Stereoselective sulfoxide formation from a thioproline derivative

Article abstract of DOI:10.1016/S0957-4166(02)00134-9

Oxidation of the PEP inhibitor, thioprolylpyrrolidine derivative 3 affords a mixture of the two possible trans- and cis-sulfoxide isomers 4 and 5. 3-Chloroperbenzoic acid oxidation resulted almost exclusive formation of the trans-isomer (α-sulfoxide, 4, d.e. >99% in CHCl₃), whereas when NaIO₄ was used the cis isomer (β-sulfoxide, 5) was also obtained, the ratio of the isomers varying with the reaction conditions applied. The structures of the separated isomers 4 and 5 were assigned on the basis of the aromatic solvent-induced shifts (ASIS) in the NMR spectra.

Full text of DOI:10.1016/S0957-4166(02)00134-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 491–495
†
Stereoselective sulfoxide formation from a thioproline derivative
K a´ roly K a´ nai, Benjamin Pod a´ nyi,* S a´ ndor Bokotey, F e´ lix Hajd u´ and Istv a´ n Hermecz
Chinoin Pharmaceutical and Chemical Works Co. Ltd, H-1045 Budapest, T o´ u. 1-5, Hungary
Received 8 February 2002; accepted 13 March 2002
Abstract—Oxidation of the PEP inhibitor, thioprolylpyrrolidine derivative 3 affords a mixture of the two possible trans- and
cis-sulfoxide isomers 4 and 5. 3-Chloroperbenzoic acid oxidation resulted almost exclusive formation of the trans-isomer
(
a-sulfoxide, 4, d.e. >99% in CHCl ), whereas when NaIO was used the cis isomer (b-sulfoxide, 5) was also obtained, the ratio
3
4
of the isomers varying with the reaction conditions applied. The structures of the separated isomers 4 and 5 were assigned on the
basis of the aromatic solvent-induced shifts (ASIS) in the NMR spectra. © 2002 Elsevier Science Ltd. All rights reserved.
7
–9
10
1. Introduction
sulfur atom or sulfoxide group in order to increase
11
the biological activity and/or water solubility.
Prolyl-oligopeptidase (PEP; EC 3.4.21.26) seems to play
1,2
an important role in the degradation of neuropep-
tides capable of changing the performance in learning
and memory tasks in both animals and humans. Its
inhibitors are therefore promising drug candidates for
Whereas the stereoselective chemical oxidation of sulfur
centers to 2–1a5fford sulfoxides has been widely
1
investigated
(the stereoselectivity rarely exceeds
95% e.e.), that of thioproline is not explored. The
3,4
the treatment and prevention of diseases with associ-
ated memory loss, such as Alzheimer’s disease and
senile dementia.
oxidation of Z-thioprolylpyrrolidine has recently been
10
reported using 3-chloroperbenzoic acid (MCPBA),
but no structural characterization of the product was
1
6
described. In our PEP inhibitor project we have devel-
oped a highly stereoselective oxidation of the model
A potent class of PEP inhibitors contains a prolylpyrro-
3
,5
lidine moiety,
which is thought to be crucial for
compound,
2-{3-oxo-3-[(4R)-4-(1-pyrrolidinylcar-
6
enzyme recognition. Several structural changes have
been made in the prolylpyrrolidine moiety, e.g. replace-
ment of one of the pyrrolidine methylene groups with a
bonyl)-1,3-thiazolidin-3-yl]propyl}-1H-isoindole-1,3-
(2H)-dione 3 and elucidated the structures of the
diastereomeric S-oxides 4 and 5 formed in the reaction.
Scheme 1. Synthesis of thioprolylpyrrolidine 3.
*
Corresponding author. Tel.: +36 1 3692500; fax: +36 1 3705597; e-mail: benjamin.podanyi@sanofi-synthelabo.com
Dedicated to Professor Andr a´ s Messmer on the occasion of his 80th birthday.
†
0
957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00134-9

4
92
K. K a´ nai et al. / Tetrahedron: Asymmetry 13 (2002) 491–495
2
. Results and discussion
from the values determined in CDCl . Lower ASIS
values are therefore expected for hydrogens on the side
3
2
.1. Chemistry
of the thioproline on which the oxygen atom is situated
than for the hydrogens on the opposite side, because
during solvation the benzene molecules avoid the nega-
tively charged oxygen atom of the sulfoxide moiety.
