Application of novel sulfonamides in enantioselective organocatalyzed cyclopropanation

Article abstract of DOI:10.1016/j.tetasy.2007.05.030

Three novel aryl sulfonamides derived from (2S)-indoline-2-carboxylic acid have been obtained and used as organocatalysts. The catalysts incorporate diverse functionality on the phenyl ring, enabling steric, and electronic fine tuning of the catalysts. Th

Full text of DOI:10.1016/j.tetasy.2007.05.030

Tetrahedron: Asymmetry 18 (2007) 1403–1409
Application of novel sulfonamides in enantioselective
organocatalyzed cyclopropanation
a
a
a,b,
*
´
´
Antti Hartikka, Adam T. Slosarczyk and Per I. Arvidsson
aDepartment of Biochemistry and Organic Chemistry, Uppsala University, Box 576, S-75123 Uppsala, Sweden
bMedicinal Chemistry, Discovery CNS and Pain Control, AstraZeneca R&D So¨derta¨lje, S-15185 So¨derta¨lje, Sweden
Received 25 April 2007; accepted 29 May 2007
Available online 9 July 2007
Abstract—Three novel aryl sulfonamides derived from (2S)-indoline-2-carboxylic acid have been obtained and used as organocatalysts.
The catalysts incorporate diverse functionality on the phenyl ring, enabling steric, and electronic fine tuning of the catalysts. The catalysts
facilitate the reaction between a range of a,b-unsaturated aldehydes and sulfur ylides, thus providing cyclopropane products in enantio-
meric excesses of up to 99%.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
arsenium ylides,9 and telleronium ylides.10 This methodo-
logy allows for a wide range of structurally divergent sub-
strates to be reacted and may thus be used to create a
plethora of cyclopropane architectures.
The cyclopropane unit is a common structural constituent
in many naturally occurring compounds. Currently over
4000 natural isolates are known and more than a hundred
are known to be therapeutically active.1 Development in
the synthetic methodology that allows the construction of
these structures in a stereo-controllable manner has
attracted the attention of many research groups over the
last twenty years.2 Early synthetic methodology develop-
ment focused on the stereoselective formation of function-
alized cyclopropane adducts; however, the most recent
synthetic development has focused on enantioselective con-
struction of diversely substituted cyclopropane adducts.3
Herein we wish to report our results concerning the enan-
tioselective organocatalyzed cyclopropanation reaction.
The reaction was initially disclosed by Ley et al., utilizing
modified cinchona alkaloids,11 while MacMillan et al.
made use of a dihydroindol carboxylic acid as a catalyst.12
We reasoned that substitution of the carboxylic acid of (S)-
(ꢀ)-indoline-2-carboxylic acid to the corresponding (S)-
(ꢀ)-indoline-2-aryl sulfonamide should allow fine tuning
of the catalyst structure by varying the substitution on
the phenyl ring of the aryl sulfonamide.
Early development in stereoselective cyclopropanation
reactions utilized Simmons–Smith type of reagents.4 An
increasingly important reaction type features a nucleophile
containing an internal leaving group moiety. Here, the
nucleophile undergoes an intermolecular Michael addition
to a a,b-unsaturated carbonyl compound, and thus forms
an enolate; this step is followed by an intramolecular ring
closure with loss of a leaving group, present either on the
Michael acceptor or on the initial nucleophile, thus furnish-
ing a cyclopropanated product.5 The most commonly
employed nucleophiles in this kind of reaction are
a-halocarbanions,6 sulfur ylides,7 phosphorous ylides,8
2. Results and discussion
To investigate the potential of aryl sulfonamides in enan-
tioselective cyclopropanation we synthesized three different
catalysts, that is, 1–3, containing differently substituted
phenyl rings.
Catalyst 1 was synthesized by converting (S)-(ꢀ)-indoline-
2-carboxylic acid 4 to the Boc protected derivative 5, fol-
lowed by direct coupling with p-nitrophenyl sulfonamide
to give 6, which was further Boc deprotected to give cata-
lyst 1 (Scheme 1). Direct coupling was necessary due to the
poor nucleophilicity of p-nitrophenyl sulfonamide.
*
Corresponding author. Tel.: +46 (0)855325923; fax: +46
(0)855328892; e-mail: Per.Arvidsson@astrazeneca.com
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.05.030

1404
A. Hartikka et al. / Tetrahedron: Asymmetry 18 (2007) 1403–1409
O
O
O
S
O
O
S
O
NO2
O
CH3
N
H
N
H
N
H
N
H
1
2
O
N S
H
O
N
H
3
O
O
OH
ii
i
N
OH
96%
63%
N
H
O
O
4
5
O
O
O
O
iii
84%
N S
NO2
N
HN S
O
NO2
H
O
N
H
O
O
6
1
Scheme 1. Reagents and conditions: (i) Boc2O, Na2CO3, H2O, t-BuOH, rt, 12 h; (ii) DMAP, EDCI, 4-nitrophenyl sulfonamide, t-BuOH–1,2-
dichloroethane (1:1), rt, 12 h; (iii) 50% TFA in DCM, rt, 1 h.
