Preparation of saccharin derivatives of amino acids as potential peptidomimetic building blocks

Article abstract of DOI:10.1080/00397910802149105

We present a useful route for the preparation of saccharin derivatives of amino acids. Sixteen new compounds, saccharin-derived amino acids, were synthesized, all of them bearing additional functional groups either at the 5- or 6-position of the saccharin skeleton, thus rendering the compounds more amenable to functionalization. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802149105

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Preparation of Saccharin
Derivatives of Amino Acids
as Potential Peptidomimetic
Building Blocks
Žiga Jakopin a & Marija Sollner Dolenc a
a Faculty of Pharmacy, University of Ljubljana,
Ljubljana, Slovenia
Version of record first published: 30 Sep 2008.
To cite this article: Žiga Jakopin & Marija Sollner Dolenc (2008): Preparation of
Saccharin Derivatives of Amino Acids as Potential Peptidomimetic Building Blocks,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 38:20, 3422-3438
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Synthetic Communications1, 38: 3422–3438, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802149105
Preparation of Saccharin Derivatives of
Amino Acids as Potential Peptidomimetic
Building Blocks
ˇ
Ziga Jakopin and Marija Sollner Dolenc
Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
Abstract: We present a useful route for the preparation of saccharin derivatives
of amino acids. Sixteen new compounds, saccharin-derived amino acids, were
synthesized, all of them bearing additional functional groups either at the 5- or
6-position of the saccharin skeleton, thus rendering the compounds more
amenable to functionalization.
Keywords: Amino acid, bidentate ligands, oxidative cyclization, peptidomimetic,
Saccharin
INTRODUCTION
Saccharin, 1,2-benzisothiazole-3-one-1,1-dioxide, is a well-known hetero-
cyclic compound and has been used as a sweetener in the form of its
sodium salt since 1885. Yet it is also a heterocycle of pharmaceutical
importance, being a key structural element of certain CNS-active drugs.[1]
It has attracted more and more attention after the synthesis of enzyme-
activated inhibitors of serine proteases based on the saccharin scaffold
was reported.[2–4] Another report revealed derivatives of saccharin as
human leukocyte elastase inhibitors.[5] Since then, it has been widely
incorporated into a variety of biologically active compounds. A recent
Received March 31, 2008.
Address correspondence to Marija Sollner Dolenc, Faculty of Pharmacy,
ꢀ
University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia. E-mail: marija.
ˇ
sollner@ffa.uni-lj.si
3422

Saccharin Derivatives of Amino Acids
3423
report also utilized the saccharin scaffold as part of the imidomethyl
prodrug of certain phenolic drugs.[6]
Various methods for constructing the saccharin ring system have
already been devised.[1,7–10] Most of these are difficult to carry out, and
their yields are poor. Saccharines were prepared by reacting the sodium
salt of saccharin with different halogenocompounds.[11–14] In the cases
where halogenoderivatives of amino acids were used, racemization
occurred during the reaction.[15] A similar but successful attempt made
use of 3,3-dichloro-3H-benz[c][1,2]oxathiol 1,1-dioxide as a versatile sub-
strate for reaction with amino acids.[15]
Since most of the published procedures are limited to the preparation
of alkyl and alkoxy substituted saccharins, we overcame this problem by
providing a novel route toward disubstituted saccharins capable of being
incorporated into larger molecules as peptidomimetic building blocks.
Based on the report of the successful cyclization of N-alkyl-o-methyl-
arenesulfonamides to saccharin derivatives, utilizing the H5IO6-CrO3
oxidation system,[16] we present a route to N-substituted saccharins
obtained by CrO3-catalyzed oxidation of the corresponding sulfonamide
derivatives of various amino acids.
We designed those compounds by combining the saccharin moiety
and amino acid moiety, using the latter’s N-terminal as part of the sac-
charin heterocycle. Similar compounds have already been published by
other research groups,[11,15] but our compounds allow for further deriva-
tization at different parts of the molecule, that is at the benzene moiety of
the saccharin heterocycle as well as at the C-terminus of the attached
amino acid. The different substituents at the 6- and 5-positions of the sac-
charin scaffold render the final compounds more amenable to subsequent
chemical manipulation, because the nitro group can easily be converted
to an amino group, aryl bromides and aryl fluorides allow for cross-
coupling reactions and aromatic nucleophilic substitutions, respectively,
and the methoxy group can be easily deprotected.
Herein we describe the synthesis and properties of 16 new saccharin
derivatives of amino acids, in which their N-terminals are used as nitro-
gens of saccharin moieties (depicted in Scheme 1 and Table 1). The
Scheme 1.

ˇ
Z. Jakopin and M. S. Dolenc
3424
Table 1. Saccharin derivatives obtained via Scheme 1
Entry
1
Product
R
X
Yield (%)
1
2
1a
1b
2a
2b
H
6-NO2
6-NO2
25
27
3
4
1c
1d
2c
2d
6-NO2
6-NO2
8
9
5
6
1e
1f
2e
2f
6-NO2
6-NO2
15
—
7
8
1g
1h
3a
3b
H
6-Br
6-Br
28
33
9
1i
3c
3d
3e
6-Br
6-Br
6-Br
—
—
10
11
1j
1k
13
(Continued )

Saccharin Derivatives of Amino Acids
3425
Table 1. Continued
Entry
12
1
Product
R
X
Yield (%)
—
1l
3f
6-Br
13
14
1m
1n
4a
4b
H
6-F
6-F
37
40
15
16
1o
1p
4c
4d
6-F
6-F
17
16
17
18
1q
1r
4e
4f
6-F
6-F
14
—
19
20
1s
1t
5a
5b
H
5-MeO
5-MeO
17
23
21
1u
5c
5-MeO
—
(Continued )

