Copper(I)-catalyzed enantioselective 1,3-dipolar cycloaddition of azomethine ylides with vinyl sulfones

Article abstract of DOI:10.1055/s-2007-965926

The combination of copper(I)-Taniaphos (5 mol%) is an efficient Lewis acid catalyst for the promotion of the asymmetric 1,3-dipolar cycloaddition of azomethine ylides to aryl vinyl sulfones, providing 3-sulfonylpyrrolidines in good yields and with nearly

Full text of DOI:10.1055/s-2007-965926

950
PRACTICAL SYNTHETIC PROCEDURES
Copper(I)-Catalyzed Enantioselective 1,3-Dipolar Cycloaddition of
Azomethine Ylides with Vinyl Sulfones
E
nantioselective
o
1,3-Dipolar
m
Cycloaddition of
A
á
z
omethine
s
Y
lides with
V
in
L
yl Sulfones lamas, Ramón Gómez Arrayás, Juan Carlos Carretero*
Departamento de Química Orgánica, Universidad Autónoma de Madrid, Cantoblanco,
28049 Madrid, Spain
Fax +34(914)973966; E-mail: juancarlos.carretero@uam.es
PSP
Received 16 November 2006
No79
Abstract: The combination of copper(I)–Taniaphos (5 mol%) is an efficient Lewis acid catalyst for the promotion of the asymmetric 1,3-
dipolar cycloaddition of azomethine ylides to aryl vinyl sulfones, providing 3-sulfonylpyrrolidines in good yields and with nearly complete
exo-selectivity and good enantiocontrol (typically 65–85% ee). The transformation of the cycloadducts into cis-2,5-disubstituted pyrro-
lidines of high enantiopurity (>99% ee) has been accomplished after simple recrystallization followed by N-methylation and subsequent
reductive desulfonylation.
Key words: copper, azomethine ylides, 1,3-dipolar cycloaddition, ferrocene ligand, asymmetric catalysis, vinyl sulfones, pyrrolidines
SO2Ph
R2
Cu(MeCN)4ClO4 (5 mol%)
1. recryst.
R2
SO2Ph
2. NaH, MeI
Taniaphos (5 mol%)
MeO2C
N
R1
R1
Ph
MeO2C
MeO2C
N
N
3. Na(Hg)
Na2HPO4
Me
H
Et3N, toluene, 0 °C
>99% ee
38–92% yield
41–85% ee
(R1 = Ph, R2 = H)
Ph2P
NMe2
PPh2
Fe
Taniaphos
Scheme 1
P,P, P,N, and P,S). Despite the high levels of asymmetric
induction achieved, a drawback of these procedures is that
Introduction
The substituted pyrrolidine ring is a key structural unit they have generally been applied to a narrow range of ac-
that is found in a diverse array of biologically interesting tivated alkenes, typically commercially available carbon-
natural products, as well as being a highly valuable syn- yl dipolarophiles such as acrylates, maleates, fumarates,
thetic building block.1 In addition to this, the last decade and maleimides.
has witnessed an explosive growth of applications of pro-
Unlike these conjugated monoactivated or diactivated
line derivatives as amine catalysts in the field of asymmet-
alkenes, which introduce at least three or four carbon at-
ric organocatalysis.2 Among the current available
oms into the structure of the cycloadducts, vinyl sulfones
methods for the construction of enantioenriched function-
have been scarcely studied in this catalytic asymmetric
alized pyrrolidines, the catalytic asymmetric 1,3-dipolar
transformation. In addition to the highly electron-defi-
cycloaddition of azomethine ylides with activated alkenes
cient character of the C=C bond, the great chemical versa-
is one of the most powerful and convergent strategies.3
tility of the sulfonyl group9 and the high regiocontrol
Since the first reports, described independently by Jør-
typically associated with sulfonyl-substituted dipolaro-
gensen et al.4 and Zhang et al.5a in 2002, this area of re-
philes,9a,10 makes them a very attractive class of substrates
search has received increased attention. As a result, a
to study. Additionally, well-established general desulfo-
number of efficient procedures have been published that
nylation protocols11 for the resulting cycloadducts should
use organometallic Lewis acids based on the combination
allow the conversion of the vinyl sulfone moiety into a
of zinc(II),4,6 silver(I),5 copper(I),7 and copper(II)8 salts
synthetic equivalent of ethene, which is not suitable for
with bidentate ligands of varied coordination modes (N,N,
this type of reaction. Prior to our work, this reaction had
been reported only as an example of a moderately enan-
SYNTHESIS 2007, No. 6, pp 0950–0956
Advanced online publication: 08.02.2007
DOI: 10.1055/s-2007-965926; Art ID: Z23806SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
7
tioselective cycloaddition of a vinyl sulfone with an azo-
methine (70% ee) using an stoichiometric amount of
silver(I) trifluoromethanesulfonate and a chiralP,P-ligand.12

PRACTICAL SYNTHETIC PROCEDURES
1,3-Dipolar Cycloaddition of Azomethine Ylides
951
Here we report an efficient catalytic asymmetric synthesis Having established the combination copper(I)–Taniaphos
of highly functionalized pyrrolidines based on the combi- as the optimal catalyst system, the influence of the nature
nation of copper(I)–Taniaphos as chiral Lewis acid sys- of the arylsulfonyl substituent on the reactivity and enan-
tem.13 This new protocol features nearly complete exo- tioselectivity was next investigated. A representative set
selectivity and good enantioselectivity (typically 65–85% of vinyl sulfones, 2b–e,16 of varied steric and electronic
ee), which can be enhanced by simple recrystallization.
properties, were surveyed in the reaction with 1a under
the optimized conditions [copper(I)–Taniaphos (10
mol%)]. The results are given in Table 1 (entries 2–5).