Catalysts 2 and 3 could, however, be synthesized by react-
ing 5 with p-nitrophenol yielding the active ester 7 in high
yield. Catalysts 2 and 3 were then prepared by reacting the
active ester with suitable sulfonamides, which after Boc-
deprotection furnished the final catalysts products 2 and
3 (Scheme 2).
demonstrates that the nature of the aryl group affects the
reaction outcome, and that the large 2,4,6-tri-isopropyl-
benzene moiety in 3 is too bulky to provide good stereo-
selectivity in the current reaction. The fact that identical
stereoselectivities were obtained independent of the reac-
tion time concludes that no epimerization occurred during
the course of the reaction.
Catalysts 1–3 were assessed in the enantioselective organo-
catalytic cyclopropanation reaction between 2-(dimethyl-
k4-sulfanylidene)-1-phenyl-ethanone and crotonaldehyde.2
After this initial catalyst and time screening, the optimal
reaction conditions were employed in an expanded sub-
strate study where both the enal and sulfur ylide structure
were varied. The results of this investigation are shown in
Table 2. It can be seen that catalyst 2 gives products in
slightly higher enantiomeric excess than catalyst 1,
The results, as presented in Table 1, show that while cata-
lysts 1 and 2 provide products with high enantiomeric
excess catalyst 3 gave less good results. This result clearly
O
O
O
OH
ii
i
N
N
O
NO2
OH
96%
80%
N
H
O
O
O
O
4
5
7
R2
R2
O
R2
O
O
O
N S
R1
iii or iv
v
N S
R1
H
O
N
H
O
N
H
O
O
R2
1
O
8 R1 = CH3, R2 = H (83%)
9 R1, R2 = i-Pr (80%)
2 R1 = CH3, R2 = H (61%)
3 R1, R2 = i-Pr (47%)
Scheme 2. Reagents and conditions: (i) Boc2O, Na2CO3, H2O, t-BuOH, rt, 12 h; (ii) p-nitrophenol, DIPCDI, Pyridine; (iii) p-toluene sulfonamide, DMF,
NaH, rt, 12 h; (iv) 2,4,6-tris(isopropylbenzene) sulfonamide, DMF, NaH, rt, 12 h; (v) 50% TFA in DCM, rt, 1 h.

A. Hartikka et al. / Tetrahedron: Asymmetry 18 (2007) 1403–1409
1405
Table 1. Catalyst assessment using catalysts 1–3 in the representative reaction between 2-(dimethyl-k-sulfanylidene)-1-phenyl-ethanone and croton-
aldehyde
O
O
H3C
20 mol % 1, 2 or 3
Ph
+
S
+
H3C
O
Ph
19 h, 38 h, or 72 h
-
CHCl3
CHO
Entrya
Time (h)
Catalyst
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
19
19
19
38
38
38
72
72
1
2
3
1
2
3
1
2
36
53
18
45
55
30
57
61
88
88
80
88
88
80
88
88
a Reaction was conducted at 4 °C.
b Isolated yield.
c Enantiomeric excess was determined by correlation through GC–MS analysis of a reference sample.12
although the difference is small as might be expected from
the similar steric nature of the substituents. Somewhat
more surprising is that the electronic properties of the
two different catalysts, that is, the electron withdrawing
properties of the p-nitro substituent in catalyst 1, do not
affect the reaction outcome in a more positive way. One
might expect that the reaction rate, and possibly also the
stereoselectivity, should benefit from a postulated tighter
binding of the transition state comprising catalyst 1, which
is expected to have a more acidic sulfonamide proton than
catalyst 2 in CHCl3. Such effects were seen with sulfon-
amide substituted proline derivatives in other organocata-
lyzed reactions.13 The lack of such correlations in the
present reaction remains unclear, but it should be noted
that the observed differences are small, and relates to iso-
lated yields.
anation reaction. The mechanistic postulate of this reaction
highlights the role of directed electrostatic activation be-
tween the negatively charged catalyst carboxylate and the
thionium part of the sulfur ylide. We have shown that sub-
stitution of the carboxylic acid to the corresponding aryl
sulfonamide retains the structural requirements in respect
to the directed electrostatic activation model, thus enabling
highly stereoselective reactions. Although none of these
catalysts perform as well as the indolin-2-carboxylic acid
used in MacMillan’s first disclosure on this reaction se-
quence,12 this study has still demonstrated the potential
of sulfonamide modified indole derivatives as novel kinds
of modular catalyst structures, most likely of use in a vari-
ety of organocatalytic processes.
