14, which was used in the next step
without purification.
standard. Chemical shifts are expressed in d (ppm) units downfield
from TMS. 13C NMR spectra were determined at 100 MHz. Mass
spectra were recorded on a Bruker Dalton ESquire 3000 plus liquid
chromatography–mass spectrum (direct injection). HRMS spectra
were recorded on a Shimadzu LCMS-IT-TOF apparatus. Optical
rotations were measured with a Perkin–Elmer 341 automatic po-
larimeter. Silica gel (300–400 mesh) was used for flash column
chromatography, eluting (unless otherwise stated) with an ethyl
acetate–petroleum ether (PE) (60–90 ꢁC) mixture. THF was distilled
over sodium benzophenone ketyl under N2. Dichloromethane was
distilled over calcium hydride under N2. Water used as the additive
in the coupling reactions was doubly distilled and deaerated with
argon for 24 h prior to use. Sm was purchased from Yuelong New
Materials Co. Ltd. (China).
To
a CH2Cl2 (12.6 mL) solution of the crude N-hydrox-
ypyrrolidine 14 was added portionwise active manganese dioxide
(407 mg, 4.7 mmol) at 0 ꢁC and under a N2 atmosphere. The sus-
pension was stirred at room temperature overnight. The resultant
mixture was washed with EtOAc, and the filtrate concentrated
under reduced pressure. Chromatography of the residue on silica
gel (eluent:EtOAc–PE, 1:1) gave compound 8 (904 mg, 78%) as
20
a colorless oil. Rf 0.12 (EtOAc–PE¼1:2); [
a
]
þ78.8 (c 1.39, CHCl3)
D
20
4.2. General procedure for the preparation of chiral cyclic
nitrones
{lit.15
1454, 1435, 1356, 1285, 1090, 1068, 1028 cmꢀ1; 1H NMR (400 MHz,
CDCl3) 7.42–7.28 (m, 10H, Ph-H), 6.89–6.86 (m, 1H, H-2), 4.68–
[
a]
þ76.7 (c 0.88, CHCl3)}; IR (film): 3062, 3030, 2866, 1579,
D
d
4.2.1. (2S,3S)-2,3-Bis(benzyloxy)butane-1,4-diol (12). A THF solu-
tion (5 mL) of the known diester15 11 (1.86 g, 4.81 mmol) was added
dropwise to a suspension of LiAlH4 (403 mg, 10.6 mmol) in THF
(10 mL) under a N2 atmosphere. The white suspension was vigor-
ously stirred and refluxed for 4.5 h. The mixture was cooled to 0 ꢁC,
and quenched by successive dropwise addition of H2O (0.4 mL),
10%NaOH solution (0.8 mL), and H2O (1.2 mL). After diluting with
ethanol (60 mL), the mixture was refluxed for 3 h. The suspension
was filtered through Celite and washed with ethanol for several
times. The solvent was dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (eluent:EtOAc–PE, 1:1) to give
4.65 (m, 1H, H-3), 4.58 (d, 1H, J¼11.7 Hz, PhCH2), 4.55 (d, 1H,
J¼11.7 Hz, PhCH2), 4.54 (s, 2H, PhCH2), 4.28 (dt, 1H, J¼1.6, 6.5 Hz, H-
4), 4.26–4.22 (m, 1H, H-5), 3.90–3.81 (m, 1H, H-5); 13C NMR
(100 MHz, CDCl3) d 136.9, 136.7, 132.2, 128.7 (2C), 128.6 (2C), 128.3,
128.3, 128.0 (2C), 127.9 (2C), 83.7, 78.4, 72.0, 71.9, 66.9; MS (ESI, m/
z): 320 (MþNaþ, 100), 298 (MþHþ, 68). Anal. Calcd for C18H19NO3:
C, 72.71; H, 6.44; N, 4.71. Found: C, 72.32; H, 6.16; N, 4.93.
4.3. General procedure for the SmI2-mediated
hydroxyalkylations of nitrone 8
a-
To a slurry of Sm powder (flame dried under Ar atmosphere,
826 mg, 5.49 mol) in THF (50 mL) was added I2 (1.270 g,
5.00 mmol) at rt, and the mixture was stirred for 2 h at 45 ꢁC to give
a SmI2 (0.1 M in THF) reagent as a dark blue solution.
To a stirring and carefully deoxygenated solution of nitrone 8
(143 mg, 0.48 mmol) and a carbonyl compound (1.44 mmol) in THF
diol 12 (1.438 g, 99%) as a white solid. Rf 0.24 (EtOAc–PE¼1:1); mp
51–52 ꢁC (EtOAc–PE) {lit.19a mp 50–52 ꢁC}; [
a
]
þ13.1 (c 4.89,
20
D
20
ethanol) {lit.19b
[
a]
þ13.2 (c 4.91, ethanol)}; IR (film): 3440, 2917,
D
1584, 1462, 1408, 1084 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.40–7.28
(m, 10H, Ph-H), 4.66 (d, 2H, J¼11.9 Hz, PhCH2), 4.64 (d, 2H,
J¼11.9 Hz, PhCH2), 3.83 (br d, 2H, J¼9.9 Hz, –CH2OH), 3.72 (br d, 2H,
J¼9.9 Hz, –CH2OH), 3.70–3.67 (m, overlapped, 2H, –CHOBn), 2.38–
(10 mL) was added H2O (225 mL, 12.5 mmol) under an Ar atmo-
sphere. The mixture was cooled to ꢀ78 ꢁC, and to which a freshly
2.27 (br, 2H, OH); 13C NMR (100 MHz, CDCl3)
d
137.9 (2C), 128.6
prepared THF solution of SmI2 (0.1 mol Lꢀ1, 22 mL, 2.2 mmol) was

S.-F. Wu et al. / Tetrahedron 66 (2010) 1653–1660
1657
added. After the reaction was judged to be completed by TLC
monitoring, saturated aqueous solutions of Na2S2O3 (4 mL) and
NaHCO3 (15 mL) were added successively. The yellow mixture was
extracted with EtOAc (3ꢂ30 mL), and the combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (eluent:EtOAc–PE) to
give the coupling product 9.