Scope and Limitations
Except for the electronically rich 2-(dimethylamino)phe-
nyl sulfone 2e17 (Table 1, entry 5), which led to the recov-
ery of the starting material unaltered, in all cases a single
diastereomer 3 was detected and isolated in good yields
(71–87%), the configuration of which was assigned by
Based on previous results obtained in our research group
for the asymmetric 1,3-dipolar cycloaddition of azometh-
ine ylides with a,b-unsaturated carbonyl compounds and
nitriles,7a an extensive ligand screening13 was initially per-
formed using the model reaction of methyl N-ben-
zylideneglycinate (1a) with phenyl vinyl sulfone (2a) in
the presence of catalytic amounts of tetrakis(acetoni-
trile)copper(I) perchlorate14 (10 mol%), chiral ligand (10
mol%), and triethylamine as base (18 mol%) in toluene at
0 °C. Among the tested ligands,15 Taniaphos provided the
highest level of enantiocontrol and excellent reactivity, af-
fording the exo-cycloadduct 3a as the sole product in 87%
isolated yield and 83% ee (Table 1, entry 1). Interestingly,
a simple recrystallization of this sample (CH2Cl2–hexane,
–20 °C) afforded 3a in enantiomerically pure form (>99%
ee). The relative and absolute (2R,4S,5R)-configuration of
3a was unequivocally established by X-ray diffraction
analysis.13 A decrease of the catalyst loading from 10 to 5
mol% did not affect the enantioselectivity of the reaction
(83% ee in both cases), resulting only in lower reactivity
(24 h instead of 4 h at 0 °C). This protocol worked equally
well scaling up the reaction by a factor of 15, highlighting
the synthetic value of the method from a practical point of
view. Thus, results obtained starting from 3 mmol of both
1a and 2a (80% yield, 83% ee) were comparable to those
previously obtained on a 0.2 mmol scale (87% yield, 83%
ee).
1
chemical analogy with 3a and the similarity of their H
NMR data. However, in comparison with 2a, none of the
substrates 2b–e produced an enhancement in the enantio-
selectivity, only the 2-thienyl vinyl sulfone (2c) provided
comparable results (entry 3) to the parent 2a. The poten-
tially coordinating 2-pyridyl derivative 2d18 gave the low-
est enantiocontrol (50% ee, Table 1, entry 4).
Disappointingly a major limitation was found when this
procedure was extended to b-substituted vinyl sufones,
which shows that the reaction has a high sensitivity to
steric effects. For example, the reaction of phenyl prop-1-
enyl sulfone (4a) with 1a under the optimized conditions,
resulted in less than 10% conversion after 24 hours
(Scheme 2). As an exception, the electronically activated
vinyl sulfone 4b19 with a trifluoromethyl substituent in the
b-position showed enhanced reactivity, producing with
complete regio- and exo-selectivity the pyrrolidine 5b in
74% yield, albeit with low enantioselectivity (20% ee,
Scheme 2). The high reactivity associated with this partic-
ular substrate allowed to the reaction temperature to be
lowered to –78 °C, which gave a significant increase in
the asymmetric induction to 68% ee, although the yield
was negatively affected (40%). Unexpectedly, the allenyl
phenyl sulfone (6) was recovered unaltered after 24 hours
of reaction with 1a at 0 °C under the optimized conditions.
Table 1 Influence of the Arylsulfonyl Group
SO2Ar
SO2Ar
[Cu(MeCN)4]ClO4/Taniaphos (10 mol%)
Et3N, toluene, 0 °C
+
Ph
E
N
Ph
E
N
H
3a–e
1a (E = CO2Me)
2a–e
Entry
Sulfone
Ar
Time (h)
Product
3a
Yielda (%)
eeb (%)
83
1
2
3
4
5
2a
2b
2c
2d
2e
Ph
4
24
3
87
71
87
72
2-naphthyl
2-thienyl
2-pyridyl
3b
75c
3c
83
3
3d
50
d
d
2-(Me2N)C6H4
24
3e
–
–
a Isolated yield after chromatography.
b Determined by HPLC (Chiralpak AS-H).
c Determined by HPLC from its N-methyl derivative.
d Starting material was recovered unchanged.
Synthesis 2007, No. 6, 950–956 © Thieme Stuttgart · New York

952
T. Llamas et al.
PRACTICAL SYNTHETIC PROCEDURES
[Cu(MeCN)4]ClO4/
Taniaphos
(5 mol%)
cases, providing in good yields (71–92%) a single pyrro-
lidine 7a–i with enantioselectivities depending on the par-
ticular aryl group. The para- and meta-substituted
aromatic rings gave enantioselectivities very similar to
that of the model reaction (82–85% ee), whereas the reac-
tion with bulkier imines, such as the 2-naphthyl imine 1g
(entry 6) and the 2-tolyl imine 1h (entry 7), was signifi-
cantly less enantioselective (65% and 41% ee, respective-
ly). Aliphatic imines (entry 8) and the a-substituted 1,3-
dipole precursor 1j (entry 9) were also suitable substrates,
the latter giving rise to the pyrrolidine 7i with a stereogen-
ic quaternary center at C5 (80% ee). However, in this case
the chemical yield was much lower, most likely due to the
steric effects introduced by the a-methyl substituent.
SO2Ar
Ph
R
R
1a
+
SO2Ph
4a,b
MeO2C
Et3N, toluene, 24 h
N
H
5a,b
Product
R
Substrate
T (°C)
0
Yield (%) ee (%)
b
5aa
5b
–
–
4a
4b
4b
Me
0
74
40
20
68
CF3
CF3
–78
5b
a Using Cu(I)-Taniaphos (10 mol%).
b No reaction.
Cu(I)-Taniaphos
(10 mol%)
SO2Ph
+
1a
•
Et3N, toluene
Finally, to illustrate some synthetic possibilities of the
enantioenriched 3-sulfonylated pyrrolidine products, we
explored some desulfonylation reactions10 (Scheme 3).
After N-methylation with iodomethane (NaH, DMF, r.t.)
of a recrystallized sample of 3a (>99% ee) and further re-
ductive desulfonylation of the resulting pyrrolidine 8 with
sodium amalgam, the enantiomerically pure cis-1,5-di-
substituted pyrrolidine 9 was isolated in 61% yield.20 It
must be noted that, in the sequence 1,3-dipolar cycloaddi-
tion/desulfonylation the phenyl vinyl sulfone acts as a
synthetic equivalent of ethene, an unactivated alkene un-
suitable the reaction with azomethine ylides.
