Synthesis of a new chiral pyrrolidine

Article abstract of DOI:10.3390/molecules15031501

The synthesis of a new chiral pyrrolidine has been performed using 2,3-O-isopropylidene-D-erythronolactol as a suitable starting material.

Full text of DOI:10.3390/molecules15031501

Molecules 2010, 15, 1501-1512; doi:10.3390/molecules15031501
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of a New Chiral Pyrrolidine †
Mari Fe. Flores, Marta G. Núñez, Rosalina F. Moro, Narciso M. Garrido, Isidro S. Marcos,
Enrique F. Iglesias, Pilar García and David Díez *
Departamento de Química Orgánica, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008,
Salamanca, Spain
†
This paper is dedicated to Prof. Pelayo Camps on occasion of his 65th birthday.
* Author to whom correspondence should be addressed; E-Mail: ddm@usal.es;
Tel.: +34-923-294-474; Fax: +34-923-294-574.
Received: 8 December 2009; in revised form: 2 February 2010 / Accepted: 5 March 2010 /
Published: 9 March 2010
Abstract: The synthesis of a new chiral pyrrolidine has been performed using 2,3-O-iso-
propylidene-D-erythronolactol as a suitable starting material.
Keywords: organocatalysis; pyrrolidines; sulfones; nitrones
1. Introduction
In the last years there has been a growing interest in organocatalysis [1–6], a new field which has
quickly attracted researchers’ attention due to its potential for saving costs, time and energy compared
to classic catalysis. Among the many known organocatalysts L-proline is perhaps the one which has
been most studied. This fact has led to the appearance of many analogues [7–14]. In the seminal paper
of List, Lerner and Barbas III [15], it is described how in the aldol reaction the catalytic activity of
L-proline increases using trans-4-hydroxy-L-proline and also how the enantiomeric excess reverses
using cis-4-hydroxy-D-proline, (Figure 1).

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Figure 1. L-proline and two analogues.
In our research group we have achieved the synthesis of several chiral pyrrolidines from
sulfonylbutadiene 1 or 2,3-O-iso-propylidene-D-erythronolactol (2) (Scheme 1).
Scheme 1. Synthesis of several pyrrolidines from a sulfonylbutadiene or 2,3-O-iso-
propylidene-D-erythronolactol.
Starting from sulfonylbutadiene 1, pyrrolidines 5 and 6 were obtained through vinyl sulfones 3 and
4, respectively [16–17]. In order to increase the yields, a new route for the synthesis of compound 6
was devised starting from 2,3-O-iso-propylidene-D-erythronolactol (2) through vinylsulfone 4 [18].
This pyrrolidine 6 has been proved to be an organocatalyst for the intramolecular oxa-Michael reaction
[19–20]. Moreover, compound 7, which has been reported to catalyze Michael reactions [21], has been
synthesized from intermediate vinylsulfone 4 (Scheme 1).
2. Results and Discussion
In this paper we describe our studies on the synthesis of the epimer at C-2 of pyrrolidine 6, as we
are interested in comparing the properties of both diastereoisomers in organocatalytic reactions. In
previous studies with PPY-derivatives, we had observed the epimerization of that stereogenic center
when it was treated with bases [22]. Taking this into account, we first tried the epimerization at C-2 in
compound 8, obtained directly from 4 by treatment with benzylamine. However, although several