J¼11.5 Hz, PhCH2), 3.98 (d, 1H, J¼5.4 Hz, H-4), 3.70 (d, 1H, J¼4.6 Hz,
H-3), 3.46 (d, 1H, J¼11.4 Hz, H-5), 3.29 (dd, 1H, J¼4.6, 7.3 Hz, H-2),
3.23 (dd, 1H, J¼5.4, 11.4 Hz, H-5); 13C NMR (100 MHz, CDCl3)
d
140.0, 137.4, 137.2, 133.6, 128.6 (2C), 128.5 (2C), 128.4 (2C), 128.3
(2C) 128.0, 127.9 (2C), 127.8, 127.7 (2C), 83.7, 80.3, 78.7, 74.5, 71.6,
71.5, 61.5; MS (ESI, m/z): 462 (MþNaþ, 100), 440 (MþHþ, 51). Anal.
Calcd for C25H26ClNO4: C, 64.77; H, 6.04; N, 4.20. Found: C, 64.91; H,
6.42; N, 4.45.
4.3.1. (2R,3S,4S)-3,4-Bis(benzyloxy)-2-(hydroxydiphenylmethyl)-N-
4.3.4. (2S,3S,4S)-3,4-Bis(benzyloxy)-2-[hydroxy(4-methox-
hydroxypyrrolidine (9a). Following the general procedure, the
yphenyl)methyl]-N-hydroxypyrrolidine (9d). Following the general
SmI2-mediated
a-hydroxyalkylations of 8 (134 mg, 0.451 mmol)
procedure, the SmI2-mediated a-hydroxyalkylations of 8 (160 mg,
with benzophenone (246 mg, 1.35 mmol) gave compound 9a as
0.54 mmol) with 4-methoxybenzaldehyde (0.2 mL, 1.61 mmol)
gave compound 9d as a mixture of two diastereomers in 72:28 ratio
(determined by 1H NMR, dH 3.27, 3.14) (eluent:EtOAc–PE¼1:3;
98 mg, combined yield: 42%). A part of the major diastereomer was
a single diastereomer (eluent:EtOAc–PE¼1:10; 196 mg) in 90%
20
yield. 9a: colorless wax. Rf 0.60 (EtOAc–PE¼1:4); [
a]
ꢀ30.3 (c
D
0.98, CHCl3); IR (film): 3437, 2922, 2853, 1585, 1402, 1122,
1084 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
7.74–7.68 (m, 2H, Ph-H),
isolated in pure form from column chromatographic separation.
20
7.67–7.61 (m, 2H, Ph-H), 7.36–7.13 (m, 16H, Ph-H), 4.53 (d, 1H,
J¼11.8 Hz, PhCH2), 4.38 (d, 1H, J¼11.8 Hz, PhCH2), 4.25 (br
d, 1H, J¼2.7 Hz, H-2), 4.16 (br s, 1H, OH, D2O exchangeable), 4.11
(d, 1H, J¼11.0 Hz, PhCH2), 4.00 (d, 1H, J¼11.0 Hz, PhCH2), 3.96 (br s,
1H, OH, D2O exchangeable), 3.93–3.89 (m, 1H, H-3), 3.81 (d, 1H,
J¼4.2 Hz, H-4), 3.45 (d, 1H, J¼10.6 Hz, H-5), 3.26 (dd, 1H, J¼4.2,
Major diastereomer: Rf 0.10 (EtOAc–PE¼1:3); colorless wax; [
a]
D
þ12.6 (c 2.29, CHCl3); IR (film): 3404, 3030, 2921, 1612, 1513, 1454,
1394, 1247, 1173, 1029 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
7.36–7.18
(m, 10H, Ph-H), 6.91–6.84 (m, 4H, Ph-H), 4.75 (d, J¼8.3 Hz, 1H,
ArCH), 4.50 (d, 1H, J¼12.0 Hz, PhCH2), 4.42 (d, 1H, J¼12.0 Hz,
PhCH2), 4.05 (d, 1H, J¼11.6 Hz, PhCH2), 4.00 (d, 1H, J¼11.6 Hz,
PhCH2), 3.98–3.95 (m,1H, J¼5.4 Hz, H-4), 3.79 (s, 3H, OCH3), 3.66 (d,
1H, J¼4.5 Hz, H-3), 3.46 (d, 1H, J¼11.5 Hz, H-5), 3.32 (dd, 1H, J¼4.5,
8.3 Hz, H-2), 3.24 (dd, 1H, J¼5.4, 11.5 Hz, H-5); 13C NMR (100 MHz,
10.6 Hz, H-5); 13C NMR (100 MHz, CDCl3)
d 146.4, 145.0, 137.6,
137.4, 128.5 (2C), 128.4 (2C), 128.1 (2C), 128.0 (2C), 127.9 (2C), 127.9,
127.9 (2C), 127.8, 126.8, 126.6, 126.2 (2C), 126.1 (2C), 83.4, 81.0, 77.9,
72.1, 70.8, 60.9; MS (ESI, m/z): 482 (MþHþ, 100), 504 (MþNaþ, 81).
