Synthesis of a Series of Hexitol and Aminodeoxyhexitol Mononitrate Derivatives Containing a Sulfur Group and Pharmacological Evaluation on Isolated Rat Aortas

Article abstract of DOI:10.1002/(sici)1099-0690(199805)1998:5<933::aid-ejoc933>3.0.co;2-j

As part of our research into new organic nitrates for the treatment of angina pectoris, we have investigated a series of hexitol and aminodeoxyhexitol mononitrate derivatives containing a sulfur group. Since the depletion of tissue stores of sulfhydryl groups appears to play an important role in the development of this phenomenon, the addition of a sulfur group to a nitrate derivative could prevent the development of nitrate tolerance during a long-term treatment. Before studying the duration of action, and the possible influence on tolerance phenomenon, it was important to check the vasorelaxing effects of our compounds compared to those of commercial organic nitrates of similar structures such as isosorbide mononitrate or isosorbide dinitrate. All the compounds were tested on isolated rat aortas; some of these products exhibited an interesting activity.

Full text of DOI:10.1002/(sici)1099-0690(199805)1998:5<933::aid-ejoc933>3.0.co;2-j

FULL PAPER
Synthesis of a Series of Hexitol and Aminodeoxyhexitol Mononitrate
Derivatives Containing a Sulfur Group and Pharmacological Evaluation on
Isolated Rat Aortas
a,b
b
b
b
c
Jean Pierre Nallet*a,b, Anne Lise Megard , Christian Arnaud , Denis Bouchu , Pierre Lanteri , Marie-Luce Bea ,
´
´
´
Vincent Richardc, and Alain Berdeauxc
Laboratoires Hoechst, Tour Roussel-Hoechsta,
1, Terrasse Bellini, F-92800 Puteaux, France
b
´
`
Laboratoire de Chimiometrie et Synthese Organique, CPE Lyon ,
´
43, Bd du 11 Novembre 1918, F-69616 Villeurbanne Cedex, France
c
´
´
´
Departement de Pharmacologie, Faculte de Medecine Paris-Sud ,
´
ˆ
´
63, Rue Gabriel Peri, F-94276 Le Kremlin-Bicetre Cedex, France
Received October 9, 1997
Keywords: Nitric acid derivatives / Nitric oxide / Angina pectoris / Thiol derivatives
As part of our research into new organic nitrates for the treat-
studying the duration of action, and the possible influence
ment of angina pectoris, we have investigated a series of he- on tolerance phenomenon, it was important to check the va-
xitol and aminodeoxyhexitol mononitrate derivatives
sorelaxing effects of our compounds compared to those of
containing a sulfur group. Since the depletion of tissue stores commercial organic nitrates of similar structures such as iso-
of sulfhydryl groups appears to play an important role in the
development of this phenomenon, the addition of a sulfur
group to a nitrate derivative could prevent the development
of nitrate tolerance during a long-term treatment. Before
sorbide mononitrate or isosorbide dinitrate. All the com-
pounds were tested on isolated rat aortas; some of these pro-
ducts exhibited an interesting activity.
Organic nitrates, for example nitroglycerin, constitute the duces the development of tolerance which limits their ef-
most widely used treatment for angina pectoris. Although ficiency. This has been explained by an intracellular de-
not conclusively demonstrated[1], it now seems well-docu- pletion in thiol groups[7]. As it is known that the phenom-
mented that these compounds are transformed during the enon can be avoided or reduced by simultaneous adminis-
enzymatic or thiol-mediated metabolism as depicted in Fig- tration of -cysteine derivatives[8][9][10], we have postulated
ure 1; they induce, by release of nitric oxide, stimulation that new compounds containing a nitrate moiety linked to
of soluble guanylate cyclase and consequently relaxation of cysteine, or masked cysteine, may provide the basis for
vascular smooth muscle cells[2][3][4][5][6]
.
structures devoid of tolerance development.
For the design of new drugs, we have decided to combine
the most easily obtained hexitol mononitrates 1, 2 and the
aminodeoxyhexitol mononitrates 3, 4 with -cysteine de-
rivatives (Figure 2). Due to the instability of the free SϪH
group, protected or masked cysteines were used for the dif-
ferent syntheses.
Figure 1. Postulated metabolism of organic nitrates and the devel-
opment of nitrate tolerance
Figure 2. Syntheses of nitrate and deoxyhexitolnitrates and their
derivatives (Y ϭ thioamino acid part; Z ϭ O or N)
Nevertheless, in order to obtain a long-lasting effect,
drugs have to be administered continuously, and this in-
Eur. J. Org. Chem. 1998, 933Ϫ943
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1434Ϫ193X/98/0505Ϫ0933 $ 17.50ϩ.50/0
933

J. P. Nallet et al.
FULL PAPER
Chemistry
Taking into account a very interesting activity in the
pharmacological test for compound 8c, we did not try to
obtain the stable compound bearing a free SH group, but
decided to investigate the coupling between 5-amino-5-de-
oxy-1,4:3,6-dianhydro--iditol-2-nitrate (3) and different
substituted thioprolines. The compounds obtained are
given in Table 2.
The pathway for our synthesis (Figure 2) consists of a
coupling reaction between the acid group of -cysteine de-
rivatives and hydroxy or amino group of the hexitol moiety
by means of 1,3-dicyclohexylcarbodiimide (DCC) or 1-
cyclohexyl-3-(2-morpholinoethyl)carbodiimide
metho-p-
toluenesulfonate as coupling agent (1-hydroxybenzotriazole
is added to prevent racemization). Among the hexitol ni-
trates used, 1,4:3,6-dianhydro--glucitol-5-nitrate (1) is
commercialy available and 1,4:3,6-dianhydro--glucitol-2-
nitrate (2) is synthesized according to the procedure de-
scribed by Hayward[11]. Among the deoxyhexitol nitrates,
Since Ratner et al.[14] and Woodward et al.[15] have stud-
ied the stability of thioproline and shown the faster de-
composition of 2,2-dimethylthioproline in aqueous medium
to give cysteine and acetone, we decided to prepare 9 and
10 (Table 2). We determined, as indicated by the NMR
spectra, that the ring-opening occurred slowly when 10 was
in an H2O or D2O solution, in accord with previous re-
5-amino-5-deoxy-1,4:3,6-dianhydro--iditol-2-nitrate
(3)
and 2-amino-2-deoxy-1,4:3,6-dianhydro--glucitol-5-nitrate
(4) are prepared according to the method described by
Klessing[12]. From these starting materials, different prod-
ucts were obtained (Table 1). Compounds 5aϪ5d were pre-
pared with S-acetamidomethyl-N-tert-butoxycarbonyl)--
cysteine. The Boc group is then easily removed in acidic
medium to give the corresponding 6aϪ6d derivatives (Table
1). Several attempts to remove the acetamidomethyl sub-
stituent under usual reaction conditions did not lead to
stable compounds with a free SH group.
sults[15][16][17]
.
Attempts to isolate and purify 12 did not lead to a pure
compound; only a mixture with an oxidized compound
(probably 13) as major component could be recovered (Fig-
ure 3). Compounds 14 and 15 (Table 2) were synthesized to
evaluate the effect of acyl and benzoyl groups on activity.
Different 2-substituted thioprolines were prepared by reac-
tion of -cysteine on the corresponding aldehydes[18][19]
(Figure 4). With the use of results published by Szilagyi et
al.[19], the mixtures of two diastereomers in various ratios
[16a/17a (CH3): 35:65; 16b/17b (C6H5): 40:60; 16c/17c (n-
Table 1. Isolated and purified solid compounds
1
C4H9): 50:50] were determined by comparison of their H-
NMR spectra with that of the compound 16d (2R, 4R),
obtained according to the method of Baxter et al.[20]
.
When tert-butoxycarbonyl was used as the N-protecting
group, only one diastereomer (18aϪ18d) was obtained. The
configuration of each compound was determined by anal-
ogy with the results of Szilagyi[19], who measured the sum
(J4-H,5-H ϩ J4-H,5Ј-H) ϭ 12.5 Hz (at 100°C in [D6]DMSO)
for
cis-3-acetyl-2(R)-phenylthiazolidine-4(R)-carboxylic
acid and 6.5 Hz for trans-3-acetyl-2(S)-phenylthiazolidine-
4(R)-carboxylic acid. In our compounds, this sum of coup-
ling constants equals 13.5 Hz for 18a, 13 Hz for 18b in
[D6]DMSO, and 14.2 Hz for 18c in C5D5N. All these com-
pounds were therefore assigned cis isomers. Each thiazolidi-
necarboxylic acid derivative 18aϪ18d reacted with 3 and
gave only one diastereomer, 19aϪ19d. From the sums
(J7-H,8-H ϩ J7-H,8Ј-H) ϭ 14.7 Hz for 19a, 13.5 Hz for 19b,
15.6 Hz for 19c and 13 Hz for 19d, (2R) and (4R) configura-
tions were attributed to asymmetric centers of the thiazolid-
ine ring. After treatment in acidic medium (HCl in Me-
(a)
This oily compound was not pure enough to be tested.
