Sulfone chemistry for the synthesis of C-branched pyrrolidines

Article abstract of DOI:10.1016/j.tetasy.2011.08.001

The synthesis of a C-branched homopyrrolidinol has been achieved by making use of the reactivity of the sulfone group in four different ways. The stereochemistry of the two compounds has been established by X-ray diffraction analysis.

Full text of DOI:10.1016/j.tetasy.2011.08.001

Tetrahedron: Asymmetry 22 (2011) 1467–1472
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Tetrahedron: Asymmetry
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Sulfone chemistry for the synthesis of C-branched pyrrolidines
Mari F. Flores a, Pilar García a, Narciso M. Garrido a, Isidro S. Marcos a, Francisca Sanz b, David Díez a,
⇑
a Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caidos 1-5, 37008 Salamanca, Spain
b Servicio General de Rayos X, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caidos 1-5, 37008 Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a C-branched homopyrrolidinol has been achieved by making use of the reactivity of the
sulfone group in four different ways. The stereochemistry of the two compounds has been established by
X-ray diffraction analysis.
Received 12 July 2011
Accepted 20 July 2011
Available online 6 September 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated to Professor Pilar Basabe on the
occasion of her 65th birthday
1. Introduction
biologically active iminosugars such as DIM XII,14 or organocata-
lysts such as XIV (Fig. 2).15
The sulfone group is one of the most versatile functional groups
in organic chemistry.1
Herein we have employed step by step the reactivity of the sul-
fone group for the synthesis of C-branched homoprolinols, that is,
From a methodological point of view, sulfones have been em-
ployed in the synthesis of many of the most demanding and
sophisticated complex molecules.2 The excellent properties of this
group, both as a powerful electron withdrawing group and as an
easily removed substituent,3 have made it increasingly important
in synthetic chemistry; for example in the synthesis of peptide-
based inhibitors.4
the stabilization of an anion at the a-position of the sulfone and
the addition to a nitrone,16 the 1,3 dipolar cycloaddition of a vinyl
sulfone and a nitrone,17 and the formation and reduction of the
aldehyde formed18 by the opening of the isoxazolidine and a des-
ulfonylation reaction.2
2. Results and discussion
In our research group we are interested in the chemistry of this
functionality in the form of allyl sulfones such as I (Fig. 1), which
can be transformed into dienyl sulfone II by treatment with n-
BuLi.5 This compound is very useful in organic synthesis because
it can be transformed into isosorbide analogues III, and generates
four sterereocenters in one step.6 Allyl sulfone I was used as the
starting material for the synthesis of vinylcyclopropanols IV,7
which allowed us to obtain aminoacids V8 and VI9 (Fig. 1).
The Sharpless epoxidation of II led to both enantiomers of VII.10
One of these chiral epoxides was easily transformed into vinyl
sulfone VIII, which can also be obtained without difficulty from
It is well known that proline and proline derivatives play unique
and important roles in the conformation of peptides and proteins.
As a result, many analogues of these compounds have been
synthesized.
Moreover, C-branched proline derivatives have attracted much
attention since the substitution at C-2 can change the properties
of the aminoacid or their derivatives.19 Recently, the synthesis of
the Me-C2 of proline 1, or tetrazol analogues 2, which increased
the output as organocatalysts,20 has been described. Barker and
co-workers have studied the influence of
a
-methyl substitution
-oxidation
D
-erithronolactol.11 Compound VIII proved to be the most versatile
of proline-based organocatalysts on the asymmetric
a
of all, since it could be cyclisized into sulfone IX10 (Fig. 1). Recently,
our attention was focused on the synthesis of chiral organocata-
lysts. Thus, we decided to use vinyl sulfone VIII for the synthesis
of organocatalysts, synthons, and biologically active compounds
(Fig. 2).
Vinyl sulfone VIII was transformed into chiral catalyst X
(Fig. 2).12 The diastereoselective epoxidation of VIII gave epoxide
XI,13 which was transformed into vinylbromides such as XIII13 or
of aldehydes21 while Fleet and co-workers have described the syn-
thesis of C-branched iminosugars, 3, with interesting biological
activities22 (Fig. 3).
Due to the importance of the C-branched pyrrolidine skeleton,
we decided to develop a new methodology to obtain these kinds
of compounds in a simple manner using the reactivity of the sul-
fone group.
Nitrone 4 was chosen as the starting material, as it is a known
compound used in the synthesis of many natural and biologically
active compounds, such as polyhydroxypyrrolidines or polyhydr-
oxypyrrolizidines, and we were able to obtain an X-ray structure.23
⇑
Corresponding author. Tel.: +34 923 294474; fax: +34 923 294574.
E-mail address: ddm@usal.es (D. Díez).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.08.001

1468
M. F. Flores et al. / Tetrahedron: Asymmetry 22 (2011) 1467–1472
O
ref. 5
H
HO
SO2Ph
O
SO2Ph
I
II
ref. 6
OH
ref. 10
ref. 7
H
OR
O
O
PhO2S
HO
SO2Ph
H
O
VII
SO2Ph
H
H
IV
ref. 9
III
ref. 8
OR
ref. 11
SO2Ph
O
O
MeOOC
OR
O
O
ref.10
NH2
COOMe
NH2
H
H
TsO
N
H
SO2Ph
V
VI
VIII
IX
Figure 1. The use of allyl I and dienyl sulfones II as synthons.