Anal. Calcd for C31H31NO4: C, 77.31; H, 6.49; N, 2.91. Found: C,
77.12; H, 6.47; N, 2.89.
CDCl3)
d 159.3, 137.6, 137.4, 133.3, 128.5 (2C), 128.3 (2C), 128.2 (2C),
127.8 (2C), 127.6 (2C), 127.6, 113.8 (2C), 113.6, 80.7, 79.0, 77.7, 75.2,
71.5, 71.3, 61.2, 55.2; MS (ESI, m/z): 436 (MþHþ, 100), 458 (MþNaþ,
18); HRMS (ESI) calcd for [C26H29NO5þH]þ: 436.2124; found:
436.2127.
4.3.2. (2R,3S,4S)-3,4-Bis(benzyloxy)-2-(1-hydroxy-1-phenylethyl)-
N-hydroxypyrrolidine (9b). Following the general procedure, the
SmI2-mediated
a
-hydroxyalkylations of 8 (100 mg, 0.336 mmol)
4.3.5. (2S,3S,4S)-2-{(Benzo[d][1,3]dioxol-5-yl)hydroxymethyl}-3,4-
with acetophenone (0.12 mL, 1.01 mmol) gave compound 9b as
a mixture of two diastereomers in 84:16 ratio (determined by 1H
NMR, dH 3.32, 3.13) (eluent:EtOAc–PE¼1:4; 68 mg, combined yield:
50%). A part of the major diastereomer was isolated in pure form
bis(benzyloxy)-N-hydroxypyrrolidine (9e). Following the general
procedure, the SmI2-mediated a-hydroxyalkylations of 8 (100 mg,
0.34 mmol) with piperonal (151 mg, 1.01 mmol) gave compound 9e
as a mixture of two diastereomers in 83:17 ratio (determined by 1H
NMR, dH 3.26, 3.15) (eluent:EtOAc–PE¼1:3; 139 mg, combined
yield: 92%). A part of the major diastereomer was isolated in pure
from column chromatographic separation. Major diastereomer: Rf
20
0.39 (EtOAc–PE¼1:3); colorless wax; [
a]
þ2.7 (c 0.48, CHCl3); IR
D
(film): 3342, 3030, 2922, 2851, 1600, 1495, 1453, 1207, 1096,
form from column chromatographic separation. Major di-
20
1028 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
7.52–7.48 (m, 2H, Ph-H),
astereomer: Rf 0.15 (EtOAc–PE¼1:3); colorless wax; [
a
]
þ7.5 (c
D
7.39–7.28 (m, 12H, Ph-H), 7.24–7.20 (m, 1H, Ph-H), 4.58 (d, 1H,
J¼11.8 Hz, PhCH2), 4.52 (2d, overlapped, 2H, J¼11.8 Hz, J¼11.4 Hz,
PhCH2), 4.48 (d, 1H, J¼11.4 Hz, PhCH2), 4.18 (d, 1H, J¼3.7 Hz, H-3),
3.90 (d, 1H, J¼4.7 Hz, H-4), 3.42 (d, 1H, J¼3.7 Hz, H-2), 3.41 (d, 1H,
J¼10.8 Hz, H-5), 3.13 (dd, 1H, J¼4.7, 10.8 Hz, H-5), 1.54 (s, 3H, CH3);
0.47, CHCl3); IR (film): 3373, 3030, 2922, 1605, 1503, 1488, 1443,
1246, 1095, 1039 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
7.37–7.22 (m,
8H, Ph-H), 6.99–6.93 (m, 2H, Ph-H), 6.92–6.88 (m, 1H, Ph-H), 6.83–
6.78 (m, 1H, Ph-H), 6.74–6.70 (m, 1H, Ph-H), 5.92–5.87 (m, 2H,
OCH2O), 4.72 (d, 1H, J¼8.3 Hz, ArCH), 4.51 (d, 1H, J¼12.0 Hz, PhCH2),
4.42 (d, 1H, J¼12.0 Hz, PhCH2), 4.11 (d, 1H, J¼11.6 Hz, PhCH2), 4.02
(d, 1H, J¼11.6 Hz, PhCH2), 3.96 (d, 1H, J¼5.2 Hz, H-4), 3.66 (d, 1H,
J¼4.5 Hz, H-3), 3.47 (d, 1H, J¼11.5 Hz, H-5), 3.28 (dd, 1H, J¼4.5,
8.3 Hz, H-2), 3.23 (dd, 1H, J¼5.2, 11.5 Hz, H-5); 13C NMR (100 MHz,
13C NMR (100 MHz, CDCl3)
d 147.0, 137.6, 137.5, 128.5 (2C), 128.5
(2C), 128.2 (2C), 128.0 (2C), 127.9 (2C), 127.9 (2C), 127.8, 126.7, 125.4,
82.9, 82.1, 78.2, 73.7, 71.7, 71.0, 60.8, 26.8; MS (ESI, m/z): 420
(MþHþ, 100), 442 (MþNaþ, 77). Anal. Calcd for C26H29NO4: C,
74.44; H, 6.97; N, 3.34. Found: C, 74.51; H, 7.30; N, 3.01.