ˇ
Z. Jakopin and M. S. Dolenc
3426
Table 1. Continued
Entry
22
1
Product
R
X
Yield (%)
—
1v
5d
5-MeO
23
24
1x
1y
5e
5f
5-MeO
5-MeO
16
—
synthesized compounds constitute a set of potentially useful peptidomi-
metic building blocks susceptible to further functionalization. Their pre-
paration is simple and rapid. In addition, the products are easy to purify
by extraction and washing, without the need for further purification.
However, the chemical nature of the starting sulfonamides limits the
yields of the reactions to a moderate level.
RESULTS AND DISCUSSION
Although sulfonylated derivatives of primary amines were successfully
oxidized according to the published procedure,[16] in our case sulfony-
lated amino acids were used as the starting material. The reaction condi-
tions therefore had to be altered and optimized to enable a smooth course
of the oxidation, hence affording the desired products.
Because longer reaction times are required for substrates with
halogen or electron-withdrawing substituents, a higher catalyst loading
was used to shorten the reaction times and improve yields. At a load-
ing of 5 mol% CrO3, the reaction did not proceed either at room
temperature or when heated to reflux, which prompted us to raise
the catalyst loading to 20 mol%. Under those conditions, the reac-
tion was still not completed at room temperature in 24 h; however,
heating the mixture overnight under reflux afforded the desired pro-
duct. Optimal conditions were realized when employing 50 mol%
CrO3, which brought about ready entry to the saccharin nucleus at
room temperature in 2 h.

Saccharin Derivatives of Amino Acids
3427
Table 2. Optimization of the reaction with respect to the solvent, catalyst loading,
and temperaturea
Catalyst loading
(mol% CrO3)
Solvent
eb
T
Yield (%)
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Ethyl acetate
37.5
37.5
37.5
37.5
37.5
6.0
5
5
Rt No product detected
Reflux No product detected
20
20
50
50
50
50
50
50
50
Rt
Not determined
15
25
No product detected
<10
No product detected
18
No product detected
No product detected
Reflux
Rt
Rt
Rt
Rt
1,2-Dichloroethane 10.3
Dioxane
Acetic acid
Acetone
DMF
2.2
6.2
20.7
36.7
Rt
Rt
Rt
aReaction conditions: 1 equiv. of sulfonamide 1a, 7 equiv. of periodic acid, 7
equiv. of acetic acid anhydride, 5, 20, or 50 mol% CrO3, 20 ml of solvent.
bDielectric constant.
In a previous report, acetonitrile, was chosen as the most appropriate
solvent because of the poor solubility of CrO3 in most other organic sol-
vents.[17] Therefore, test reactions were performed using more polar sol-
vents in attempts to improve the solubility of CrO3 and thus improve
the yield (Table 2 and Scheme 2). Our findings confirmed that acetonitrile
is indeed the solvent of choice for this reaction, although acetic acid also
proved useful.
The relatively low yields can be ascribed mostly to the great extent of
the competitive side reaction, that is, oxidation of the a-CH of the
N-alkyl group, which is greatly influenced by the group attached to the
ß-position relative to the nitrogen atom.[18] We concluded that the pre-
sence of electron-accepting and electron-withdrawing groups within indi-
vidual amino acids determines the extent of the side reaction.
Scheme 2.

ˇ
Z. Jakopin and M. S. Dolenc
3428
Figure 1. Dimers formed via an intermolecular oxidation.
In the cases of L- and D-Val derivatives of 6-Br (1i, 1j) and 5-MeO
series (1u, 1v), none of the expected products could be isolated; instead,
dimers were formed by an intermolecular oxidation (shown in Fig. 1).
These dimeric structures were fully assignated using 1H NMR, 13C NMR,
NMR correlation spectroscopy (COSY), heteronuclear single quantum
coherence (HSQC), and heteronuclear multiple bond correlation (HMBC)
spectra, which made it feasible to address another aspect of this reaction,
that is, the retention of chiral configuration of starting amino acid deri-
vatives. The absence of racemization under the reaction conditions
was unambiguously shown by fully assignated proton and 13C NMR
spectra of the aforementioned dimeric structures. The spectra did not
show any duplication of resonance signals, indicating that the isolated
products were not a mixture of diastereomers. These results, as well as
the determined specific rotations of the final compounds, led us to the
assumption that the stereochemistry of the starting compounds was not
compromised.
Additionally, none of the desired products (2f, 3f, 4f, and 5f) could be
generated by oxidation of the sulfonylated L-Phe derivatives, thus
indicating the great extent of the competitive side reaction resulting
from the contribution of the benzylic group attached to the a-C of
phenylalanine.
CONCLUSION
To summarize, we report a novel route for the preparation of saccharin
derivatives of amino acids. Sixteen new compounds, saccharin-derived
amino acids, were synthesized using this method, which is tolerant of
a variety of functional groups. The additional functional groups at the

Saccharin Derivatives of Amino Acids
3429
5- and 6-position of the saccharin skeleton make the compounds more
amenable to derivatization, which gives this procedure advantages over
currently available methods.
EXPERIMENTAL
Chemicals from Aldrich Chemical Co. and Fluka were used without
further purification. Analytical thin-layer chromatography (TLC) was per-
formed on Merck silica-gel (60 F 254) plates (0.25 mm). The components
were visualized with ultraviolet light and charred with 20% sulphuric acid
in ethanol and ninhydrin. Melting points were determined on a Reichert
1
hot-stage microscope and are uncorrected. H NMR, 13C NMR, COSY,
HSQC, and HMBC spectra were recorded on a Bruker Avance DPX300
spectrometer in CDCl3 solution with TMS as the internal standard. IR
spectra were obtained on a Perkin-Elmer 1600 Fourier transfer-infrared
spectroscopy (FT-IR) spectrometer. Microanalyses were performed on a
240C Perkin-Elmer CHN analyzer. Mass spectra were obtained using a
VG-Analytical Autospec Q mass spectrometer. Optical rotation was deter-
mined on a Perkin-Elmer polarimeter 1241 MC using a 1-dm cell.
General Procedure for the Preparation of Saccharins from Sulfonylated
Amino Acids (1a–y) and Characterization of Products
Periodic acid (7.0 mmol) was suspended in 20 mL of acetonitrile, and
the mixture was stirred vigorously for 45 min. Chromium trioxide
(0.5 mmol) and acetic acid anhydride (7.0 mmol) were then added,
ꢀ
and the solution was cooled to 0 C. The addition of sulfonylated
amino acid (1.0 mmol) followed, and the reaction mixture was stirred
ꢀ
at 0 C for another half an hour, when the mixture was allowed to
warm to room temperature. After 2 additional hours of stirring, the oxi-
dation was complete, as indicated by TLC on the basis of the corre-
sponding starting sulfonylated amino acid. The solvent was
evaporated under reduced pressure, and the residue was extracted with
ethyl acetate (50 mL). The solids were removed by filtration and rinsed
with another portion of ethyl acetate (30 mL). The organic phase was
extracted with a saturated solution of sodium thiosulfate (Na2S2O3)
(2 ꢁ 20 mL), 1 M NaOH solution (3 ꢁ 20 mL), water (2 ꢁ 10 mL), and
brine (20 mL) and dried over anhydrous Na2SO4. After removing the
solvent under reduced pressure, the crude product was obtained, which
needed no further purification.

