A novel 2 H -azirin-3-amine as a synthon for a sulfur-containing dipeptide segment

Article abstract of DOI:10.1080/17415993.2013.774401

Starting with tetrahydro-2H-thiopyran-4-carboxylic acid and methyl prolinate, the novel 2H-azirin-3-amine [S]-N-(1-aza-6-thiaspiro[2.5]oct-1-en-2- yl)proline methyl ester was synthesized. In reactions with benzoic acid, thiobenzoic acid and Boc-valine, respectively, its usefulness as a synthon for the dipeptide [S]-N-[(4-aminotetrahydro-2H-thiopyran-4-yl)carbonyl]proline in peptide synthesis was demonstrated.

Full text of DOI:10.1080/17415993.2013.774401

Journal of Sulfur Chemistry, 2014
Vol. 35, No. 1, 14–23, http://dx.doi.org/10.1080/17415993.2013.774401
A novel 2H-azirin-3-amine as a synthon for a sulfur-containing
dipeptide segment
Svetlana A. Stoykova, Anthony Linden and Heinz Heimgartner*
Institute of Organic Chemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
(Received 10 January 2013; final version received 5 February 2013)
Starting with tetrahydro-2H-thiopyran-4-carboxylic acid and methyl prolinate, the novel 2H-azirin-3-
amine (S)-N-(1-aza-6-thiaspiro[2.5]oct-1-en-2-yl)proline methyl ester was synthesized. In reactions with
benzoic acid, thiobenzoic acid and Boc-valine, respectively, its usefulness as a synthon for the dipeptide
(
S)-N-[(4-aminotetrahydro-2H-thiopyran-4-yl)carbonyl]proline in peptide synthesis was demonstrated.
O
S
N
L.R.
N
1. COCl ,Toluene
2
S
S
S
Toluene
80 °C
2. DABCO,THF
CO Me
CO Me
2
2
3
. NaN ,DMF/THF
3
S
O
Boc-Val-OH
N
H
N
N
THF, 0 °C to rt
Boc
N
N
CO Me
H
2
CO Me
O
2
Keywords: 2H-azirin-3-amines; N-(1-aza-6-thiaspiro[2.5]oct-1-en-2-yl)proline methyl ester; α-amino
acids; 4-aminotetrahydro-2H-thiopyran-4-carboxylic acid; sulfur-heterocyclic amino acids
1
.
Introduction
In the past, we have shown that 2,2-disubstituted 2H-azirin-3-amines 1 are building blocks for
,2-disubstituted α-amino acids in the synthesis of heterocycles as well as of peptides (1–3). The
2
smooth coupling reaction with N-protected amino acids or peptides 2 to give extended peptide
amides 3 does not need any additional reagent, and the subsequent hydrolysis of the terminal
amide group leading to peptides 4 occurs selectively (Scheme 1). This method has been used
successfully toward the synthesis of natural peptaibol antibiotics (4–10).
Spiroheterocyclic 2H-azirines of type 1b, which serve as synthons for heterocyclic
α-amino carboxylic acids, form a special class of these synthons (11–15). For example, the
tetrahydro-2H-thiopyran derivative 1b (X = S, n = 1) has been used to prepare tripeptides
*Corresponding author. Email: heimgart@oci.uzh.ch
©
2013 Taylor & Francis

Journal of Sulfur Chemistry 15
R
R
O
H
N
N(Me)Ph
CH Cl2
2
N
COOH
+
N
N(Me)Ph
H
H
N
rt
O
2
1a
3
3
NHCl
H O/THF
2
H N
COOH
2
R
X
(CH2)
n
H
N
N(Me)Ph
COOH
N
H
N
S
O
1
b X=NR,O,S
5
4
n =0,1
Scheme 1. Reaction of 2H-azirin-3-amines with amino acids and selective hydrolysis; the
azirine/oxazolone method’.