CDCl3) d 147.8, 147.2, 137.5, 137.4, 135.2, 128.7, 128.5 (2C), 128.2 (2C),
127.8 (2C), 127.6, 127.5 (2C), 120.5, 108.0, 107.6, 100.9, 84.0, 80.6,
78.8, 75.5, 71.5, 71.3, 61.3; MS (ESI, m/z): 472 (MþNaþ, 100), 450
(MþHþ, 34). Anal. Calcd for C26H27NO6: C, 69.47; H, 6.05; N, 3.12.
Found: C, 69.80; H, 6.03; N, 2.94.
4.3.3. (2S,3S,4S)-3,4-Bis(benzyloxy)-2-[(4-chlorophenyl)hydrox-
ymethyl]-N-hydroxypyrrolidine (9c). Following the general pro-
cedure, the SmI2-mediated
a-hydroxyalkylations of 8 (100 mg,
0.34 mmol) with 4-chlorobenzaldehyde (142 mg, 1.01 mmol) gave
compound 9c as a mixture of two diastereomers in 85:15 ratio
(determined by 1H NMR, dH 3.29, 3.16) (eluent:EtOAc–PE¼1:4;
111 mg, combined yield: 75%). A part of the major diastereomer was
4.3.6. (3S,4S)-3,4-Bis(benzyloxy)-2-(1-hydroxybutyl)-N-hydrox-
ypyrrolidine (9f). Following the general procedure, the SmI2-me-
diated
a-hydroxyalkylations of 8 (100 mg, 0.336 mmol) with
isolated in pure form from column chromatographic separation.
butyraldehyde (0.127 mL, 1.44 mmol) gave compound 9f as a mix-
ture of four inseparable diastereomers in 43:27:17:13 ratio (de-
termined by HPLC) (eluent:EtOAc–PE¼1:3; 112 mg, combined
yield: 90%). Rf 0.20 (EtOAc–PE¼1:3); colorless wax; IR (film): 3341,
3030, 2957, 2925, 2870, 1587, 1496, 1454, 1360, 1094, 1028 cmꢀ1; 1H
20
Major diastereomer: Rf 0.31 (EtOAc–PE¼1:2); colorless wax; [
a]
D
þ4.2 (c 1.19, CHCl3); IR (film): 3432, 3033, 2898, 1596, 1490, 1454,
1410, 1145, 1088, 1028, 1014 cmꢀ1 1H NMR (400 MHz, CDCl3)
7.42–7.22 (m, 12H, Ph-H), 6.97–6.90 (m, 2H, Ph-H), 4.77 (d, 1H,
;
d
J¼7.3 Hz, ArCH), 4.52 (d, 1H, J¼11.9 Hz, PhCH2), 4.44 (d, 1H,
NMR (400 MHz, CDCl3)
4H, PhCH2), 4.05–4.00, 4.00–3.96 (2 m, 1H, CH2CHOH), 3.95–3.90,
d 7.40–7.22 (m, 10H, Ph-H), 4.64–4.39 (m,
J¼11.9 Hz, PhCH2), 4.18 (d, 1H, J¼11.5 Hz, PhCH2), 4.09 (d, 1H,

1658
S.-F. Wu et al. / Tetrahedron 66 (2010) 1653–1660
3.74–3.67 (2 m, 1H, H-3), 3.88, 3.84 (2d, 1H, J¼5.1, 5.0 Hz, H-4), 3.46
(br t, 1H, J¼10.5 Hz, H-5), 3.23, 3.11 (2dd, 1H, J¼5.0, 10.5 Hz; J¼5.1,
10.5 Hz, H-5), 2.99, 2.83 (br t, d,1H, J¼5.3, 5.5 Hz, H-2), 1.61–1.33 (br
m, 4H, CH3CH2CH2), 0.94–0.83 (m, 3H, CH3); 13C NMR (100 MHz,
ꢀ78 ꢁC, and to which an acyl chloride (1.50 mmol) and a freshly
prepared THF solution of SmI2 (0.1 mol Lꢀ1, 17.5 mL, 1.75 mmol)
were added successively. After the reaction was judged to be
completed by TLC monitoring, saturated aqueous solutions of
Na2S2O3 (30 mL) and NaHCO3 (40 mL) were added successively. The
yellow mixture was extracted with EtOAc (3ꢂ40 mL), and the
combined organic layers were washed with brine, dried over an-
hydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by flash chromatography on silica gel
to yield the coupling product 10.
CDCl3)
d 138.1, 137.9, 128.6 (2C), 128.4 (2C), 128.4, 128.1, 127.8 (2C),
127.8, 127.7, 127.7, 79.9, 78.3, 78.3, 71.2, 71.1, 68.1, 56.7, 47.4, 36.9,
35.4, 27.9, 19.4, 18.9, 14.1; MS (ESI, m/z): 372 (MþHþ, 100), 394
(MþNaþ, 59). Anal. Calcd for C22H29NO4: C, 71.13; H, 7.87; N, 3.77.