4. Experimental
Still, as seen in Table 2 both aliphatic and aromatic alde-
hydes were transformed into the corresponding cycloprop-
anated products in fair yields and high enantiomeric
excesses. The results show that the allylether substituted
a,b-unsaturated aldehydes react slower, only giving 25%
and 21% isolated yield after 38 h with catalyst 2 (Table 2,
entries 9–12), whereas straight carbon chain a,b-unsatu-
rated aldehydes constitute more reactive substrate giving
products in 52–58% isolated yield (Table 2, entries 1–6
and 13–16). Also the investigated aromatic trans-cinnamal-
dehyde gave the product in quite low yield (Table 2, entries
7 and 8), but very high enantioselectivities. The results col-
lected suggest that catalyst 2 is the most suitable of these
two catalysts to be employed in the enantioselective organ-
ocatalytic cyclopropanation reaction, as it generally pro-
vides the products in some 10% higher yield and
enantioselectivity.
Chemicals and solvents were either purchased puriss p.A
from commercial suppliers or purified by standard tech-
niques. For thin layer chromatography (TLC), precoated
0.25 mm silica plates (Macherey–Nagel 60 AlugramÒ Sil
G/UV254) were used and spots were visualized either by
UV light or by a solution composed of p-anisaldehyde
(2.3 ml), concentrated H2SO4 (3.5 ml), acetic acid (1 ml),
and 100 ml ethanol followed by heating. 1H NMR
500 MHz spectra were recorded on a Varian Unity
500 MHz and 13C NMR 75 MHz spectra were recorded
with a Varian Unity 300 MHz spectrometer at ambient
temperature using deuterated chloroform, methanol, or
dimethylsulfoxide as solvents. Chemical shifts (d) are re-
ported in parts per million using residual chloroform,
methanol or dimethylsulfoxide as internal reference (1H d
7.26, 3.34, and 2.49, respectively) or (13C d 77, 49.9, and
39.5, respectively) and coupling constants (J) are given in
Hertz. Infrared spectra was recorded on a Perkin–Elmer
Spectrum 100 FT/IR spectrometer. Enantiomeric excesses
were determined using a high pressure liquid chromatogra-
phy (HPLC) system equipped with a column consisting of
a chiral stationary phase. The HPLC system consisted of
a Gilson 322 pump, Gilson 233 XL autosampler, and an
3. Conclusion
Structurally diverse aryl sulfonamide containing catalysts
were synthesized in order to investigate the utility of these
catalysts in the enantioselective organocatalytic cycloprop-

1406
A. Hartikka et al. / Tetrahedron: Asymmetry 18 (2007) 1403–1409
Table 2. Scope of the enantioselective organocatalytic cyclopropanation using sulfonamide based catalysts 1 and 2
O
O
R1
20 mol % 1 or 2
R2
+
S
+
R1
O
R2
CHCl3
-
38 h
CHO
Entrya
R1
R2
Catalyst
Product
Yieldc (%)
ded (%)
eee (%)
O
1b
2b
CH3
CH3
Ph
Ph
1
2
45
55
95
95
88
88
H3C
CHO
O
n-Pr
n-Pr
Ph
3
4
C3H7
C3H7
Ph
Ph
1
2
25
52
96
97
94
98
CHO
O
5
6
C3H7
C3H7
PhBr
PhBr
1
2
50
58
96
96
95
99
Br
CHO
O
7
8
Ph
Ph
Ph
Ph
1
2
20
28
95
94
92
97
CHO
O
AllO
AllO
9
10
C3H5OCH2
C3H5OCH2
Ph
Ph
1
2
16
25
97
96
93
99
CHO
O
11
12
C3H5OCH2
C3H5OCH2
PhBr
PhBr
1
2
20
21
95
94
91
99
Br
CHO
O
13
14
C5H9
C5H9
Ph
Ph
1
2
43
52
96
95
90
99
3
3
CHO
O
15
16
C5H9
C5H9
PhBr
PhBr
1
2
48
57
97
98
92
94
Br
CHO
a Reaction performed at ꢀ10 °C for 38 h.
b Reaction performed at 4 °C for 38 h.
c Isolated yield after column chromatography.
d Diastereomeric excess was determined by 1H NMR or GLC analysis.
e Enantiomeric excess was determined by GLC or HPLC analysis and correlated to a reference sample generated with (S)-(ꢀ)-indoline-2-carboxylic acid 4.