Since Thiazolidine-4(R)-carboxylic acid (-thioproline) is COOEt), compounds 19 gave a mixture of two dia-
known to generate -cysteine upon metabolism in the stereomers 20 and 21 due to an interconversion via the
liver[13], we have synthesized compounds 7aϪ7c (Table 1) Schiff base (Figure 4).
by the reaction between N-tert-butoxycarbonylthiazolidine-
4(R)-carboxylic acid (N-tBoc--thioproline) and the nitrate
Pharmacological Results
derivatives 1Ϫ4. After treatment in an acidic medium, de-
An in vitro test was used to investigate the pharmacologi-
rivatives 8aϪ8c are obtained (Table 1). N-tBoc--thiopro- cal activity of our products. Vasorelaxation was evaluated
line must be used rather than -thioproline to avoid the for- in vitro by means of a test on isolated rat aortas without
mation of dioxopiperazines. Indeed the poor yield obtained endothelium and precontracted with norepinephrine[21][22]
.
in the preparation of 8d is due to the direct reaction be- The relaxation caused by different substances was measured
tween -thioproline and the aminonitrate 4. It is interesting upon addition of increasing doses of each compound; this
to note that no epimerisation occurred during these reac- relaxation was calculated with reference to the maximal
tions.
contraction obtained with norepinephrin (0.1 µ). Struc-
934
Eur. J. Org. Chem. 1998, 933Ϫ943

Hexitol and Aminodeoxyhexitol Mononitrate Derivatives Containing a Sulfur Group
Table 2. Synthesized compounds according to the following R moieties
FULL PAPER
(a)
This oily compound was not pure enough to be tested.
Figure 3. Hydrolysis of compound 10 leading to 12 and further, by first group of compounds (Table 1), and with compounds
oxidation, to disulfide 13
11, 14, 15, 19a and with mixtures 20a ϩ 21a, 20b ϩ 21b,
and 20c ϩ 21c in the second group (Table 2), the mixture
20b ϩ 21b giving the strongest effect. Results concerning
relaxation of isolated rat aortas are given in Table 3; com-
pared to IS-5MN (isosorbide mononitrate), the most used
and commercialy available mononitrate, some of our prod-
ucts exhibited greater activity (Table 3); compared to ISDN
(isosorbide dinitrate), only the mixture 20b ϩ 21b is more
interesting. Our compounds proved less active than nitro-
glycerin which is known to have a very strong effect but
also only a short-term activity. It is noticeable that com-
pound 8c, which results from the reaction of 3 and thiopro-
line, has a better effect than 3 or the mixture of 3 and thio-
proline.
Figure 4. Syntheses of compounds 16, 17, 18, 19, and mixtures of
20 ϩ 21 (a: R ϭ CH3; b: R ϭ C6H5; c: R ϭ n-C4H9; d: R ϭ
COOCH3)
Conclusion
This study presents a series of new organic nitrates con-
taining thiol groups. Several of these compounds had
greater vasorelaxing effects than isosorbide mononitrate,
and one of them has a good effect compared to isosorbide
dinitrate. The most interesting compounds will be evaluated
to determine their duration of action and, therefore, will be
investigated in a pharmacological model for tolerance in
the dog.
Experimental Section
Melting points were determined with a Büchi apparatus and are
uncorrected. All compounds are colorless. Ϫ Optical rotations were
measured in solution with a Perkin Elmer 241 polarimeter. Ϫ IR
spectra were recorded with a Perkin Elmer 1720 X FT-IR spec-
1
trometer (KBr pellets for solids and films for liquids). Ϫ H-NMR
spectra were recorded at 200 MHz with a Bruker AC 200 spec-
trometer or at 300 MHz with a Bruker AM 300 spectrometer. TMS
was used as internal reference standard. The numbering of the dif-
ferent hydrogen atoms is indicated in Table 1. Ϫ Microanalyses
´ ´
were performed by Societe Franc¸aise Hoechst or Service Central
dЈAnalyse du C.N.R.S. and results obtained were within ± 0.4% of
the calculated values except for compounds 6b and 10. Most of
our compounds contained water, which was detected by H-NMR
tures giving a relaxation higher than 80% with an IC50
lower than 20 µ were of particularly interest. In Table 3,
we noted that these critera were obtained with compound
1
spectroscopy. The presence of water was also confirmed by Karl
8c (IC50 ϭ 10 µ and maximal relaxation ϭ 100%) in the Fischer analyses for some of them. This is the reason why some of
Eur. J. Org. Chem. 1998, 933Ϫ943 935

J. P. Nallet et al.
FULL PAPER
The precipitate formed was then filtered, washed with ether and
Table 3. Relaxation of isolated rat aortas (without endithelium)
precontracted with 0.1µ norepinephrine (n ϭ 2Ϫ3); IS-5-MN: iso-
sorbide-5-mononitrate; ISDN: isosorbide-2,5-dinitrate; NTG: ni-
troglycerine
recrystallized from ethanol/acetone to give 2.15 g (85%) of 6a; mp
20
152Ϫ155°C, [α]D ϭ ϩ55 (c ϭ 0.6 in water). Ϫ IR: ν˜ ϭ 3233
1
cmϪ1, 3058, 2931, 1745, 1636, 1282, 1231, 1190 . Ϫ H NMR: see
Table 4. Ϫ C12H19N3O8S·0.8 H2O (365 ϩ 0.8 H2O): calcd.C 34.62,
H 5.22, Cl 8.51, N 10.09, O 33.82; found C 34.7, H 5.23, Cl 8.63,
N 9.71, O 34.08.
Compound
IC50 (µ)
Max. Relaxation [%]
5a
28
80
85
5b
70
5-O-[S-(Acetamidomethyl)-N-tert-butoxycarbonyl)]--cysteinyl-
2-O-nitro-1,4:3,6-dianhydro--glucitol (5b): 1,4:3,6-Dianhydro--
glucitol-2-nitrate (2) (3.5 g, 18 mmol), S-acetamidomethyl-N-tBoc-
-cysteine (5.3 g, 18 mmol), DCC (3.78 g, 18 mmol), HOBt (2.43
g, 18 mmol) and 4-pyrrolidinopyridine (0.3 g, 2 mmol) were stirred
at room temp. in 150 ml of dry dichloromethane for 24 h. After
the same treatment as described for 5a and flash chromatography
with ethyl acetate/heptane (4:3 then 9:1), the product was recrys-
tallized from acetone/diisopropyl ether (2:3); 3.95 g (46%) of 5b
was obtained; mp 115°C, [α]D20 ϭ ϩ11 (c ϭ 0.6 in ethanol). Ϫ IR:
5c
>100
63
50
5d
70
6a
100
31
6b
>100
>100
33
14
6c
25
6d
92
7a
72
20
>100
>100
10
>100
25
15
75
7b
100
40
8a
8b
35
8c
100
38
8d
ν ϭ 3358 cmϪ1, 1753, 1683, 1645, 1625, 1524, 1294, 1222. Ϫ 1H
˜
10
83
NMR: see Table 4. Ϫ C17H27N3O10S (465): calcd. C 43.87, H 5.85,
N 9.03, found C 43.8, H 5.9, N 9.0.
11
100
71
14
18.6
10.4
19.7
7.65
precipitates
1.13
20.5
5
15
100
92
5ϪO-[S-(Acetamidomethyl)]--cysteinyl-2-O-nitro-1,4:3,6-dian-
hydro--glucitol Hydrochloride (6b): 2.3 g (4.9 mmol) of 5b was
added to 21 ml of 2  hydrochloric acid in ethyl acetate, and the
solution was stirred for 1 h at room temp. A precipitate was then
filtered, washed with ether and recrystallized from ethanol. 1.75 g
19a
20a ؉ 21a
19b
100
Ϫ
20b ؉ 21b
19c
100
96
100
75
20c ؉ 21c
19d
20
50.8
(88%) of 6b was obtained; mp 161Ϫ162°C, [α]D ϭ ϩ31.6 (c ϭ
0.6 in water). Ϫ IR: ν ϭ 3173 cmϪ1, 3054, 2616, 1738, 1641, 1568,
˜
IS-5-MN
ISDN
NTG
3
3 ϩ thiazolidine-4- 21
carboxylic acid
>100
2.2
0.1
21
30
1
1279, 1094, 860. Ϫ H NMR see Table 4. Ϫ C12H19N3O8S (365):
100
100
87
calcd.C 35.86, H 5.01, N 10.45; found C 35.4, H 4.9, N 10.3.