Found: C, 71.11; H, 7.65; N, 3.45.
4.4. (2R,3S,4S)-3,4-Bis(benzyloxy)-2-(diphenylhydroxymethyl)
pyrrolidine (18)
4.6.1. 1-((3S)-3-(Benzyloxy)-1-hydroxypyrrolidin-2-yl)ethanone
(10a). Following the general procedure, the SmI2-mediated C-ac-
ylation of 6 (103 mg, 0.54 mmol) with acetyl chloride (0.12 mL,
1.62 mmol) gave compound 10a as a mixture of two inseparable
diastereomers in 78:22 ratio (determined by 1H NMR, dH 5.62, 5.26)
(eluent:EtOAc–PE¼1:1; 101 mg, combined yield: 80%). Colorless
wax. Rf 0.20 (EtOAc–PE¼2:1); IR (film): 3342, 2961, 1629, 1453,
A stirring and carefully deoxygenated solution of the coupling
product 9a (131 mg, 0.27 mmol) in THF (10 mL) was cooled to
ꢀ78 ꢁC under an Ar atmosphere. A freshly prepared THF solution of
SmI2 (0.1 mol Lꢀ1, 10.9 mL, 1.09 mmol) was then added. After stir-
ring at ꢀ78 ꢁC for 1 h, the temperature was allowed to warm-up
and the mixture was stirred overnight. The reaction was quenched
by introduction of air, which was followed by successive addition of
saturated aqueous solutions of Na2S2O3 (4 mL) and NaHCO3
(20 mL). The yellow mixture was extracted with EtOAc (3ꢂ20 mL),
and the combined organic layers were washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography on
;
1354, 1261, 1084, 1066 cmꢀ1 1H NMR (400 MHz, CDCl3, two iso-
mers)
d
7.39–7.27 (m, 5H, Ph-H), 5.66–5.58 (m, 1H, H-2), 5.29–5.23
(m, 1H, H-2, for minor isomer), 4.63 (d, 1H, J¼11.9 Hz, PhCH2), 4.62
(d, 1H, J¼11.9 Hz, PhCH2, for minor isomer), 4.55 (d, 1H, J¼11.9 Hz,
PhCH2, for minor isomer), 4.54 (d, 1H, J¼11.9 Hz, PhCH2), 4.18–4.15
(m, 1H, OH), 4.00 (m, 1H, H-3, for minor isomer), 3.98 (m, 1H, H-3),
3.67–3.54 (m, 2H, H-5), 2.33–2.22 (m, 1H, H-4), 2.17 (s, 3H, CH3, for
minor isomer), 2.07 (s, 3H, CH3), 2.11–2.02 (m, 1H, H-4); 13C NMR
silica gel (eluent:EtOAc–PE, 1:3) to yield pyrrolidine 18 (44 mg,
yield: 70%) as a colorless wax. Rf 0.13 (EtOAc–PE: 1:5); [
20
a
]
þ42.5 (c
(100 MHz, CDCl3) d 171.6, 137.6, 128.6, 128.5, 128.4 (2C), 127.8, 127.7
D
1.9, CHCl3); IR (film): 3361, 3061, 3029, 2918, 2850,1597,1494,1385,
(2C), 127.5, 84.0, 81.7, 71.3, 71.1, 45.5, 43.7, 29.1, 26.6, 22.3; MS (ESI,
m/z): 258 (MþNaþ, 100), 274 (MþHþ, 26); HRMS (ESI) calcd for
[C13H17NO3þNa]þ: 258.1106; found: 258.1107.
1363, 1092, 1028 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
7.69–7.63 (m,
2H, Ph-H), 7.62–7.56 (m, 2H, Ph-H), 7.37–7.34 (m, 4H, Ph-H), 7.31–
7.13 (m, 10H, Ph-H), 7.05–6.98 (m, 2H, Ph-H), 4.52 (d, 1H, J¼11.8 Hz,
PhCH2), 4.46 (d, 1H, J¼11.8 Hz, PhCH2), 4.29 (d, 1H, J¼3.2 Hz, H-2),
4.04 (d, 1H, J¼10.9 Hz, PhCH2), 3.92–3.90 (m, 1H, H-3), 3.89 (d, 1H,
J¼10.9 Hz, PhCH2, overlapped with H-3), 3.88 (d, 1H, J¼0.5, 3.7 Hz,
H-4), 3.21 (dd, 1H, J¼0.5, 10.8 Hz, H-5), 3.15 (dd, 1H, J¼3.7, 10.8 Hz,
4.6.2. 1-((3S)-3-(Benzyloxy)-1-hydroxypyrrolidin-2-yl)propan-1-one
(10b). Following the general procedure, the SmI2-mediated C-ac-
ylation of 6 (156 mg, 0.82 mmol) with propionyl chloride (0.21 mL,
2.45 mmol) gave compound 10b as a mixture of two inseparable
diastereomers in 77:23 ratio (determined by 1H NMR, dH 5.64, 5.30)
(eluent:EtOAc–PE¼1:2; 148 mg, combined yield: 73%). Colorless
wax. Rf 0.42 (EtOAc–PE¼1:1); IR (film): 3345, 3331, 2940, 1628,
H-5); 13C NMR (100 M Hz, CDCl3)
d 147.0, 145.2, 137.8, 137.7, 128.5
(2C), 128.3 (2C), 128.3 (2C), 128.1 (2C), 127.9 (2C), 127.8, 127.7, 127.7,
126.6, 126.5, 126.0, 126.0 (2C), 83.9, 81.7, 77.3, 72.0, 71.6, 70.6, 50.5;
MS (ESI, m/z): 466 (MþHþ, 100), 488 (MþNaþ, 48); HRMS (ESI)
calcd for [C31H31NO3þH]þ: 466.2382; found: 466.2393.