6
Scheme 2
Next, to establish the scope of this 1,3-dipolar cycloaddi-
tion with regard to the dipole component, a variety of sub-
stituted azomethine ylide precursors were studied in the
reaction with phenyl vinyl sulfone (2a) using copper(I)–
Taniaphos (5 mol%). The results are collected in Table 2.
In contrast to the limited substitution pattern suitable at
the dipolarophile, this cycloaddition procedure proved to
be general with regard to the substitution at the iminic car-
bon of the dipole. Both electronically rich and electroni-
cally poor arenes, as well as substitution at para, meta,
and ortho positions, were well tolerated (Table 2, entries
1–7). The reaction was highly exo-stereoselective in all
In summary, the combination copper(I)–Taniaphos (5
mol%) as the catalyst system has led to the development
of a general and efficient exo-selective protocol for the
catalytic enantioselective 1,3-dipolar cycloaddition of vi-
Table 2 Scope with Regard to the Dipole Component
SO2Ph
R2
SO2Ph
R2
E
[Cu(MeCN)4]ClO4/Taniaphos (5 mol%)
Et3N, toluene, 0 °C
+
E
N
R1
R1
N
H
7a–i
1b–j
2a
Entry
Azomethine ylide R1
R2
H
Product
7a
Yielda (%)
eeb (%)
82
1
2c
3
4
5
6
7
8
9
1b
1c
1d
1e
1f
4-FC6H4
91
71
83
71
74
92
71
50
45d
4-MeOC6H4
3-FC6H4
3-MeOC6H4
3-Tol
H
7b
84
H
7c
85c
85
H
7d
H
7e
79c
41
1g
1h
1i
2-Tol
H
7f
2-naphthyl
Cy
H
7g
65
H
7h
69
1j
Ph
Me
7i
80
a Isolated yield after chromatographic purification.
b Determined by HPLC (Chiralpak AS-H).
c Determined by HPLC from its N-methyl derivative.
d Other isomer was isolated in 4% yield (configuration not determined).
Synthesis 2007, No. 6, 950–956 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
1,3-Dipolar Cycloaddition of Azomethine Ylides
953
13C NMR (75 MHz): d = 173.2, 141.0, 138.0, 133.8, 129.2, 128.5,
SO2Ph
Na(Hg)
128.5, 127.8, 126.8, 70.1, 62.7, 59.3, 52.3, 31.1.
NaH, MeI
Na2HPO4
3a
MS (EI): m/z (%) = 346.0 (M+ + H, 100).
Ph
MeO2C
DMF, r.t.
92%
MeOH–THF, r.t.
N
Me
HRMS (EI): m/z [M + H]+ calcd for C18H20NO4S: 346.1121; found:
346.1115.
8
The remaining cycloadditions (products 5b, 7a–i) were carried out
according to the typical procedure, but at 0.2 mmol substrate scale.
MeO2C
Ph
+
Ph
MeO2C
N
Me
NHMe
Methyl (2R,3S,4S,5R)-5-Phenyl-4-(phenylsulfonyl)-3-(trifluo-
romethyl)pyrrolidine-2-carboxylate (5b)
9: 61%, >99% ee
10: 28%
The typical procedure was followed, except for cooling the mixture
to –78 °C before the addition of phenyl 3,3,3-trifluoroprop-1-enyl
sulfone. Colorless oil; yield: 40%; 68% ee; HPLC (Daicel Chiral-
pak AS-H, i-PrOH–hexane, 40:60, flow rate 0.8 mL/min, 210 nm):
tR = 9.8 min (2R,3S,4S,5R)-isomer and 13.8 min (2S,3R,4R,5S)-iso-
mer.
Scheme 3
nyl sulfones with azomethine ylides. The resulting 3-sul-
fonylpyrrolidines can be transformed into cis-2,5-
disubstituted pyrrolidines of high enantiopurity after re-
ductive desulfonylation.
[a]D20 –19 (c 0.3, CHCl3).
1H NMR (300 MHz): d = 7.77–7.71 (m, 2 H), 7.56–7.49 (m, 1 H),
7.44–7.36 (m, 2 H), 7.20–7.09 (m, 5 H), 4.57 (dd, J = 9.8, 7.1 Hz, 1
H), 4.14 (dd, J = 11.2, 7.1 Hz, 1 H), 3.79–3.69 (m, 4 H), 3.61–3.51
(m, 1 H), 2.57 (t, 11.0 Hz, 1 H).
Procedures
Described herein is the typical procedure for the 1,3-dipolar cy-
cloaddition of phenyl vinyl sulfone with the glycine or alanine me-
thyl ester Schiff bases 1a–j depicted in Table 1 and Table 2. The
procedure for the transformation of the 3-sulfonylated cycloadduct
into the corresponding cis-2,5-disubstituted pyrrolidine is also de-
scribed in detail.
13C NMR (75 MHz): d = 168.3, 138.2, 137.1, 134.4, 129.4, 128.8,
128.5, 128.4, 127.0, 125.5 (q, J = 282.2 Hz), 70.7, 63.1, 61.4, 52.5,
49.4 (q, J = 26.4 Hz).
Methyl (2R,4S,5R)-5-(4-Fluorophenyl)-4-(phenylsulfonyl)pyr-
rolidine-2-carboxylate (7a)
All the reactions were carried out in anhydrous solvents and under
argon atmosphere. Melting points were taken in open-end capillary
tubes. NMR spectra were recorded at 300 MHz (1H), 75 MHz (13C),
at r.t. in CDCl3 [calibrated at d = 7.26 (1H), and d = 77.0 (13C)]. Op-
tical rotation was obtained on a Perkin-Elmer 241 polarimeter. MS
spectra were recorded on a VG AutoSpec mass spectrometer. HPLC
experiments were conducted using Daicel Chiralpak AS-H column.
Flash column chromatography was performed using silica gel
Merck-60 (230–400 mesh). Methyl (E)-N-benzylideneglycinate
(1a) and phenyl vinyl sulfone (2a) were purchased from commer-
cial sources. The known azomethine ylide precursors 1a–j were
prepared according to literature procedures.21
Yellow solid; yield: 91%; mp 75–76 °C; 82% ee; HPLC (Daicel
Chiralpak AS-H, i-PrOH–hexane, 40:60, flow rate 0.8 mL/min, 210
nm): tR = 32.4 min (2R,4S,5R)-isomer and 49.0 min (2S,4R,5S)-iso-
mer.