Agilent 1100 diodo-array detector. Details concerning mo-
bile phase compositions and column types are presented
below individually for each compound. GC–MS determina-
tion of enantiomeric excesses was done using a Varian CP-
8410 auto injector and a Varian Satum 2100T GC–MS sys-
tem equipped with a chiral stationary phase column, using
helium at 10 psi as carrier gas. Details concerning the col-
umns and temperature programs used are given specifically
for each compound below. Purity confirmations of the pre-
pared catalysts were assessed using a HPLC system
coupled to an MS detector and an evaporative light-
scattering detector (ELSD); the system consisted of a
Gilson 322 pump, Gilson 233 XL autosampler and a Gilson
UV/VIS 152 detector, coupled in series with a Finnigan
AQA mass spectrometer and an ELSD (Sedex 85 CC) from
Sedere. The reverse phase HPLC analysis was done using a
Phenomenex Gemini C18 (3 m, 3.0U150 mm) column
employing acetonitrile–water (both containing 0.1% formic

A. Hartikka et al. / Tetrahedron: Asymmetry 18 (2007) 1403–1409
1407
acid) as mobile phase (gradient: 5–95% acetonitrile in
6 min+6 min at 95%, flow 1.0 mL/min). High-resolution
ESI mass spectra were recorded on a Bruker micrOTOFQ.
These data were collected in positive ion mode. The spec-
trometer was calibrated with the standard tune mix. The
sample was dissolved in the mixture acetonitrile–water
1:1 containing 0.1% of formic acid and infused at a flow
rate of 3 ll/min, the endplate voltage was set to ꢀ500 V
and the capillary to +4500 V.
NMR (CD3OD, 75 MHz): d 36.7, 65.1, 111.9, 112.5,
121.3, 125.2, 126.1, 129.1, 129.4, 130.3, 130.4, 183.2; IR
(neat): mmax 3230, 1680, 1600, 1535, 1276, 1189, 865,
23
740 cmꢀ1; ½aꢁD ¼ þ5:5 (c 1.0, MeOH); HR ESI-MS: m/z:
calcd for C15H13N3O5S: 347.0575; found: 348.0658
[M+H]+.
4.3. (S)-N-[(4-Methylphenyl)sulfonyl]indoline-2-
carboxamide 2
4.1. (S)-Boc-indoline-2-carboxylic acid14
5
Boc-(S)-(ꢀ)-indolin-2-carboxylic acid (1.4 g, 5.4 mmol)
was dissolved in 15 ml dry pyridine and (0.93 ml, 1.11 g,
8.8 mmol) DIPCDI was added. Afterwards (1.24 g,
8.8 mmol) p-nitrophenol was added. The solution was stir-
red overnight at ambient temperature and then diluted by
20 ml ethyl acetate. The solution was extracted by 2% ice
cold sulfuric acid until the aqueous phase became acidic
after extraction. The organic layer was dried with MgSO4
and purified by means of column chromatography on silica
gel with dichloromethane as mobile phase resulting in Boc-
(S)-(ꢀ)-indolin-2-nitrophenyl ester (1.39 g; 68%). To a
solution of p-toluenesulfonamide (0.32 g, 1.87 mmol) in
10 ml of absolute DMF was added sodium hydride
(134 mg, 3.34 mmol). After stirring for approximately 1 h
at ambient temperature, Boc-(S)-(ꢀ)-indolin-2-nitrophenyl
ester (0.41 g, 1.44 mmol), dissolved in 5 ml of absolute
DMF, was added. The yellow solution was stirred over-
night at room temperature. The mixture was then poured
onto crushed ice and the pH was adjusted to 3 by citric acid
addition. During the addition a white precipitate appeared,
which was filtered and washed with water. The white solid
was dried under high vacuum resulting in the Boc protected
toluenesulfonamide (0.5 g; 83%). The deprotection was
performed by addition of a mixture of 50% TFA in
DCM (10 ml). The mixture was stirred for an hour at room
temperature followed by concentration under reduced pres-
sure to give a yellow oil, which was dissolved in methanol
followed by addition of 0.5 g of a MP-TsOH resin. The
mixture was stirred overnight followed by filtration of the
resin. The resin was washed with methanol and subse-
quently the product was released from the resin by addition
of a saturated ammonia solution of methanol, which fur-
nished the product as a yellow oil after concentration
(0.20 g; 44% overall yield). 1H NMR (CD3OD,
500 MHz): d 2.34 (s, 3H), 3.13 (dd, J = 15.9, 5.9 Hz, 1H),
3.26 (m, 1H), 4.13 (m, 1H), 6.66 (m, 2H), 6.96 (t, J =
7.6 Hz, 1H), 6.99 (d, J = 7.3 Hz, 1H), 7.22 (d, J = 8.1 Hz,
2H), 7.77 (m, 2H); 13C NMR (CD3OD, 75 MHz): d 22.2,
36.7, 64.9, 112.5, 121.3, 126.1, 129.0, 129.1, 130.4, 130.6,
(S)-(ꢀ)-Indolin-2-carboxylic acid (1 g, 6.13 mmol) was
added to a solution of 0.5 g of sodium carbonate in
100 ml water. To the mixture was added di-tert-butyl dicar-
bonate (1.65 g, 7.32 mmol) solubilized in 20 ml of t-butyl
alcohol after which the mixture was stirred overnight at
ambient temperature. The solution was then washed with
n-pentane followed by cooling of the aqueous phase to
0 °C and a 40% aqueous solution of KHSO4 was added
until pH 3 was reached. The cloudy mixture was extracted
with ethyl acetate followed by washing of the organic phase
with water. The organic phase was dried with magnesium
sulfate followed by filtration and concentration under
reduced pressure to give a colorless solid (1.55 g; 96%).