(
1,3-Dioxo-1H-isoindole-2-yl)propionic acid 1 was pre-
1
7
pared according to the literature method starting from
H-isoindole-1,3-dione and 3-aminopropionic acid.
1
1
Reaction of propionyl chloride, formed from 1 with
SOCl2 and (4R)-4-(1-pyrrolidinylcarbonyl)-1,3-thiazo-
lidine hydrochloride salt in the presence of NEt in
CH Cl gave the desired thioprolylpyrrolidine 3 in good
yield (Scheme 1). When 3 was oxidized with NaIO in
aqueous MeOH, the corresponding sulfoxide isomers 4
and 5 were obtained respectively with moderate
diastereoselectivity, which varied slightly with tempera-
ture (see Table 1). The diastereomeric sulfoxides 4 and
The assignments of the H NMR signals of the two
isomers 4 and 5 were supported by 2D NOESY mea-
surements. The assignment of the trans amide rotamers
4t and 5t was based on the NOE interaction between
the C(5)ꢀH2 and C(8)ꢀH2 methylene protons, which
proved that the trans amide rotamer is the predominant
1
8
3
2
2
4
form in CDCl3 and C D6 solutions. The NOESY
6
exchange peaks helped to identify the signals of the
corresponding cis amide rotamers 4c and 5c. The
assignments of the hydrogens of the diastereotopic
C(5)ꢀH and C(3)ꢀH methylene groups were based on
5
were separated by means of column chromatography.
The diastereoselectivity increased when MCPBA was
used as the oxidant in MeOH. Excellent diastereoselec-
2
2
their NOESY cross-peak intensity ratios in the knowl-
edge of the a-steric position of 2-H. The full assignment
was performed in CDCl and also in C D . The chemi-
tivity was achieved in CHCl with MCPBA for sulfox-
3
ide 4. In this case the diastereoselectivity seemed to be
little dependent on the temperature. The ratio of the
isomers 4 and 5 were determined from the crude reac-
tion mixtures by use of an RP-HPLC method (see
Section 4).
3
6
6
cal shifts in CDCl together with the ASIS values are
3
listed in Table 2.
The ASIS data on both trans- and cis-amide rotamers
of the minor isomer 5 unambiguously prove that the
configuration of the sulfoxide bond is b because the
induced shifts of the b-protons are smaller than those
of the a-hydrogen; the minor isomer has therefore the
cis structure 5. We observed intense NOE cross-peaks
between 2-H and 2%-H2 methylene protons in the
NOESY spectra of both 4t and 5t amide rotamers. As
thoroughly analyzed earlier in the case of a prolylpyrro-
2
.2. Structure elucidation
The RP-HPLC study of the products demonstrated that
the two isomers (a major one and a minor one) were
obtained in different ratios. Four sets of signals were
1
13
observed in the H and C NMR spectra of the
products, since both isomers exhibit hindered rotation
around the thioproline amide bond resulting in separate
signals for the trans and cis amide rotamers (see
Scheme 2). The sulfoxide isomers 4 and 5 were sepa-
rated by column chromatography in order to simplify
their structural assignment by NMR. Their structures
could be identified via the aromatic solvent-induced
20
lidine derivative this interaction indicates that the
NꢀC(1)ꢀC(2)ꢀN torsion angle in the predominant con-
formation is about 115°. This in turn means that the
amide group connected to C(1) also points in the
b-direction. The benzene molecules therefore prefer to
solvate the a-side of the thiazolidinyl ring 5 so as to
avoid interaction with the negatively charged oxygens
of the sulfoxide and amide moieties.
1
9
shifts (ASIS), where solvation by benzene results in a
chemical shift decrease. The ASIS values are calculated
by subtracting the measured chemical shifts in C D6
6
Table 1. Oxidation of the thioprolylpyrrolidine 3 to the a/b-sulfoxide isomers 4 and 5
Oxidant
NaIO4
Solvent
Temp. (°C)
Time (h)
Yielda (%)
D.e.a (%)
79.0
73.4
71.0
a-Sulfoxide 4
b-Sulfoxide 5
0
25
8
8
8
54
77
80
89.5
89.7
85.5
10.5
10.3
14.5
b
Aq. MeOH
50
0
25
0
25
7
7
7
7
65
68
72
80
99.6
99.6
96.6
92.7
99.8
99.8
99.3
96.4
0.2
0.2
0.7
3.6
b
MCPBA
CHCl3
MeOH
5
a
Diastereomeric excess determined by HPLC analysis.
b
The 1H NMR spectra of the crude reaction mixtures indicated a similar isomer ratio.