[a]D20 –22 (c 0.50, CHCl3).
1H NMR (300 MHz): d = 7.85–7.75 (m, 2 H), 7.62 (t, J = 7.4 Hz, 1
H), 7.54–7.45 (m, 2 H), 7.26–7.15 (m, 2 H), 6.90 (t, J = 8.6 Hz, 1
H), 4.73 (d, J = 5.8 Hz, 1 H), 4.16 (t, J = 7.9 Hz, 1 H), 3.76 (s, 3 H),
3.60 (m, 1 H), 2.76 (ddd, J = 10.3, 5.6, 4.9 Hz, 1 H), 2.55 (br s, 1
H), 2.34 (dt, J = 14.0, 8.8 Hz, 1 H).
13C NMR (75 MHz): d = 173.2, 162.1 (d, JF-C = 246.4 Hz), 137.8,
136.8 (d, JF-C = 2.7 Hz), 133.9, 129.3, 128.6 (d, JF-C = 8.2 Hz),
128.4, 115.3 (d, JF-C = 21.4 Hz), 70.0, 61.9, 59.1, 52.3, 30.9.
Methyl (2R,4S,5R)-5-Phenyl-4-(phenylsulfonyl)pyrrolidine-2-
carboxylate (3a); Typical Procedure
MS (FAB): m/z (%) = 364.1 (M+ + H, 100).
A soln of Taniaphos ligand (103.1 mg, 0.15 mmol) and
[Cu(MeCN)4]ClO4 (48.0 mg, 0.15 mmol) in toluene (7 mL) was
stirred at r.t. for 30 min. Then a soln of methyl N-benzylideneglyci-
nate (1a, 534.0 mg, 3.0 mmol) in toluene (2 mL) and Et3N (75.0 mL,
0.54 mmol) were added successively. The mixture was cooled to 0
°C and a soln of phenyl vinyl sulfone (2a, 504 mg, 3.0 mmol) in tol-
uene (2 mL) was added. The resulting soln was stirred at 0 °C for 24
h, and then it was filtered through Celite and concentrated. The res-
idue was purified by flash chromatography (n-hexane–EtOAc, 3:1)
to afford 3a as a white solid; yield: 865 mg (80%); mp 101–102 °C;
83% ee; HPLC (Daicel Chiralpak AS-H, i-PrOH–hexane, 40:60,
flow rate 0.8 mL/min, 210 nm): tR = 28.7 min (2R,4S,5R)-isomer
and 32.3 min (2S,4R,5S)-isomer.
Methyl (2R,4S,5R)-5-(4-Methoxyphenyl)-4-(phenylsulfo-
nyl)pyrrolidine-2-carboxylate (7b)
Yellow oil; yield: 71%; 84% ee; HPLC (Daicel Chiralpak AS-H, i-
PrOH–hexane, 40:60, flow rate 0.8 mL/min, 210 nm): tR = 47.4 min
(2R,4S,5R)-isomer and 60.5 min (2S,4R,5S)-isomer.
[a]D20 –17 (c 0.40, CHCl3).
1H NMR (300 MHz): d = 7.85–7.77 (m, 2 H), 7.63–7.54 (m, 1 H),
7.52–7.40 (m, 2 H), 7.13 (d, J = 8.7 Hz, 2 H), 6.74 (d, J = 8.7 Hz, 2
H), 4.66 (d, J = 6.1 Hz, 1 H), 4.13 (t, J = 7.9 Hz, 1 H), 3.84–3.67 (m,
6 H), 3.66–3.57 (m, 1 H), 2.70 (ddd, J = 13.9, 7.6, 4.8 Hz, 1 H), 2.49
(br s, 1 H), 2.35 (dt, J = 13.8, 8.9 Hz, 1 H).
13C NMR (75 MHz): d = 173.3, 159.1, 138.0, 133.7, 132.9, 129.2,
128.4, 127.9, 113.9, 69.9, 62.3, 59.1, 55.2, 52.3, 31.2.
[a]D20 –14 (c 0.50, CHCl3).
Recrystallization (CH2Cl2–n-hexane, –20 °C) afforded the
(2R,4S,5R)-isomer; >99% ee.
[a]D20 –21 (c 0.50, CHCl3).
1H NMR (300 MHz): d = 7.85–7.77 (m, 2 H), 7.63–7.56 (m, 1 H),
7.52–7.44 (m, 2 H), 7.21 (br s, 5 H), 4.73 (d, J = 5.4 Hz, 1 H), 4.18
(t, J = 7.9 Hz, 1 H), 3.77 (s, 3 H), 3.66 (m, 1 H), 2.70 (ddd, J = 14.0,
7.5, 4.4 Hz, 1 H), 2.56 (br s, 1 H), 2.36 (dt, J = 14.0, 8.9 Hz, 1 H).
MS (FAB): m/z (%) = 376.1 (M+ + H, 100).
HRMS (EI): m/z [M + H]+ calcd for C19H22NO5S: 376.1222; found:
376.1219.
Methyl (2R,4S,5R)-5-(3-Fluorophenyl)-4-(phenylsulfonyl)pyr-
rolidine-2-carboxylate (7c)
Orange oil; yield: 83%; 85% ee.
Synthesis 2007, No. 6, 950–956 © Thieme Stuttgart · New York

954
T. Llamas et al.
PRACTICAL SYNTHETIC PROCEDURES
MS (FAB): m/z (%) = 360.0 (M+ + H, 100).
[a]D20 +61 (c 0.30, CHCl3).
1H NMR (300 MHz): d = 7.89–7.73 (m, 2 H), 7.67–7.59 (m, 1 H),
7.55–7.47 (m, 2 H), 7.21–7.18 (m, 1 H), 7.05–6.94 (m, 2 H), 6.92–
6.87 (m, 1 H), 4.77 (d, J = 5.4 Hz, 1 H), 4.20 (t, J = 7.9 Hz, 1 H),
3.76 (s, 3 H), 3.65–3.56 (m, 1 H), 2.76 (ddd, J = 14.0, 7.4, 4.1 Hz,
1 H), 2.45–2.17 (m, 2 H).
HRMS (EI): m/z [M + H]+ calcd for C19H22NO4S: 360.1264; found:
360.1269.