Molecules 2010, 15
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bases were used, none of them gave the epimerization. Therefore, we devised the following synthesis
for the required compound 12 (Scheme 2).
Scheme 2. Epimerization of C-2 in compound 8.
O
O
O
O
O
O
4
3
g
2
1´
N
Bn
9
N
Bn
8
N
H
SO2Ph
SO2Ph
SO2Ph
12
e
c or d
f
O
O
O
O
O
O
a
b
N
H
N
Bz
N
Bz
SO2Ph
SO2Ph
SO2Ph
6
10
11
a. PhCOCl, Py., 0 ºC-r.t., 97%; b. n-BuLi, THF, -78 ºC-r.t., 50%; c NH2-NH2, EtOH, reflux, 0%; d.
HCl 6M, reflux, 0%; e. LiAlH4, THF, 0 ºC-r.t., 30%; f. BH3·THF, THF, 0 ºC-40 ºC, 15%; g. H2,
Pd/C, MeOH, r.t., 80%.
Benzoylation of pyrrolidine 6 gave derivative 10 as outlined in Scheme 2. When this compound
was submitted to treatment with n-BuLi, the C-2 epimer 11 was obtained in moderate yield. Once the
required stereochemistry at C-2 in 11 was achieved, we proceeded to deprotect the nitrogen to obtain
the desired pyrrolidine 12. This step was not as simple as it was thought initially, since the desired
direct debenzoylation did not take place under several conditions. Finally, it was necessary to reduce
the benzoyl to benzyl group and then deprotect under the usual conditions. Although, the final
deprotection took place in good yield, the previous transformation from benzoyl to benzylderivative
was only achieved in low yield, making useless this procedure to synthesise 12.
Scheme 3. Synthesis of 12 from 2,3-O-iso-propylidene-D-erythronolactol.
n.O.e
O
O
O
O
O
O
O
O
n.O.e
a
b
H
H
H
n.O.e
H
H
PhO2S
N
O
OH
H
N
OH
O
2
N
OH
13
14
SO2Ph
O
c or d
14
e or f
g
n.O.e
n.O.e
O
O
n.O.e
H
H
O
O
O
O
O
H
H
+
H
N
H
N
H
N
N
H
6
SO2Ph
SO2Ph
SO2Ph
SO2Ph
6
12
OH
15
a. 1. NH2OSiMe2t-Bu, Py., r.t., 15h.; 2. MsCl, 0 ºC, 2h, 50%; b. MeSO2Ph, n-BuLi, THF, -78 ºC,
48%; c. H2, Pd(OH)2/C, HCl / MeOH, 4atm, 27%; d. H2, Pd/C, MeOH, 39%; e. In, NH4Cl/EtOH,
reflux, 24h, 92%; f. Zn, NH4Cl/MeOH, reflux, 2h, 50%; g. In(cat), Zn, NH4Cl/MeOH reflux or r.t.,
see Table 1.

Molecules 2010, 15
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Therefore, we devised a new synthesis of compound 12 starting from 2,3-O-iso-propylidene-D-
erythronolactol (2). Goti [23–25] and Wightman and Closa [26–28] have obtained nitrone 13 from
compound 2. Besides, Merino and Goti have applied this versatile nitrone to the synthesis of
iminocyclitols, pyrrolizidines and indolizidines [29–30], observing that the addition of organometallics
to 13 took place to give the trans compounds. With this procedure in mind, we were able to achieve
the desired compound 12 in a simple manner, as depicted in Scheme 3.
When compound 13 was treated with lithio(phenylsulfonyl)methane, only hydroxylamine 14 was
obtained stereoselectively in moderate yield. The stereochemistry of 14 was established studying its
NMR spectra (whose assignment is given in the Experimental section) and by the observation of the
nOes that this molecule displays (Scheme 3). The nOes of the enantiomer of compound 6 has already
been reported by our research group [16]. Once this compound 14 was synthesized, different reduction
conditions to obtain the pyrrolidine ring were tested.
Hydrogenation under different conditions either Pd(OH)2 or Pd on carbon only leads to the
pyrrolidine 6. When 14 was submitted to reduction with stoichiometric indium or with zinc,
hydroxylamine 15 with inversion at C-2 was obtained. Thus, it was necessary to choose the adequate
conditions to reduce the hydroxylamine to the required pyrrolidine 12 without epimerization at C-2.
This was achieved using catalytic indium and stoichiometric Zn [29–31] (Table 1, entry 8).
Table 1. Reduction conditions of hydroxylamine 14 to pyrrolidines 6 and 12.
Zn
Equiv.
η
(%)
15
Ratio
6/12
Entry
Tª
t(h)
1
2
3
4
5
6
7
8
9
6
4
4
4
2
2
2
4
3
2
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
r.t.
1
2
1
0.5
1
1.5
2
5.5
4
4
40/60
36/64
30/70
NDa
10
15
NDa
NDa
10
NDa
40/60
15/85
5/95
45/55
NDa
20
40
r.t.
r.t.
8
10
NDa
a Not determined.
Having obtained our desired compounds 6 and 12, they were tested as organocatalysts in Michael
addition reactions of cyclohexanone to nitrostyrene, as shown in Table 2.