‘
containing 4-aminotetrahydro-2H-thiopyran-4-carboxylic acid (5) (12). This heterocyclic amino
acid has been described as a cyclic homocysteine (16) or methionine analog (17) and was prepared
via Strecker synthesis (18), the Bucherer–Bergs reaction (17, 19), or the Ugi reaction (20). The
crystal structure of 5 has been published in 1976 (21). The interest in amino acid 5 is based on
the biological activities of some of its derivatives, e.g., as inhibitors of S-adenosyl L-methionine
synthetase (19), glycogen phosphorylase inhibitor (22), or ecdysone agonist (23).
Heterocyclic amino acids of type 5 have also been used in the synthesis of conforma-
tionally restricted peptides (24). Like other α,α-disubstituted α-amino acids, the presence of
5
forces peptides to form β-turns (12) or helical conformations. In our studies toward the
synthesis of such sterically congested oligopeptides with a helical conformation by using
the ‘azirine/oxazolone method’ (25–29), we introduced N-(2,2-dimethyl-2H-azirin-3-yl)proline
methyl ester as a dipeptide (Aib-Pro) synthon (30–32) as well as other dipeptide (Xaa-Pro) syn-
thons, including those with Xaa being a heterocyclic α-amino acid (13, 33, 34). The aim of the
present study was the synthesis of (S)-N-(1-aza-6-thiaspiro[2.5]oct-1-en-2-yl)proline methyl ester
(
1c) and its use as a (S)-N-[(4-aminotetrahydro-2H-thiopyran-2-yl)carbonyl]proline (Tht-Pro)
synthon.
2
2
.
Results and discussion
.1. Synthesis of the heterospirocyclic azirine 1c
As the method of Villalgordo and Heimgartner (35) for the synthesis of 2H-azirin-3-amines 1,
used by Strässler for the preparation of 1b (n = 1) (12), is limited to N-alkyl-N-phenyl deriva-
tives, we decided to prepare N-[(tetrahydro-2H-thiopyran-4-yl)thiocarbonyl]-L-proline methyl
ester (9), with the aim of following the protocol of the aminoazirine synthesis published by
Rens and Ghosez (36) and modified by Dietliker and Heimgartner (37). Thus, tetrahydro-2H-
thiopyran-4-carboxylic acid chloride (6) (12) was reacted with L-proline methyl ester (7) to
give N-[(tetrahydro-2H-thiopyran-4-yl)carbonyl]-L-proline methyl ester (8) in 85% yield, which
was converted to 9 by thionation with Lawesson reagent in 67% yield (Scheme 2). In anal-
ogy to the procedure described in Luykx et al. (30) and to the protocol for the synthesis of 1b

1
6 S.A. Stoykova et al.
(
X = O, n = 1) [34], consecutive treatment of a solution of 9 in CH2Cl2 and catalytic amounts
of DMF with COCl2, evaporation of the solvent, dissolution of the residue in THF, addition of
1
6
,4-diazabicyclo[2.2.2]octane (DABCO), filtration, and reaction with NaN3 gave azirine 1c in
7% yield. Because of the decomposition of the crude product during its purification using col-
umn chromatography (CC) (SiO2), the compound was used in the next reactions without further
purification.
O
S
COCl
AcOEt
Et N
N
L.R.
N
+
CO Me
S
S
N
H
2
3
Toluene
80°C
S
CO Me
CO Me
2
2
6
7
8
9
1
. COCl ,Toluene
S
2
N
2
. DABCO,THF
N
CO Me
2
3
. NaN ,DMF/THF
3
1
c
Scheme 2. Synthesis of the dipeptide (Tht-Pro) synthon 1c.
2
.2. Reactions of 1c with carboxylic and thiocarboxylic acids
For the chemical characterization of 1c, reactions with thiobenzoic acid (PhCOSH) and 4-
◦
bromobenzoic acid (p-BrBz-OH) were performed in THF at 0 C to room temperature (34) (for
reactions of 1c with H2O and H2S, see Budzowski et al. (38)). After chromatographic workup of
the mixture of the reaction with p-BrBz-OH, p-bromobenzoyl-dipeptide methyl ester 10 was iso-
latedin45%yield. Similarly, aftersuccessfulchromatography, theN-benzoylatedendothiopeptide
methyl ester 11 was obtained in 85% yield (Scheme 3).