K. K a´ nai et al. / Tetrahedron: Asymmetry 13 (2002) 491–495
493
Scheme 2. Amide rotamers of 4 and 5 isomers.
1
a
Table 2. The H NMR chemical shifts in CDCl and the ASIS values of the thioprolyl ring of the 4 and 5 isomers (ppm)
3
Isomer
Rotamer
H-2a
H-3a
H-3b
H-5a
H-5b
trans
a-sulfoxide
cis
trans
cis
trans
cis
4t
4c
5t
5c
5.63 (0.20)
5.30 (0.28)
5.10 (0.41)
4.90 (0.40)
3.26 (0.66)
3.56 (0.73)
3.77 (0.71)
3.79 (0.70)
3.19 (0.59)
2.97 (0.91)
3.02 (0.29)
3.15 (0.25)
4.86 (0.68)
5.52 (0.10)
5.18 (0.64)
5.60 (0.24)
4.47 (0.68)
4.19 (0.54)
4.47 (0.20)
4.30 (0.03)
b-sulfoxide
a
The ASIS values are given in brackets.
The ASIS values for the cis amide rotamer of isomer 4
support the a-steric position of the sulfoxide oxygen,
while no significant differences were measured for the
trans amide rotamer between the ASIS data on the a-
and b-hydrogens. We explain this phenomena by the
competitive effect of the sulfoxide oxygen and the
amide oxygen connected to C(1) during solvation, since
the former points to the a-, and the later one to the
b-direction. Similarly larger differences were observed
in the ASIS values of the cis isomer as for the trans
form during the NMR study of N-acetyl-4-methoxycar-
C(1) carboxamide moiety is assumed. First, its position
adjacent to the reaction center allows the oxidant to
approach from the less hindered a-face of the substrate
3 resulting in a higher amount of a-sulfoxide 4. Fur-
thermore, the negatively charged oxygen atom in the
amide moiety might unfavorably interact with the aro-
matic part of a reagent such as MCPBA analogously
with the effect observed in C D6 during the ASIS
6
measurement. Consequently, higher diastereomeric
excesses were obtained for 4 with MCPBA than with
NaIO4.
21
bonyl-1,3-thiazolidine-1-oxide,
where the isomeric
structure was unambiguously elucidated by X-ray crys-
22
tallographic analysis.
3
. Conclusion
2
.3. Discussion of the origin of the stereoselectivity
In conclusion, the oxidation of thioprolylpyrrolidine
derivative 3 to the corresponding sulfoxides 4 and 5
proceeded with excellent diastereoselectivity when
MCPBA was applied for the oxidation of thioproline
The origin of the observed diastereoselectivity might be
given if the participation of the sterically encumbered

4
94
K. K a´ nai et al. / Tetrahedron: Asymmetry 13 (2002) 491–495
moiety. The biological activities of these oxygenated
derivatives will be reported elsewhere.
(DMSO-d ) l (ppm) cis amide rotamer 3c: 1.7–2.0 (m,
4H, H-3%a,b, H-4%a,b), 2.40, 2.65 (ddd, J=16.0, 9.2, 7.0
Hz, 1H; ddd, J=16.0, 8.7, 5.7 Hz, 1H, H-8a,b), 3.13
6
(
dd, J=11.6, 3.8 Hz, 1H, H-3b), 3.2–3.7 (m, 5H, H-3a,
4
. Experimental
H-2%a,b, H-5%a,b), 3.76 (m, 2H, H-9a,b), 4.33 (d, J=9.6,
Hz, 1H, H-5b), 4.76 (d, J=9.6 Hz, 1H, H-5a), 5.07 (dd,
J=7.4, 3.8 Hz, 1H, H-2a), 7.8–8.0 (m, 4H, aromatic
hydrogens). The ratio of amide rotamers 3t and 3c in
DMSO-d : 68:32 (in C D : 92:8). Anal. calcd for
1
H NMR spectra were recorded on a Bruker Avance
DRX 400 spectrometer (400 MHz, l=0 (TMS), in
DMSO-d , CDCl and C D solvents). Chemical shifts
6
3
6
6
6
6
6
are expressed in ppm, J values are given in Hz. All 2D
C H N SO : C, 58.90; H, 5.47; N, 10.85. Found: C,
58.79; H, 5.10; N, 10.92%.