1496, 1437, 1337, 1308, 1205, 1068, 1028 cmꢀ1 1H NMR (400 MHz,
;
CDCl3, two isomers) d 7.41–7.27 (m, 5H, Ph-H), 5.68–5.59 (m, 1H, H-
2), 5.32–5.27 (m, 1H, H-2, for minor isomer), 4.63 (d, 1H, J¼11.8 Hz,
PhCH2), 4.54 (d,1H, J¼11.8 Hz, PhCH2), 4.34 (m,1H, OH), 4.10 (m,1H,
OH, for minor isomer), 4.00 (m, 1H, H-3, for minor isomer), 3.97 (m,
1H, H-3), 3.66–3.52 (m, 2H, H-5), 2.35–2.21 (m, 2H, H-4), 2.18–1.98
(m, 2H, CH2CH3), 1.19–1.10 (m, 3H, CH3); 13C NMR (100 MHz, CDCl3)
4.5. Procedure for the SmI2-mediated one-pot reductive
coupling-in situ N–O bond cleavage of nitrone 8
To a THF solution (10 mL) of nitrone 8 (124 mg, 0.42 mmol) and
benzophenone (228 mg, 1.25 mmol) was added H2O (194
m
L,
d 174.8, 137.7, 128.4 (2C), 127.8 (2C), 127.7 (2C), 127.5, 84.4, 81.6, 71.3,
10.9 mmol) under an Ar atmosphere. The mixture was cooled to
ꢀ78 ꢁC, and to which a freshly prepared THF solution of SmI2
(0.1 mol$Lꢀ1,19 mL,1.9 mmol) was added. After stirringat ꢀ78 ꢁC for
1 h, another 0.1 M THF solution of SmI2 (25 mL, 2.5 mmol) was
added; 5 min later the reactionwas allowed to warm-up, and stirred
at rt for 4 h. The reaction was quenched by introduction of air, which
was followed by successive addition of saturated aqueous solutions
of Na2S2O3 (4 mL) and NaHCO3 (20 mL). The yellow mixture was
extracted with EtOAc (3ꢂ20 mL), and the combined organic layers
were washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (eluent:EtOAc–PE, 1:3) to yield
pyrrolidine 18 (124 mg, yield: 64%) as a colorless wax.
44.7, 29.2, 27.6, 26.5; MS (ESI, m/z): 272 (MþNaþ, 100), 288 (MþKþ,
12); HRMS (ESI) calcd for [C14H19NO3þNa]þ: 272.1263; found:
272.1271.
4.6.3. 1-((3S)-3-(Benzyloxy)-1-hydroxypyrrolidin-2-yl)-3-methyl-
butan-1-one (10c). Following the general procedure, the SmI2-
mediated C-acylation of 6 (176 mg, 0.92 mmol) with 3-methyl-
butanoyl chloride (0.34 mL, 2.76 mmol) gave compound 10c as
a mixture of two inseparable diastereomers in 75:25 ratio (de-
termined by 1H NMR, dH 5.65, 5.31) (eluent:EtOAc–PE¼1:3; 202 mg,
combined yield: 79%). Colorless wax. Rf 0.22 (EtOAc–PE¼1:3); IR
(film): 3346, 2956, 2869, 1624, 1496, 1453, 1342, 1206, 1169, 1106,
1069 cmꢀ1; 1H NMR (400 MHz, CDCl3, two isomers)
d 7.41–7.28 (m,
5H, Ph-H), 5.70–5.60 (m, 1H, H-2), 5.35–5.26 (m, 1H, H-2, for minor
isomer), 4.64 (d, 1H, J¼11.8 Hz, PhCH2), 4.55 (d, 1H, J¼11.8 Hz,
PhCH2), 4.00 (m, 1H, H-3, for minor isomer), 3.98 (m, 1H, H-3), 3.62
(m, 2H, H-5), 3.36 (m, 2H, H-5, for minor isomer), 2.44–2.18 (m, 2H,
H-4), 2.17 (m, 1H, –CH(CH3)2), 2.16–1.96 (m, 2H, –CH2CO–), 0.97 (m,
4.6. General procedure for the SmI2-mediated C-acylation of
nitrone 6
To a stirring and carefully deoxygenated solution of nitrone 6
(95 mg, 0.50 mmol) in THF (10 mL) was added H2O (0.23 mL,
13 mmol) under an Ar atmosphere. The mixture was cooled to
6H, CH3); 13C NMR (100 MHz, CDCl3)
127.9, 127.8 (2C), 127.7 (2C), 84.5, 81.6, 71.3, 45.0, 43.3, 42.9, 41.9,
d 173.8, 137.7, 128.7, 128.4 (2C),

S.-F. Wu et al. / Tetrahedron 66 (2010) 1653–1660
1659
29.7, 29.2, 25.2, 22.6, 22.6; MS (ESI, m/z): 300 (MþNaþ, 100), 316
(MþKþ, 23); HRMS (ESI) calcd for [C16H23NO3þNa]þ: 300.1576;
found 300.1577.