With the aim of testing the utility of 1c as a dipeptide synthon (Tht-Pro) in peptide synthesis,
the reaction with Boc-protected L-valine (Boc-Val-OH) was carried out in THF. A solution of
◦
◦
Boc-Val-OH (1 mol-equiv.) in THF was cooled to 0 C. Then, 1c (2 mol-equiv.) was added at 0 C,
and the mixture was stirred for 43 h at room temperature. After chromatographic purification of
the product, the N-protected tripeptide methyl ester Boc-Val-Tht-Pro-OMe (12) was obtained in
4
4% yield as a white foam (Scheme 3). Suitable single crystals of 12 could be obtained from
CHCl3/hexane by slow evaporation of the solvent, and its structure was established by an X-ray
crystal structure analysis (Figure 1).
Although there is no intramolecular H-bond present, the peptide backbone of 12 adopts a
conformation resembling β-turns of Aib-containing oligopeptides. The torsion angles φ (C(6)-
C(5)-N(4)-C(3)) and ψ (N(4)-C(5)-C(6)-N(7)) of the tetrahydro-2H-thiopyran-4-yl (Tht) residue
◦
◦
are 53.1(2) and 38.9(2) , respectively. They are close to the values expected for an amino acid
in a β-turn of type I or III. Each N-H group of the molecule acts as a donor for intermolec-
ular H-bonds: N(1)-H forms an intermolecular H-bond with the ester carbonyl O-atom at the
ꢀ
◦
opposite end of a neighboring molecule (N(1)· · · O(9 ): 2.955(2) Å, N-H· · · O angle: 170(2) ).
This interaction links the molecules into extended one-dimensional chains which run parallel to
the [010] direction and have a graph set motif (40) of C(11). N(4)-H interacts with the sec-
ꢀ
ꢀ
ondary amide O-atom of a different neighboring molecule (N(4)· · · O(6 ): 2.976(2)Å, angle

Journal of Sulfur Chemistry 17
COOH
S
O
Br
N
N
H
THF, 0 °C to rt
O
CO2Me
Br
1
0 (45%)
S
O
PhCOSH
S
N
N
Ph
N
THF, 0 °C to rt
H
N
CO Me
S
CO Me
2
2
1c
11 (85%)
S
O
Boc-Val-OH
H
N
N
THF, 0 °C to rt
Boc
N
H
O
CO2Me
12 (44%)
Scheme 3. Reactions of 1c with carboxylic, thiocarboxylic, and amino acids.
Figure 1. ORTEP plot (39) of the molecular structure of 12 (with 50% probability ellipsoids; arbitrary numbering of
atoms).

1
8 S.A. Stoykova et al.
Figure 2. Crystal packing diagram of 12, showing the H-bonding interactions (uninvolved H-atoms omitted for clarity).
◦
1
67(2) ), and thereby links the molecules into extended one-dimensional chains which run parallel
to the [100] direction and have a graph set motif of C(5). The combination of both interac-
tions links the molecules into a two-dimensional network, which lies parallel to the (001) plane
(
Figure 2).
3
.
Conclusions
The studies presented show that the new spirocyclic N-(2H-azirin-3-yl)proline derivative 1c can
be prepared according to previously reported protocols. In the reactions with PhCOSH, p-BrBz-
OH, and N-protected α-amino acids, 1c behaves like other 2H-azirin-3-amines (= 3-amino-2H-
azirines) that have been used extensively as building blocks for α, α-disubstituted glycines in
peptide synthesis. The novel amino azirine 1c was shown to be a synthon for the dipeptide N-[(4-
aminotetrahydro-2H-thiopyran-4-yl)carbonyl]-L-proline (Tht-Pro). In the crystal, the prepared
tripeptide Boc-Val-Tht-Pro-OMe (12) adopts a β-turn conformation, despite the lack of the typical
intramolecuar hydrogen bond. This is a further proof of the intrinsic property of α,α-disubstituted
α-amino acids to stabilize β-turns or 310-helical structures in peptides (see Stoykova et al. (32)
and references cited therein).

Journal of Sulfur Chemistry 19
4
4
.