5-N-[S-(Acetamidomethyl)-N-(tert-butoxycarbonyl)]--cy-
steinamidyl-5-deoxy-2-O-nitro-1,4:3,6-dianhydro--iditol (5c): N-
tBoc-S-acetamidomethyl--cysteine (3.95 g, 13.5 mmol), DCC (2.8
g, 13.5 mmol), and HOBt (1.82 g, 13.5 mmol) were successively
added, at room temp, to a stirred solution of 5-amino-5-deoxy-
1,4:3,6-dianhydro--iditol-2-nitrate (2.56 g, 13.5 mmol) in 120 ml
of dry dichloromethane. After 24 h, DCU was removed by fil-
tration and the pasty compound purified by flash chromatography
(ethyl acetate). After recrystallization from ethyl acetate, 5.9 g
85
our analyses were calculated for net formulas including fractions
of 1 H2O. Ϫ For chromatographic purifications, silica gel of type
Kieselgel 60, 230Ϫ400 mesh ASTM was used. Ϫ The following
abbreviations are used: DCC (1,3-dicyclohexylcarbodiimide), CMC
[1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluene-
sulfonate], HOBt (1-hydroxybenzotriazole hydrate), DCU (dicyclo-
hexylurea). Reagents were obtained from Sigma-Aldrich Co.
(Saint-Quentin-Fallavier, France).
20
(94%) of 5c was obtained; mp 152°C, [α]D ϭ ϩ26 (c ϭ 0.6 in
acetone). Ϫ IR: ν˜ ϭ 3317 cmϪ1, 1715, 1685, 1657, 1632, 1554, 1527,
1
1274, 1171, 856. Ϫ H NMR: see Table 4. Ϫ C17H28N4O9S (463):
calcd. C 43.96, H 6.07, N 12.06; found C 44.1, H 6.0, N 12.0.
2-O-[S-(Acetamidomethyl)-N-(tert-butoxycarbonyl)]--cystei-
nyl-5-O-nitro-1,4:3,6-dianhydro--glucitol (5a): 1,4:3,6-Dianhydro-
-glucitol-5-nitrate (1.91 g, 10 mmol), S-acetamidomethyl-N-tBoc-
-cysteine (3.5 g, 12 mmol), DCC (2.47 g, 12 mmol), HOBt (1.6 g,
12 mmol) and 4-pyrrolidinopyridine (0.2 g, 1.3 mmol) were stirred
at room temp. in 100 ml of dry dichloromethane for 6 h. DCU was
removed by filtration and the solution was washed successively with
30 ml of 5% aqueous acetic acid, 30 ml of water, 30 ml of sodium
bicarbonate solution, and water. Purification by flash chromatogra-
phy [ethyl acetate/heptane (1:1 then 4:1)] and recrystallization from
acetone/diisopropyl ether (1:1) gave 3.4 g (73%) of 5a, mp
5-N-[S-(Acetamidomethyl)]--cysteinamidyl-5-deoxy-2-O-nitro-
1,4:3,6-dianhydro--iditol Hydrochloride (6c): 2 g (4.3 mmol) of 5c
was added to 13 ml of 1.6  methanolic hydrochloric acid, and the
solution was stirred for 24 h at room temp. A white solid was then
filtered and the filtrate purified by flash chromatography [ethyl
acetate, then ethyl acetate/methanol (4:1 then 7:3)]. The viscous oil
was crystallized from pyridine and acetone and recrystallized from
ethanol/acetone, then from ethanol to give 0.95 g (55%) of 6c; mp
20
183°C, [α]D ϭ ϩ28 (c ϭ 0.6 in water). Ϫ IR: ν˜ ϭ 3196 cmϪ1
,
1684, 1628, 1546, 1282, 1095, 859. Ϫ 1H NMR: see Table 4. Ϫ
C12H20N4O7S·0.15 H2O (364 ϩ 0.15 H2O): calcd. C 35.71, H 5.31,
N 13.88; found C 35.7, H 5.3, N 13.7.
20
105Ϫ106°C, [α]D ϭ ϩ59 (c ϭ 0.50, in acetone). Ϫ IR: ν˜ ϭ 3343
cmϪ1, 1738, 1678, 1645, 1526, 1282, 1100, 847. Ϫ 1H NMR: see
Table 4. Ϫ C17H27N3O10S (465): calcd. C 43.87, H 5.85, N 9.03, O
34.37; found C 43.8, H 5.8, N 8.7, O 34.11.
2-N-[S-(Acetamidomethyl)-N-(tert-butoxycarbonyl)]--cystein-
amido-2-deoxy-5-O-nitro-1,4:3,6-dianhydro--glucitol (5d): S-aceta-
midomethyl-N-tBoc--cysteine (6.4 g, 21.8 mmol), DCC (4.53 g,
2ϪO-[S-(Acetamidomethyl)]--cysteinyl-5-O-nitro-1,4:3,6-dianhy- 21.9 mmol), and HOBt (2.95 g, 21.8 mmol) were succesively added
dro--glucitol Hydrochloride (6a): 2.9 g (6.2 mmol) of 5a was added at room temp. to a stirred solution of 2-amino-2-deoxy-1,4:3,6-di-
to 24 ml of 2  hydrochloric acid in ethyl acetate (obtained by anhydro--glucitol-5-nitrate (4.15 g, 21.8 mmol) in 200 ml of dry
bubbling gaseous HCl into dry AcOEt and adjusting the value of dichloromethane. After 24 h, DCU was removed by filtration and
2  by dilution), and the solution was stirred for 5 h at room temp. the compound purified by flash chromatography [ethyl acetate then
936
Eur. J. Org. Chem. 1998, 933Ϫ943

Hexitol and Aminodeoxyhexitol Mononitrate Derivatives Containing a Sulfur Group
FULL PAPER
1
Table 4. H-NMR chemical shifts (δ; TMS) of 5* and 6* in C5D5N (300 MHz)
NH2, NH-
HCl Boc
NH-
CO
NH-
Acm
1-H,
1Ј-H
2-H
3-H
4-H
5-H
6-H,
6Ј-H
7-H
8-H,
8Ј-H
9-H,
9Ј-H
CH3
tBu
5a
8.76
9.5
4. 16
5.5
4.74
5.21,
5.5,
4.06
5.06
3.5
4.74
2.08
1.49
1 H, d
1 H, m 1 H, d 2 H, m 1 H, m 1 H, t
2 H, m 2 H, m 1 H, m 1 H, dd 2 H, m 3 H, s 9 H, s
8.4 Hz
10.7 Hz
5.1 Hz
3.86
13.8,
1 H, dd
11.4,
5.7 Hz
3.39
4.06
1 H, m
5.4 Hz
1 H, dd
13.8,
7.8 Hz
5b
8.66
1 H, d
8.4 Hz
9.43
4.33
5.56
4.7
5.03
5.4
4.06
5.17
3.57
4.8
2.08
1.49
1 H, m 1 H, dd 1 H, d 1 H, d 1 H, t
1 H, m 1 H, dd 1 H,
1 H, dd 1 H, dd 3 H, s 9 H, s
11.7,
3.2 Hz 5.5 Hz 5.5 Hz
10.4,
ddd
13.9,
14,
3.6 Hz
4.22
3.1 Hz 8.7, 8.4, 5.3 Hz 6.3 Hz
3.89
5.3 Hz 3.38
4.73
1 H, d
11.7 Hz
1 H, dd
10.4,
1 H, dd 1 H, m
13.9,
8.7 Hz
5 Hz
5c
8.45
9.09
9.5
4.13
5.53
5.01
5.06
4.72
4.0
5.12
3.41
4.93
2.03
1.47
1 H, d 1 H, d 1 H, m 1 H, dd 1 H, m 1 H, d 1 H, d 1 H, m 1 H, dd 1 H, m 1 H, dd 1 H, dd 3 H, s 9 H, s
8.4 Hz 6.9 Hz
11.4,
4.1 Hz 4.1 Hz
9.6,
13.9,
5.2 Hz; 9.3 Hz
3.19 4.4
1 H, dd 1 H, dd
13.9, 13.6,
8.6 Hz 5.6 Hz
13.6,
4 Hz
4.7 Hz
3.92
4.07
1 H, d
11.4 Hz
1 H, d
9.6 Hz
5d
8.48
9.19
9.48
4.05
4.7
4.78
5.12
5.45
4.0
5.08
3.41 4.89
2.02
1.46
1 H, d 1 H, d 1 H, m 1 H, d 1 H, m 1 H, d 1 H, t
1 H, ddd 1 H, m 1 H, m 1 H, dd 1 H, dd 3 H, s 9 H, s
8.7 Hz 6.4 Hz
10.6 Hz
4.0
1 H, m
5 Hz
5 Hz
5.4,
3.83
13.7,
6.3 Hz 7.2 Hz
3.23 4.45
1 H, dd 1 H, dd
13.7, 13.4,