Molecules 2010, 15
Table 2. Solvent effects on the asymmetric Michael addition of cyclohexanone to trans--
1505
nitrostyrene with catalysts 6 and 12.
O
O
Ph
1'
15% mol catalyst
solvent, 16h, r.t.
NO2
Ph
2
+
NO2
Entry[a] Solv. Catalyst Yield [%][b] d.r.[%] [c] ee[%][d] Conf.
6
12
6
1
2
3
4
CHCl3
CHCl3
DMSO
DMSO
-
-
-
-
2R, 1’S
35
20
-
>95
>95
-
38
69
-
2S, 1’R
12
-
[a] For experimental conditions see the Experimental section. [b] Yield of the isolated product. [c]
1
Determined by H-NMR spectroscopic analysis. [d] Determined by chiral high-performance liquid
chromatography (HPLC) analysis (Daicel Chiralpak AD, 25 cm/4.6 mm/5 ).
As can be observed, both compounds 6 and 12 are organocatalysts. However, their behaviour is
rather different depending on the solvent chosen to carry out the reaction. It is worthy mentioning that
compound 12 lead to the opposite enantiomer of 6 in the Michael addition, as a result of the
stereochemistry change in C-2 position. The absolute configuration of the addition product was
established by comparison of the HPLC data with the ones reported by us [21] and others [32–33].
3. Conclusions
The synthesis of a new chiral pyrrolidine 12, has been achieved from the same starting material,
2,3-O-iso-propylidene-D-erythronolactol through two different methodologies. In addition, the
reduction of the chiral hydroxylamine into pyrrolidine has been studied under different conditions.
4. Experimental
4.1. General
1H-NMR and 13C-NMR spectra were recorded in CDCl3 at 200 and 400 MHz (1H) or 50 and
100 MHz (13C) on Varian 200 VX and BRUKER DRX 400 instruments, respectively. Multiplicities
were determined by DEPT experiments. IR spectra were registered using a BOMEM 100 FTIR
spectrophotometer. Optical rotations were determined using a Perkin-Elmer 241 polarimeter in a 1 dm
cell and are given in units of 10-1 deg cm2 g-1. Concentrations are quoted in g per 100mL. The electron
impact (EI) mass spectra were run on a VG-TS 250 spectrometer using a 70 eV ionizing voltage.
HRMS were recorded using a VG Platform (Fisons) spectrometer using Chemical Ionization
(ammonia as gas) or Fast Atom Bombardment (FAB) techniques. Thin layer chromatography (tlc) was
performed on aluminum sheets coated with 60 F254 silica. Sheets were visualized using iodine, UV
light or 1% aqueous KMnO4 solution. Column chromatography (CC) was performed with Merck silica