ˇ
Z. Jakopin and M. S. Dolenc
3430
Methyl 2-(6-Nitro-1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-
2-yl)acetate (2a)
Yellow solid; Mp 134–137 ꢀC; 1H NMR (300 MHz, CDCl3): d
(ppm) ¼ 3.83 (s, 3H, CH3), 4.50 (s, 2H, CH2), 8.31 (d, 1H, J ¼ 8.4 Hz,
Ar-H4), 8.71 (dd, 1H, J1 ¼ 8.4 Hz, J2 ¼ 1.8 Hz, Ar-H5), 8.80 (d, 1H,
J ¼ 1.8 Hz, Ar-H7); 13C NMR (75 MHz, CDCl3): d (ppm) ¼ 38.30
(CH2), 52.08 (CH3), 116.28 (C-7), 126.01 (C-5), 128.46 (C-4), 130.22
(C-3a), 137.92 (C-7a), 150.70 (C-6), 155.71 (C-3), 164.71 (CO). MS (EI)
m=z: 301 (MH)þ; IR (KBr, cmꢂ1): 1762, 1735, 1617, 1542, 1448, 1418,
1354, 1316, 1215, 1186, 1110, 1064, 994, 961, 906, 889, 862, 777, 732,
715, 692, 660, 629, 595, 582, 560, 518. Anal. calcd. for C10H8N2O7S ꢁ 0.5
0.5 H2O (%): C, 38.84; H, 2.93; N, 9.06. Found: C, 38.55; H, 2.79; N, 9.03.
Methyl (2S)-2-(6-Nitro-1,1,3-trioxo-1,3-dihydro-2H-1,2-
benzisothiazol-2-yl)propanoate (2b)
Yellow solid; Mp 123–125 ꢀC; [a]D ꢂ 25.1 (c 1.95, CH2Cl2); 1H NMR
(300MHz, CDCl3): d (ppm) ¼ 1.90 (d, 3H, J¼ 7.2 Hz, CH3-CH), 3.79
(s, 3H, CH3), 4.89 (q, 1H, J¼ 7.5 Hz, CH), 8.28 (d, 1H, J ¼ 8.4 Hz,
Ar-H4), 8.69 (dd, 1H, J1 ¼ 8.4 Hz, J2 ¼ 1.8Hz, Ar-H5), 8.76 (d, 1H, J ¼
1.8 Hz, Ar-H7); MS (EI) m=z: 315 (MH)þ; IR (KBr, cmꢂ1): 1734, 1636,
1540, 1465, 1345, 1294, 1246, 1222, 1187, 1110, 1092, 1049, 994, 974, 912,
879, 847, 736, 700, 665, 644, 584, 529. Anal. calcd. for C11H10N2O7S (%):
C, 42.04; H, 3.21; N, 8.91. Found: C, 42.20; H, 3.26; N, 8.86.
Methyl (2S)-2-(6-Nitro-1,1,3-trioxo-1,3-dihydro-2H-1,2-
benzisothiazol-2-yl)-3-methylbutanoate (2c)
Beige solid; Mp 136–139 ꢀC; [a]D ꢂ58.6 (c 1.40, CH2Cl2); 1H NMR
(300MHz, CDCl3): d (ppm) ¼ 1.05 (d, 3H, J ¼ 6.9Hz, CH3CH), 1.20 (d,
3H, J ¼ 6.6Hz, CH3CH), 2.81–2.95 (m, 1H, CHCH3), 3.77 (s, 3H, CH3O),
4.41 (d, 1H, J ¼ 9.3 Hz, NHCH), 8.29 (d, 1H, J ¼ 8.4 Hz, Ar-H4), 8.69 (dd,
1H, J1 ¼ 8.4 Hz, J2 ¼ 1.8 Hz, Ar-H5), 8.76 (d, 1H, J¼ 1.8 Hz, Ar-H7); MS
(EI) m=z: 343 (MH)þ; IR (KBr, cmꢂ1): 3434, 1754, 1728, 1636, 1542, 1438,
1355, 1290, 1274, 1248, 1194, 1139, 1047, 993, 889, 858, 732, 661, 584, 526.
HRMS calcd. for C13H14N2O7S m=z: 343.0600 (MH)þ; Found: 343.0608.
Methyl (2R)-2-(6-Nitro-1,1,3-trioxo-1,3-dihydro-2H-1,2-
benzisothiazol-2-yl)-3-methylbutanoate (2d)
Beige solid; mp 136–139 ꢀC; [a]D þ 51.8 (c 2.15, CH2Cl2); 1H NMR
(300 MHz, CDCl3): d (ppm) ¼ 1.05 (d, 3H, J ¼ 6.9 Hz, CH3CH), 1.20