HO
OH
OH
OH
OH
N
H
XII
O
Br
O
O
ref.13
TsO
ref. 14
SO2Ph
XIII
H
SO2Ph
H
N
N
O
O
O
O
O
O
ref. 13
ref. 12
O
ref. 15
TsO
N
H
SO2Ph
NHSO2CF3
X
VIII
XI
XIV
Figure 2. Vinyl sulfone VIII used as a starting material in the synthesis of useful synthons.
HO
OH
O
O
O
O
O
O
OH
N
N
H
N
H
N
a
b
N
H
HN
O
N
OH
N
O
N
N
O
SO2Ph
OH
SO2Ph
1
2
3
4
5
6
Figure 3. Me-branched pyrrolidines.
Scheme 1. Reagents and conditions: (a) MeSO2Ph, n-BuLi, THF, ꢀ78 °C, (48%); (b)
MnO2, DCM, 0 °C, 2 h, (98%).
The addition of the lithium derivative of methyl phenyl sulfone
to nitrone 4 under the usual conditions stereoselectively led to
hydroxylamine 5 (Scheme 1). We had previously used this reaction
in the synthesis of an organocatalyst.24 Hydroxylamine 5 was sub-
jected to air oxidation and gave nitrone 6 in low yield. In order to
increase the yield, hydroxylamine 5 was oxidised to the required
nitrone by treatment with manganese dioxide25 in nearly quantita-
tive yield (Scheme 1). The structure of nitrone 6 was established by
X-ray determination.26
Several solvents were tested but no reaction took place. Using tol-
uene at reflux gave a mixture of isoxazolidines, which were ob-
tained in 70% yield, as depicted in Scheme 2.
After chromatographic separation of isomers 7–10, the stereo-
chemical assignment of each of the products was determined by
NMR spectroscopy. Fortunately, we were able to crystallize isoxaz-
olidines 8 and 9, and determine their structures by X-ray analysis27
(Fig. 4).
We were able to obtain nitrone 6 in sufficient yield, to tackle the
synthesis of a C-branched substituted pyrrolidine. First, we studied
the 1,3-dipolar cycloaddition of nitrone 6 and phenyl vinyl sulfone.
The stereochemistry of compounds 7 and 10 were established
by NMR studies; particularly the 13C NMR resonances of C-3

M. F. Flores et al. / Tetrahedron: Asymmetry 22 (2011) 1467–1472
1469
O
O
O
O
O
O
O
O
O
O
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
SO2Ph
a
4
4
+
+
+
N
N
N
N
O
N
2
O
O
O
SO2Ph
O
2
SO2Ph
SO2Ph
7
8
9
10
6
b
b
c
b
HO
OH
O
O
O
O
O
O
SO2Ph
CH2OH
SO2Ph
CH2OH
d
e
N
H
N
H
N
H
N
H
CH2OH
CH2OH
14
13
11
12
Scheme 2. Reagents and conditions: (a) phenyl vinyl sulfone, toluene, reflux 110 °C, 24 h (70%), ratio 1.0/3.5/1.4/1.0. (b) Na(Hg) 5%, MeOH, rt, 2 h, (40%). (c) Na(Hg) 5%, MeOH,
rt, 2 h, (15%). (d) Na(Hg) 5%, MeOH, 35° C, 20 h, (57%). (e) HCl 6 M, MeOH, rt, 1.5 h, (65%).
dine 12, although in low yield. On the other hand, isoxazolidine 7
did not give any product.
It is worth mentioning that when the sulfonyl group at C-2 was
removed, we managed the cleavage of the N–O bond and the
reduction of the aldehyde intermediate formed.
Several conditions using a Na(Hg) amalgam were tested to
eliminate both sulfonyl groups in one step; however the reaction
did not take place in any case. We also attempted alternative meth-
ods for the desulfonylation, such as Mg–MeOH–NiBr2, which had
been successfully used in obtaining dideoxyaminosugars,29 but
this was unsuccessful in giving the desired product.
Finally, slightly heating the pyrrolidine in MeOH at 35 °C and
using 6 equiv of the Na(Hg) amalgam gave the desired pyrrolidine
13. With compound 13 in hand, our final step was its deprotection
Figure 4. X-ray structures of isoxazolidines 8 and 9.
under the usual conditions,6 employing HCl 6 M in MeOH to afford
a C-branched homopyrrolidinol 14 in a moderate yield. We have
thus provided a new route to obtain C-branched homopyrrolidines
starting from easily available nitrones using the sulfone reactivity.
for both compounds as shown in Figure 5.
(79.2 ppm) for 7 and C-2 (96.2 ppm) in 10 and the NOEs observed
Further reduction of the phenyl sulfonyl group present in the
3. Conclusions
isoxazolidines afforded the desired C-branched proline derivative.