The product was considered sufficiently pure and used
directly in next steps. 1H NMR (CD3OD, 500 MHz):
d 1.53 (s, 9H), 3.85 (dd, J = 16.6, 3.9 Hz, 1H), 3.55
(dd, J = 11.7, 4.9 Hz, 1H), 4.81 (d, J = 10.5 Hz, 1H), 6.94
(td, J = 7.6, 1.0 Hz, 1H), 7.12 (d, J = 7.3 Hz, 1H), 7.17
(t, J = 7.8 Hz, 1H), 7.82 (d, J = 6.8 Hz, 1H).
4.2. (S)-N-[(4-Nitrophenyl)sulfonyl]indoline-2-
carboxamide 1
Boc-(S)-(ꢀ)-indolin-2-carboxylic acid (300 mg, 1.83 mmol),
DMAP (673 mg, 5.49 mmol), EDCI (707 mg, 3.66 mmol),
and 4-nitrobenzenesulfonamide (557 mg, 2.75 mmol) were
dissolved in 15 ml of a 1:1 mixture of tert-butyl alcohol
and 1,2 dichloroethane. The solution was stirred 12 h at
ambient temperature. Ethyl acetate (10 ml) and Amber-
lyst-15 (protonated form, 3.0 g) were added, and stirring
was continued for 2 h. The mixture was passed through a
plug of silica gel (1 cm) and washed with ethyl acetate.
The filtrate was concentrated under reduced pressure
followed by purification of the residue by means of column
chromatography (silica gel, 100% ethyl acetate) to give pure
Boc protected N-sulfonylcarboxamide (0.52 g; 63%).
Deprotection of the Boc group was done using 50% TFA
in DCM, which after concentration under reduced pressure
gave a brown oil that was further purified by a catch and
release procedure utilizing solid-state bound MP-TsOH. A
mixture of the product and MP-TsOH (0.5 g) was stirred
overnight followed by filtration of the resin. The resin was
washed with methanol and subsequently the product was
released from the resin by addition of a saturated ammonia
solution of methanol. This provided the product as a light
brown oil after concentration (0.3 g; 47% overall yield).
1H NMR (CD3OD, 500 MHz) d 3.15 (dd, J = 16.1,
5.8 Hz, 1H), 2.26 (dd, J = 16.1, 10.0 Hz, 1H), 4.11
(m, 1H), 6.64 (m, 2H), 6.93 (t, J = 7.6 Hz, 1H), 6.98
(d, J = 8.0 Hz, 1H), 8.06 (m, 2H), 8.22 (m, 2H); 13C
142.8, 143.9, 152.9, 182.4; IR (neat): mmax 3200, 1650,
23
1535, 1485, 1230, 1134, 890, 725 cmꢀ1; ½aꢁD ¼ ꢀ5:4 (c
1.0, MeOH); HR ESI-MS: m/z: calcd for C16H16N2O3S:
316.0881; found: 317.0936 [M+H]+.