Experimental
.1. General
All purchased chemicals were of analytical grade and used without further purification; solvents
were purified by standard procedures. TLC was performed using pre-coated aluminium sheets
(
Merck silica gel 60F254), and CC on silica gel C-560 (230–400 mesh; Uetikon-Chemie). Melting
points were determined on a Büchi Melting Point B-450 apparatus and are not corrected. IR spectra
−
1
1
were recorded on a Perkin-Elmer, Spectrum one FT-IR spectrophotometer in KBr (cm ), H (300
1
3
or 600 MHz) and C NMR spectra (75.6 or 150 MHz) on a Bruker AC-300 or Bruker DRX-600
13
spectrometer in CDCl3 (ppm, J in Hz), C-signal multiplicity from DEPT spectra, and mass
spectra on a Finnigan SSQ-700 (CI with NH3) or Finnigan TSQ-700 (ESI) instrument, significant
peaks in m/z (rel. %).
4
.2. Synthesis of (S)-N-[(tetrahydro-2H-thiopyran-4-yl)carbonyl]proline methyl ester (8)
To cooled MeOH (8 ml) was slowly added SOCl2 (1.73 ml) keeping the temperature below
◦
0
C. Then, (S)-proline (2.53 g, 21.97 mmol) was added, and the mixture was heated at reflux
for 1 h. Excess MeOH was evaporated, the sticky pale-yellow crude methyl (S)-prolinate (7)
was dissolved in AcOEt (8 ml), Et3N (6.12 ml) and tetrahydro-2H-thiopyran-4-carbonyl chloride
◦
(
6, 3.62 g, 21.97 mmol) (12) were added at 0 C, and the mixture was stirred at r.t. overnight. After
evaporation of AcOEt, the residue was dissolved in CH2Cl2, the solution was washed with sat.
aqueous NaCl solution, dried over MgSO4, CH2Cl2 was evaporated, and the residue was distilled
◦
(
bulb-to-bulb, 190 C/5.10–2 mbar): 4.81 g (85%) of 8. Pale yellow oil: IR (film): 2951s, 1744s,
1
9
643s, 1434s, 1357m, 1303w, 1271m, 1239w, 1197s, 1175s, 1116w, 1096w, 1029w, 1012w,
34m, 733m. H-NMR: 4.49–4.45 (m, CH(α)(Pro)); 3.72 (s, MeO); 3.68–3.65, 3.58–3.53 (2m,
1
CH2(δ)(Pro)); 2.73–2.71 (m, CH2(2), CH2(6)(Tht)); 2.46–2.42 (m, CH(4)(Tht)); 2.20–2.06 (m, 3
13
H); 2.02–1.89 (m, 5 H). C-NMR: 173.5, 172.7 (2s, 2 C=O); 58.5 (d, CH(α)(Pro)); 52.0 (q, MeO);
4
2
6.7 (t, CH2(δ)(Pro)); 42.5 (d, C(4)(Tht)); 30.1, 29.8 (2t, C(2), C(6)(Tht)); 29.5 (t, CH2(β)(Pro));
+
7.7, 27.6 (2t, C(3), C(5)(Tht)); 24.7 (t, CH2(γ )(Pro)). CI-MS: 275 (30, [M + NH4] ), 258 (100,
+
[
M + H] ).
4
.3. Synthesis of (S)-N-[(tetrahydro-2H-thiopyran-4-yl)thiocarbonyl]proline methyl ester (9)
To a solution of 8 (3.89 g, 15.1 mmol) in abs. toluene (46 ml) was added the Lawesson reagent
(
7.4 g, 18.3 mmol), and the mixture was stirred at reflux for 4 h and then at r.t. overnight. Then,
the mixture was filtered (Celite), the solvent evaporated, and the crude product was purified
by gradient chromatography (SiO2, CH2Cl2/MeOH from 200:1 to 150:1) to give 2.77 g (67%)
1
of 9. Pale-yellow oil: H-NMR: 5.15 (dd, J = 8.6, 8.4 CH(α)(Pro)); 3.91–3.85, 3.77–3.75 (2m,
1
3
CH2(δ)(Pro)); 3.72 (s, MeO); 2.84–2.63 (m, 5 H); 2.31–2.00 (m, 8 H). C-NMR: 206.1 (s, C=S);
1
3
70.9 (s, C=O); 64.9 (d, CH(α)(Pro)); 52.2 (q, MeO); 50.2 (t, CH2(δ)(Pro)); 49.0 (d, C(4)(Tht));
3.4, 32.9 (2t, C(2), C(6)(Tht)); 28.6, 28.2 (2t, C(3), C(5)(Tht)); 28.0 (t, CH2(β)(Pro)); 24.5 (t,
+
CH2(γ )(Pro)). EI-MS: 273 (100, M ), 226 (37), 212 (43).