Compounds 7, 8, 9, and 10 were thus submitted to desulfonylation
under the usual conditions.28
When compounds 8 and 9 were treated with an Na(Hg) amal-
gam, only pyrrolidine 11 was obtained in moderate yield. Under
these reaction conditions, only one sulfone was removed. Similar
results were also observed for isoxazolidine 10, providing pyrroli-
In conclusion, the synthesis of a C-branched homoprolinol
derivative has been achieved from chiral nitrone 1, in only five
steps. The synthesis was carried out using only sulfone chemistry,
which corroborates the versatility of the sulfone group. Moreover,
the structures of two compounds have been determined by X-ray
SO2Ph
SO2Ph
H
H
H
Me
O
Me
O
H
H
H
Me
Me
SO2Ph
H
O
O
O
H
H
H
N
H
N
O
H
H
H
H
H
SO2Ph
7
10
Figure 5. Main NOEs for the structure determination of 7 and 10.

1470
M. F. Flores et al. / Tetrahedron: Asymmetry 22 (2011) 1467–1472
analysis, which gives more value to the sulfone group and its capa-
bility to form crystals easily.
HA-3), 1.33 (3H, s, Me-acetonide), 1.26 (3H, s, Me-acetonide).13
C
NMR (CDCl3, 100 MHz) d (ppm): 140.6, 137.0, 134.5, 133.1, 129.4,
129.1, 128.0, 127.8, 111.4, 95.7, 79.1, 77.7, 76.4, 59.3, 57.5, 34.4,
25.8, 24.6.; HRMS (ESI): calcd for
502.0964; found 502.0940.
C
22H25NO7S2Na, [M+Na]+:
4. Experimental
4.1. General
4.2.3. (2R,3aS,4S,5R)-2-Phenylsulfonyl-3a-phenylsulfonylmeth-
yl-4,5-isopropylidenedioxy-hexahydropyrrolo[1,2-b]isoxazole 9
Unless otherwise stated, all chemicals were purchased with the
highest purity commercially available and were used without fur-
ther purification. IR spectra were recorded on a BOMEM 100 FT-IR
or an AVATAR 370 FT-IR Thermo Nicolet spectrophotometers. 1H
and 13C NMR spectra were performed in CDCl3 and referenced to
the residual peak of CHCl3 at d 7.26 ppm and d 77.0 ppm, for 1H
and 13C NMR, respectively, using Varian 200 VX and Bruker DRX
400 instruments. Chemical shifts are reported in d ppm and cou-
pling constants (J) are given in Hertz. Mass spectra were performed
at a VG-TS 250 spectrometer at 70 eV ionizing voltage. Mass spec-
tra are presented as m/z (% rel int.). HRMS were recorded on a VG
Platform (Fisons) spectrometer using chemical ionization (ammo-
nia as gas) or the Fast Atom Bombardment (FAB) technique. For
some of the samples, QSTAR XL spectrometer was employed for
electrospray ionization (ESI). Optical rotations were determined
on a Perkin-Elmer 241 polarimeter in 1 dm cells. THF were distilled
from sodium, and dichloromethane was distilled from calcium hy-
dride under argon atmosphere.
½
a 2D0
ꢂ
¼ ꢀ45:2 (c 0.46, CHCl3). IR (film)
m
(cmꢀ1) 3424, 3060,
2974, 2917, 1626, 1581, 1458, 1311, 1140; 1H NMR (CDCl3,
400 MHz) d (ppm): 8.02 (2H, d, J = 8.1 Hz, H ortho0), 7.94 (2H, d,
J = 8.3 Hz, H ortho), 7.68–7.54 (6H, m, HAr), 5.14 (1H, dd, J = 4.2
and 9.8 Hz, H-2), 4.94 (1H, d, J = 6.2 Hz, H-4), 4.85 (1H, dt, J = 1.7
and 6.2 Hz, H-5), 3.97 (1H, d, J = 13.2 Hz, HB-10), 3.88 (1H, dd,
J = 4.2 and 15 Hz, HB-3), 3.82 (1H, d, J = 13.2 Hz, HA-10), 3.38 (1H,
dd, J = 1.7 and 12.6 Hz, HB-6), 2.88 (1H, dd, J = 6.2 and 12.6 Hz,
HA-6), 2.48 (1H, dd, J = 9.8 and 15 Hz, HA-3), 1.36 (3H, s, Me-aceto-
nide), 1.28 (3H, s, Me-acetonide).13C NMR (CDCl3, 100 MHz) d
(ppm): 141.7, 136.3, 134.3, 133.5, 129.5, 129.4, 128.9, 127.9,
112.1, 92.5, 82.0, 77.3, 75.6, 58.8, 58.1, 35.9, 27.2, 24.8.; HRMS
(ESI): calcd for
502.0984.