19 21 3 4
NOESY NMR spectra were recorded in CDCl and
3
C D solvents using the standard Bruker pulse
sequences.
6
6
4.3. 2-{3-[(1R,4R)-1-Oxido-4-(1-pyrrolidinylcarbonyl)-
1
4
,3-thiazolidine-3-yl]propyl}-1H-isoindole-1,3(2H)-dione
The reversed phase HPLC tests were carried out on a
32
Waters instrument controlled by Millennium soft-
ware. The samples were dissolved in acetonitrile (c=1
mg/mL) then filtered through a 0.45 mm membrane
filter, and 10 mL of this solution was injected onto the
column by using a Waters 717 autosampler. Reversed
phase chromatographic conditions were as follows: sta-
tionary phase: Inertsil ODS2, 5 mm, 250×4.0 mm; gradi-
ent elution with a mixture of acetonitrile and 25 mM
NaH PO solution (pH 3.0 with cc. H PO ). Linear
gradient: acetonitrile content from 5 to 65% during 50
min. Flow rate: 1 mL/min. Detection wavelength: 207
nm. The trans isomer 4 eluted at 27.8 min, while the cis
isomer 5 eluted at 28.5 min.
To a stirred solution of compound 3 (0.97 g, 2.5 mmol)
in chloroform (10 mL) was slowly added MCPBA (0.72
g, 2.5 mmol). After stirring at 25°C for 7 h, aqueous
NaHCO3 was added to the reaction mixture. The
aqueous layer was extracted with CHCl (3×15 mL).
3
The combined organic layers were dried over MgSO4,
filtered and evaporated. The yellow foam residue was
purified by column of silica gel with CHCl –MeOH
2
4
3
4
3
40:1 as eluent. The a-sulfoxide isomer 4 was obtained.
Compound 4 a-sulfoxide (0.64 g, 63%; a white powder;
2
0
1
mp: 74–75°C); [h] =−84.5 (c=1, EtOH). H NMR
D
(CDCl ) l (ppm) a-sulfoxide trans amide rotamer 4t:
.8–2.2 (m, 4H, H-3%a,b, H-4%a,b), 2.81 (ddd, J=15.5,
3
1
4
1
.1. (1,3-Dioxo-1,3-dihydroisoindole-2-yl)propionic acid
9.3, 6.1 Hz, 1H, H-8a), 2.92 (ddd, J=15.5, 9.3, 6.1 Hz,
1H, H-8b), 3.19 (dd, J=13.8, 7.5 Hz, 1H, H-3b), 3.26
(
ddd, J=13.8, 7.5, 2.1 Hz, 1H, H-3a), 3.3–3.6 (m, 4H,
(
1,3-Dioxo-1,3-dihydroisoindole-2-yl)propionic acid 1
H-2%a,b, H-5%a,b), 4.04 (m, 2H, H-9ab), 4.47 (d, J=12.0
Hz, 1H, H-5b), 4.86 (dd, J=12.0, 2.1 Hz, 1H, H-5a),
1
7
was prepared according to the literary procedure,
starting from 1H-isoindole-1,3-dione and 3-aminopro-
pionic acid in 87–91% yield, mp: 149–151°C.
5.63 (t, J=7.5 Hz, 1H, H-2a), 7.6–7.9 (m, 4H, aromatic
1
hydrogens); H NMR (CDCl ) l (ppm) a-sulfoxide cis
3
amide rotamer 4c: 1.8–2.2 (m, 4H, H-3%a,b, H-4%a,b),
2.7 (m, 1H, H-8a), 2.9 (m, 1H, H-8b), 2.97 (dd, J=
ꢀ13, 8.2 Hz, 1H, H-3b), 3.56 (ddd, J=ꢀ13, 8.2, 2.7
Hz, 1H, H-3a), 3.3–3.6 (m, 4H, H-2%a,b, H-5%a,b), 3.9–
4.2 (m, 2H, H-9a,b), 4.19 (d, J=13.0 Hz, 1H, H-5b),
5.52 (dd, J=13.0, 2.7 Hz, 1H, H-5a), 5.30 (t, J=8.2
Hz, 1H, H-2a), 7.6–7.9 (m, 4H, aromatic hydrogens),
4
.2. 2-{3-oxo-3-[(4R)-4-(1-Pyrrolidinylcarbonyl)-1,3-thi-
azolidine-3-yl]propyl}-1H-iso-indole-1,3(2H)-dione 3
A
mixture of (1,3-dioxo-1,3-dihydroisoindole-2-yl)-
propionic acid 1 (2.36 g, 10.77 mmol) and SOCl (10
2
mL) was heated under reflux for 1 h. The excess SOCl2
was removed by distillation under reduced pressure.