4.4. (S)-N-[(2,4,6-Triisopropylphenyl)sulfonyl]indoline-2-
carboxamide 3
To a solution of 2,4,6-tris(isopropylbenzene)sulfonamide
(0.62 g, 2.197 mmol) were added sodium hydride (150 mg,
8.14 mmol) and Boc-(S)-(ꢀ)-indolin-2-nitrophenyl ester
(0.65 g, 1.69 mmol) (prepared as described above) dis-
solved in 5 ml of absolute DMF. The light yellow solution

1408
A. Hartikka et al. / Tetrahedron: Asymmetry 18 (2007) 1403–1409
was stirred overnight at room temperature. The mixture
was then poured onto crushed ice and the pH was adjusted
to 3 by citric acid addition. During the addition a white
precipitate appeared, which was filtered and washed with
water. The white solid was dried under high vacuum result-
ing in the Boc protected derivative. Boc-deprotection was
performed by addition of a mixture of 50% TFA in
DCM to the residue. The mixture was stirred for an hour
at room temperature followed by concentration under re-
duced pressure to give a yellow oil, which was dissolved
in methanol followed by addition of 0.5 g MP-TsOH resin.
The mixture was stirred overnight followed by filtration of
the resin. The resin was washed with methanol and subse-
quently the product was released from the resin by addition
of a saturated ammonia in methanol, which furnished the
product as a yellow oil (0.2 g; 27% overall yield). 1H
NMR (CD3OD, 500 MHz): d 1.62 (d, J = 6.8 Hz, 6H),
1.19 (d, J = 6.8 Hz, 12H), 2.84 (m, 1H), 3.27 (m, 2H),
4.11 (m, 1H), 4.46 (m, 3H), 6.65 (m, 2H), 6.94 (t,
J = 7.6 Hz, 1H), 6.98 (d, J = 7.32 Hz, 1H), 7.10 (s, 2H).
13C NMR (CD3OD, 75 MHz): d 22.7, 23.6, 29.2, 34.2,
61.0, 113.9, 123.9, 124.9, 128.1, 129.3, 132, 151.6, 154.3,
4.7. (1R,2S,3R)–2-Benzoyl-3-propyl-cyclopropane-
carbaldehyde (Table 2, entries 3 and 4)
Prepared according to the general procedure. Purification
was performed by means of flash chromatography (silica
gel, 15% Et2O in n-pentane). The pure products were ob-
1
tained as light yellow oils. The H NMR and 13C NMR
spectroscopic data were in good agreement with data
reported earlier.12 The enantiomeric excess and diastereo-
meric excess were determined by GLC using Astec Chiral-
dex b-DM (30 m 0.25 mm), column (155 °C isotherm for
*
90 min), ramp to (175 °C, 5 °C/min and isotherm for
18 min) and ramp to (220 °C, 10 °C/min, hold 0.5 min).
Major diastereomer: major enantiomer tR = 31.8 min and
minor enantiomer tR = 33.4 min. Minor diastereomer:
major enantiomer tR = 20.1 min and minor enantiomer
tR = 19.8 min. MS (EI): m/z (rel intensity): 217 ([M+H]+,
32), 174 (13), 173 (100), 145 (33), 144 (4), 117 (23), 116
(4), 115 (13), 106 (7), 105 (82), 104 (5), 78 (5), 77 (44), 76 (3).
4.8. (1R,2S,3R)-2-(40-Bromo-benzoyl)-3-propyl-cyclo-
propanecarbaldehyde (Table 2, entries 5 and 6)
159.4, 182.5; IR (neat): mmax 3150, 1720, 1650, 1535,
23
1180, 1056, 830, 740 cmꢀ1; ½aꢁD ¼ ꢀ47:2 (c 1.0, MeOH);
Prepared according to the general procedure. Purification
was done by means of flash chromatography (silica gel,
15% Et2O in n-pentane). The pure products were obtained
ESI-MS: m/z: calcd for C24H32N2O3S: 428.2; found:
429.2 [M+H]+.
1
as light yellow oils. The H NMR and 13C NMR spectro-
scopic data were in good agreement with data reported ear-
lier.12 The enantiomeric excess and diastereomeric excess
were determined by GLC using Astec Chiraldex b-DM
4.5. General procedure for the enantioselective organo-
catalytic cyclopropanation
(30 m 0.25 mm), column (180 °C isotherm for 110 min),
*
To a 30 ml flask equipped with a magnetic stirring bar were
added chloroform (21 ml), aldehyde (0.5 mmol), and
0.025 mmol of the N-arylsulfonamide catalysts 1, 2, or 3.
The mixture was cooled to the desired temperature followed
by addition of 2-(dimethyl-k4-sulfanylidene)-1-phenyl-etha-
none (0.127 mmol; 23 mg) or 2-(dimethyl-k4-sulfanylidene)-
1-(40-bromophenyl)-ethanone (0.127 mmol; 33 mg). The
resulting homogenous yellow mixture was stirred for 38 h
after which the cold solution was filtered through a pad of
silica. The filtrate was concentrated under reduced pressure
to give the crude product as yellow oil, which was further
purified by means of column chromatography.
ramp to (220 °C, 10 °C/min, hold 0.50 min). Major diaste-
reomer: major enantiomer tR = 39.5 min and minor enan-
tiomer tR = 40.6 min. Minor diastereomer: major
enantiomer tR = 23.1 min and minor enantiomer tR =
22.5 min. MS (EI) m/z (rel. intensity): 295 ([M+H]+, 4),
294 (M+, 1), 296 (2), 251 (99), 252 (15), 253 (100), 254
(13), 183 (65), 184 (8), 185 (65), 186 (7), 155 (23).