Molecules 2010, 15
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gel 60 (70–230 mesh). Solvents and reagents were generally distilled prior to use: dichloromethane
(DCM) from KOH.
4.2. Preparation of (2S,3S,4R)-N-Benzoyl-2-phenylsulfonylmethyl-3,4-isopropylidenedioxypyrrolidine
(10)
To a solution of pyrrolidine 6 (40 mg, 0.13 mmol) in pyridine (0.5 mL) at 0 ºC was added PhCOCl
(20 µL) and the mixture was stirred for 3 h. The reaction was quenched by the addition of water
(0.2 mL) at 0 ºC and then the mixture was extracted with EtOAc (3 × 10 mL). The combined organic
layers were washed with aqueous solutions of CuSO4 (20%), NaHCO3 (5%) and brine. After drying
(Na2SO4), filtering, and concentrating, the crude residue was purified by flash chromatography (silica
gel, n-hexane/EtOAc 8:2) to give benzoyl derivative 10 (52 mg, 97%). IR (film)  (cm-1) 3066, 2987,
2939, 1643, 1584, 1447, 1383, 1307, 1249, 1215, 1153, 1085; 1H-NMR (400 MHz) δ = 8.03–7.34 (m,
10H), 4.83 (t, J = 5.8 Hz, 1H), 4.66–4.61 (m, 2H), 3.98 (dd, J = 14.0 and 3.7 Hz, 1H), 3.84 (dd,
13
J = 14.0 and 9.0 Hz, 1H), 3.59 (m, 2H), 1.54 (s, 3H), 1.32 (s, 3H); C-NMR (100 MHz) δ = 171.3,
139.7, 135.3, 133.6, 130.8, 129.1, 128.3, 128.1, 127.7, 113.1, 78.7, 77.5, 54.8, 54.5, 53.2, 27.1, 25.2;
HRMS (ESI) C21H24NO5S requires (M+H+) 402.1369; found 402.1364. []D20 = - 67.1 (c 1.4, CHCl3).
4.3. Preparation of (2R,3S,4R)-N-Benzoyl-2-phenylsulfonylmethyl-3,4-isopropylidenedioxypyrrolidine
(11)
A solution of pyrrolidine 10 (40 mg, 0.10 mmol) in THF (1 mL) under argon at -78 ºC, was added
n-BuLi (75 µL, 1.6 M in hexanes). The resulting mixture was stirred for 3 h, allowing to warm to rt,
whereupon the reaction was quenched with saturated aqueous solution of NH4Cl (0.2 mL) and
extracted with EtOAc (3 × 10 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, n-hexane/EtOAc 7:3) to obtain 11 (20 mg, 50%). IR (film)  (cm-1) 3064, 2978, 2938, 1634,
1
1577, 1413, 1319, 1217, 1152, 1074, 1046, 858; H-NMR (400 MHz) δ = 7.98–7.38 (m, 10H),
5.25–5.23 (m, 1H), 4.85 (m, 1H), 4.79 (m, 1H), 3.89 (dd, J = 14.0 and 3.6 Hz, 1H), 3.78–3.71 (m, 2H),
13
3.44 (d, J = 14.0 Hz, 1H), 1.44 (s, 3H), 1.33 (s, 3H); C-NMR (100 MHz) δ = 170.0, 139.6, 135.5,
134.0, 130.2, 129.4, 128.3, 127.8, 127.2, 112.2, 82.5, 79.6, 60.2, 54.8, 54.7, 26.9, 24.9; HRMS (ESI)
C21H23NO5S requires (M+Na) 424.1195; found 424.1189. []D20 = + 33.9 (c 1.1, CHCl3).
4.4. Preparation of (2R,3S,4R)-N-Benzyl-2-phenylsulfonylmethyl-3,4-isopropylidenedioxypyrrolidine
(9)
Scheme 2, step e: LiAlH4 (7 mg, 0.19 mmol) was added to a solution of 11 (38 mg, 0.1 mmol) in dry
THF (1 mL) at 0 ºC. The resulting mixture was stirred for 1h, allowing to warm to rt, whereupon the
reaction was quenched with wet ether, dried (Na2SO4), filtered, and concentrated. The resulting crude
residue was purified by flash chromatography (silica gel, n-hexane/EtOAc 8:2) to yield benzyl
derivative 9 (10 mg, 30%). IR (film)  (cm-1) 2983, 2942, 1454, 1377, 1307, 1209, 1148, 1086, 1054;
1H-NMR (400 MHz) δ = 7.90–7.15 (m, 10H), 4.70 (m, 1H), 4.64 (m, 1H), 3.81 (d, J = 13.3 Hz, 1H),
3.55 (d, J = 13.3 Hz, 1H), 3.32–3.27 (m, 2H), 3.13 (dd, J = 13.5 and 9.0 Hz, 1H), 2.87 (dd,