Methyl (2R,4S,5R)-5-(2-Naphthyl)-4-(phenylsulfonyl)pyrroli-
dine-2-carboxylate (7g)
White solid; yield: 71%; mp 147–148 °C; 65% ee; HPLC (Daicel
Chiralpak AS-H, i-PrOH–hexane 40:60, flow rate 0.8 mL/min, 210
nm): tR = 46.3 min (2S,4R,5S)-isomer and 50.4 min (2R,4S,5R)-iso-
mer.
13C NMR (75 MHz): d = 173.1, 162.8 (d, JF–C = 246.4 Hz), 144.0 (d,
JF-C = 7.1 Hz), 137.8, 134.0, 130.1 (d, JF-C = 8.2 Hz), 129.6, 128.5,
122.4 (d, JF-C = 2.7 Hz), 114.7 (d, JF-C = 21.4 Hz), 113.8 (d, JF-C
=
22.5 Hz), 70.2, 61.9, 59.2, 52.4, 30.7.
MS (FAB): m/z (%) = 364.1 (M+ + H, 100).
[a]D20 –46 (c 0.50, CHCl3).
1H NMR (300 MHz): d = 7.85–7.65 (m, 5 H), 7.61 (br s, 1 H), 7.54–
7.32 (m, 6 H), 4.90 (d, J = 5.5 Hz, 1 H), 4.25 (t, J = 7.9 Hz, 1 H),
3.82–3.69 (m, 4 H), 2.83–2.53 (m, 2 H), 2.43 (dt, J = 14.0, 8.9 Hz,
1 H). 13C NMR (75 MHz): d = 173.2, 138.3, 137.9, 133.8, 133.0,
132.9, 129.2, 128.5, 128.5, 127.9, 127.5, 126.2, 126.1, 126.0, 124.2,
70.0, 62.8, 59.3, 52.3, 30.9.
MS (FAB): m/z (%) = 396.2 (M+ + H, 100).
HRMS (EI): m/z [M + H]+ calcd for C22H22NO4S: 396.1272; found:
HRMS (EI): m/z [M + H]+ calcd for C18H19FNO4S: 364.1028;
found: 364.1019.
Methyl (2R,4S,5R)-5-(3-Methoxyphenyl)-4-(phenylsulfo-
nyl)pyrrolidine-2-carboxylate (7d)
Yellow oil; yield: 71%; 85% ee; HPLC (Daicel Chiralpak AS-H, i-
PrOH–hexane, 40:60, flow rate 0.8 mL/min, 210 nm): tR = 59.4 min
(2S,4R,5S)-isomer and 67.5 min (2R,4S,5R)-isomer.
[a]D20 –16 (c 0.85, CHCl3).
396.1269.
1H NMR (300 MHz): d = 7.87–7.75 (m, 2 H), 7.65–7.55 (m, 1 H),
7.54–7.41 (m, 2 H), 7.16–7.08 (m, 1 H), 6.82–6.70 (m, 3 H), 4.72
(d, J = 5.3 Hz, 1 H), 4.19 (t, J = 7.9 Hz, 1 H), 3.78–3.71 (m, 5 H),
3.69–3.59 (m, 1 H), 2.69 (ddd, J = 13.9, 7.4, 4.8 Hz, 1 H), 2.49 (br
s, 1 H), 2.45–2.27 (m, 2 H).
13C NMR (75 MHz): d = 173.3, 159.7, 142.9, 137.9, 133.8, 129.6,
129.2, 128.5, 118.8, 113.4, 112.3, 70.3, 62.6, 59.4, 55.1, 52.3, 30.9.
Methyl (2R,4S,5R)-5-Cyclohexyl-4-(phenylsulfonyl)pyrroli-
dine-2-carboxylate (7h)
Colorless oil; yield: 50%; 69% ee; HPLC (Daicel Chiralpak AS-H,
i-PrOH–hexane, 40:60, flow rate 0.8 mL/min, 210 nm): tR = 22.7
min (2R,4S,5R)-isomer and 25.3 min (2S,4R,5S)-isomer.
[a]D20 +3 (c 0.31, CHCl3).
1H NMR (300 MHz): d = 7.95–7.85 (m, 2 H), 7.72–7.54 (m, 3 H),
3.99 (dd, J = 9.6, 7.1 Hz, 1 H), 3.71 (s, 3 H), 3.57–3.39 (m, 2 H),
2.50 (ddd, J = 14.1, 6.9, 2.5 Hz, 1 H), 2.20–1.96 (m, 2 H), 1.77–1.54
(m, 5 H), 1.32–0.81 (m, 6 H).
MS (FAB): m/z (%) = 376.0 (M+ + H, 100).
HRMS (EI): m/z [M + H]+ calcd for C19H22NO5S: 376.1232; found:
376.1219.
13C NMR (75 MHz): d = 173.4, 138.2, 133.9, 129.4, 128.7, 66.0,
Methyl (2R,4S,5R)-4-(Phenylsulfonyl)-5-(3-tolyl)pyrrolidine-2-
carboxylate (7e)
White solid; yield: 74%; 79% ee; mp 93–94 °C.
63.9, 59.3, 52.2, 42.1, 31.7, 30.3, 28.2, 26.2, 26.1, 25.9.
MS (FAB): m/z (%) = 352.0 (M+ + H, 100).
[a]D20 –19 (c 0.27, CHCl3).
HRMS (EI): m/z [M + H]+ calcd for C18H26NO4S: 352.1584; found:
352.1583.
1H NMR (300 MHz): d = 7.87–7.75 (m, 2 H), 7.63–7.54 (m, 1 H),
7.51–7.42 (m, 2 H), 7.15–7.05 (m, 1 H), 7.04–6.95 (m, 2 H), 6.94–
6.87 (m, 1 H), 4.65 (d, J = 5.8 Hz, 1 H), 4.17 (t, J = 7.8 Hz, 1 H),
3.76 (s, 3 H), 3.71–3.61 (m, 1 H), 2.80–2.64 (m, 1 H), 2.62–2.30 (m,
2 H), 2.24 (s, 3 H).
13C NMR (75 MHz): d = 173.2, 140.6, 138.1, 138.0, 133.8, 129.1,
128.6, 128.5, 127.5, 123.8, 70.0, 62.9, 59.3, 52.3, 31.1, 21.3.