Saccharin Derivatives of Amino Acids
3431
(d, 3H, J ¼ 6.6 Hz, CH3CH), 2.81–2.95 (m, 1H, CHCH3), 3.77 (s, 3H,
CH3O), 4.41 (d, 1H, J ¼ 9.3 Hz, NHCH), 8.29 (d, 1H, J ¼ 8.1 Hz, Ar-
H4), 8.69 (dd, 1H, J1 ¼ 8.1 Hz, J2 ¼ 1.8 Hz, Ar-H5), 8.77 (d, 1H,
J ¼ 1.8 Hz, Ar-H7); MS (EI) m=z: 343 (MH)þ; IR (KBr, cmꢂ1): 1728,
1634, 1542, 1355, 1290, 1274, 1249, 1194, 1139, 1048, 993, 890, 732,
661, 584, 526. HRMS calcd. for C13H14N2O7S m=z: 343.0600 (MH)þ;
Found: 343.0603.
Dimethyl (2R)-2-(6-Nitro-1,1,3-trioxo-1,3-dihydro-2H-1,2-
benzisothiazol-2-yl)pentanedioate (2e)
1
Green oil; [a]D þ 57.6 (c 1.70, CH2Cl2); H NMR (300 MHz, CDCl3): d
(ppm) ¼ 2.48–2.78 (m, 4H, 2 ꢁ CH2), 3.69 (s, 3H, CH3O), 3.79 (s, 3H,
CH3O), 4.89–4.94 (m, 1H, NHCH), 8.28 (d, 1H, J ¼ 8.4 Hz, Ar-H4),
8.69 (dd, 1H, J1 ¼ 8.4 Hz, J2 ¼ 1.8 Hz, Ar-H5), 8.77 (d, 1H, J ¼ 1.8 Hz,
Ar-H7); MS (EI) m=z: 386 Mþ; IR (NaCl, cmꢂ1): 3462, 3102, 2956,
2290, 1738, 1612, 1543, 1438, 1351, 1290, 1263, 1241, 1190, 1109, 1081,
1031, 982, 886, 862, 821, 778, 732, 663, 585. Anal. calcd. for
C14H14N2O9S (%): C, 43.52; H, 3.65; N, 7.25. Found: C, 43.75; H,
3.91; N, 7.03.
Methyl 2-(6-Bromo-1,1,3-trioxo-1,3-dihydro-2H-1,2-
benzisothiazol-2-yl)acetate (3a)
Brown solid; mp 135–137 ꢀC; 1H NMR (300 MHz, CDCl3):
d
(ppm) ¼ 3.81 (s, 3H, CH3O), 4.45 (s, 2H, CH2), 7.95 (d, 1H, J ¼ 7.8 Hz,
Ar-H4), 7.99 (dd, 1H, J1 ¼ 7.8 Hz, J2 ¼ 1.5 Hz, Ar-H5), 8.09 (d, 1H,
J ¼ 1.5 Hz, Ar-H7); MS (EI) m=z: 335 (MH)þ; IR (KBr, cmꢂ1): 1740,
1636, 1415, 1338, 1298, 1227, 1178, 1077, 1000, 959, 896, 877, 843, 761,
715, 689, 665, 626, 592, 520. Anal. calcd. for C10H8BrNO5S (%): C,
35.94; H, 2.41; N, 4.19. Found: C, 35.97; H, 2.45; N, 4.22.
Methyl (2S)-2-(6-Bromo-1,1,3-trioxo-1,3-dihydro-2H-1,2-
benzisothiazol-2-yl)propanoate (3b)
Beige solid; mp 117–119 ꢀC; [a]D ꢂ20.7 (c 2.85, CH2Cl2); 1H NMR
(300 MHz, CDCl3): d (ppm) ¼ 1.86 (d, 3H, J ¼ 7.5 Hz, CH3-CH), 3.77
(s, 3H, CH3O), 4.83 (q, 1H, J ¼ 7.5 Hz, NHCH), 7.91 (d, 1H, J ¼ 8.1 Hz,
Hz, Ar-H4), 7.97 (dd, 1H, J1 ¼ 8.1 Hz, J2 ¼ 1.5 Hz, Ar-H5), 8.06 (d, 1H,
J ¼ 1.5 Hz, Ar-H7); MS (EI) m=z: 349 (MH)þ; IR (KBr, cmꢂ1): 3453,
3086, 1745, 1730, 1585, 1457, 1437, 1398, 1345, 1324, 1283, 1237, 1185,