4.9. (1R,2S,3R)-2-Benzoyl-3-phenyl-cyclopropanecarb-
aldehyde (Table 2, entries 7 and 8)
Prepared according to the general procedure. Purification
was done by means of flash chromatography (silica gel,
15% Et2O in n-pentane). The pure products were obtained
1
4.6. (1R,2S,3R)-2-Benzoyl-3-methyl-cyclopropane-
carbaldehyde (Table 2, entries 1 and 2)
as light yellow oils. The H NMR and 13C NMR spectro-
scopic data were in good agreement with data reported
earlier.12 The product (1R,2S,3R)-2-benzoyl-3-phenyl-
cyclopropane-carbaldehyde was dissolved in methanol–
acetate buffer pH 4.5 (1:1) after which sodium cyano boro-
hydride was added. The reaction was stirred for 8 h after
which the mixture was concentrated under reduced pres-
sure. To the residue was added 2 ml of brine followed by
extraction of the mixture with ethyl acetate. The ethyl ace-
tate was removed under reduced pressure providing the
product as yellow oil. The product was further purified
by means of column chromatography (silica gel; 70%
EtOAc in n-pentane) to give the product as a colorless
oil. 1H NMR (500 MHz; CDCl3): d 8.02–7.98 (m, 2H),
7.60–7.53 (m, 1H), 7.35–7.28 (m, 2H), 7.27–7.14 (m, 5H),
4.15 (m, 2H), 3.90 (dd, J = 12.1, 8.3 Hz, 1H), 3.02 (dd,
J = 8.8, 5.1 Hz, 1H), 2.94 (td, J = 5.7, 1.3 Hz, 1H), 2.42–
Prepared according to the general procedure. Purification
was performed by means of flash chromatography (silica
gel, 15% Et2O in n-pentane). The pure products were
1
obtained as light yellow oils. The H NMR and 13C NMR
spectroscopic data were in good agreement with data
reported earlier.12 The enantiomeric excess was determined
by GLC using Astec Chiraldex r-TA (30 m 0.25 mm),
*
column (160 °C isotherm for 60 min), ramp to (180 °C by
10 °C/min, hold 0.5 min). Major diastereomer: major enan-
tiomer tR = 10.9 min and minor enantiomer tR = 11.5 min.
MS (EI) m/z (rel. intensity): 187 (M+, 1), 171 (4), 144 (3),
115 (10), 105 (100), 89 (2), 77 (46), 69 (5), 51 (22). The dia-
1
stereomeric ratio was determined by H NMR analysis on
the crude reaction mixture.

A. Hartikka et al. / Tetrahedron: Asymmetry 18 (2007) 1403–1409
1409
2.33 (m, 1H). The enantiomeric excess was determined by
4.13. (1R,2S,3R)-2-(40-Bromo-benzoyl)-3-hex-5-enyl-cyclo-
propanecarbaldehyde (Table 2, entries 15 and 16)
HPLC equipped with chiral column Chiralcel AD (25%
2-propanol in hexane, 1 ml/min, 254 nm); Major diastereo-
mer: major enantiomer tR = 21.6 min and minor enantio-
mer tR = 28.3 min. Minor diastereomer: major enantiomer
tR = 12.3 min and minor enantiomer tR = 13.8 min.
Prepared according to the general procedure. Purification
was performed by means of flash chromatography (silica
gel, 15% Et2O in n-pentane). The pure products were ob-
1
tained as light yellow oils. The H NMR and 13C NMR
4.10. (1R,2S,3R)-2-Allyloxymethyl-3-benzoyl-cyclo-
propanecarbaldehyde (Table 2, entries 9 and 10)
spectroscopic data were in good agreement with data re-
ported earlier.12 The enantiomeric excess and diastereo-
meric excess were determined by GLC using Astec
Prepared according to the general procedure. Purification
was done by means of flash chromatography (silica gel,
15% Et2O in n-pentane) furnishing pure products as
light yellow oils. The 1H NMR and 13C NMR spectroscopic
data were in good agreement with data reported earlier.12
The enantiomeric excess and diastereomeric excess were
determined by GLC using Astec Chiraldex b-DM
Chiraldex b-DM (30 m 0.25 mm), column (195 °C iso-
*
therm for 150 min), ramp to 220 °C by 10 °C/min, 220 °C
hold 0.5 min. Major diastereomer: major enantiomer
tR = 41.5 min and minor enantiomer tR = 42.2 min. Minor
diastereomer: major enantiomer tR = 26.6 min and minor
enantiomer tR = 26.2 min. MS (EI) m/z (rel. intensity):
334 (M+, 1), 323 (8), 322 (4), 321 (8), 320 (2), 225 (23),
224 (12), 223 (22), 222 (4), 185 (100), 184 (13), 183 (98),
182 (4), 157 (41), 156 (7), 155 (36), 154 (4).