7.9 Hz 5.2 Hz
13.4,
5.2 Hz 1 H, dd
11.4,
5.4 Hz
6a 8.11
9.85
4.09
5.53
5.05
5.26
5.53
4.09
4.88
3.8 4.88
2.12
3 H, m
1 H, t 2 H, m 1 H, m 1 H, t 1 H, t
1 H, m 1 H, m 1 H, m 2 H, d 1 H, m 3 H, s
6 Hz
5.2 Hz 5.2 Hz
3.89
5.4 Hz 4.76
1 H, dd
11.3,
1 H, dd
13.5,
5.3 Hz
6. Hz
6b 9.35
3 H, m
9.92
4.24
5.6
4.74
5.08
5.5
4.14
5.08
3.84
4.91
2.13
1 H, m 1 H, dd 1 H, d 1 H, d 1 H, m 1 H, m 1 H, m 1 H, m 2 H, m 1 H, dd 3 H, s
11.5,
3.4 Hz 5.2 Hz
3.95
13.5,
3.6 Hz
4.14
1 H, dd
10.6,
6 Hz
4.82
1 H, m
5.1 Hz
1 H, dd
13.5,
6.3 Hz
6c 7.2
3 H, m
10.61
10.26
4.15
5.53
5.17
5.28
4.73
4.06
5.20
3.97
4.82 ;
2.15
1 H, d 1 H, t 1 H, dd 1 H, d 1 H, d 1 H, d 1 H, m 2 H,m 1 H, m 1 H,dd 1 H, dd 3 H, s
6.5 Hz 6.3 Hz 11.4,
2.7 Hz 4.2 Hz 4.2 Hz
14.3,
4.0 Hz 6.2 Hz
3.39 4.72
1 H, dd 1 H, dd
14.3, 13.5,
13.5,
4.15 Hz
4.06
1 H, m
9.6 Hz 6.5 Hz
6d
3.97
4.36
4.51
5.07
5.56
4.1
4.18
3.09, 1 H 4.37
2.0
2 H, m 1 H, d 1 H, d 1 H, dd 1 H, ddd 1 H, dd 1 H, dd dd, 14.3, 1 H, d 3 H, s
3.1 Hz 5 Hz
5.2, 5 Hz 5.3, 5.2, 11.5,
7.2,
6.2 Hz 14 Hz
4.29
2.2 Hz 2.2 Hz 6.2 Hz 3.03
3.97
1 H, m
1 H, dd 1 H, d
14.3,
7.2 Hz
14 Hz
ethyl acetate/methanol (95:5)]. After recrystallization from ethyl ϩ78 (c ϭ 0.6 in ethanol). Ϫ IR: ν˜ ϭ 3306 cmϪ1, 1689, 1657, 1633,
20
acetate, 4.5 g (44%) of 5d was obtained; mp 90Ϫ92°C, [α]D
ϭ
1549, 1509, 1282, 1173, 1088, 858. Ϫ 1H NMR: see Table 4. Ϫ
Eur. J. Org. Chem. 1998, 933Ϫ943
937

J. P. Nallet et al.
C17H28N4O9S·0.6 H2O (464 ϩ 0.6 H2O): calcd. C 42.9, H 6.2, N tion of 5-amino-5-deoxy-1,4:3,6-dianhydro--iditol-2-nitrate (5 g,
FULL PAPER
11.7, O 32.4; found C 42.96, H 6.18, N 11.78, O 32.31.
26.3 mmol) in 300 ml of dry dichloromethane. After 24 h, the same
treatment as described for 5a and flash chromatography [ethyl acet-
ate then ethyl acetate/methanol (9:1)] gave 10.5 g of an oil corre-
sponding to 7c. This oil did not crystallize and was used immedi-
ately in the next step. 10.5 g of 7c was added to 80 ml of 2 
hydrochloric acid in ethyl acetate, and the solution was stirred for
3 h at room temp. A precipitate was then filtered, washed with
ether and recrystallized from methanol. 7.35 g (81%) of 8c was
2-N-[S-(Acetamidomethyl)]--cysteinamido-2-deoxy-5-O-nitro-
1,4:3,6-dianhydro--glucitol Hydrochloride (6d): 4.3 g (9.25 mmol)
of 5d was added to 23 ml of 2.2  methanolic hydrochloric acid,
and the solution was stirred for 18 h at room temp. The solution
was concentrated and the residue purified by flash chromatography
[ethyl acetate then ethyl acetate/methanol (4:1 then 7:3 and then
3:2)]. After recrystallization from ethanol, 3.1 g (83%) of 6d was
20
obtained; mp 185Ϫ195°C (dec.), [α]D ϭ Ϫ60 (c ϭ 2 in water). Ϫ
20
obtained; mp 94Ϫ95°C, [α]D ϭ ϩ74 (c ϭ 0.6 in water). Ϫ IR:
IR: ν˜ ϭ 3271 cmϪ1, 2932, 1692, 1652, 1553, 1283, 859. Ϫ 1H NMR:
see Table 5. Ϫ C10H15N3O6S (305): calcd. C 35.14, H 4.72, Cl 10.37,
N 12.30; found C 35.1, H 4.5, Cl 10.4, N 12.1.
ν ϭ 3243 cmϪ1, 3060, 1690, 1635, 1553, 1486, 1282, 1093, 857. Ϫ
˜
1H NMR: see Table 4. Ϫ C12H20N4O7S·0.8 H2O (364 ϩ 0.8 H2O):
calcd. C 34.71, H 5.23, Cl 8.53, N 13.49; found C 34.7, H 5.4, Cl
8.6, N 13.3.
2-Deoxy-5-O-nitro-2-[{[4(R)-thiazolidinyl]carbonyl}amino]-
1,4:3,6-dianhydro--glucitol Hydrochloride (8d): -Thioproline (3.1
g, 23.3 mmol), DCC (4,8 g, 23.3 mmol), and HOBt (3.15 g, 23.3
mmol) were successively added at room temp. to a stirred solution
of 2-amino-2-deoxy-1,4:3,6-dianhydro--glucitol-5-nitrate (4.45 g,
23.4 mmol) in 200 ml of dry dichloromethane. After 24 h, DCU
was removed by filtration and the compound purified by flash
chromatography [ethyl acetate then ethyl acetate/methanol (9:1)].
The oily compound was dissolved in dichloromethane and after
treatment with dry hydrogen chloride and concentration, the resi-
due was crystallized and recrystallized from methanol to give 2.3 g
2-O-[(3-tert-Butoxycarbonyl-4(R)-thiazolidinyl)carbonyl]-5-O-
nitro-1,4:3,6-dianhydro--glucitol (7a): 1,4:3,6-Dianhydro--gluci-
tol-5-nitrate (5 g, 26.1 mmol), N-tBoc--thioproline (6.15 g, 26.3
mmol), DCC (5.4 g, 26.1 mmol), HOBt (3.55 g, 26.2 mmol) and 4-
pyrrolidinopyridine (0.435 g, 2.9 mmol) were stirred at room temp.
in 225 ml of dry dichloromethane for 24 h. After the same treat-
ment as described for 5a, recrystallization from ethyl acetate and
washing with petroleum ether, 5.5 g (51%) of 7a was obtained; mp
20
106Ϫ110°C, [α]D ϭ ϩ10 (c ϭ 0.6 in acetone). Ϫ IR: ν ϭ 1756
˜
cmϪ1, 1702, 1645, 1391, 1282, 1167, 1101, 854. Ϫ 1H NMR: see
Table 5. Ϫ C15H22N2O9S (406): calcd. C 44.33, H 5.45, N 6.89;
found C 44.4, H 5.5, N 6.8.
20
(29%) of 8d; mp 187Ϫ188°C (dec.), [α]D ϭ ϩ11 (c ϭ 0.6 in
water). Ϫ IR: ν˜ ϭ 3196 cmϪ1, 3072, 2821, 2702, 2553, 1666, 1569,
1
1281, 1096, 844. Ϫ H NMR: see Table 5. Ϫ C10H15N3O6S (305):
5-O-Nitro-2-O-{[4(R)-thiazolidinyl]carbonyl}-1,4:3,6-dian-
hydro--glucitol Hydrochloride (8a): 2.5 g (6.1 mmol) of 7a was ad-
ded to 32 ml of 2  hydrochloric acid in ethyl acetate, and the
solution was stirred for 1 h at room temp. A precipitate was then
filtered, washed with ether and recrystallized from ethanol. 2.85 g
(76%) of 8a was obtained; mp 183°C (dec.), [α]D20 ϭ ϩ42 (c ϭ 0.6
in water). Ϫ IR: ν˜ ϭ 1757 cmϪ1, 1628, 1284, 1226, 1098, 852. Ϫ
1H NMR: see Table 5. Ϫ C10H14N2O7S (313): calcd. C 35.04, H
4.41, N 8.17; found C 34.7, H 4.4, N 8.1.
calcd. C 35.14, H 4.72, Cl 10.37, N 12.30, S 9.38; found C 35.2, H
4.7, Cl 10.3, N 11.7; S, 9.2.