C
22H25NO7S2Na, [M+Na]+: 502.0964; found
4.2.4. (2R,3aR,4S,5R)-2-Phenylsulfonyl-3a-phenylsulfonylm-
ethyl-4,5-isopropylidenedioxy-hexahydropyrrolo[1,2-b]-
isoxazole 10
½
a 2D0
ꢂ
¼ ꢀ55:7 (c 1.24, CHCl3). IR (film)
m
(cmꢀ1) 3383, 3068,
4.2. Cycloaddition of nitrone 6 to phenyl vinyl sulfone
2983, 2938, 1446, 1368, 1303, 1148, 1074; 1H NMR (CDCl3,
400 MHz) d (ppm): 7.93 (2H, s, H ortho0), 7.91 (2H, s, H ortho),
7.68–7.51 (6H, m, HAr), 5.11 (1H, dd, J = 7.4 and 9.4 Hz, H-2),
4.94 (1H, d, J = 7 Hz, H-4), 4.66 (1H, dd, J = 6.4 and 11.5 Hz, H-5),
3.62 (1H, dd, J = 6.4 and 10.5 Hz, HA-6), 3.54 (1H, dd, J = 6.4 and
10.5 Hz, HB-6), 3.37 (1H, dd, J = 9.4 and 14.2 Hz, HA-3), 3.33 (1H,
d, J = 14.4 Hz, HA-1), 3.25 (1H, d, J = 14.4 Hz, HB-1), 3.08 (1H, dd,
J = 7.4 and 14.2 Hz, HB-3), 1.63 (3H, s, Me-acetonide), 1.29 (3H, s,
Me-acetonide).13C NMR (CDCl3, 100 MHz) d (ppm): 140.4, 136.9,
134.3, 134.1, 129.3, 129.3, 129.2, 128.1, 114.9, 96.2, 80.4, 76.9,
74.9, 60.9, 58.5, 33.4, 26.5, 24.8.; HRMS (ESI): calcd for
Phenyl vinyl sulfone (850 mg, 5.04 mmol) was added to a solu-
tion of nitrone 6 (1.26 g, 4.06 mmol) in toluene (13.5 mL) at rt. The
resulting mixture was heated at reflux for 24 h, then it was
quenched with saturated aqueous solution of NH4Cl and the prod-
uct was extracted with EtOAc (3 ꢁ 15 mL). The combined organic
layers were washed with brine, dried (Na2SO4), filtered, and
concentrated. The resulting crude residue was purified by flash
chromatography (silica gel, hexane/EtOAc 6:4) to obtain isoxazoli-
dines 7, 8, 9, and 10 in 70% yield (ratio 1.0/3.5/1.4/1.0).
C
22H25NO7S2Na, [M+Na]+: 502.0964; found 502.0964.
4.2.1. (3S,3aS,4S,5R)-3-Phenylsulfonyl-3a-phenylsulfonylm-
ethyl-4,5-isopropylidenedioxy-hexahydropyrrolo[1,2-b]-
isoxazole 7
4.3. Desulfonylation of 8 to yield 11
½
a 2D0
ꢂ
¼ þ8:2 (c 0.22, CHCl3). IR (film)
m
(cmꢀ1) 3412, 2921, 1638,
1446, 1381; 1H NMR (CDCl3, 400 MHz) d (ppm): 8.06–7.99 (4H, m,
H ortho0 and H ortho), 7.65–7.54 (6H, m, HAr), 5.52 (1H, dd, J = 7.4
and 9.3 Hz, H-3), 5.48 (1H, d, J = 6.4 Hz, H-4), 4.93 (1H, dt, J = 1.8
and 6.4 Hz, H-5), 4.26 (1H, dd, J = 7.4 and 9.4 Hz, HA-2), 3.97 (1H,
t, J = 9.4 Hz, HB-2), 3.96 (1H, d, J = 15 Hz, HA-10), 3.38 (1H, dd,
J = 6.4 and 12.7 Hz, HA-6), 3.30 (1H, d, J = 15 Hz, HB-10), 3.15 (1H,
dd, J = 1.8 and 12.7 Hz, HB-6), 1.33 (3H, s, Me-acetonide), 1.26
(3H, s, Me-acetonide).13C NMR (CDCl3, 100 MHz) d (ppm): 140.3,
139.5, 134.5, 133.8, 129.7, 129.2, 128.8, 128.0, 112.1, 79.2, 78.9,
77.7, 77.3, 67.2, 58.1, 55.9, 25.7, 24.0; HRMS (ESI): calcd for
To a solution of isoxazolidine 8 (66 mg, 0.14 mmol) in MeOH
(1.5 mL) was added 200 mg (0.42 mmol) of 5% Na (Hg) amalgam
at rt. The mixture was stirred for 2 h at this temperature under
an argon atmosphere. Next, it was filtered to eliminate the Hg res-
idue and concentrated under pressure. The reaction product was
then extracted with DCM (3 ꢁ 15 mL). The combined organic lay-
ers were washed with brine, dried (Na2SO4), filtered, and concen-
trated. The resulting crude residue was purified by flash
chromatography (silica gel, n-hexane/EtOAc 6:4) to give pyrroli-
dine 11 (19 mg, 40%).
C
22H25NO7S2Na, [M+Na]+: 502.0964; found 502.0983.