The residue was dissolved in CH Cl (15 mL) and
1
the ratio of 4t and 4c: 94:6; H NMR (C D ) l (ppm)
6
6
a-sulfoxide trans amide rotamer 4t: 1.0–1.5 (m, 4H,
H-3%a,b, H-4%a,b), 2.41 (ddd, J=15.2, 9.2, 6.0 Hz, 1H,
H-8a), 2.59 (ddd, J=15.2, 9.2, 6.0 Hz, 1H, H-8b), 2.60
(m, 2H, H-3a,b), 2.68 (dt, J=10.2, 7.3 Hz, 1H, H-5%b),
3.12 (dt, J=12.1, 6.7 Hz, 1H, H-2%b), 3.32 (dt, J=12.1,
6.7 Hz, 1H, H-2%a), 3.68 (dt, J=10.2, 7.3 Hz, 1H,
H-5%a), 3.79 (d, J=12.1 Hz, 1H, H-5b), 3.88 (ddd,
J=14.8, 8.9, 6.0 Hz, 1H, H-9a), 4.04 (ddd, J=14.8, 8.9,
6.0 Hz, 1H, H-9b), 4.18 (dd, J=12.1, 1.6 Hz, 1H,
H-5a), 5.43 (t, J=7.5 Hz, 1H, H-2a), 6.7–6.9, 7.3–7.5
2
2
added to a solution of (4R)-4-(1-pyrrolidinylcarbonyl)-
18
1,3-thiazolidine HCl salt (2.40 g, 10.77 mmol) in
CH Cl (30 mL) and Et N (2.73 g, 3.74 mL, 26.9 mmol)
2
2
3
at −5°C. The resulting solution was stirred at room
temperature for 3 h and washed with 30% aqueous
citric acid, water, saturated aqueous NaHCO3 and
brine, consecutively. The organic layer was dried over
MgSO and evaporated to dryness. The resulting solid
was crystallized from CHCl /n-hexane to give the
4
3
2
0
1
product 3 (3.13 g, 74%); mp: 172–174°C); [h] =−91.4
(m, 4H, aromatic hydrogens); H NMR (C D ) l (ppm)
D
6
6
1
(
c=1, EtOH). H NMR (DMSO-d ) l (ppm) trans
a-sulfoxide cis amide rotamer 4c: 1.0–1.5 (m, 4H, H-
3%a,b, H-4%a,b), 2.06 (m, 1H, H-3b), 2.83 (m, 1H, H-3a),
3.01 (m, 1H, H-5%a), 3.50 (m, 1H, H-2%a), 3.65 (m, 1H,
H-5b), 5.02 (m, 1H, H-2a), 5.42 (m, 1H, H-5a), 6.6–6.9,
7.3–7.7 (m, 4H, aromatic hydrogens), the ratio of 4t
and 4c: 96:4. Anal. calcd for C H N SO : C, 56.56; H,
6
amide rotamer 3t: 1.7–2.0 (m, 4H, H-3%a,b, H-4%a,b),
2
9
.72, 2.88 (ddd, J=16.5, 9.2, 6.2 Hz, 1H; ddd, J=16.5,
.2, 6.2 Hz, 1H, H-8a,b), 2.97 (dd, J=11.6, 5.6 Hz, 1H,
H-3b), 3.2–3.7 (m, 5H, H-3a, H-2%a,b, H-5%a,b), 3.76
(
(
m, 2H, H-9a,b), 4.47 (d, J=8.8, Hz, 1H, H-5b), 4.77
19
21
3
5
d, J=8.8 Hz, 1H, H-5a), 4.93 (dd, J=7.6, 5.6 Hz, 1H,
5.25; N, 10.42; S, 7.93. Found: C, 56.43; H, 5.23; N,
10.38; S, 7.88%.