5-Deoxy-2-O-nitro-5-[{[3-formyl-2,2-dimethyl-4(R)-thiazo-
lidinyl]carbonyl}amino]-1,4:3,6-dianhydro--iditol (9): 5-Amino-5-
deoxy-1,4:3,6-dianhydro--iditol-2-nitrate (2.94 g, 15.5 mmol), -3-
formyl-2,2-dimethylthiazolidine-4-carboxylic acid[24] (2.95 g, 15,5
mmol), DCC (3.20 g, 15.5 mmol) and HOBt (2.1 g, 15.5 mmol)
were stirred at room temp. in 150 ml of dry dichloromethane for
24 h. DCU was removed by filtration and the solid compound was
purified by flash chromatography (ethyl acetate then methanol).
After recrystallization from methanol, 3.05 g (54%) of 9 was ob-
5-O-{[3-tert-Butoxycarbonyl-4(R)-thiazolidinyl]carbonyl}-2-O-
nitro-1,4:3,6-dianhydro--glucitol (7b): 1,4:3,6-Dianhydro--gluci-
tol-2-nitrate (6 g, 31.4 mmol), N-tBoc--thioproline (7.38 g, 31.6
mmol), DCC (6.48 g, 31.4 mmol), HOBt (4.26 g, 31.5 mmol), and
4-pyrrolidinopyridine (0.52 g, 3.5 mmol) were stirred at room temp.
in 270 ml of dry dichloromethane (stabilized with amylene) for 24
h. After the same treatment as desribed for 5a and recrystallization
from ethyl acetate/petroleum ether, 7.6 g (60%) of 7b was obtained;
20
tained; mp 158°C, [α]D ϭ 59 (c ϭ 0.6 in acetone). Ϫ IR: ν˜ ϭ
1
1688 cmϪ1, 1646, 1573, 1376, 1361, 1287, 1101, 853. Ϫ H NMR:
see Table 6. Ϫ C13H19N3O7S (361): calcd. C 43.20, H 5.30, N 11.63;
found C 43.0, H 5.3, N 11.7.
5-Deoxy-5-[{[2,2-dimethyl-4(R)-thiazolidinyl]carbonyl}amino]-
2-O-nitro-1,4:3,6-dianhydro--iditol Hydrochloride (10): 5-Amino-5-
deoxy-1,4:3,6-dianhydro--iditol-2-nitrate (3 g, 15.8 mmol), -2,2-
dimethylthiazolidine-4-carboxylic acid[24] (3.07 g, 15,5 mmol),
DCC (3.26 g, 15.7 mmol), and HOBt (2.14 g, 15.7 mmol) were
stirred at room temp. in 130 ml of dry dichloromethane for 24 h.
DCU was removed by filtration and the oily compound was puri-
fied by flash chromatography (ethyl acetate) then dissolved in di-
chloromethane and dry hydrogen chloride was slowly bubbled into
the solution. After concentration, the residue was crystallized and
recrystallized from methanol to give 2.7g (47%) of 10; mp 196°C
mp 93°C, [α]D20 ϭ Ϫ15 (c ϭ 0.6 in ethanol). Ϫ IR: ν ϭ 1765 cmϪ1
,
˜
1697, 1640, 1382, 1367, 1307, 1274, 1194, 1164, 1091, 863. Ϫ 1H
NMR: see Table 5. Ϫ C15H22N2O9S·0.15 H2O (406 ϩ 0.15 H2O):
calcd. C 44.03, H 5.48, N 6.84; found C 44.0, H 5.4, N 6.8.
2-O-Nitro-5-O-{[4(R)-thiazolidinyl]carbonyl}-1,4:3,6-dian-
hydro--glucitol Hydrochloride (8b): 6.8 g (16.7 mmol) of 7b was
added to 65 ml of 2  hydrochloric acid in ethyl acetate, and the
solution was stirred for 1 h at room temp. A precipitate was then
filtered, washed with ether and recrystallized from methanol. 2.35
20
20
g (40%) of 8b was obtained; mp 175°C (dec.), [α]D ϭ ϩ15 (c ϭ
(dec.), [α]D ϭ Ϫ12 to ϩ17 (c ϭ 0.6 in water) (variation in 1 h
0.6 in water). Ϫ IR: ν˜ ϭ 1761 cmϪ1, 1635, 1309, 1279, 1250, 1201,
1097, 906, 862. Ϫ 1H NMR: see Table 5. Ϫ C10H14N2O7S·0.15
H2O (306 ϩ 0.15 H2O): calcd. C 34.75, H 4.45, N 8.10; found C
34.7, H 4.4, N 7.9.
˜
due to instability of this compound in water). Ϫ IR: ν ϭ 3055
1
cmϪ1, 1693, 1634, 1562, 1281, 1098, 856. Ϫ H NMR: see Table 6.
Ϫ C12H19N3O6S (333): calcd. C 38.78, H 5.43, Cl 10.01, N 11.30,
O 25.82, S 8.62; found C 38.51, H 5.43, Cl 9.92, N 11.12, O 25.48,
S 9.16.
5-Deoxy-2-O-nitro-5-({[4(R)-thiazolidinyl]carbonyl}amino)-
1,4:3,6-dianhydro--iditol Hydrochloride (8c): N-tBoc--thioproline
(6.13 g, 26.3 mmol), DCC (5.43 g, 26.3 mmol) and HOBt (3.55 g,
26.3 mmol) were successively added at room temp. to a stirred solu-
5-[{[3-Acetyl-4(R)-thiazolidinyl]carbonyl}amino]-5-deoxy-2-O-
nitro-1,4:3,6-dianhydro--iditol (14): 5-Amino-5-deoxy-1,4:3,6-di-
anhydro--iditol-2-nitrate (2 g, 10.5 mmol), 3-acetyl-thiazolidine-
938
Eur. J. Org. Chem. 1998, 933Ϫ943

Hexitol and Aminodeoxyhexitol Mononitrate Derivatives Containing a Sulfur Group
FULL PAPER
1
Table 5. H-NMR chemical shifts (δ; TMS) of 7[a] and 8[a] in C5D5N (300 MHz)
NH,HCl NH
1-H,1Ј-H
2-H
3-H
4-H
5-H
6-H,6Ј-H 7-H
8-H
9-H
tBu
7a
7b
4.12
5.54
4.57Ϫ4.7 5.18
5.51
4.1
5.09
3.30
4.57Ϫ4.7 1.47
2 H, m
1 H, m 1 H, m 1 H, m 1 H, m
1 H, m
3.90
1 H, m
2 H, m
2 H, m 9 H, s
1 H, m
4.26
2 H, m
5.61
4.72
5.05
5.41
3.98
2 H, m
5.05
1 H, m
3.38
2 H, m
4.72
1.51
1 H, m 1 H, m 1 H, m 1 H, m
2 H, m 9 H, s
8a 8.8
2 H, m
4.15
5.46
1 H, d
2.6 Hz
4.62
1 H, d
4.9 Hz
5.17
5.54
4.07
4.2
3.22
4.51
1 H, d
10.8 Hz
4.07
1 H, dd 1 H, ddd 1 H, m
1 H, dd
1 H, dd
1 H, d
5.3,
4.9 Hz
5.54, 5.3, 3.92
2.2 Hz
7, 6.4 Hz 10.2, 7 Hz 9 Hz
1 H, dd,
3.09
4.29
1 H, d
9 Hz
1 H, m
11.3,
1 H, dd
10.2,
5.4 Hz
6.4 Hz
8b 11.08
4.23
2 H, m
5.59
1 H, d
3 Hz
4.76
1 H, d
5.3 Hz
5.09
5.43
4.04
4.35
3.31
4.56
2 H, s
1 H, dd 1 H, ddd 1 H, dd
1 H, dd
7.1,
1 H, dd
10.1,
1 H, d
9.1 Hz
5.5,
5.3 Hz
5.5, 5.1,
3.7 Hz
10.4,
3.7 Hz
3.95
6.4 Hz
7.1 Hz
3.21
4.34
1 H, d
9.1 Hz
1 H, dd
10.4,
1 H, dd
10.1,
5.1 Hz
6.4 Hz
8c 9.5
9.1
4.15
5.52
4.9
4.9
4.72
4.07
4.31
3.52
4.32
2 H, m 1 H, m 1 H, dd
1 H, dd 1 H, m 1 H, m 1 H, m
1 H, dd
9.5,
1 H, dd
1 H, dd
1 H, d
9.3 Hz
11.45,
4.1 Hz
4.08
1 H, dd
11.45, 1.6 Hz
4.1,
1.6 Hz
7, 5.6 Hz 10,5,
5 Hz
3.98
6 Hz
3.22
4.27
1 H, d
9.3 Hz
1 H, dd
9.5,
1 H, dd
10, 7 Hz
2.5 Hz
8d 11.03
9.27
4.09
4.73
4.76
5.19
5.49
4.07
4.41
3.47
4.39
2 H, s
1 H, d 2 H, m
6.8 Hz
1 H, m 1 H, d
5 Hz
1 H, dd 1 H, dt
5.3, 5 Hz 5.3, 5.3,
2 Hz
1 H, dd
11.4,
1 H, dd
1 H, dd
1 H, d
9.4 Hz
7, 6.1 Hz 10.1,
2 Hz
3.88
6.1 Hz
3.34
4.29
1 H, d
9.3 Hz
1 H, dd
11.4,
1 H, dd
10.1,
5.3 Hz
7 Hz
[a]
See numbering for each compound in Table 1.