4.3.1. (2S,3S,4R)-2-Hydroxyethyl-2-phenylsulfonylmethyl-3,4-
isopropylidenedioxypyrrolidine 11
4.2.2. (2S,3aS,4S,5R)-2-Phenylsulfonyl-3a-phenylsulfonylm-
ethyl-4,5-isopropylidenedioxy-hexahydropyrrolo[1,2-b]-
isoxazole 8
½
a 2D0
ꢂ
¼ ꢀ11:0 (c 0.59, MeOH). IR (film)
m
(cmꢀ1) 3318, 2917,
2848, 1638, 1446, 1385, 1303, 1144, 1078; 1H NMR (CDCl3,
200 MHz) d (ppm): 7.94 (2H, d, J = 8.0 Hz, H ortho), 7.68–7.54
(3H, m, Hpara and Hmeta), 4.80 (1H, dd, J = 4.5 and 5.6 Hz, H-4),
4.48 (1H, d, J = 5.6 Hz, H-3), 4.05 (1H, dt, J = 2.2 and 10 Hz, HA-20),
3.78–3.81 (1H, m, HB-20), 3.68 (1H, d, J = 7.8 Hz, HA-1’’), 3.60 (1H,
d, J = 7.8 Hz, HB-1’’), 3.12 (1H, dd, J = 4.5 and 13.8 Hz, HA-5), 2.95
(1H, d, J = 13.8 Hz, HB-5), 2.15- 2.03 (2H, m, CH2–10), 1.39 (3H, s,
½
a 2D0
ꢂ
¼ ꢀ104:7 (c 0.46, CHCl3). IR (film)
m
(cmꢀ1) 3375, 3048,
2983, 2925, 1450, 1381, 1315, 1148; 1H NMR (CDCl3, 400 MHz) d
(ppm): 7.94–7.87 (4H, m, H ortho0 and H ortho), 7.68–7.54 (6H,
m, HAr), 5.18 (1H, dd, J = 6.9 and 9.7 Hz, H-2), 4.96 (1H, bt,
J = 6.2 Hz, H-5), 4.80 (1H, d, J = 6.2 Hz, H-4), 3.92 (1H, dd, J = 1.2
and 14.4 Hz, HA-10), 3.77 (1H, dd, J = 6.2 and 12.4 Hz, HA-6), 3.61
(1H, dd, J = 9.7 and 14 Hz, HB-3), 3.58 (1H, d, J = 12.4 Hz, HB-6),
3.22 (1H, d, J = 14.4 Hz, HB-10), 2.65 (1H, dd, J = 6.9 and 14 Hz,
Me-acetonide), 1.29 (3H, s, Me-acetonide).13
50 MHz) d (ppm): 141.9, 133.8, 129.3, 128.0, 111.4, 85.6, 82.4,
C NMR (CDCl3,

M. F. Flores et al. / Tetrahedron: Asymmetry 22 (2011) 1467–1472
1471
67.4, 59.9, 57.8, 50.7, 31.6, 26.2, 24.2.; HRMS (ESI): calcd for
16H24NO5S, [M+H]+: 342.1369; found 342.1361.
4.6.1. (2S,3S,4R)-2-Hydroxyethyl-2-methyl-3,4-dihydroxypyrrol-
C
idine 14
½
a 2D0
ꢂ
¼ ꢀ32:9 (c 0.4, H2O). IR (film)
m
(cmꢀ1) 3456, 2870, 1431,
1388, 1103, 1052, 772; 1H NMR (CDCl3, 200 MHz) d (ppm): 4.40
(1H, m, H-4), 4.10 (1H, t, J = 6.8 Hz, HA-20), 3,94 (1H, d, J = 5.0 Hz,
H-3), 3.70–3.61 (1H, m, HB-20), 3.45 (1H, dd, J = 6.0 and 13.4 Hz,
HA-5), 3.08 (1H, dd, J = 6.0 and 13.4 Hz, HB-5), 2.08–2.03 (1H, m,
HA-10), 1.85–1.80 (1H, m, HB-10),1.34 (3H, s, CH3–1’’). 13C NMR
(CDCl3, 50 MHz) d (ppm): 75.9, 69.4, 67.5, 57.2, 48.1, 37.9, 17.3.;
HRMS (ESI): calcd for C7H16NO3, [M+H]+: 162.2068; found
162.2070.
4.4. Desulfonylation of 10 to yield 12
To a solution of isoxazolidine 10 (97.4 mg, 0.20 mmol) in MeOH
(2.5 mL) was added 290 mg (0.60 mmol) of 5% Na (Hg) amalgam at
rt. The mixture was stirred for 2 h at this temperature under an ar-
gon atmosphere. Next, it was filtered to eliminate the Hg residue
and concentrated under reduced pressure. The reaction product
was then extracted with DCM (3 ꢁ 15 mL). The combined organic
layers were washed with brine, dried (Na2SO4), filtered, and con-
centrated. The resulting crude residue was purified by flash chro-
matography (silica gel, n-hexane/EtOAc 6:4) to give pyrrolidine
12 (10 mg, 15%).
Acknowledgments
The authors thank the Junta de Castilla y León for financial sup-
port (GR178, SA001A09 and EUI2008-000173), MICINN (CTQ2009-
11172) and for the doctoral fellowship awarded to M.F.F.