44.8, 36.3, 36.1, 30.6, 29.1; MS (ESI, m/z): 348 (MþNaþ, 100), 364
(MþKþ, 24); HRMS (ESI) calcd for [C20H23NO3þNa]þ: 348.1576;
found: 348.1587.
4.6.4. 1-((3S)-3-(Benzyloxy)-1-hydroxypyrrolidin-2-yl)-2,2-dime-
thylpropan-1-one (10d). Following the general procedure, the
SmI2-mediated C-acylation of 6 (93 mg, 0.49 mmol) with pivaloyl
chloride (0.18 mL, 1.46 mmol) gave compound 10d as a mixture of
two inseparable diastereomers in 74:26 ratio (determined by 1H
NMR, dH 5.99, 5.61) (eluent:EtOAc–PE¼1:4; 75 mg, combined yield:
56%). Colorless wax. Rf 0.28 (EtOAc–PE¼1:3); IR (film): 3354, 3031,
2960, 2870, 1732, 1640, 1529, 1479, 1454, 1365, 1207, 1102,
4.6.7. 1-((3S)-3-(Benzyloxy)-1-hydroxypyrrolidin-2-yl)ethanone
(10a) (prepared by the cross-coupling of nitrone 8 with chloracetyl
chloride). Following the general procedure, the SmI2-mediated C-
acylation of 8 (102 mg, 0.53 mmol) with chloroacetyl chloride
(0.119 mL, 1.50 mmol) gave compound 10a as a mixture of two in-
separable diastereomers in 77:23 ratio (determined by 1H NMR, dH
5.62, 5.25) (eluent:EtOAc–PE¼1:1; 56 mg, combined yield: 48%).
1029 cmꢀ1; 1H NMR (400 MHz, CDCl3, two isomers)
d 7.41–7.21 (m,
4.7. Acetic acid 2-acetyl-(S)-3-benzyloxypyrrolidin-1-yl
5H, Ph-H), 6.10–5.90 (m, 1H, H-2), 5.63–5.60 (m, 1H, H-2, for minor
isomer), 4.75 (d, 1H, J¼11.5 Hz, PhCH2), 4.64 (d, 1H, J¼11.5 Hz,
PhCH2, for minor isomer), 4.55 (d, 1H, J¼11.5 Hz, PhCH2, for minor
isomer), 4.52 (d, 1H, J¼11.5 Hz, PhCH2), 3.94 (m, 1H, H-3, for minor
isomer), 3.89 (m, 1H, H-3), 3.84–3.74 (m, 2H, H-5, for minor iso-
mer), 3.48–3.28 (m, 2H, H-5), 2.33–2.17 (m, 2H, H-4, for minor
isomer), 2.13–1.80 (m, 2H, H-4), 1.27 (m, 9H, CH3, for minor isomer),
ester (19)
To a cooled (0 ꢁC) CH2Cl2 (6 mL) solution of compound 10a
(90 mg, 0.383 mmol) and TEA (0.11 mL, 0.765 mmol) was added
dropwise acetyl chloride (0.042 mL, 0.573 mmol) under a N2 atmo-
sphere. The mixture was stirred at rt for 4.5 h, then cooled to 0 ꢁC and
treated with a saturated aqueous NH4Cl solution (3 mL). The two
phases were separated and the aqueous phase extracted with CH2Cl2
(75 mL). The combined organic phases were washed with brine
(2 mL), dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by column chro-
matography on silica gel (eluent:EtOAc–PE¼2:1) to give compound
19 (50 mg, 46%) as a colorless oil. Rf 0.5 (EtOAc–PE¼1:1); IR (film):
1.07 (m, 9H, CH3); 13C NMR (100 MHz, CDCl3)
d 178.4, 136.9, 128.6
(2C), 128.4 (2C), 128.3 (2C), 128.3 (2C), 127.7, 127.6, 82.1, 72.7, 45.9,
38.4, 36.0, 29.3, 27.3; MS (ESI, m/z): 300 (MþNaþ, 100), 278 (MþHþ,
54); HRMS (ESI) calcd for [C16H23NO3þH]þ: 278.1756; found:
278.1764.