4(R)-carboxylic acid[25] (1.84 g, 10.5 mmol), CMC (4.45 g, 10.5
2(RS)-Methylthiazolidine-4(R)-carboxylic Acid 16a
ϩ 17a:
mmol), and HOBt (1.42 g, 10.5 mmol) were stirred at room temp.
These compounds were synthesized according to the procedure de-
in 80 ml of dry dichloromethane for 24 h. After the same treatment scribed by Nagasawa et al.[16]. Ϫ IR: ν˜ ϭ 3046 cmϪ1, 1614, 1391,
as described for 5a, the solid compound was recrystallized from
ethyl acetate to give 1.6 g (44%) of 14; mp 169°C. Two conformers
1367.
20
are detected by 1H NMR [A (75%) and B (25%)], [α]D ϭ Ϫ62
N-tert-Butoxycarbonyl-2(R)-methylthiazolidine-4(R)-carboxylic
Acid (18a): This compound was synthesized according to the pro-
cedure described by Kleemann et al.[33] from 16a ϩ 17a and was
(c ϭ 1 in ethanol). Ϫ IR: ν˜ ϭ 3269 cmϪ1, 1688, 1641, 1563, 1446,
1417, 1287, 1275, 1238, 1100, 850. Ϫ 1H NMR: see Table 6. Ϫ
C12H17N3O7S (347): calcd. C 41.50, H,4.93, N 12.10; found C 41.4,
H 4.9, N 12.1.
20
obtained in 76% yield; mp 118Ϫ119°C, [α]D ϭ Ϫ67 (c ϭ 1.0 in
methanol). Ϫ IR: ν˜ ϭ 2976 cmϪ1, 1729, 1621, 1428, 1169.
5-[{[3-Benzoyl-4(R)-thiazolidinyl]carbonyl}amino]-5-deoxy-2-
O-nitro-1,4:3,6-dianhydro--iditol (15): 5-Amino-5-deoxy-1,4:3,6-
dianhydro--iditol-2-nitrate (2 g, 10.5 mmol), 3-benzoyl-thiazolid-
ine-4(R)-carboxylic acid[26] (2.5 g, 10.5 mmol), DCC (2.16 g, 10.5
mmol), and HOBt (1.42 g, 10.5 mmol) were stirred at room temp.
in 100 ml of dry dichloromethane for 24 h. After the same treat-
2(RS)-Phenylthiazolidine-4(R)-carboxylic Acid (16b ϩ 17b):
These compounds were synthesized according to the procedure de-
scribed by Paul et al.[18]. Ϫ IR: ν ϭ 1576 cmϪ1, 1436, 1382, 1306,
˜
858.
N-tert-Butoxycarbonyl-2(R)-phenylthiazolidine-4(R)-carboxylic
ment as described for 5a, the solid compound was recrystallized Acid (18b): This compound was synthesized according to the pro-
from methanol to give 2.04 g (40%) of 15; mp 166Ϫ167°C, [α]D20 ϭ cedure described by Kleemann et al.[27] from 16b ϩ 17b and was
20
Ϫ106 (c ϭ 1 in DMSO). Ϫ IR: ν˜ ϭ 3296 cmϪ1, 1689, 1631, 1275,
obtained in 89% yield; mp 172Ϫ173°C, [α]D ϭ ϩ91 (c ϭ 1.0 in
853. Ϫ 1H NMR: see Table 6. Ϫ C17H19N3O7S (409): calcd. C methanol). Ϫ IR: ν˜ ϭ 1726 cmϪ1, 1632, 1420, 1368, 1350, 1328,
49.87, H 4.68, N 10.26; found C 49.7, H 4.6, N 10.2.
1290, 1248, 1172, 1138.
Eur. J. Org. Chem. 1998, 933Ϫ943
939

J. P. Nallet et al.
FULL PAPER
1
Table 6. H-NMR chemical shifts (δ; TMS) of 9[a], 10[a], 14[a], and 15[a] in C5D5N (300 MHz)
NH
CHO Harom 1-H,
2-H
3-H
4-H
5-H
6-H,
6Ј-H
7-H
8-H,
8Ј-H
9-H,
9Ј-H
CH3gem CH3-
CO
1Ј-H
9
9.36
8.69
4.12
5.48
4.85
4.94
4.72
4.01
5.3
3.53
1.93
1 H, d 1 H, s
6.8 Hz
1 H, dd 1 H, m 1 H, d 1 H, d 1 H, m 2 H, m 1 H, dd 1 H, dd
3 H, s
1.75
11.5, 4 Hz
4.3 Hz 4.3 Hz
7.4,
5.6 Hz
12, 5.6 Hz
4.01
1 H, m
3.4
3 H, s
1 H,dd
12, 7.4 Hz
3.49
10 9.21
1 H, d
6.7 Hz
4.17
5.54
4.92
4.96
4.77
4.09
4.34
1 H, t
7.6 Hz
1.65
1 H, dd 1 H, m 1 H, d 1 H, d 1 H, m 1 H,m
2 H, m
3 H, s
1.53
11.4; 4 Hz
4.09
1 H, m
4.2 Hz 4.2 Hz
3.99
1 H,dd
9.5;
3 H, s
1.9 Hz
14 9.49
3.9Ϫ4.2 5.50
2 H, m m, B
5.47
4.83
4.95
4 Hz
5.01
3.9Ϫ4.2 5.27
2 H, m dd, A
7.2,
3.65
4.68
2 H, m
2.17
B, s
2.03
A, s
d/B
1 H, d 1 H, d m,A
dd,B
11.6,
3.6 Hz
3.48
6.1 Hz
4 Hz
4.86
m,B
m, A
4.7 Hz
9.31
4.98
m, B
d/A
dd,A
11.6,
4.7 Hz
3.44
m,B
3.31
6.1 Hz
dd, A
11.6,
7.2 Hz
15 9.13
7.65
4.11
11.4,
5.44
4.78
4.90
4.67
4.03
5.37
3.5
4.84
1 H, d
6 Hz
2 H, m 1 H, dd 5.44
1 H, d 1 H, d 1 H, m 1 H, dd 1 H, m 1 H, dd 2 H, m
7.36
3 H, m 4.3 Hz
3.99
1 H, m 4.2 Hz 4.2 Hz
9.6,
11.5,
5.1 Hz
3.92
5.8 Hz
3.41
1 H, dd
11.4,
1.8 Hz
1 H, dd
9.6,
1 H, dd
11.5,
2.2 Hz
7.4 Hz
[a]
See numbering for each compound in Table 1.
2(RS)-n-Butylthiazolidine-4(R)-carboxylic Acid (16c ϩ 17c): mmol), N-tert-butoxycarbonyl-2(R)-methylthiazolidine-4(R)-car-
These compounds were synthesized according to the procedure de- boxylic acid (18a) (3.9 g, 15.7 mmol), DCC (3.26 g, 15.7 mmol),
scribed by Paul et al.[18]. Ϫ IR: ν˜ ϭ 2956 cmϪ1, 2748, 1582, 1381, and HOBt (2.13 g, 15.7 mmol) were stirred at room temp. in 120
1297, 1140, 846, 817, 617.
ml of dry dichloromethane for 24 h. After the same treatment as
described for 5a and flash chromatography [ethyl acetate/heptane
(2:3 then 1:1)], the solid compound was recrystallized from ethyl
N-tert-Butoxycarbonyl-2(R)-n-butylthiazolidine-4(R)-carboxylic
Acid (18c): This compound was synthesized according to the pro-
cedure described by Kleemann et al.[27] from 16c ϩ 17c and was
obtained in 93% yield. Oil. Ϫ IR: ν˜ ϭ 2960 cmϪ1, 2933, 1703, 1370,
1169, 1145. Ϫ Two conformers of 18c (A and B) were detected by
1H NMR.