Methyl (2R,4S,5R)-2-Methyl-5-phenyl-4-(phenylsulfonyl)pyr-
rolidine-2-carboxylate (7i)
White solid; yield: 45%; mp 82–83 °C; 80% ee; HPLC (Daicel
Chiralpak AS-H, i-PrOH–hexane 40:60, flow rate 0.8 mL/min, 210
nm): tR = 16.6 min (2S,4R,5S)-isomer and 19.9 min (2R,4S,5R)-iso-
mer.
MS (FAB): m/z (%) = 360.0 (M+ + H, 100).
HRMS (EI): m/z [M + H]+ calcd for C19H22NO4S: 360.1263; found:
[a]D20 –5 (c 0.30, CHCl3).
1H NMR (300 MHz): d = 7.74–7.65 (m, 2 H), 7.53–7.44 (m, 1 H),
7.39–7.32 (m, 2 H), 7.15 (br s, 5 H), 4.66 (d, J = 8.3 Hz, 1 H), 3.87
(c, J = 8.6 Hz, 1 H), 3.71 (s, 3 H), 2.79 (dd, J = 13.7, 8.5 Hz, 1 H),
2.61 (br s, 1 H), 2.36 (dd, J = 13.6, 9.6 Hz, 1 H), 1.56 (s, 3 H).
13C NMR (75 MHz): d = 176.2, 139.8, 138.4, 133.6, 129.0, 128.5,
128.2, 127.8, 127.1, 69.8, 65.0, 63.3, 52.6, 38.5, 26.0.
360.1269.
Methyl (2R,4S,5R)-4-(Phenylsulfonyl)-5-(2-tolyl)pyrrolidine-2-
carboxylate (7f)
White solid; yield: 92%; mp 112–113 °C; 41% ee; HPLC (Daicel
Chiralpak AS-H, i-PrOH–hexane, 40:60, flow rate 0.8 mL/min, 210
nm): tR = 26.8 min (2S,4R,5S)-isomer and 30.1 min (2R,4S,5R)-iso-
mer.
MS (EI): m/z (%) = 360.1 (M+ + H, 100).
HRMS (EI): Calcd for C19H22NO4S: 360.1268; found: 360.1269.
[a]D20 –16 (c 0.50, CHCl3).
Methyl (2R,4S,5R)-1-Methyl-5-phenyl-4-(phenylsulfonyl)pyr-
rolidine-2-carboxylate (8); Typical Procedure
1H NMR (300 MHz): d = 7.84–7.74 (m, 2 H), 7.63–7.53 (m, 1 H),
7.51–7.41 (m, 2 H), 7.15–7.06 (m, 1 H), 7.05–6.96 (m, 2 H), 6.92
(br s, 1 H), 4.65 (d, J = 5.9 Hz, 1 H), 4.17 (t, J = 7.9 Hz, 1 H), 3.77
(s, 3 H), 3.72–3.70 (m, 1 H), 2.72 (ddd, J = 14.0, 7.1, 4.4 Hz, 1 H),
2.60–2.30 (m, 2 H), 2.24 (s, 3 H).
13C NMR (75 MHz): d = 173.2, 140.6, 138.1, 138.0, 133.8, 129.1,
129.2, 128.6, 128.5, 127.5, 123.8, 70.0, 62.9, 59.3, 52.3, 31.1, 21.3.
To a soln of 3a (500 mg, 1.4 mmol) and K2CO3 (796 mg, 5.8 mmol)
in DMF (14 mL) at r.t. was added MeI (130 mL, 2.1 mmol). The
mixture was stirred for 4 h and then Et2O (20 mL) was added. The
mixture was washed with H2O (3 × 10 mL) and the aqueous phase
was extracted with Et2O (20 mL). The combined organic phases
were dried (MgSO4) and concentrated. The residue was purified by
flash chromatography (n-hexane–EtOAc, 2:1) to afford 8 as a white
Synthesis 2007, No. 6, 950–956 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
1,3-Dipolar Cycloaddition of Azomethine Ylides
955
solid; yield: 477 mg (92%); mp 112–113 °C; 99% ee; HPLC (Daicel
Chiralpak AS-H, i-PrOH–hexane, 40:60, flow rate 0.8 mL/min, 210
nm): tR = 12.2 min (2R,4S,5R)-isomer and 15.2 min (2S,4R,5S)-iso-
mer.
1H NMR (300 MHz): d = 7.37–7.12 (m, 5 H), 3.70 (s, 3 H), 3.32–
3.25 (m, 1 H), 3.16–3.09 (m, 1 H), 2.16 (s, 3 H), 2.12–1.95 (m, 3 H),
1.82–1.70 (m, 1 H).
13C NMR (75 MHz): d = 174.4, 142.7, 128.3, 127.4, 127.2, 71.8,
68.0, 51.8, 39.8, 34.5, 27.8.
[a]D20 –34 (c 0.50, CHCl3).
1H NMR (300 MHz): d = 7.77–7.69 (m, 2 H), 7.58–7.50 (m, 1 H),
7.46–7.37 (m, 2 H), 7.21–7.09 (m, 5 H), 3.88 (dd, J = 6.4 Hz, 1 H),
3.72 (s, 3 H), 3.60 (m, 1 H), 3.50 (dd, J = 9.7, 7.2 Hz, 1 H), 2.61
(ddd, J = 13.9, 7.1, 3.6 Hz, 1 H), 2.38 (dt, J = 13.9, 9.9 Hz, 1 H),
2.22 (s, 3 H).
13C NMR (75 MHz): d = 172.1, 140.0, 137.8, 133.7, 129.1, 128.4,
128.3, 123.6, 127.4, 70.1, 68.9, 66.0, 51.9, 38.8, 29.8.
10
Colorless oil; 99% ee; HPLC (Daicel Chiralpak AS-H, i-PrOH–
hexane, 40:60, flow rate 0.8 mL/min, 210 nm): tR = 4.9 min (R)-iso-
mer and 5.2 min (S)-isomer.
[a]D20 –8 (c 0.25, CHCl3).