4
.4. Synthesis of methyl (S)-N-(1-aza-6-thiaspiro[2.5]oct-1-en-2-yl)proline methyl
ester (1c)
In a dried two-neck round-bottom flask, a solution of 9 (2.5 g, 9.14 mmol) in abs. CH2Cl2 (11 ml)
◦
and three drops of DMF was cooled to 0 C. After slow addition of 5.5 ml of a COCl2 solution in
toluene (2 M, 11 mmol), the mixture was stirred at r.t. for 1 h, and then the solvent was evaporated.

2
0 S.A. Stoykova et al.
◦
The residue was dissolved in THF (22.5 ml), DABCO (1.23 g, 11 mmol) was added at 0 C, and
the mixture was stirred at r.t. for 40 min. The solid was removed by filtration underAr and washed
with THF. To the pale yellow solution was added NaN3 (1.78 g, 27.42 mmol), the mixture was
stirred at r.t. overnight, filtered through a Celite pad, and the solvent was evaporated. The residue
was dissolved in AcOEt, the solution was washed with sat. aqueous NaHCO3 and NaCl solution,
the organic layer was dried over MgSO4, and evaporated. The crude product 1c was obtained in
67% yield. It could not be purified by chromatography because of decomposition; therefore, it
was used without further purification.
4
.5. General procedure for reactions of 1c with PhCOSH, p-BrBz-OH, and Boc-Val-OH
◦
To a solution of the acid in dry THF at 0 C, a solution of ca. 2 mol-equiv. of 1c in dry THF was
added dropwise. The mixture was stirred at r.t.After completion of the reaction (TLC), the solvent
was evaporated in vacuo and the residue was purified by gradient CC (SiO2; CH2Cl2/MeOH).
4
.5.1. (S)-N-({4-[(4-Bromobenzoyl)amino]tetrahydro-2H-thiopyran-4-yl}carbonyl)proline
methyl ester (p-BrBz-Tht-Pro-OMe, 10)
According to the general procedure, p-BrBz-OH (196 mg, 0.975 mmol) and 1c (496 mg,
1
.950 mmol), stirring for 20 h, and CC (CH2Cl2/MeOH from 150:1 to 40:1) gave 199.8 mg (45%)
◦
of 10. White foam. M.p. 238–239 C. IR: 3331m, 2951m, 2924m, 1744s, 1651s, 1617s, 1591m,
1
1
567w, 1530s, 1482s, 1440m, 1407m, 1359m, 1315w, 1298w, 1279w, 1245w, 1207m, 1174s,
112w, 1066m, 1040w, 1011m, 760m. H-NMR (CD3OD): 7.78–7.74 (m, 2 arom. H); 7.69–7.64
1
(
2
1
m, 2 arom. H); 4.51–4.48 (m, CH(α) (Pro)); 3.78–3.75 (m, 1 H); 3.72 (s, MeO); 2.97–2.83 (m,
H); 2.76–2.52 (m, 3 H); 2.41–2.18 (m, 3 H); 2.11–1.82 (m, 5 H). C-NMR (CD3OD): 173.3,
71.0 (2s, 2 C=O); 165.5 (s, ArC=O); 132.3 (s, 1 arom. C); 131.8, 128.7 (2d, 4 arom. CH); 126.6
1
3
(
s, 1 arom. C); 60.6 (d, CH(α)(Pro)); 58.6 (s, C(4)(Tht)); 52.0 (q, MeO); 47.6 (t, CH2(δ)(Pro));
8
1
+
3
[
3.3, 32.8, 27.4, 25.7, 24.2, 23.1 (6t, 6 CH2). ESI-MS: 479 (100, [M( Br) + Na] ), 477 (96,
M( Br) + Na] ).