20
acetate to give 4.17 g (63%) of 19a; mp 129Ϫ130°C, [α]D ϭ Ϫ18
(c ϭ 1.0 in ethanol). Ϫ IR: ν˜ ϭ 3298 cmϪ1, 1704, 1667, 1646,
1546, 1405, 1274, 1097, 1083, 839. Ϫ 1H NMR: see Table 8. Ϫ
C16H25N3O8S (419): calcd. C 45.82, H 6.01, N10.02; found C 45.7,
H 6.0, N 10.0.
Thiazolidine-2(R),4(R)-dicarboxylic Acid 2-Methyl Ester (16d):
This compound was synthesized according to the procedure de-
scribed by Baxter et al.[20]. Ϫ IR: ν˜ ϭ 3040 cmϪ1, 1752, 1741, 1625,
1476, 1441, 1377, 1311, 1279, 1241, 1221, 1174, 1012.
5-[{[2(RS)-Methyl-4(R)-thiazolidinyl]carbonyl}amino]-5-de-
oxy-2-O-nitro-1,4:3,6-dianhydro--iditol
Hydrochloride
[20a
(2R,4R), 21a (2S,4R)]: 4.09 g (9.75 mmol) of 19a was added to 34
ml of 2  hydrochloric acid in ethyl acetate, and the solution was
stirred for 16 h at room temp. A precipitate was then filtered and
washed with ether. After recrystallization from methanol, 2.58 g
(74%) of 20a and 21a was obtained; mp 209°C (dec.). Ϫ [α]D20 ϭ
Ϫ55 (c ϭ 1.0 in water). Ϫ IR: ν˜ ϭ 3230 cmϪ1, 2884, 2642, 2546,
2498, 1688, 1616, 1562, 1396, 1324, 1282, 1206, 1088, 1038, 956,
892, 862. Ϫ 1H NMR (300 MHz, C5D5N) (time t0: 25% 20a, 75%
21a; time t0 ϩ 15 min: 50% 20a, 50% 21a): δ ϭ 11.13 (s, 2 H,
NH·HCl), 9.77 (d, 0.5 H, J ϭ 6.6 Hz, NH 20a), 9.08 (d, 0.5 H,
J ϭ 6.8 Hz, NH 21a), 5.53 (m, 1 H, 2-H), 5.07 (m, 1 H, 3-H or
N-tert-Butoxycarbonylthiazolidine-2(R),4(R)-dicarboxylic Acid
2-Methyl Ester (18d): This compound was synthesized according
to the procedure described by Kleemann et al.[27] from 16d and was
obtained in 70% yield; mp 77Ϫ78°C. Two conformers were de-
tected by 1H NMR [A (83%) and B (17%)]. Ϫ IR: ν˜ ϭ 3530 cmϪ1
,
1747, 1662, 1412, 1370, 1342, 1283, 1211, 1153, 1017. Ϫ 1H NMR:
see Table 7.
5-[[(3-tert-Butoxycarbonyl-2(R)-methyl-4(R)-thiazolidinyl)car-
bonyl]amino}-5-deoxy-2-O-nitro-1,4:3,6-dianhydro--iditol (19a): 5-
Amino-5-deoxy-1,4:3,6-dianhydro--iditol-2-nitrate (3 g, 15.7 4-H), 5.0 (m, 1 H, 3-H or 4-H), 4.87 (q, 0.5 H, J ϭ 6.2 Hz, 9-H
940 Eur. J. Org. Chem. 1998, 933Ϫ943

Hexitol and Aminodeoxyhexitol Mononitrate Derivatives Containing a Sulfur Group
FULL PAPER
1
Table 7. H-NMR chemical shifts (δ; TMS) of 18* in [D6]DMSO (300 MHz)[a]
Harom
2-H
4-H
5-H, 5Ј-H
CH2
CH3
tBu
18a
5.12, 1 H, q
6.2 Hz
4.61, 1 H, dd
7.3, 6.2 Hz
3.37, 1 H, dd
11.6, 7.3 Hz
3.22, 1 H, dd
11.6, 6.2 Hz
1.51, 3 H, d
6.2 Hz
1.42, 9 H, s
1.27, 9 H, s
1.52, 9 H, m
1.36, 9 H, s
18b
7.61Ϫ7.64,
2 H, m
7.23Ϫ7.33,
3 H, m
6.05, 1 H, s
4.71, 1 H, dd
6.8, 6.2 Hz
3.45, 1 H, dd
11.8, 6.8 Hz
3.17, 1 H, dd
11.85, 6.2 Hz
18c[b]
5.41, m A
5.29, m B
5.32, m A
5.03, dd B
7.4, 6.8 Hz
3.55, 2 H, m
2.32, 2 H, m
1.97, 2 H, m
1.29, 2 H, m
0.87, 3 H, A
7 Hz
0.79, 3 H, B
18d[c]
5.37, s A
5.22, s B
4.55, 1 H, m
3.47, 1 H, m
3.26, 1 H, m
3.66, 3 H, s
[a]
[b]
[c]
See numbering for each compound in Table 1. Ϫ Spectrum in C5D5N. Ϫ Spectrum at 200 MHz.
21a), 4.76 (q, 0.5 H, J ϭ 6.2 Hz, 9-H 20a), 4.75 (m, 1 H, 5-H), 20a), 1.51 (d, 1.5 H, J ϭ 6.2 Hz, CH3 21a). Ϫ C11H17N3O6S (319):
4.71 (dd, 0.5 H, J ϭ 7.3 and 4.5 Hz, 7-H 21a), 4.36 (dd, 0.5 H, calcd. C 37.13, H 5.10, Cl 9.96, N 11.81; found C 37.2, H 5.1, Cl
J ϭ 8.7 and 6.9 Hz, 7-H 20a), 4.04Ϫ4.20 (m, 4 H, 1-H and 6-H), 9.9, N 11.8.
3.74 (dd, 0.5 H, J ϭ 10.4 and 4.5 Hz, 8-H 21a), 3.59 (dd, 0.5 H,
J ϭ 10 and 6.9 Hz, 8-H 20a), 3.46 (dd, 0.5 H, J ϭ 10.4 and 7.3
Hz, 8-H 21a), 3.35 (dd, 0.5 H, J ϭ 10 and 8.7 Hz, 8-H 20a), 1.57
5-[{[3-tert-Butoxycarbonyl-2(R)-phenyl-4(R)-thiazolidinyl]car-
bonyl}amino]-5-deoxy-2-O-nitro-1,4:3,6-dianhydro--iditol (19b): 5-
(d, 1.5 H, J ϭ 6.2 Hz, CH3 20a), 1.51 (d, 1.5 H, J ϭ 6.2 Hz, CH3 Amino-5-deoxy-1,4:3,6-dianhydro--iditol-2-nitrate (5 g, 26.29
1
Table 8. H-NMR chemical shifts (δ; TMS) of 19* in C5D5N (300 MHz) at 60°C[a]
NH
Harom 1-H,
2-H
3-H
4-H
5-H
6-H,
7-H
8-H,
9-H
CH2
CH3
1.75
tBu
1Ј-H
6Ј-H
8Ј-H
19a 8.7
4.14
5.47
4.82
4.9
4.67
4.08
4.89
3.56
5.3
1.46
3 H, d 9 H, s
6.3 Hz
1 H, d
1 H, dd 1 H, m 1 H, d 1 H, d 1 H, m 1 H, dd 1 H, dd 1 H, dd 1 H, q
6.4 Hz
11.4,
4.25 Hz 4.25 Hz
9.5,
7.4,
11.7,
6.3 Hz
4.4 Hz
4.01
5 Hz
4.01
7.3 Hz 7.4 Hz
3.3, 1 H,
1 H, m
1 H, m
dd, 11.7,
7.3 Hz
19b 8.75
7.97
4.14
5.47
4.89
4.81
4.72
4.08
5.01
3.59
6.31
1.33
9 H, s
1 H, d 2 H, d 1 H, dd 1 H, m 1 H, d 1 H, d 1 H, m 1 H, dd 1 H, dd 1 H, dd 1 H, s
5.2 Hz 7.5 Hz 11.4,
4 Hz
or
4.81
1 H, d 1 H, d
4 Hz
4 Hz
or
4.89
9.6,
7.0,
11.7,
7.37
4.4 Hz
4.8 Hz 6.5 Hz 7 Hz
2 H, t 4.01
7.5 Hz 1 H, m
7.24
4.01
1 H, m
3. 33
1 H, dd
11.7,
4 Hz
1 H, t
7.5 Hz
6.5 Hz
19c 8.73
1 H, d
6.5 Hz
4.13
5.4
4.89
4.82
4.68
4.08
4.91
3.58
5.28
2.28, 1 H, 0.87
1.49
1 H, dd 1 H, d 1 H, d 1 H, d 1 H, m 1 H, dd 1 H, dd 1 H, dd 1 H, dd m (10-H) 3 H, m 9 H, s
11.4,
3.2 Hz 4 Hz
4 Hz
or
4.89
9.6,
8.1,
11.7,
8.6,
1.96, 1 H,
4.4 Hz
4.02
or
4.82
5.1 Hz 7.5 Hz 8.1 Hz 5.6 Hz m (10-H)
4.02
1 H, m
3.32
1.29Ϫ1.53
4 H, m
(11-H,
1 H, m
1 H, d 1 H, d
1 H, dd
11.7,
4 Hz
4 Hz
7.5 Hz
12-H)
19d[b] 8.4
4.10
5.46
4.64
4.47
4.22
3.98
4.54
3.51
5.49
3.79
1.39
1 H, d
6.2 Hz
1 H, dd 1 H, m 1 H, m 1 H, m 1 H, m 1 H, dd 1 H, dd 1 H, dd 1 H, s
3 H, s 9 H, s
11.5,
or
or
9.6,
7.1,
11.8,
4.3 Hz
4.00
4.85 Hz 5.9 Hz 7.1 Hz
4.47
1 H, m 1 H, m
4.64
3.73
3.20
1 H, d
11.5 Hz
1 H, dd
9.6,
1 H, dd
11.8,
2.3 Hz
5.9 Hz
[a]
[b]
See numbering for each compound in Table 1. Ϫ Spectrum in [D6]DMSO at 60°C.