ˇ
Z. Jakopin and M. S. Dolenc
3432
1139, 1085, 986, 898, 852, 763, 702, 672, 627, 596, 589, 571, 522. Anal.
calcd. for C11H10BrNO5S (%): C, 37.95; H, 2.89; N, 4.02. Found: C,
37.73; H, 2.83; N, 4.19.
Dimethyl (2R)-2-(6-Bromo-1,1,3-trioxo-1,3-dihydro-2H-1,2-
benzisothiazol-2-yl)pentanedioate (3e)
White solid; mp 117–120 ꢀC; [a]D þ 81.9 (c 2.15, CH2Cl2); 1H NMR
(300 MHz, CDCl3): d (ppm) ¼ 2.42–2.75 (m, 4H, 2 ꢁ CH2), 3.69 (s, 3H,
CH3O), 3.77 (s, 3H, CH3O), 4.76–4.89 (m, 1H, NHCH), 7.92 (d, 1H,
J ¼ 8.1 Hz, Ar-H4), 7.98 (dd, 1H, J1 ¼ 8.1 Hz, J2 ¼ 1.5 Hz, Ar-H5), 8.06
(d, 1H, J ¼ 1.5 Hz, Ar-H7); 13C NMR (75 MHz, CDCl3): d (ppm) ¼ 23.69
(b-CH2), 30.09 (c-CH2), 41.16 (CH), 51.84 (CH3), 53.22 (CH3), 124.36 (C-
7), 125.67 (C-3a), 126.71 (C-4), 130.23 (C-6), 137.81 (C-5), 139.03 (C-7a),
158.36 (C-3), 167.93 (CO), 172.54 (CO). MS (EI) m=z: 360 (M-59)þ; IR
(KBr, cmꢂ1): 3439, 1753, 1735, 1636, 1586, 1457, 1437, 1397, 1345,
1323, 1243, 1184, 1132, 1086, 1029, 1000, 983, 967, 905, 855, 826, 776,
760, 670, 640, 586, 572, 524. Anal. calcd. for C14H14BrNO7S (%): C,
40.01; H, 3.36; N, 3.33. Found: C, 39.91; H, 3.28; N, 3.42.
Methyl 2-(6-Fluoro-1,1,3-trioxo-1,3-dihydro-2H-1,2-
benzisothiazol-2-yl)-acetate (4a)
1
White solid; mp 81–85 ꢀC; H NMR (300 MHz, CDCl3): d (ppm) ¼ 3.81
(s, 3H, CH3O), 4.45 (s, 2H, CH2), 7.54 (dt, 1H, J1 ¼ 8.4 Hz,
J2 ¼ 2.4 Hz, Ar-H5), 7.64 (dd, 1H, J1 ¼ 6.6 Hz, J2 ¼ 2.1 Hz, Ar-H7), 8.12
(dd, 1H, J1 ¼ 8.4 Hz, J2 ¼ 4.5 Hz, Ar-H4); MS (EI) m=z: 273 Mþ; IR
(KBr, cmꢂ1): 3473, 1740, 1636, 1481, 1445, 1412, 1341, 1308, 1288,
1264, 1221, 1177, 1058, 1008, 953, 892, 867, 852, 764, 728, 705, 660,
617, 594, 527, 494, 458. Anal. calcd. for C10H8FNO5S (%): C, 43.96;
H, 2.95; N, 5.13. Found: C, 43.98; H, 2.97; N, 5.10.
Methyl (2S)-2-(6-Fluoro-1,1,3-trioxo-1,3-dihydro-2H-1,2-
benzisothiazol-2-yl)propanoate (4b)
White solid; mp 78–80 ꢀC; [a]D ꢂ 30.6 (c 2.45, CH2Cl2); 1H NMR
(300 MHz, CDCl3): d (ppm) ¼ 1.86 (d, 3H, J ¼ 7.5 Hz, CH3-CH), 3.78
(s, 3H, CH3O), 4.84 (q, 1H, J ¼ 7.5 Hz, NHCH), 7.52 (dt, 1H,
J1 ¼ 8.7 Hz, J2 ¼ 2.4 Hz, Ar-H5), 7.61 (dd, 1H, J1 ¼ 6.3 Hz, J2 ¼ 2.1 Hz,
Ar-H7), 8.08 (dd, 1H, J1 ¼ 8.7 Hz, J2 ¼ 4.5 Hz, Ar-H4); 13C NMR

Saccharin Derivatives of Amino Acids
3433
(75 MHz, CDCl3): d (ppm) ¼ 15.14 (CH3), 50.35 (CH), 53.53 (CH3O),
109.55 (d, J ¼ 26.7 Hz, C-7), 122.64 (d, J ¼ 23.0 Hz, C-5), 123.52 (d,
J ¼ 2.9 Hz, C-3a), 128.40 (d, J ¼ 9.5 Hz, C-4), 140.49 (d, J ¼ 9.2 Hz,
C-7a), 158.25 (C-3), 166.78 (d, J ¼ 260.5 Hz, C-6), 169.29 (CO). MS
(EI) m=z: 288 (MH)þ; IR (KBr, cmꢂ1): 1734, 1636, 1600, 1484, 1341,
1288, 1258, 1230, 1171, 1126, 1090, 1043, 991, 947, 875, 843, 774, 762,
708, 670, 656, 590, 558, 534, 504, 474. Anal. calcd. for C11H10FNO5S
(%): C, 45.99; H, 3.51; N, 4.88. Found: C, 45.99; H, 3.29; N, 4.96.
Methyl (2S)-2-(6-Fluoro-1,1,3-trioxo-1,3-dihydro-2H-1,2-
benzisothiazol-2-yl)-3-methylbutanoate (4c)
White solid; mp 77–80 ꢀC; [a]D ꢂ 54.4 (c 1.60, CH2Cl2); 1H NMR
(300 MHz, CDCl3): d (ppm) ¼ 1.04 (d, 3H, J ¼ 6.9 Hz, CH3CH), 1.18
(d, 3H, J ¼ 6.6 Hz, CH3CH), 2.81–2.93 (m, 1H, CHCH3), 3.75 (s, 3H,
CH3O), 4.38 (d, 1H, J ¼ 9.3 Hz, NHCH), 7.52 (dt, 1H, J1 ¼ 8.4 Hz,
J2 ¼ 2.1 Hz, Ar-H5), 7.61 (dd, 1H, J1 ¼ 6.3 Hz, J2 ¼ 2.1 Hz, Ar-H7), 8.09
(dd, 1H, J1 ¼ 8.4 Hz, J2 ¼ 4.5 Hz, Ar-H4); MS (EI) m=z: 316 (MH)þ; IR
(KBr, cmꢂ1): 1734, 1636, 1488, 1351, 1280, 1264, 1172, 1139, 1042,
1011, 923, 874, 853, 792, 763, 703, 668, 628, 615, 589, 544, 527. Anal.
calcd. for C13H14FNO5S ꢁ 0.1 H2O (%): C, 49.24; H, 4.51; N, 4.42.
Found: C, 49.64; H, 4.54; N, 4.40.
Methyl (2R)-2-(6-Fluoro-1,1,3-trioxo-1,3-dihydro-2H-1,2-
benzisothiazol-2-yl)-3-methylbutanoate (4d)
White solid; mp 77–80 ꢀC; [a]D þ 65.4 (c 2.80, CH2Cl2); 1H NMR (300MHz,
CDCl3): d (ppm) ¼ 1.04 (d, 3H, J ¼ 6.9 Hz, CH3CH), 1.19 (d, 3H, J ¼ 6.6 Hz,
CH3CH), 2.81–2.93 (m, 1H, CHCH3), 3.75 (s, 3H, CH3O), 4.38 (d, 1H,
J¼ 9.3 Hz, NHCH), 7.52 (dt, 1H, J1 ¼ 8.4Hz, J2 ¼ 2.1 Hz, Ar-H5), 7.61
(dd, 1H, J1 ¼ 6.3 Hz, J2 ¼ 2.1 Hz, Ar-H7), 8.09 (dd, 1H, J1 ¼ 8.4 Hz,
J2 ¼ 4.5 Hz, Ar-H4); MS (EI) m=z: 316 (MH)þ; IR (KBr, cmꢂ1): 1734,
1636, 1489, 1350, 1280, 1172, 1139, 1040, 994, 923, 876, 850, 794, 764, 668,
628, 615, 591, 544, 526. Anal. calcd. for C13H14FNO5S ꢁ 0.1 H2O (%): C,
49.24; H, 4.51; N, 4.42. Found: C, 49.22; H, 4.36; N, 4.32.
Dimethyl (2R)-2-(6-Fluoro-1,1,3-trioxo-1,3-dihydro-2H-1,2-
benzisothiazol-2-yl)pentanedioate (4e)
1
Yellow oil; [a]D þ 82.6 (c 1.90, CH2Cl2); H NMR (300 MHz, CDCl3): d
(ppm) ¼ 2.50–2.75 (m, 4H, 2 ꢁ CH2), 3.69 (s, 3H, CH3O), 3.78 (s, 3H,