1H NMR (300 MHz): d = 7.30–7.10 (m, 5 H), 6.39 (d, J = 15.7 Hz,
1 H), 6.06(dt, J = 15.7, 7.4 Hz, 1 H) 3.66 (s, 3 H), 3.26 (t, J = 6.3
Hz, 1 H), 2.54–2.47 (m, 1 H), 2.33 (s, 3 H), 1.56 (br s, 1 H).
Methyl (2R,4S,5R)-5-(3-Fluorophenyl)-1-methyl-4-(phenylsul-
fonyl)pyrrolidine-2-carboxylate
White solid; yield: 85%; mp 96–97 °C; 85% ee; HPLC (Daicel
Chiralpak AS-H, i-PrOH–hexane, 40:60, flow rate 0.8 mL/min, 210
nm): tR = 12.9 min (2R,4S,5R)-isomer and 19.7 min (2S,4R,5S)-iso-
mer.
13C NMR (75 MHz): d = 174.9, 137.1, 133.2, 128.5, 127.3, 126.2,
124.9, 63.0, 51.7, 36.8, 34.7.
Acknowledgment
[a]D20 –30 (c 0.53, CHCl3).
We thank the Ministerio de Educación y Ciencia (MEC, BQU2003-
0508), and Consejería de Educación de la Comunidad Autónoma de
Madrid (CAM) and the Universidad Autónoma de Madrid (UAM)
(Project UAM/CAM 08/PPQ/001) for the financial support. T.L.
thanks the CAM for a Predoctoral Fellowship. Solvias AG is also
gratefully acknowledged for a generous gift of several chiral ligands,
including Taniaphos.
1H NMR (300 MHz): d = 7.85–7.71 (m, 2 H), 7.65–7.57 (m, 1 H),
7.53–7.44 (m, 2 H), 7.21–7.11 (m, 1 H), 7.02–6.83 (m, 3 H), 3.94
(d, J = 6.1 Hz, 1 H), 3.76 (s, 3 H), 3.62–3.47 (m, 2 H), 2.61 (ddd,
J = 13.9, 7.1, 3.5 Hz, 1 H), 2.37 (dt, J = 13.9, 9.9 Hz, 1 H), 2.27 (s,
3 H).
13C NMR (75 MHz): d = 172.2, 162.8 (d, JF-C = 246.4 Hz), 143.1 (d,
JF-C = 7.1 Hz), 137.8, 133.9, 130.0 (d, JF-C = 8.2 Hz), 129.3, 128.6,
123.2 (d, JF-C = 2.7 Hz), 114.7 (d, JF-C = 20.9 Hz), 114.3 (d, JF-C
22.5 Hz), 69.6, 69.2, 66.1, 52.1, 39.0, 30.0.
=
References
(1) For reviews on pyrrolidine natural product synthesis, see:
(a) Harwood, L. M.; Vickers, R. J. In Synthetic Applications
of 1,3-Dipolar Cycloaddition Chemistry Toward
Heterocycles and Natural Products; Padwa, A.; Pearson,
W., Eds.; Wiley & Sons: New York, 2002, Chap. 3.
(b) Michael, J. P. Nat. Prod. Rep. 2004, 21, 625. (c) Cheng,
Y.; Huang, Z.-T.; Wang, M.-X. Curr. Org. Chem. 2004, 8,
325.
(2) For recent reviews on asymmetric amino catalysis using
proline or related catalysts, see: (a) Berkessel, A.; Gröger,
H. Asymmetric Organocatalysis; VCH: Weinheim, 2004.
(b) List, B. Chem. Commun. 2006, 819; and references cited
therein.
Methyl (2R,4S,5R)-1-Methyl-4-(phenylsulfonyl)-5-(3-tolyl)pyr-
rolidine-2-carboxylate
White solid; yield: 88%; mp 89–90 °C; 79% ee; HPLC (Daicel
Chiralpak AS-H, i-PrOH–hexane 40:60, flow rate 0.8 mL/min, 210
nm): tR = 14.4 min (2R,4S,5R)-isomer and 18.9 min (2S,4R,5S)-iso-
mer.
[a]D20 –39 (c 0.54, CHCl3).
1H NMR (300 MHz): d = 7.80–7.73 (m, 2 H), 7.61–7.53 (m, 1 H),
7.49–7.40 (m, 2 H), 7.11–7.94 (m, 3 H), 6.86 (br s, 1 H), 3.81 (d,
J = 6.4 Hz, 1 H), 3.76 (s, 3 H), 3.67–3.58 (m, 1 H), 3.50 (dd, J = 9.7,
7.2 Hz, 1 H), 2.66 (ddd, J = 13.8, 7.1, 3.6 Hz, 1 H), 2.41 (dt,
J = 13.9, 9.9 Hz, 1 H), 2.23 (s, 3 H), 2.21 (s, 3 H).
13C NMR (75 MHz): d = 172.3, 139.9, 138.0, 137.9, 133.7, 129.1,
128.6, 128.5, 128.3, 128.2, 124.6, 70.5, 69.0, 66.2, 52.1, 38.9, 29.8,
21.2.
(3) For a recent review, see: Nájera, C.; Sansano, J. M. Angew.
Chem. Int. Ed. 2005, 44, 6272.
(4) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K.
A. Angew. Chem. Int. Ed. 2002, 41, 4236.
(5) (a) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc.
2002, 124, 13400. (b) Chen, C.; Li, X.; Schreiber, S. L. J.
Am. Chem. Soc. 2003, 125, 10174. (c) Knöpfel, T. F.;
Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M.
Angew. Chem. Int. Ed. 2004, 43, 5971. (d) Stohler, R.;
Wahl, F.; Pfaltz, A. Synthesis 2005, 1431. (e) Zeng, W.;
Zhou, Y.-G. Org. Lett. 2005, 7, 5055.
(6) Dogan, ; Koyuncu, H.; Garner, P.; Bulut, A.; Youngs, W. J.;
Panzner, M. Org. Lett. 2006, 8, 4687.
(7) (a) Cabrera, S.; Gómez-Arrayás, R.; Carretero, J. C. J. Am.