4.4.1. (2R,3S,4R)-2-Hydroxyethyl-2-phenylsulfonylmethyl-3,4-
isopropylidenedioxypyrrolidine 12
References
½
a 2D0
ꢂ
¼ ꢀ22:5 (c 1.03, MeOH). IR (film)
m
(cmꢀ1) 3412, 2983,
2929, 2864, 1389, 1213, 1144, 1086; 1H NMR (CDCl3, 200 MHz) d
(ppm): 7.94 (2H, d, J = 8.0 Hz, H ortho), 7.62–7.58 (3H, m, Hpara
and Hmeta), 4.72 (1H, dd, J = 4.4 and 5.8 Hz, H-4), 4.55 (1H, d,
J = 5.8 Hz, H-3), 3.80–3.70 (2H, m, CH2–200), 3.32 (1H, d,
J = 14.6 Hz, HA-1’’), 3.20 (1H, d, J = 14.6 Hz, HB-1’’), 3.02 (1H, d,
J = 13.4 Hz, HB-5), 2.83 (1H, dd, J = 4.4 and 13.4 Hz, HA-5), 2.35–
2.22 (2H, m, CH2-10), 1.48 (3H, s, Me-acetonide), 1.30 (3H, s, Me-
acetonide).13C NMR (CDCl3, 50 MHz) d (ppm): 141.5, 134.0, 129.5,
127.9, 111.9, 85.5, 81.8, 67.5, 56.7, 50.6, 35.0, 26.2, 24.5.; HRMS
(ESI): calcd for C16H24NO5S, [M+H]+: 342.1369; found 342.1372
1. (a) Patai, S.; Rappoport, Z.; Stirling, C. The Chemistry of Sulphones and Sulfoxides;
Jonh Wiley and Sons: ChiChester, 1988; (b) Simpkins, N. S. Sulphones in Organic
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(d) Najera, C.; Sansano, J. M. Recent Res. Devel. Org. Chem. 1998, 2, 637; (e)
Chinchilla, R.; Najera, C. Recent Res. Devel. Org. Chem. 1997, 1, 437.
2. Ley, S. V.; Armstrong, A.; Díez-Martín, D.; Ford, M. J.; Grice, P.; Knight, J. G.;
Kolb, H. C.; Madin, A.; Marby, C. A.; Mukherjee, S.; Shaw, A. N.; Slawin, A. M. Z.;
Vile, S.; White, A. D.; Williams, D. J.; Woods, M. J. Chem. Soc., Perkin Trans. 1
1991, 667.
3. Najera, C.; Yus, M. Tetrahedron 1999, 55, 10547.
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J. A.; Walker, K. A. M.; Martin, R.; Van Wart, H.; Browner, M. F. Nat Struct. Biol.
1999, 6, 217.
5. (a) Urones, J. G.; Marcos, I. S.; Garrido, N. M.; Basabe, P.; Bastida, A. J.; San
Feliciano, S. G.; Diez, D.; Goodman, J. M. Synlett 1998, 1361; (b) Diez Martín, D.;
San Feliciano, S. G.; Marcos, I. S.; Basabe, P.; Urones, J. G. Synthesis 2001, 1069.
6. Urones, J. G.; Marcos, I. S.; Garrido, N. M.; Basabe, P.; San Feliciano, S. G.; Coca,
R.; Diez, D. Synlett 1998, 1364.
7. (a) Diez, D.; García, P.; Pacheco, M. P.; Marcos, I. S.; Garrido, N. M.; Basabe, P.;
Urones, J. G. Synlett 2002, 355; (b) Diez, D.; García, P.; Marcos, I. S.; Garrido, N.
M.; Basabe, P.; Urones, J. G. Synthesis 2003, 53; (c) Diez, D.; García, P.;
Fernández, P.; Marcos, I. S.; Garrido, N. M.; Basabe, P.; Broughton, H. B.; Urones,
J. G. Synlett 2005, 158.
4.5. Desulfonylation of 11 to yield 13
To a solution of pyrrolidine 11 (50.0 mg, 0.15 mmol) in MeOH
(2.5 mL) was added 460 mg (0.90 mmol) of 5% Na (Hg) amalgam
at rt. The mixture was stirred for 20 h at 35 °C under an argon
atmosphere. Then, it was filtered to eliminate the Hg residue and
concentrated under reduced pressure. The reaction product was
extracted with DCM (3 ꢁ 15 mL). The combined organic layers
were washed with brine, dried (Na2SO4), filtered, and concen-
trated. The resulting crude residue was purified by flash chroma-
tography (silica gel, n-hexane/EtOAc 2:8) to give the desired
pyrrolidine 13 (17 mg, 57%).
8. Diez, D.; García, P.; Marcos, I. S.; Garrido, N. M.; Basabe, P.; Broughton, H. B.;
Urones, J. G. Org. Lett. 2003, 5, 3687.