7
9
+
4
.5.2. (S)-N-{[4-(Benzoylamino)tetrahydro-2H-thiopyran-4-yl]thiocarbonyl}proline methyl
ester (Bz-Tht-Ψ (CS)-Pro-OMe, 11)
According to the general procedure, PhCOSH (28 mg, 0.203 mmol) and 1c (103.4 mg,
0
.407 mmol), stirring for 90 h, and CC (CH2Cl2/MeOH from 150:1 to 110:1) gave 67.7 mg
◦
(
85%) of 11. White foam. M.p. 139–140 C. IR: 3452m, 2949m, 2924m, 1741s, 1638s, 1601w,
1
9
579m, 1449w, 1409s, 1348w, 1276m, 1248m, 1203m, 1171s, 1107m, 1057w, 1043w, 1001m,
65m, 877m, 799m, 716s, 646m. H-NMR (CD3OD): 7.59 (d, J = 7.0, 2 arom. H); 7.61–7.48
1
(
m, 3 arom. H); 5.06 (broad d, J = 6.3, CH(α) (Pro)); 4.06–4.00 (m, 1 H); 3.68 (s, MeO); 3.59–
3
3
.53 (m, 1 H); 3.21–3.11 (m, 1 H); 2.91–2.80 (m, 3 H); 2.59–2.55 (m, 3 H); 2.25–1.90 (m, 5 H).
1
C-NMR (CD3OD): 206.2 (s, C=S); 173.1 (s, C=O); 168.9 (s, PhC=O); 135.3 (s, 1 arom. C);
1
5
3
33.1, 129.8, 127.8 (3d, 5 arom. CH); 70.2 (d, CH(α) (Pro)); 64.6 (s, C(4)(Tht)); 54.0 (q, MeO);
+
3.7 (t, CH2(δ)(Pro); 36.8, 36.1, 28.5, 26.9, 24.9, 24.1 (6t, 6 CH2). CI-MS: 410 (32, [M + NH4] ),
93 (100, [M + H] ), 361 (78, [M – OMe] ), 272 (17).
+
+
4
.5.3. (S)-N-{[4-({(2S)-2-[(tert-Butoxycarbonyl)amino]-3-methylbutanoyl}amino)tetrahydro-
2
H-thiopyran-4-yl]carbonyl}proline methyl ester (Boc-Val-Tht-Pro-OMe, 12)
According to the general procedure, Boc-Val-OH (126.4 mg, 0.582 mmol) and 1c (296 mg,
1
.164 mmol), stirring for 43 h, and CC (CH2Cl2/MeOH from 150:1 to 110:1) gave 120 mg
◦
(
44%) of 12. White foam. M.p. 225–226 C. IR: 3370s, 3321s, 2974m, 1732s, 1711s, 1686s,

Journal of Sulfur Chemistry 21
1
1
4
603s, 1528s, 1427m, 1391w, 1361m, 1322w, 1276w, 1245m, 1220m, 1171s, 1097m, 1068w,
1
039w, 985m, 924m, 881m, 609m. H-NMR: 7.24 (s, NH); 5.06 (d, J = 8.9, NH(Val)); 4.58–
.50 (m, CH(α)(Pro)); 3.86–3.83 (m, CH(α)(Val)); 3.71 (s, MeO); 3.64–3.62, 3.60–3.51 (2m,
CH2(δ)(Pro)); 3.10–2.87 (m, 1 H); 2.68–2.59 (m, 4 H); 2.20–2.16 (m, CH(β)(Val)); 2.12–1.98
1
3
(
1
(
m, 5 H); 1.89–1.83 (m, 2 H); 1.46 (s, 9 H, Me3C); 1.00–0.94 (2d, J = 6.8, 2 Me(Val)). C-NMR:
73.0, 170.3, 170.0 (3s, 3 C=O); 155.9 (s, C=O(Boc)); 80.1 (s, Me3C); 60.5 (d, CH(α)(Pro)); 60.1
d, CH(α)(Val)); 58.1 (s, C(4)(Tht)); 51.9 (q, MeO); 47.4 (t, CH2(δ)(Pro)); 33.3, 33.2 (2t, C(2),
C(6)(Tht)); 30.1 (d, CH(β)(Val)); 28.2 (q, Me3C); 27.5 (t, CH2(β)(Pro)); 25.9 (t, CH2(γ )(Pro));
+
2
4.2, 23.2 (2t, C(3), C(5)(Tht)); 19.5, 17.9 (2q, 2 Me(Val)). ESI-MS: 494 (100, [M + Na] ).