Chem. Soc. 2005, 127, 16394. (b) Gao, W.; Zhang, X.;
Raghunath, M. Org. Lett. 2005, 7, 4241. (c) Yan, X.-X.;
Peng, Q.; Zhang, Y.; Zhang, K.; Hong, W.; Hou, X.-L.; Wu,
Y.-D. Angew. Chem. Int. Ed. 2006, 45, 1979.
Methyl (2R,5S)-1-Methyl-5-phenylpyrrolidine-2-carboxylate
(9) and Methyl (R,E)-2-(Methylamino)-5-phenylpentanoate
(10); Typical Procedure
A mixture of a >99% ee sample of sulfone 8 (128 mg, 0.36 mmol),
5% Na(Hg) (570 mg) and Na2HPO4 (186 mg, 1.3 mmol) in MeOH–
THF (2:1, 6 mL) was stirred at r.t. for 5 h. Then it was poured into
CH2Cl2 (20 mL), filtered and washed with H2O (2 × 10 mL). The
aqueous phase was extracted with CH2Cl2 (3 × 10 mL) and the com-
bined organic phase was dried (MgSO4) and concentrated. The res-
idue was purified by flash chromatography (n-hexane–EtOAc, 4:1
to EtOAc) to afford 9 (48 mg, 61%) followed by 10 (23 mg, 28%).
9
Colorless oil; 99% ee; HPLC (Daicel Chiralpak AS-H, i-PrOH–
hexane 5:95, flow rate 0.3 mL/min, 210 nm): tR = 14.8 min (2R,5S)-
isomer and 16.2 min (2S,5R)-isomer.
[a]D20 –55 (c 0.45, CHCl3).
(8) Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.; Kasano, Y.;
Minakata, S.; Komatsu, M. Org. Lett. 2003, 5, 5043.
(9) (a) Simpkins, N. S. Sulfones in Organic Synthesis;
Pergamon Press: Oxford, 1993. (b) Tanaka, K.; Kaji, A. In
The Chemistry of Sulphones and Sulphoxides; Patai, S.;
Synthesis 2007, No. 6, 950–956 © Thieme Stuttgart · New York

956
T. Llamas et al.
PRACTICAL SYNTHETIC PROCEDURES
Rappoport, Z.; Stirling, C., Eds.; Wiley: New York, 1988,
Chap 15, 759. (c) Fuchs, P. L.; Braish, T. F. Chem. Rev.
1986, 86, 903.
(16) Sulfones 2b–d were readily available by reaction of the
corresponding aryl disulfide with vinylmagnesium bromide
and subsequent oxidation of the resulting sulfide to sulfone
with Na2WO4·2 H2O/H2O2. On the other hand, 2e was
prepared from 2-(dimethylamino)phenyl methyl sulfone and
formaldehyde. See the Supporting Information in reference
13 for details.
(17) For the use of 2-(dimethylamino)phenyl vinyl sulfones in
Heck reactions, see: (a) Mauleón, P.; Alonso, I.; Carretero,
J. C. Angew. Chem. Int. Ed. 2001, 40, 1291. (b) Mauleón,
P.; Núñez, A. A.; Alonso, I.; Carretero, J. C. Chem. Eur. J.
2003, 9, 1511.
(10) For examples on the participation of vinyl sulfones in
noncatalytic asymmetric 1,3-dipolar cycloaddition with
azomethine ylides, see: (a) Plancquaert, M.-A.; Redon, M.;
Janousek, Z.; Viehe, H. G. Tetrahedron 1996, 52, 4383.
(b) Clark, R. B.; Pearson, W. H. Org. Lett. 1999, 1, 349.
(c) Laduron, F.; Viehe, H. G. Tetrahedron Lett. 2002, 58,
3543. (d) Wittland, C.; Risch, N. J. Prakt. Chem. 2000, 342,
311. (e) Garner, P.; Kaniskan, H.; Hu, J.; Youngs, W. J.;
Panzner, M. Org. Lett. 2006, 8, 3647.
(11) For a review on desulfonylation/functionalization strategies,
see: Nájera, C.; Yus, M. Tetrahedron 1999, 55, 10547.
(12) Grigg, R. Tetrahedron: Asymmetry 1995, 6, 2475.
(13) For a recent communication paper of this work, see: Llamas,
T.; Gómez-Arrayás, R.; Carretero, J. C. Org. Lett. 2006, 8,
1795.
(18) For the use of 2-pyridyl sulfones in transition-metal-
catalyzed processes, see: (a) Llamas, T.; Gómez-Arrayás,
R.; Carretero, J. C. Adv. Synth. Catal. 2004, 346, 1.
(b) Mauleón, P.; Carretero, J. C. Org. Lett. 2004, 6, 3195.
(c) Mauleón, P.; Carretero, J. C. Chem. Commun. 2005,
4961.
(14) The silver(I) acetate catalyzed reaction between 1a and 2a
was also studied, providing generally poorer reactivities and
enantioselectivities. Interestingly, Taniaphos proved to be
also the best ligand in the silver-promoted reaction.
(15) A number of well-established commercially available P,P-
ligands such as Binap, Chiraphos, Norphos, and Phanephos
led to low to moderate enantioselectivities (19–42% ee).
Very poor results (<10% ee) were obtained with BOX,
PyBOX and phosphoramidite ligands. Ferrocene-based
ligands gave superior results in this reaction, the Fesulphos
family and the Solvias’ ligands Walphos and Taniaphos
providing enantioselectivities in the range of 50–83% ee (see
ref. 13).
(19) Tsuge, H.; Okano, T.; Eguchi, S. J. Chem. Soc., Perkin
Trans. 1 1995, 2761.
(20) The acyclic g,d-unsaturated a-amino ester, methyl (R,E)-2-
(methylamino)-5-phenylpent-4-enoate (10, see Scheme 3),
was also isolated as a byproduct in 28% yield in the
desulfonylation step as a result of a Julia-like reaction
involving the cleavage of the C–N bond. For related Julia-
like reactions, see: Iradier, F.; Gómez-Arrayás, R.;
Carretero, J. C. Org. Lett. 2001, 3, 2957; and references cited
therein.
(21) Experimental details and analytical data regarding the
preparation of imines 1a–j are found within the Supporting
Information of reference 13.
Synthesis 2007, No. 6, 950–956 © Thieme Stuttgart · New York