ˇ
Z. Jakopin and M. S. Dolenc
3434
CH3O), 4.84–4.90 (m, 1H, NHCH), 7.53 (dt, 1H, J1 ¼ 8.4 Hz, J2 ¼ 2.1 Hz,
Ar-H5), 7.61 (dd, 1H, J1 ¼ 6.3 Hz, J2 ¼ 2.1 Hz, Ar-H7), 8.09 (dd, 1H,
J1 ¼ 8.4 Hz, J2 ¼ 4.5 Hz, Ar-H4); MS (EI) m=z: 360 (MH)þ; IR (NaCl,
cmꢂ1): 3448, 3102, 2956, 2362, 1735, 1601, 1508, 1485, 1438, 1343,
1286, 1261, 1174, 1079, 1030, 865, 820, 764, 670, 590. Anal. calcd. for
C14H14FNO7S (%): C, 46.80; H, 3.93; N, 3.90. Found: C, 47.32; H,
4.12; N, 4.13.
Methyl 2-(5-Methoxy-1,1,3-trioxo-1,3-dihydro-2H-1,2-
benzisothiazol-2-yl)acetate (5a)
Orange solid; mp 86–89 ꢀC; 1H NMR (300 MHz, CDCl3): d (ppm) ¼ 3.81
(s, 3H, CH3O), 3.96 (s, 3H, CH3OAr), 4.44 (s, 2H, CH2), 7.34 (dd, 1H,
J1 ¼ 8.4 Hz, J2 ¼ 2.4 Hz, Ar-H6), 7.51 (d, 1H, J ¼ 2.4 Hz, Ar-H4), 7.84
(d, 1H, J ¼ 8.4 Hz, Ar-H7); 13C NMR (75 MHz, CDCl3): d (ppm) ¼ 38.96
(CH2), 52.89 (CH3O), 56.30 (CH3OAr), 108.76 (C-4), 121.82 (C-6),
122.74 (C-7), 129.30 (C-7a), 129.63 (C-3a), 158.75 (C-3), 164.55 (C-5),
166.38 (CO). MS (EI) m=z: 285 Mþ; IR (KBr, cmꢂ1): 1760, 1636, 1484,
1438, 1375, 1337, 1313, 1228, 1186, 1137, 1060, 1021, 966, 877, 846,
828, 763, 698, 584, 572, 504, 495. Anal. calcd. for C11H11NO6S (%): C,
46.31; H, 3.89; N, 4.91. Found: C, 46.57; H, 4.00; N, 4.72.
Methyl (2S)-2-(5-Methoxy-1,1,3-trioxo-1,3-dihydro-2H-
1,2-benzisothiazol-2-yl)propanoate (5b)
1
Orange solid; mp 115–118 ꢀC; [a]D ꢂ 20.5 (c 2.20, CH2Cl2); H NMR
(300 MHz, CDCl3): d (ppm) ¼ 1.85 (d, 3H, J ¼ 7.5 Hz, CH3-CH), 3.77
(s, 3H, CH3O), 3.95 (s, 3H, CH3OAr), 4.81 (q, 1H, J ¼ 7.5 Hz, NHCH),
7.32 (dd, 1H, J1 ¼ 8.4 Hz, J2 ¼ 1.8 Hz, Ar-H6), 7.47 (d, 1H, J ¼ 2.4 Hz,
Ar-H4), 7.80 (d, 1H, J ¼ 8.7 Hz, Ar-H7); MS (EI) m=z: 299 Mþ; IR
(KBr, cmꢂ1): 1741, 1720, 1607, 1484, 1435, 1324, 1294, 1263, 1244,
1179, 1159, 1092, 1068, 1056, 1022, 986, 951, 928, 907, 882, 859, 837,
780, 769, 701, 667, 604, 573, 536. Anal. calcd. for C12H13NO6S (%): C,
48.16; H, 4.38; N, 4.68. Found: C, 48.16; H, 4.32; N, 4.47.
Dimethyl (2R)-2-(5-Methoxy-1,1,3-trioxo-1,3-dihydro-
2H-1,2-benzisothiazol-2-yl)pentanedioate (5e)
1
Yellow oil; [a]D þ 69.7 (c 1.75, CH2Cl2); H NMR (300 MHz, CDCl3): d
(ppm) ¼ 2.48–2.75 (m, 4H, 2 ꢁ CH2), 3.69 (s, 3H, CH3O), 3.77 (s, 3H,
CH3O), 3.95 (s, 3H, CH3OAr), 4.80–4.85 (m, 1H, NHCH), 7.33 (dd,