9. (a) Diez, D.; García, P.; Marcos, I. S.; Garrido, N. M.; Basabe, P.; Broughton, H. B.;
Urones, J. G. Tetrahedron 2005, 61, 3687; See too: (b) Diez, D.; García, P.;
Marcos, I. S.; Garrido, N. M.; Basabe, P.; Broughton, H. B.; Urones, J. G.
Tetrahedron 2005, 61, 11641; (c) Diez, D.; García, P.; Moro, R. F.; Marcos, I. S.;
Garrido, N. M.; Basabe, P.; Broughton, H. B.; Urones, J. G. Synthesis 2005, 3327.
10. (a) Diez, D.; Beneitez, M. T.; Marcos, I. S.; Garrido, N. M.; Basabe, P.; Urones, J. G.
Synlett 2001, 655; (b) Diez, D.; Beneitez, M. T.; Marcos, I. S.; Garrido, N. M.;
Basabe, P.; Urones, J. G. Tetrahedron: Asymmetry 2002, 13, 639.
11. (a) Diez, D.; Beneitez, M. T.; Marcos, I. S.; Garrido, N. M.; Basabe, P.; Urones, J. G.
Synlett 2003, 729; (b) Diez, D.; Núñez, M. G.; Beneitez, A.; Moro, R. F.; Marcos, I.
S.; Basabe, P.; Broughton, H. B.; Urones, J. G. Synlett 2009, 390.
12. Diez, D.; Gil, M. J.; Moro, R. F.; Garrido, N. M.; Marcos, I. S.; Basabe, P.; Sanz, F.;
Broughton, H. B.; Urones, J. G. Tetrahedron: Asymmetry 2005, 16, 2980.
13. Diez, D.; Beneitez, M. T.; Marcos, I. S.; Garrido, N. M.; Basabe, P.; Sanz, F.;
Broughton, H. B.; Urones, J. G. Org. Lett. 2003, 5, 4361.
14. Diez, D.; Beneitez, M. T.; Gil, M. J.; Moro, R. F.; Marcos, I. S.; Garrido, N. M.;
Basabe, P.; Urones, J. G. Synthesis 2005, 565.
15. Diez, D.; Gil, M. J.; Moro, R. F.; Marcos, I. S.; García, P.; Basabe, P.; Garrido, N. M.;
Broughton, H. B.; Urones, J. G. Tetrahedron 2007, 63, 740.
16. (a) Merino, P.; Lanaspa, A.; Merchan, F.; Tejero, T. Tetrahedron: Asymmetry
1997, 8, 2381; (b) Merino, P.; Castillo, E.; Merchan, F.; Tejero, T. Tetrahedron:
Asymmetry 1725, 1997, 8; (c) Murga, J.; Portholes, R.; Falomir, E.; Carda, M.;
Marco, A. J. Tetrahedron: Asymmetry 1807, 2005, 16; (d) Delso, I.; Tejero, T.;
Goti, A.; Merino, P. Tetrahedron 2010, 66, 1220.
4.5.1. (2S,3S,4R)-2-Hydroxyethyl-2-methyl-3,4-
isopropylidenedioxypyrrolidine 13
½
a 2D0
ꢂ
¼ ꢀ12:3 (c 0.3, MeOH). IR (film)
m
(cmꢀ1) 3307, 2925, 2856,
1605, 1381, 1123, 1082, 772; 1H NMR (CDCl3, 400 MHz) d (ppm):
4.75 (1H, dd, J = 4 and 5.4 Hz, H-4), 4.12 (1H, d, J = 5.4 Hz, H-3),
4.10–4.05 (1H, m, HA-20), 3.68–3.57 (1H, m, HB-200), 3.04 (1H, dd,
J = 4 and 14 Hz, HA-5), 2.97 (1H, d, J = 14 Hz, HB-5), 1.78–1.65
(1H, m, HA-10), 1.47 (3H, s, Me-acetonide), 1.29 (3H, s, CH3-1’’),
1.30 (3H, s, Me-acetonide), 1.15–1.05 (1H, m, HB-10).13C NMR
(CDCl3, 50 MHz) d (ppm): 111.1, 87.8, 83.2, 76.6, 66.2, 60.1, 51.0,
34.1, 26.3, 24.1, 18.7.; HRMS (ESI): calcd for C10H20NO3, [M+H]+:
202.1437; found 202.1418.
17. Brandi, A.; Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. Eur. J. 2009, 15,
7808.
18. (a) Chemla, F. J. Chem. Soc. Perkin Trans. 1 2002, 275. and references cited
therein; (b) Wee, A. G. H.; McLeod, D. D. J. Org. Chem. 2003, 68, 6268; (c)
Jackson, R. F. W.; Standen, S. P.; Clegg, W.; McCamley, A. J. Chem. Soc., Perkin
Trans. 1 1995, 141; (d) see also reference 13.