Molecules 2010, 15
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J = 10.7 and 5.3 Hz, 1H), 2.68 (d, J = 10.7 Hz, 1H), 1.50 (s, 3H),1.28 (s, 3H); 13C-NMR (100 MHz) δ
= 139.4, 137.0, 133.7, 129.2, 128.3, 128.1, 127.1, 112.4, 84.3, 78.7, 63.4, 57.3, 56.6, 55.1, 27.0, 25.0;
HRMS (ESI) C21H25NO4S requires (M+Na) 410.1402; found 410.1397; []D20 = + 20.2 (c 1.0, CHCl3).
Scheme 2, step f: To a solution of 11 (38 mg, 0.1 mmol) in dry THF (1 mL) under argon at rt, was
added BH3·THF (0.12 mL, 1M in THF). After stirring for 2 h at 40 ºC, the reaction was quenched by
the addition of water (0.3 mL) and extracted with Et2O (3 × 10 mL). The combined organic layers
were washed with H2O and brine, dried (Na2SO4), filtered, and concentrated. The resulting crude
residue was purified by flash chromatography (silica gel, n-hexane/EtOAc 8:2) to obtain benzyl
derivative 9 (5 mg, 15%).
4.5. Preparation of (2R,3S,4R)-2-Phenylsulfonylmethyl-3,4-isopropylidenedioxypyrrolidine (12)
Scheme 2, step g: To a solution of pyrrolidine 9 (10 mg, 0.03 mmol) in MeOH (0.5 mL) was
hydrogenated in the presence of a catalytic amount of Pd/C with a H2 balloon at room temperature for
24 h. The catalyst was filtered through a pad of Celite® and washed with MeOH. After concentrating,
compound 12 (6 mg, 80%) was obtained. IR (film)  (cm-1) 3317, 2985, 2936, 1448, 1375, 1306, 1209,
1
1144, 1083, 1046, 865; H-NMR (400 MHz) δ = 7.93 (m, 2H), 7.65–7.54 (m, 3H), 4.67 (dd,
J = 4.4 and 5.3 Hz, 1H), 4.57 (d, J = 5.3 Hz, 1H), 3.57 (t, J= 6.4 Hz, 1H), 3.13 (d, J = 13.2 Hz, 1H),
13
3.05 (d, J = 13.6 Hz, 1H), 2.69 (dd, J = 4.4 and 13.2 Hz, 1H), 1.44 (s, 3H), 1.27 (s, 3H); C-NMR
(100 MHz) δ = 139.4, 133.8, 129.3, 128.1, 111.6, 85.0, 84.9, 60.3, 57.2, 51.8, 26.2, 24.1; HRMS (ESI)
C14H20NO4S requires (M+H+) 298.1113; found 298.1115; []D20 = - 13.1 (c 1.7, CHCl3).
4.6. Preparation of (3S,4R)-3,4-Isopropylidenedioxypyrroline-1-oxide (13)
To a solution of lactol 2 (1.34 g, 8.54 mmol) in dry pyridine (8.6 mL) containing 3 Å activated
molecular sieves (pellets, 10 g) was added a solution of NH2OSiMe2t-Bu (1.51 g, 10.25 mmol) in
pyridine (8.6 mL) and the mixture was stirred at rt for 16 h. The reaction mixture was cooled to 0 ºC,
and methanesulfonyl chloride (0.8 mL, 10.25 mmol) was added slowly during 40 min. The reaction
was stirred for 2 h at 0º C, warmed to rt and stirred for 4 h. The mixture was then dilueted with CH2Cl2
(9 mL), filtered through Celite®, and concentrated. The resulting crude residue was purified by flash
chromatography (silica gel, CH2Cl2/EtOAc/MeOH 15/7/1) to give pure nitrone 13 (635 mg, 50%). IR
1
(film)  (cm-1) 3084, 2993, 2980, 1579; H-NMR (400 MHz) δ = 6.82 (q, J= 1.5 Hz, 1H), 5.24 (d,
J = 6.2, 1H), 4.86 (ddd, J= 6.2, 5.1 and 1.5 Hz, 1H), 4.07–3.99 (m, 2H), 1.40 (s, 3H), 1.31 (s, 3H);
HRMS (ESI) C7H12NO3 requires (M+H+) 158.1785; found 158.0822; []D20 = -26.9 (c 1.1, CH2Cl2).
4.7. Preparation of (2R,3S,4R)-2-Phenylsulfonylmethyl-1-hydroxy-3,4-isopropylidenedioxypyrrolidine
(14)
To a stirred solution of MeSO2Ph (520 mg, 2.58 mmol) in THF (4.7 mL) was added slowly n-BuLi
(1. 9 mL, 2.58 mmol) and the mixture was reacted at 0 ºC for 10 min. Afterwards, the reaction mixture
was cooled to -78 ºC and stirred for 10 min at this temperature. Then, it was added into a solution of
nitrone 13 (320 mg, 2.03 mmol) in THF (6.7 mL) and the mixture was stirred at -78 ºC for 30 min and
then for 2 h allowing to warm to rt. The reaction was quenched with saturated aqueous solution of