Saccharin Derivatives of Amino Acids
3435
1H, J1 ¼ 8.4 Hz, J2 ¼ 2.4 Hz, Ar-H6), 7.48 (d, 1H, J ¼ 2.4 Hz, Ar-H4), 7.81
(d, 1H, J ¼ 8.4 Hz, Ar-H7); MS (EI) m=z: 372 (MH)þ; IR (NaCl, cmꢂ1):
3448, 3099, 2954, 2291, 1735, 1604, 1508, 1485, 1437, 1335, 1299, 1246,
1185, 1139, 1071, 1044, 1015, 879, 832, 804, 763, 696. Anal. calcd. for
C15H17NO8S ꢁ 0.5 H2O (%): C, 47.36; H, 4.77; N, 3.68. Found: C,
47.51; H, 4.47; N, 3.40.
Methyl (2S)-2-({[5-Bromo-2-({[(5-bromo-2-methylphenyl)sulfonyl]-
[(1S)-1-(methoxycarbonyl)]-2-methylpropyl]amino}carbonyl)phenyl]-
sulfonyl}amino)-3-methylbutanoate (6a)
Yellow solid; mp 72–76 ꢀC; [a]D ꢂ 47.2 (c 3.20, CH2Cl2); 1H NMR
(300 MHz, CDCl3): d (ppm) ¼ 0.88–0.93 (m, 6H, CH3-11 and CH3-12),
1.04 (d, 3H, J ¼ 6.6 Hz, CH3-16), 1.18 (d, 3H, J¼ 6.6 Hz, CH3-17), 1.97–
2.09 (m, 1H, CH-10), 2.62 (s, 3H, CH3-26), 2.80–2.92 (m, 1H, CH-15),
3.51 (s, 3H, CH3-9), 3.68–3.73 (m, 1H, CH-7), 3.75 (s, 3H, CH3-19), 4.37
(d, 1H, J ¼ 9.6 Hz, CH-14), 5.14 (d, 1H, J ¼ 10.2 Hz, SO2NH), 7.18 (d,
1H, J ¼ 8.1 Hz, H-24), 7.56 (dd, 1H, J1 ¼ 8.1 Hz, J2 ¼ 2.1Hz, H-23), 7.91–
7.99 (m, 2H, H-2 and H-3), 8.06–8.07 (m, 2H, H-6 and H-21);13C NMR
(75 MHz, CDCl3): d (ppm) ¼ 17.52 (C-11), 18.84 (C-12), 19.70 (C-17),
19.83 (C-26), 20.66 (C-16), 28.23 (C-15), 31.58 (C-10), 52.30 (C-9), 52.74
(C-19), 60.31 (C-14), 61.08 (C-7), 119.37 (C-22), 124.20 (C-21), 125.55
(C-1), 126.72 (C-3), 130.07 (C-4), 132.06 (C-6), 134.01 (C-24), 135.66
(C-23), 136.41 (C-25), 137.71 (C-2), 138.90 (C-5), 139.21 (C-20), 158.21
(C-13), 168.01 (C-18), 171.75 (C-8); MS (ESI) m=z: 763 (MNa)þ; IR (KBr,
cmꢂ1): 3468, 1756, 1734, 1715, 1636, 1586, 1448, 1348, 1325, 1276, 1254,
1182, 1167, 1139, 1078, 1063, 1015, 990, 921, 892, 874, 845, 822, 763, 708,
662, 603, 585, 527. Anal. calcd. for C26H32Br2N2O9S2 ꢁ 2 H2O (%): C,
40.22; H, 4.67; N, 3.61. Found: C, 39.98; H, 4.24; N, 3.63.
Methyl (2R)-2-({[5-Bromo-2-({[(5-bromo-2-methylphenyl)sulfonyl]-
[(1R)-1-(methoxycarbonyl)]-2-methylpropyl]amino}carbonyl)phenyl]-
sulfonyl}amino)-3-methylbutanoate (6b)
Yellow solid; mp 72–76 ꢀC; [a]D þ 56.7 (c 1.20, CH2Cl2); 1H NMR
(300 MHz, CDCl3): d (ppm) ¼ 0.88–0.93 (m, 6H, CH3-11 and CH3-12),
1.04 (d, 3H, J ¼ 6.6 Hz, CH3-16), 1.18 (d, 3H, J¼ 6.6 Hz, CH3-17), 1.97–
2.08 (m, 1H, CH-10), 2.62 (s, 3H, CH3-26), 2.80–2.92 (m, 1H, CH-15),
3.51 (s, 3H, CH3-9), 3.68–3.77 (m, 1H, CH-7), 3.75 (s, 3H, CH3-19), 4.37
(d, 1H, J¼ 9.6 Hz, CH-14), 5.14 (d, 1H, J ¼ 10.2 Hz, SO2NH), 7.18 (d, 1H,
J¼ 8.1 Hz, H-24), 7.56 (dd, 1H, J1 ¼ 8.1 Hz, J2 ¼ 2.1Hz, H-23), 7.91–7.99
(m, 2H, H-2 and H-3), 8.05–8.07 (m, 2H, H-6 and H-21); 13C NMR
(75 MHz, CDCl3): d (ppm) ¼ 17.53 (C-11), 18.86 (C-12), 19.72 (C-17),