19. (a) De Poli, M.; Moretto, A.; Crisma, M.; Peggion, C.; Formaggio, F.; Kaptein, B.;
Broxterman, Q. B.; Toniolo, C. Chem. Eur. J. 2009, 15, 8015. and references cited
therein; For the synthesis of iminosugars using nitrone chemistry see (b) Li, Y.-
X.; Huan, M.-H.; Yamashita, Y.; Kato, A.; Jia, Y.-M.; Wang, W.-B.; Fleet, G. W. J.;
4.6. Deprotection of 13 to yield 14
To a solution of pyrrolidine 13 (15.0 mg, 0.07 mmol) in MeOH
(1.5 mL) was added 2–3 drops of HCl 6 M at rt. The mixture was
stirred for 1.5 h under an argon atmosphere. Then, it was diluted
with MeOH and concentrated under reduced pressure to give pyr-
rolidine 13 (7.3 mg, 65%).

1472
M. F. Flores et al. / Tetrahedron: Asymmetry 22 (2011) 1467–1472
Nash, R. J.; Yu, C.-Y. Org. Biomol. Chem. 2011, 9, 3405. and references cited
refinement for all non-hydrogen atoms.
therein.
(a) Crystal data for 8: C22H25N1O7S2, M = 479.55, monoclinic, space group P21
20. Tong, S.-T.; Harris, P. W.; Brimble, M. A.; Barker, D. Eur. J. Org. Chem. 2008, 164.
21. Tong, S.-T.; Harris, P. W. R.; Brimble, M. A.; Barker, D. Tetrahedron 2009, 65,
4801.
22. (a) Otero, J. M.; Soengas, R. G.; Estevez, J. C.; Estevez, R. J.; Watkin, D. J.; Evinson,
E. L.; Nash, R. J.; Fleet, W. J. Org. Lett. 2007, 9, 623; (b) da Cruz, F. P.; Horne, G.;
Fleet, G. W. J. Tetrahedron Lett. 2008, 49, 6812.
(n° 4), a = 9.0271(3) Å, b = 14.4516(5) Å, c = 9.4376(4) Å, a = c 90,
b = 109.507(3)°, V = 1160.52(7) Å3, Z = 2, Dc = 1.372 Mg/m3, m = (Cu–
K ) = 0.790 mmꢀ1, F(0 0 0) = 504. 6864 reflections were collected at 4.97 6 2h
a
6 66.05 and merged to give 3336 unique reflections (Rint = 0.0282), of which
3142 with I > 2rI were considered to be observed. Final values are R = 0.0354,
wR = 0.0843, GOF = 1.074, max/min residual electron density 0.177 and ꢀ0.191
23. Flores, M. F.; García, P.; Garrido, N. M.; Sanz, F.; Diez, D. Acta Cryst. 2011, E67,
o1115.
e. Åꢀ3
.
(b) Crystal data for 9: C22H25N1O7S2, M = 479.55, orthorhombic, space group
24. (a) Flores, M. F.; Núñez, M. G.; Moro, R. F.; Garrido, N. M.; Marcos, I. S.; Iglesias,
E. F.; García, P.; Diez, D. Molecules 2010, 15, 1501; For the addition of
organometallics to nitrones see: (b) Delso, I.; Tejero, T.; Goti, A.; Merino, P. J.
Org. Chem. 2011, 76, 4139. and references cited therein.
25. Cicchi, S.; Marradi, M.; Goti, A.; Brandi, A. Tetrahedron Lett. 2001, 42, 6503.
26. Flores, M. F.; García, P.; Garrido, N. M.; Sanz, F.; Diez, D. Acta Cryst. 2011, E67,
o1116.
P212121 (n° 19), a = 9.4439(3) Å, b = 11.5345(4) Å, c = 20.6737(7) Å,
a = b c 90°,
V = 2252.00(13) Å3, Z = 4, Dc = 1.414 Mg/m3, m = (Cu-K ) = 2.528 mmꢀ1
,
a
F(0 0 0) = 1008. 11481 reflections were collected at 4.28 6 2h 6 67.04 and
merged to give 3738 unique reflections (Rint = 0.0298), of which 3665 with I > 2
r
I were considered to be observed. Final values are R = 0.0275, wR = 0.0713,
GOF = 1.054, max/min residual electron density 0.212 and -0.225 e. Åꢀ3
.
Crystallographic data (excluding structure factors) for the structure reported in
this paper have been deposited at the Cambridge Crystallographic Data Centre
as supplementary material numbers CCDC CCDC 824817 and 824818,
respectively.
27. Suitable single crystals of 8 and 9 were mounted on glass fiber for data
collection on a Bruker Kappa APEX II CCD diffractometer. Data were collected
at 298(2) K using Cu K radiation (k = 1.54178 Å) and
x scan technique, and
a
were corrected for Lorentz and polarization effects. Structure solution,
refinement, and data output were carried out with the SHELXTLTM program
package. The structures were solved by direct methods combined with
difference Fourier synthesis and refined by full-matrix least-squares
procedures, with anisotropic thermal parameters in the last cycles of
28. (a) Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R. Tetrahedron Lett.
1976, 3477; (b) López-Perez, A.; Adrio, J.; Carretero, J. C. Angew. Chem. Int. 2009,
48, 340; (c) Flick, A. C.; Arevalo, M. J.; Lee, H. I.; Padwa, A. J. Org. Chem. 2010, 75,
1992.
29. Das, I.; Pathak, T. Org Lett. 2006, 8, 1303.