Suitable crystals of 12 for the X-ray crystal-structure determination were grown from
CHCl3/hexane by slow evaporation of the solvent at r.t.
5
.
X-ray crystal-structure determination of 12
All measurements were made on a Nonius KappaCCD area-detector diffractometer (41)
using graphite-monochromated MoKα radiation (λ = 0.71073Å) and an Oxford Cryosystems
Cryostream 700 cooler. Data reduction was performed with HKL Denzo and Scalepack (42).
The intensities were corrected for Lorentz and polarization effects, and an absorption correc-
tion based on the multi-scan method (43) was applied. Equivalent reflections, other than Friedel
1
pairs, were merged. Data collection and refinement parameters are given below, and views of
the molecule and the crystal packing are shown in Figures 1 and 2. The structures was solved by
direct methods using SIR92 (44), which revealed the positions of all non-H-atoms. The non-H-
atoms were refined anisotropically. The amide H-atoms were placed in the positions indicated by
a difference electron density map, and their positions were allowed to refine together with indi-
vidual isotropic displacement parameters. All remaining H-atoms were placed in geometrically
calculated positions and refined using a riding model where each H-atom was assigned a fixed
isotropic displacement parameter with a value equal to 1.2Ueq of its parent C-atom (1.5Ueq for the
2
methyl groups). Refinement of the structure was carried out on F using full-matrix least-squares
2
2 2
procedures, which minimized the function ꢀw(F − F ) . A correction for secondary extinction
o
c
was applied. Refinement of the absolute structure parameter (45) yielded a value of –0.01(5),
which confidently confirms that the refined coordinates represent the true enantiomorph. Neutral
atom scattering factors for non-H-atoms were taken from ref. (46), and the scattering factors for
H-atoms were taken from ref. (47). Anomalous dispersion effects were included in Fc (48); the
values for f and f were those of ref. (49). The values of the mass attenuation coefficients are
those of ref. (50). All calculations were performed using the SHELXL97 (51) program.
ꢀ
ꢀꢀ
5
.1. Crystal data for 12
C22H37N3O6S, M = 471.61, crystallized from CH3Cl/hexane, colorless, tablet, crystal dimen-
sions 0.07 × 0.15 × 0.18 mm, triclinic, space group P1, Z = 1, reflections for cell determi-
◦
nation 23944, 2θ range for cell determination 4–55 , a = 6.1889(2)Å, b = 10.0211(3)Å,
◦
◦
◦
3
c = 10.8337(4)Å, α = 95.567(1) , β = 96.425(1) , γ = 107.156(1) , V = 631.96(4)Å , T =
3
−1
1
5
60(1) K, DX = 1.239 g/cm , μ(MoKα) = 0.168 mm , scan type φ and ω, 2θ(max) =
◦
5 , transmission factors (min; max) = 0.883; 0.990, total reflections measured 14952,
symmetry-independent reflections 5406, reflections with I > 2σ(I) 4984, reflections used
in refinement 5406, parameters refined 304, restraints 3; R(F) [I > 2σ(I) reflections] =
2
2
2
o
2
−1
0
(
.0335, wR(F ) [all data] = 0.0843 (w = [σ (F ) + (0.0367P) + 0.0767P] , where P =
2
o
2
c
F + 2F )/3), goodness of fit 1.052, secondary extinction coefficient 0.075(8), final ꢁmax/σ
3
0
.001, ꢁρ (max; min) = 0.23; −0.20 e/Å .

2
2 S.A. Stoykova et al.
Acknowledgements
We thank the analytical services of our institute for spectra and analyses, and the Swiss National Science Foundation and
F. Hoffmann-La Roche AG, Basel, for financial support.
Note
1
.
CCDC-890143 contains the supplementary crystallographic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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