ˇ
Z. Jakopin and M. S. Dolenc
3436
19.85 (C-26), 20.68 (C-16), 28.25 (C-15), 31.61 (C-10), 52.33 (C-9), 52.77
(C-19), 60.35 (C-14), 61.10 (C-7), 119.40 (C-22), 124.22 (C-21), 125.58
(C-1), 126.73 (C-3), 130.09 (C-4), 132.10 (C-6), 134.03 (C-24), 135.69
(C-23), 136.43 (C-25), 137.72 (C-2), 138.93 (C-5), 139.25 (C-20), 158.23
(C-13), 168.04 (C-18), 171.78 (C-8); MS (ESI) m=z: 763 (MNa)þ; IR (KBr,
cmꢂ1): 3478, 2970, 1757, 1734, 1714, 1586, 1438, 1349, 1325, 1276, 1253,
1182, 1167, 1139, 1078, 1063, 1015, 990, 922, 892, 874, 845, 825, 800, 763,
708, 698, 663, 603, 585, 527. Anal. calcd. for C26H32Br2N2O9S2 ꢁ H2O
(%): C, 41.17; H, 4.52; N, 3.69. Found: C, 40.98; H, 4.15; N, 3.88.
Methyl (2S)-2-{[5-Methoxy-2-({[(1S)-1-(methoxycarbonyl)-2-
methylpropyl]amino}sulfonyl)benzoyl][(4-methoxy-2-
methylphenyl)sulfonyl]amino}-3-methylbutanoate (7a)
1
Brown oil; [a]D ꢂ 80.5 (c 1.55, CH2Cl2); H NMR (300 MHz, CDCl3): d
(ppm) ¼ 0.86–0.90 (m, 6H, CH3-11 and CH3-12), 1.04 (d, 3H, J ¼ 6.6 Hz,
Hz, CH3-16), 1.18 (d, 3H, J ¼ 6.6 Hz, CH3-17), 1.94–2.04 (m, 1H, CH-10),
2.63 (s, 3H, CH3-26), 2.83–2.94 (m, 1H, CH-15), 3.50 (s, 3H, CH3-9), 3.60–
3.66 (m, 1H, CH-7), 3.75 (s, 3H, CH3-19), 3.84 (s, 3H, CH3-28), 3.95 (s,
3H, CH3-27), 4.35 (d, 1H, J ¼ 9.3 Hz, CH-14), 5.06 (d, 1H, J ¼ 9.9 Hz,
SO2NH), 6.74–6.79 (m, 2H, H-22 and H-24), 7.32 (dd, 1H, J1 ¼ 8.4 Hz,
J2 ¼ 2.4 Hz, H-1), 7.48 (d, 1H, J ¼ 2.4 Hz, H-3), 7.79–7.89 (m, 2H, H-6
and H-21); 13C NMR (75 MHz, CDCl3): d (ppm) ¼ 17.61 (C-11), 18.86
(C-12), 19.71 (C-16), 20.56 (C-26), 20.71 (C-17), 28.21 (C-15), 31.57 (C-
10), 52.21 (C-9), 52.67 (C-19), 55.47 (C-28), 56.31 (C-27), 60.08 (C-14),
60.96 (C-7), 108.67 (C-3), 110.44 (C-24), 117.94 (C-22), 121.88 (C-1),
122.55 (C-6), 129.15 (C-20 or C-4), 129.16 (C-4 or C-20), 129.44 (C-5),
132.15 (C-21), 139.86 (C-25), 158.96 (C-13), 162.84 (C-23), 164.54 (C-2),
168.33 (C-18), 172.08 (C-8); MS (ESI) m=z: 665 (MNa)þ; IR (NaCl,
cmꢂ1): 3304, 3099, 2967, 1737, 1602, 1570, 1508, 1485, 1465, 1436, 1391,
1337, 1298, 1247, 1187, 1135, 1069, 1043, 1015, 935, 868, 829, 763, 720,
665. Anal. calcd. for C28H38N2O11S2 ꢁ H2O (%): C, 50.90; H, 6.10; N,
4.24. Found: C, 50.85; H, 5.82; N, 4.71.
Methyl (2R)-2-{[5-Methoxy-2-({[(1R)-1-(methoxycarbonyl)-2-
methylpropyl]amino}sulfonyl)benzoyl][(4-methoxy-2-methylphenyl)-
sulfonyl]amino}-3-methylbutanoate (7b)
1
Brown oil; [a]D þ 86.7 (c 1.35, CH2Cl2); H NMR (300 MHz, CDCl3): d
(ppm) ¼ 0.86–0.90 (m, 6H, CH3-11 and CH3-12), 1.04 (d, 3H, J ¼ 6.6 Hz,
Hz, CH3-16), 1.18 (d, 3H, J ¼ 6.6 Hz, CH3-17), 1.93–2.04 (m, 1H,

Saccharin Derivatives of Amino Acids
3437
CH-10), 2.63 (s, 3H, CH3-26), 2.82–2.94 (m, 1H, CH-15), 3.50 (s, 3H,
CH3-9), 3.60–3.65 (m, 1H, CH-7), 3.75 (s, 3H, CH3-19), 3.84 (s, 3H,
CH3-28), 3.95 (s, 3H, CH3-27), 4.35 (d, 1H, J ¼ 9.3 Hz, CH-14), 5.06
(d, 1H, J ¼ 9.9 Hz, SO2NH), 6.74–6.79 (m, 2H, H-22 and H-24), 7.32
(dd, 1H, J1 ¼ 8.4 Hz, J2 ¼ 2.4 Hz, H-1), 7.48 (d, 1H, J ¼ 2.4 Hz, H-3),
7.79–7.89 (m, 2H, H-6 and H-21); 13C NMR (75 MHz, CDCl3): d
(ppm) ¼ 17.59 (C-11), 18.84 (C-12), 19.69 (C-16), 20.54 (C-26), 20.69
(C-17), 28.19 (C-15), 31.55 (C-10), 52.19 (C-9), 52.65 (C-19), 55.45 (C-
28), 56.29 (C-27), 60.06 (C-14), 60.94 (C-7), 108.65 (C-3), 110.42 (C-
24), 117.92 (C-22), 121.86 (C-1), 122.53 (C-6), 129.13 (C-20 or C-4),
129.14 (C-4 or C-20), 129.42 (C-5), 132.13 (C-21), 139.84 (C-25), 158.94
(C-13), 162.82 (C-23), 164.52 (C-2), 168.31 (C-18), 172.06 (C-8); MS
(ESI) m=z: 665 (MNa)þ; IR (NaCl, cmꢂ1): 3304, 3099, 2967, 1737,
1602, 1570, 1508, 1485, 1465, 1436, 1391, 1337, 1298, 1247, 1187, 1135,
1069, 1043, 1015, 935, 868, 829, 763, 720, 665. Anal. calcd. for
C28H38N2O11S2 H2O (%): C, 50.90; H, 6.10; N, 4.24. Found: C, 50.96;
H, 5.92; N, 4.58.
ACKNOWLEDGMENTS
This work was supported financially by the Slovenian Research Agency.
The authors thank Roger Pain for his critical reading of the manuscript.
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