1
H-2a), 7.8–8.0 (m, 4H, aromatic hydrogens); H NMR

K. K a´ nai et al. / Tetrahedron: Asymmetry 13 (2002) 491–495
495
4.4. 2-{3-[(1S,4R)-1-Oxido-4-(1-pyrrolidinylcarbonyl)-
1,3-thiazolidine-3-yl]propyl}-1H-isoindole-1,3(2H)-dione
5
References
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2
To a stirred solution of compound 3 (2.55 g, 6.58
953–963.
mmol) in MeOH (15 mL) and H O (5 mL) at 50°C was
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2
added a solution of NaIO (1.54 g, 7.24 mmol) and the
4
resulting mixture was stirred at the same temperature
for 8 h. The white precipitate formed was filtered off.
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4. Cacabelos, R.; Alvarez, A.; Lombardi, V.; Fern a´ ndez-
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3
bined organic phases were dried over MgSO . The
4
organic solvent was removed in vacuo and the residue
6
. F u¨ l o¨ p, V.; B o¨ cskei, Z.; Polg a´ r, L. Cell 1998, 94, 161–170.
was purified by column of silica gel with CHCl –MeOH
3
7. Tsuru, D.; Yoshimoto, T.; Koriyama, N.; Furukawa, S.
4
0:1 as eluent to afford the a-sulfoxide 4 (1.68 g; 63%)
J. Biochem. 1988, 104, 580–586.
and b-sulfoxide 5 (0.12 g; 5%) isomers: compound 5
8
. K a´ nai, K.; Erd o˜ , S.; Sus a´ n, E.; Feh e´ r, M.; Sipos, J.;
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b-sulfoxide (0.12 g, 5%; white powder; mp: 104–105°C).
Anal. calcd for C H N SO : C, 56.56; H, 5.25; N,
1
9
21
3
5
1
7
0.42; S, 7.93. Found: C, 56.38; H, 5.21; N, 10.34; S,
9
. Umemura, K.; Kondo, K.; Ikeda, Y.; Nishimoto, M.;
Hiraga, Y.; Yoshida, Y.; Nakashima, M. J. Clin. Phar-
macol. 1999, 39, 462–470.
1
.88%. H NMR (CDCl ) l (ppm) b-sulfoxide trans
3
amide rotamer 5t: 1.8–2.2 (m, 4H, H-3%a,b, H-4%a,b),
2
1
3
.75–2.86 (m, 2H, H-8a,b), 3.02 (dd, J=12.5, 7.1 Hz,
H, H-3b), 3.40 (ddd, J=13.8, 9.4, 7.9 Hz, 1H, H-5%b),
.45 (dt, J=12.3, 7.0, 7.0 Hz, 1H, H-2%b), 3.56 (dt,
1
1
1
0. Yoshimoto, T.; Tsuru, D.; Yamamoto, N.; Ikezawa, R.;
Furukawa, S. Agric. Biol. Chem. 1991, 55, 37–43.
1. Caron, G.; Gaillard, P.; Carrupt, P.-A.; Testa, B. Helv.
Chim. Acta 1997, 80, 449–462.
2. Uemura, S. In Comprehensive Organic Synthesis; Trost,
B. M.; Fleming, I.; Steven, V. L., Eds.; Pergamon Press,
J=12.3, 7.0, 7.0 Hz, 1H, H-2%a), 3.77 (dd, J=12.5, 8.4
Hz, 1H, H-3a), 3.81 (ddd, J=13.8, 9.4, 7.0 Hz, 1H,
H-5%a), 4.01 (t, J=7.5 Hz, 2H, H-9a,b), 4.47 (d, J=10.2
Hz, 1H, H-5b), 5.10 (dd, J=8.4, 7.1 Hz, 1H, H-2a),
1
991; Vol. 7, pp. 757–787.
3. Kagan, H. B. Heteroar. Chem. [Int. Conf., 2nd] 1989,
07–219; CA, 1991, 115, 28320.
4. Conte, V.; Di Furia, F.; Licini, G.; Modena, G. Catal.
Met. Complexes 1991, 12, 91–105.