Molecules 2010, 15
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NH4Cl and the product 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, n-hexane/EtOAc 1:1) to obtain hydroxylamine 14 (300 mg, 48%).
IR (film)  (cm-1) 3428, 3207, 2987, 2925, 2856, 1581, 1442 , 1385, 1295, 1131, 1074, 845; 1H-NMR
(400 MHz) δ = 7.96 (m, 2H), 7.67–7.53 (m, 3H), 6.25 (s, 1H), 4.75 (m, 1H), 4.62 (dd, J = 4.2 and
6.0 Hz, 1H), 3.69 (dd, J = 6.4 and 14.0 Hz, 1H), 3.44 (m, 1H), 3.37 (m, 1H), 3.25 (dd, J = 6.8 and 14.0
Hz, 1H), 3.12 (dd, J = 4.4 and 12.4 Hz, 1H), 1.43 (s, 3H), 1.27 (s, 3H); 13C-NMR (100 MHz)
δ = 139.4, 133.9, 129.3, 128.1, 113.7, 82.2, 77.2, 67.3, 62.3, 54.1, 26.7, 24.7; HRMS (ESI)
C14H19NO5S requires (M + Na) 336.0882; found 336.0877; []D20 = -20.8 (c 2.2, CHCl3).
4.8. Preparation of (2S,3S,4R)-2-Phenylsulfonylmethyl-3,4-isopropylidenedioxypyrrolidine (6)
Scheme 3, step c: A stirred solution of hydroxylamine 14 (50 mg, 0.16 mmol) in a 12:1 solution of
HCl/MeOH (1 mL) was hydrogenated in the presence of a catalytic amount of Pd (OH)2/C, at a
hydrogen pressure of 4 atm for 48 h. The catalyst was filtered through a pad of Celite,® washed with
MeOH and concentrated. The product was purified by flash chromatography (silica gel, n-
hexane/EtOAc 1:1) to provide pyrrolidine 6 (13 mg, 27%). IR (film)  (cm-1) 3000, 2936, 1447, 1381,
1
1308, 1148, 1086, 650 cm-1; H-NMR (400 MHz) δ = 7.93 (m, 2H), 7.69–7.50 (m, 3H), 4.67 (dd,
J = 4.0 and 5.3 Hz, 1H), 4.54 (dd, J = 4.0 and 5.3 Hz, 1H), 3.57 (dd, J = 5.0 and 14.0 Hz, 1H), 3.36
(dd, J = 7.0 and 14.0 Hz, 1H), 3.22 (m, 1H), 3.13 (d, J = 12.7 Hz, 1H), 2.69 (dd, J = 4.0 and 12.7 Hz,
1H), 2.20 (s, 1H), 1.41 (s, 3H) and 1.25 (s, 3H); 13C-NMR (100 MHz) δ = 139.7, 133.7, 129.2, 127.2,
111.1, 81.0, 80.8, 57.1, 55.9, 52.6, 25.7, 24.0; HRMS (ESI) C14H20NO4S requires (M+H+) 298.1113;
found 298.1128; []D20 = - 37.3 (c 0.5, CHCl3).
(Scheme 3, step d): A stirred solution of hydroxylamine 14 (66 mg, 0.21 mmol) in 1 mL of MeOH was
hydrogenated in the presence of a catalytic amount of Pd/C with a H2 balloon at room temperature for
24 h. The catalyst was filtered through a pad of Celite,® washed with MeOH and concentrated. The
product was purified by flash chromatography (silica gel, n-hexane/EtOAc 1:1) to provide pyrrolidine
6 (24 mg, 39%).
4.9. Preparation of (2R,3S,4R)-2-Phenylsulfonylmethyl-1-hydroxy-3,4-isopropylidenedioxypyrrolidine
(15)
(Scheme 3, step e): To a stirred solution of hydroxylamine 14 (32.1 mg, 0.10 mmol) in a 2:1
solution of EtOH /saturated aqueous NH4Cl (18.5 mL), powdered indium (14 g, 0.12 mmol) was added
and the mixture was heated under reflux. After 24 h the reaction mixture was cooled, filtered through
Celite,® and concentrated under reduced pressure. A saturated aqueous Na2CO3 solution (5 mL) was
then added, and the product 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 1:1) to obtain hydroxylamine 15 (28.8 mg, 92%).
IR (film)  (cm-1) 3448, 2985, 2933, 2854, 1448, 1383, 1306, 1085, 856; 1H-NMR (400 MHz) δ = 7.97
(m, 2H), 7.67–7.52 (m, 3H), 6.27 (s, 1H), 4.60 (m, 2H), 3.70 (dd, J = 8.4 and 14.o Hz, 1H), 3.50–3.38
(m, 2H), 3.05 (m, 1H), 2.70 (dd, J = 4.4 and 11.0 Hz, 1H), 1.37 (s, 3H), 1.22 (s, 3H); 13C-NMR