(30 m 0.25 mm), column (177 °C isotherm for 120 min),
*
ramp to (220 °C by 10 °C/min), hold 220 °C for 0.5 min.
Major diastereomer: major enantiomer tR = 28.1 min and
minor enantiomer tR = 29.5 min. Minor diastereomer:
major enantiomer tR = 13.5 min and minor enantiomer
tR = 14.1 min. MS (EI) m/z (rel. intensity): 245 ([M+H]+,
52), 244 (M+, 2), 173 (100), 117 (26), 116 (4), 105 (75),
104 (2), 77 (38), 76 (2).
Acknowledgments
˚
The authors wish to thank Vetenskapsradet (The Swedish
Research Council) for funding. Dr. Piotr Stefanowicz and
Professor Eugeniusz Zych, Department of Organic Chem-
istry, Faculty of Chemistry, University of Wrocław are
gratefully acknowledged for providing HR-MS data.
4.11. (1R,2S,3R)-2-Allyloxymethyl-3-(40-bromo-benzoyl)-
cyclopropanecarbaldehyde (Table 2, entries 11 and 12)
References
Prepared according to the general procedure. Purification
was done by means of flash chromatography (silica gel,
15% Et2O in n-pentane). The pure products were obtained
1. Patai, S.; Rappoport, Z. The Chemistry of the Cyclopropyl
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2. A thorough review has been published on the topic: Lebel,
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1
as light yellow oils. The H NMR and 13C NMR spectro-
scopic data were in good agreement with data reported
earlier.12 The enantiomeric excess and diastereomeric excess
were determined by GLC using Astec Chiraldex b-DM
(30 m 0.25 mm), column (200 °C isotherm for 130 min),
*
ramp to (220 °C by 10 °C), hold 0.5 min. Major dia-
stereomer: major enantiomer tR = 32.2 min and minor
enantiomer tR = 33.2 min. Minor diastereomer: major enan-
tiomer tR = 21.6 min and minor enantiomer tR = 22.3 min.
MS (EI) m/z (rel. intensity): 323 ([M+H]+, 7), 283 (5), 281
(8), 280 (1), 253 (97), 252 (16), 251 (100), 250 (4), 185 (53),
184 (8), 183 (55), 182 (2), 157 (22), 156 (4), 155 (21), 154 (1).
4.12. (1R,2S,3R)-2-Benzoyl-3-hex-5-enyl-cyclopropane-
carbaldehyde (Table 2, entries 13 and 14)
Prepared according to the general procedure. Purification
was done by means of flash chromatography (silica gel,
15% Et2O in n-pentane). The pure products were obtained
1
as light yellow oils. The H NMR and 13C NMR spectro-
scopic data were in good agreement with data reported ear-
lier.12 The enantiomeric excess and diastereomeric excess
were determined by GLC using Astec Chiraldex b-DM
(30 m 0.25 mm), column (160 °C isotherm for 150 min),
*
13. (a) Berkessel, A.; Burkhard, K.; Lex, J. Adv. Synth. Catal.
ramp to 220 °C by 10 °C/min, 220 °C hold 0.5 min. Major
diastereomer: major enantiomer tR = 60.2 min and minor
enantiomer tR = 63.1 min. Minor diastereomer: major
enantiomer tR = 47.1 min and minor enantiomer tR =
47.3 min. MS (EI) m/z (rel. intensity): 256 (M+, 3), 241
(15), 213 (20), 199 (20), 173 (50), 145 (25), 105 (100), 77 (60).
´
2004, 346, 1141; (b) Sunden, H.; Dahlin, N.; Ibrahem, I.;
Adolfsson, H.; Cordova, A. Tetrahedron Lett. 2005, 46, 3385;
(c) Wang, W.; Wang, J.; Hao, L.; Lixin, L. Tetrahedron Lett.
2004, 45, 7235.
14. Sato, S.; Watanabe, H.; Masatoshi, A. Tetrahedron: Asym-
metry 2000, 11, 4329.