2927, 1735, 1673, 1482, 1406, 1349, 1248, 1214, 1110, 1018 cmꢀ1
;
1H
4.6.5. 1-((3S)-3-(Benzyloxy)-1-hydroxypyrrolidin-2-yl)-2-phenyl-
ethanone (10e). Following the general procedure, the SmI2-medi-
ated C-acylation of 6 (90 mg, 0.47 mmol) with 2-phenylacetyl
chloride (0.19 mL, 1.41 mmol) gave compound 10e as a mixture of
two inseparable diastereomers in 75:25 ratio (determined by 1H
NMR, dH 5.65, 5.30) (eluent:EtOAc–PE¼1:2; 73 mg, combined yield:
50%). Colorless wax. Rf 0.16 (EtOAc–PE¼1:3); IR (film): 3354, 3062,
3029, 2951, 1631, 1496, 1454, 1410, 1400, 1300, 1177, 1106, 1070,
NMR (400 MHz, CDCl3, two isomers)
d 7.45–7.27 (m, 5H, Ph-H), 6.68–
6.56 (m, 1H, H-2, for minor isomer), 6.34–6.23 (m, 1H, H-2), 4.75 (d,
1H, J¼12.0 Hz, PhCH2, for minor isomer), 4.66 (d, 1H, J¼12.0 Hz,
PhCH2), 4.64 (d,1H, J¼12.0 Hz, PhCH2), 4.60 (d,1H, J¼12.0 Hz, PhCH2,
for minor isomer), 4.05–3.98 (m,1H, H-3), 3.98–3.90 (m, 1H, H-3, for
minor isomer), 3.76–3.58 (m, 2H, H-5), 2.39–2.17 (m,1H, H-4), 2.12 (s,
3H, CH3, for minor isomer), 2.07 (s, 3H, CH3), 2.11–2.05 (m, 1H, H-4),
2.04 (s, 3H, CH3, for minor isomer), 2.03 (s, 3H, CH3); 13C NMR
1030 cmꢀ1; 1H NMR (400 MHz, CDCl3, two isomers)
d 7.38–7.28 (m,
7H, Ph-H), 7.26–7.19 (m, 3H, Ph-H), 5.68–5.62 (m, 1H, H-2), 5.33–
5.27 (m, 1H, H-2, for minor isomer), 4.62 (d, 1H, J¼11.8 Hz, PhCH2),
4.47 (d, 1H, J¼11.8 Hz, PhCH2, for minor isomer), 4.53 (d, 1H,
J¼11.8 Hz, PhCH2), 4.36 (d, 1H, J¼11.8 Hz, PhCH2, for minor isomer),
3.99–3.93 (m, 1H, H-3), 3.91–3.88 (m, 1H, H-3, for minor isomer),
3.84–3.73 (m, 2H, PhCH2CO–, for minor isomer), 3.67–3.65 (m, 2H,
PhCH2CO–), 3.65–3.57 (m, 2H, H-5), 2.28–2.18 (m, 1H, H-4), 2.09–
(100 MHz, CDCl3)
d 170.4, 170.0, 129.7, 128.5 (2C), 128.4, 127.9 (2C),
127.5 (2C), 85.7, 83.7, 82.1, 79.9, 71.4, 44.6, 29.7, 29.5, 27.5, 21.9, 21.0;
MS (ESI, m/z): 300 (MþNaþ, 100), 315 (MþKþ, 39); HRMS (ESI) calcd
for [C15H19NO4þNa]þ: 300.1212; found: 300.1218.
Acknowledgements
1.98 (m, 1H, H-4); 13C NMR (100 MHz, CDCl3)
d 172.0, 137.6, 133.9,
The authors are grateful to the NSF of China (20832005) and the
National Basic Research Program (973 Program) of China (Grant No.
2010CB833206) for financial support.
129.1, 129.0 (2C), 128.9, 128.7, 128.6 (2C), 128.5, 128.4 (2C), 127.9,
127.8, 127.6 (2C), 127.4, 84.7, 81.5, 72.2, 71.3, 45.0, 42.3, 41.7, 41.1,
29.3; MS (ESI, m/z) 334 (MþNaþ, 100), 350 (MþKþ, 5); HRMS (ESI)
calcd for [C19H21NO3þNa]þ: 334.1419; found: 334.1424.
References and notes
4.6.6. 1-((3S)-3-(Benzyloxy)-1-hydroxypyrrolidin-2-yl)-3-phenyl-
propan-1-one (10f). Following the general procedure, the SmI2-
mediated C-acylation of 6 (156 mg, 0.82 mmol) with 3-phenyl-
propanoyl chloride (0.36 mL, 2.45 mmol) gave compound 10f as
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a
mixture of two inseparable diastereomers in 78:22 ratio
(determined by 1H NMR, dH 5.64, 5.23) (eluent:EtOAc–PE¼1:3;
218 mg, combined yield: 82%). Colorless wax. Rf 0.17 (EtOAc–
PE¼1:3); IR (film): 3381, 3062, 3028, 2928, 1724, 1626, 1496, 1453,
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;
d
7.43–7.11 (m, 10H, Ph-H), 5.72–5.56 (m, 1H, H-2), 5.29–5.07
(m, 1H, H-2, for minor isomer), 4.61 (d, 1H, J¼11.8 Hz, PhCH2), 4.52
(d, 1H, J¼11.8 Hz, PhCH2), 3.98–3.92 (m, 1H, H-3), 3.89–3.79 (m, 1H,
H-3), 3.65–3.55 (m, 2H, H-5, for minor isomer), 3.55–3.43 (m, 2H,
H-5), 3.04–2.92 (m, 2H, PhCH2CH2CO–), 2.90–2.61 (m, 2H, Ph
CH2CH2CO–), 2.61–2.54 (m, 2H, Ph CH2CH2CO–, for minor isomer),
2.28–2.14, 2.14–1.89 (2 m, 2H, H-4); 13C NMR (100 MHz, CDCl3)
d
173.3, 140.9, 137.6, 128.6, 128.5 (2C), 128.4 (2C), 128.4, 128.3 (2C),
128.2, 127.8, 127.8, 127.7 (2C), 127.4, 126.2, 84.2, 81.6, 78.0, 71.3, 71.0,

1660
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