Molecules 2010, 15
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(100 MHz) δ = 139.9, 134.1, 129.5, 128.3, 111.1, 77.2, 76.4, 65.9, 62.2, 54.5, 25.9, 24.4; HRMS (ESI)
C14H19NO5S requires (M + Na) 336.0882; found 336.0895; []D20 = -10.4 (c 1.3, CHCl3).
Scheme 3, step f: To a stirred solution of hydroxylamine 14 (69 mg, 0.22 mmol) in a solution of
MeOH/NH4Clsat (3.4 /5 mL), powdered Zn (29 mg, 0.44 mmol) was added at 20 ºC and the mixture
was stirred for 6h. The solvent was evaporated under vacuum and a saturated aqueous solution of
Na2CO3 (1.5 mL) was added. The mixture was extracted with EtOAc (3 × 15 mL) and the combined
organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated. The resulting crude
residue was purified by flash chromatography (silica gel, n-hexane/EtOAc 1:1) to obtain
hydroxylamine 15 (34 mg, 50%).
4.10. Preparation of (2R,3S,4R)-2-Phenylsulfonylmethyl-3,4-isopropylidenedioxypyrrolidine (12)
Scheme 3, step g, Table 1, entry 8, as example: To a stirred solution of hydroxylamine 14 (852 mg,
2.58 mmol), in methanol (37 mL), a saturated solution of NH4Cl (56 mL), powdered Zn (712 mg,
10.9 mmol) and a catalytic amount of indium dust (20 mg) were added at 20 ºC. The mixture was
stirred for 6h. The solvent was evaporated under vacuum and a saturated aqueous solution of Na2CO3
(5 mL) was added. The mixture 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, n-hexane/EtOAc 1:1) to obtain pyrrolidines 12 (248 mg,
35%) and 6 (13 mg, 2%).
4.11. (2S,1´R)-2-[1´-Phenyl-2´-nitroethyl]-cyclohexanone
To a suspension of catalyst 6 (10 mg, 15%) and 0.438 mL (4.40 mmol) of cyclohexanone in 3.5 mL
of DMSO was added 33 mg (0.22 mmol) of trans- nitrostyrene. The resulting mixture was allowed to
stir at room temperature for 16 h, whereupon the reaction was quenched with saturated aqueous
ammonium chloride (2 mL) and the aqueous layers were extracted with ethyl acetate. The combined
organic layers were dried over Na2SO4, filtered and evaporated in vacuo and the resulting residue was
purified by flash column chromatography using (hexane/EtOAc, 9/1) to give the title compound, as a
white solid (11mg, 20%). 1H-NMR (400 MHz) δ 7.34–7.16 (m, 5H, Ph), 4.93 (dd, J = 12.5 and 4.5 Hz,
1H, CH2), 4.60 (dd, J = 12.5 and 9.9 Hz, 1H, CH2), 3.76 (m, 1H, CH), 2.69 (m, 1H, CH), 2.50–1.52
(m, 8H, 4CH2). The absolute configuration was established by comparison with reported HPLC data
[21]. HPLC: Daicel Chiralpak AD; n-hexane/iPrOH: 0.45 mL min-1; max230 nm: tR (minor)-10.8 min;
tR (major)-13.1 min.
4.12. (2R,1´S)-2-[1´-Phenyl-2´-nitroethyl]-cyclohexanone
To a suspension of catalyst 12 (10 mg, 15%) and 0.438 mL (4.40 mmol) of cyclohexanone in
3.5 mL of CHCl3 was added 33 mg (0.22 mmol) of trans- nitrostyrene. The resulting mixture was
allowed to stir at room temperature for 16 h, whereupon the reaction was quenched with saturated
aqueous ammonium chloride (2 mL) and the aqueous layers were extracted with ethyl acetate. The
combined organic layers were dried over Na2SO4, filtered and evaporated in vacuo and the resulting
residue was purified by flash column chromatography using (n-hexane/EtOAc, 9/1) to give the title

Molecules 2010, 15
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compound, as a white solid (22mg, 35%). The absolute configuration was established by comparison
with reported HPLC data [21]. HPLC: Daicel Chiralpak AD; n-hexane/iPrOH: 0.45 mL min-1; max230
nm: tR (major)-10.5 min; tR (minor)-12.9 min.
Acknowledgements
Financial support for this work came from FSE, Spanish MEC (CTQ2006-08296/BQU, CTQ2009-
11172/BQU) and Junta de Castilla y León (Spain) GR-178, (SA001A09). The authors thank also A. M.
Lithgow for the NMR spectra and César Raposo for the mass spectra. M.G.N. is grateful for a FPU
doctoral fellowship of the Spanish MEC and M.F.F. to Junta de Castilla y León.
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