5
.18 (d, J=10.2 Hz, 1H, H-5a), 7.6–8.0 (m, 4H, aro-
1
1
1
1
matic hydrogens); H NMR (CDCl ) l (ppm) b-sulfox-
3
2
ide cis amide rotamer 5c: 1.8–2.2 (m, 4H, H-3%a,b,
H-4%a,b), 2.70 (m, 2H, H-8a,b), 3.15 (dd, J=13.8, 7.5
Hz, 1H, H-3b), 3.79 (m, 1H, H-3a), 4.30 (d, J=10.9
Hz, 1H, H-5b), 4.90 (m, 1H, H-2a), 5.60 (d, J=10.9
Hz, 1H, H-5a), 7.6–8.0 (m, 4H, aromatic hydrogens),
5. Kagan, H. B.; Rebiere, F.; Samuel, O. Phosphorus, Sul-
fur, Silicon Relat. Elem. 1991, 58, 89–110.
1
16. K a´ nai, K.; Erdo3 , S.; Szappanos, A.; Bence, J.; Hermecz,
the ratio of 5t and 5c: 87:13; H NMR (C D ) l (ppm)
6
6
I.; Szvoboda-Kanczel, I.; B a´ tori, S.; H e´ ja, G.; Balogh,
b-sulfoxide trans amide rotamer 5t: 1.1–1.4 (m, 4H,
H-3%a,b, H-4%a,b), 2.3–2.5 (m, 2H, H-8a,b), 2.65 (ddd,
J=14.0, 9.2, 7.1 Hz, 1H, H-5%b), 2.73 (dd, J=12.4, 6.9
Hz, 1H, H-3b), 3.06 (dd, J=12.4, 8.5 Hz, 1H, H-3a),
´
M.; Horv a´ th, A.; Sipos, J.; Barta-Bodor, V.; P a´ rk a´ nyi,
Zs.; Lakics, V.; Moln a´ r, P. HU 2426/95.
7. Griesbeck, A. G.; Kramer, W.; Lex, J.; Nerowski, F.;
Oelgem o¨ ller, M.; Peters, K.; Peters, E. M. Helv. Chim.
Acta 1997, 80, 912–933.
8. Arai, H.; Nishioka, H.; Niwa, S.; Yamanaka, T.; Tanaka,
Y.; Yoshinaga, K.; Kobayashi, N.; Miura, N.; Ikade, Y.
Chem. Pharm. Bull. 1993, 41, 1583–1588.
1
1
3
.16 (dt, J=11.9, 7.9, 7.9 Hz, 1H, H-2%b), 3.30 (ddd,
J=14.0, 10.1, 7.2 Hz, 1H, H-5%a), 3.33 (dt, J=11.9, 7.0,
.0 Hz, 1H, H-5%b), 3.75–4.0 (ddd, J=14.2, 8.4, 6.6 Hz,
7
ddd, J=14.2, 8.6, 5.9 Hz, 2H, H-9a,b), 4.27 (d, J=10.3
Hz, 1H, H-5b), 4.54 (d, J=10.3 Hz, 1H, H-5a), 4.69
1
2
2
9. Laszlo, P. Progr. Nucl. Magn. Reson. Spectrosc. 1967, 3,
(
4
dd, J=8.5, 6.9 Hz, 1H, H-2a), 6.90–6.97, 7.42–7.51 (m,
1
231–402.
H, aromatic hydrogens); H NMR (C D ) l (ppm)
6 6
0. Pod a´ nyi, B.; Bokotey, S.; K a´ nai, K.; Feh e´ r, M.; Her-
mecz, I. Magn. Reson. Chem. 1999, 37, 346–352.
1. Nachtergaele, W. A.; Anteunis, M. J. O. Bull. Soc. Chem.
Belg. 1980, 89, 749–758.
b-sulfoxide cis amide rotamer 5c: 1.1–1.4 (m, 4H, H-
3
ꢀ
%a,b, H-4%a,b), 2.60 (m, 2H, H-8a,b), 2.90 (dd, J=12.8,
7 Hz, 1H, H-3b), 3.09 (m, 1H, H-3a), 4.27 (m, 1H,
H-5b), 4.50 (t, J=ꢀ7 Hz, 1H, H-2a), 5.36 (d, J=11.4,
Hz, 1H, H-5a), 6.90–6.97, 7.42–7.51 (m, 4H, aromatic
hydrogens), the ratio of 5t and 5c: 93:7.
22. Tinant, B.; Declercq, J. P.; Germain, G.; Van Meerssche,
M. Cryst. Struct. Commun. 1982, 11, 523–527.