Eur. J. Org. Chem. 1998, 933Ϫ943
941

J. P. Nallet et al.
FULL PAPER
mmol), N-tert-butoxycarbonyl-2(R)-phenylthiazolidine-4(R)-car- C14H23N3O6S (361): calcd. C 42.31, H 6.09, N 10.58, Cl 8.81; found
boxylic acid (18b) (8.1 g, 26.29 mmol), DCC (5.4 g, 26.29 mmol), C 42.1, H 6.0, N 10.4, Cl 8.6.
and HOBt (3.6 g, 26.29 mmol) were stirred at room temp. in 200
5-[{[3-tert-Butoxycarbonyl-2(R)-methoxycarbonyl-4(R)-thia-
ml of dry dichloromethane for 24 h. After the same treatment as
zolidinyl]carbonyl}amino]-5-deoxy-2-O-nitro-1,4:3,6-dianhydro--
for 5a, the solid compound was recrystallized from ethyl acetate to
iditol (19d): 5-Amino-5-deoxy-1,4:3,6-dianhydro--iditol-2-nitrate
20
give 9.3 g (73%) of 19b; mp 115°C, [α]D ϭ ϩ87 (c ϭ 1.0 in
(1.73 g, 9.1 mmol), N-tert-butoxycarbonylthiazolidine-2(R),4(R)-
ethanol). Ϫ IR: ν˜ ϭ 3346 cmϪ1, 1702, 1636, 1544, 1394, 1368, 1284,
dicarboxylic acid 2-methyl ester (18d) (2.66 g, 9.1 mmol), DCC
1266, 1250, 1164, 1060, 844. Ϫ 1H NMR: see Table 8. Ϫ
(1.89 g, 9.1 mmol), and HOBt (1.23 g, 9.1 mmol) were stirred at
C21H27N3O8S·0.5 H2O (490): calcd. C 51.42, H 5.74, N 8.56; found
room temp. in 50 ml of dry dichloromethane for 24 h. After the
C 51.3, H 5.6, N 8.6.
same treatment as described for 5a and flash chromatography [ethyl
acetate/heptane (1:1)], the solid compound (2.45 g) was recrys-
tallized from methanol to give 2.04 g (48%) of 19d; mp 132Ϫ133°C,
[α]D20 ϭ Ϫ13 (c ϭ 1 in ethanol). Ϫ IR: ν˜ ϭ 3295 cmϪ1, 2974, 2883,
1738, 1700, 1688, 1634, 1547, 1482, 1365, 1275, 855. Ϫ H NMR:
see Table 8. Ϫ C17H25N3O10S (531): calcd. C 44.06, H 5.44, N 9.07;
5-Deoxy-2-O-nitro-5-[{[2(RS)-phenyl-4(R)-thiazolidinyl]-
carbonyl}amino]-1,4:3,6-dianhydro--iditol Hydrochloride [20b
(2R,4R), 21b (2S,4R)]: 2 g (4.15 mmol) of 19b was added to 15 ml
of 2  hydrochloric acid in ethyl acetate, and the solution was
stirred for 16 h at room temp. A precipitate (1.65 g) was then fil-
tered and washed with ether. After recrystallization from methanol,
0.95 g (50%) of 20b and 21b was obtained; mp 197°C (dec.),
1
found C 44.2, H 5.6, N 9.2.
20
[α]D ϭ Ϫ38 (c ϭ 1.0 in DMSO). Ϫ IR: ν˜ ϭ 2886 cmϪ1, 1692,
1
Pharmacology
1626, 1562, 1286, 882. Ϫ H-NMR (300 MHz, C5D5N) (50% 20b,
50% 21b): δ ϭ 10.04 (s, 2 H, NH·HCl), 9.62 (d, 0.5 H, J ϭ 6.7 Hz,
NH 20b), 9.05 (d, 0.5 H, J ϭ 6.9 Hz, NH 21b), 7.62Ϫ7.69 (m, 2
H, Ar), 7.32Ϫ7.36 (m, 3 H, Ar), 5.96 (s, 0.5 H, 9-H 21b), 5.8 (s,
0.5 H, 9-H 20b), 5.53 (m, 1 H, 2-H), 4.93Ϫ5.04 (m, 2 H, 3-H and
4-H), 4.76 (m, 1 H, 5-H), 4.66 (dd, 0.5 H, J ϭ 7.1 and 4.85 Hz, 7-
H 21b), 4.37 (dd, 0.5 H, J ϭ 8.25 and 7 Hz, 7-H 20b), 3.95Ϫ4.2
(m, 4 H, 1-H and 6-H), 3.83 (dd, 0.5 H, J ϭ 10.15 and 4.85 Hz, 8-
H 21b), 3.62 (dd, 0.5 H, J ϭ 10 and 7 Hz, 8-H 20b), 3.52 (dd, 0.5
H, J ϭ 10 and 8.25 Hz, 8-H 20b), 3.49 (dd, 0.5 H, J ϭ 10.15 and 7.1
Hz, 8-H 21b). Ϫ C16H19N3O6S·0.6 H2O (381 ϩ 0.6 H2O): calcd. C
44.83, H 4.98, Cl 8.27, N 9.80; found C 44.5, H 4.7, Cl 8.4, N 9.6.
Relaxation of Isolated Rat Aortas without Endothelium and Pre-
contracted with Norepinephrin[28]: All experiments were made in ac-
cordance with the French Ministry of Agriculture (approval no.
94148). Male Wistar rats (250Ϫ350 g) were anesthetized with so-
dium pentobarbital (60 mg/kg, i.p.), the thoracic aorta was rapidly
removed and placed in ice-cold Krebs-Ringer solution of following
composition (in m): NaCl 118, KCl 4.7, CaCl2 2.5, MgSO4 1.2,
KH2PO4 1.2, NaHCO3 25, EDTA 0.016, glucose 11. The aorta was
cleaned of adhering tissues and cut into ring segments of 3 mm
length. Endothelium was mechanically removed by gently rubbing
the intimal layer with a forceps. Each segment was mounted in 20
ml organ chambers in Krebs-Ringer solution at 37°C gassed with
a mixture of 95% O2/5% CO2 for recording of isometric tension.
Rings were mechanically stretched to a passive resting tension of 2
g, and allowed to equilibrate for 30 min. The absence of functional
endothelium was verified by the inability to relax in response to 1
µ acetylcholine (Sigma, Saint-Quentin-Fallavier, France) follow-
ing contraction with 0.1 µ norepinephrin (Sigma, Saint-Quentin-
Fallavier, France). The rings were then washed three times, allowed
to reequilibrate for 30Ϫ45 minutes, and constricted again with 0.1
µ norepinephrin. When the maximum of contraction was ob-
tained, the different compounds were added in a cumulative way,
with a range of concentration of 1 n to 100 µ with semi-log
increments. Compounds were dissolved in saline when possible,
otherwise in ethanol or dimethyl sulfoxide for the stock solution
and then diluted in saline. At the end of the experiment, the relax-
ation obtained with the highest concentration (100 µ) was calcu-
lated and referred as maximal relaxation. IC50 values (concen-
tration giving 50% of relaxation) were calculated for each com-
pound. Results are the mean of 2 or 3 values obtained from differ-
ent rats (the different tests performed were screening tests; for this
reason, each compound was tested in vitro on 2 or 3 different ani-
mals. Furthermore, variations between animals for each compound
were very small. The goal of these in vitro tests was to select the
compounds with the strongest activity (relaxation > 80% and IC50
< 20 µ) for further experimentation in vivo. Therefore we con-
sidered that statistic analyses were not very useful in this study and
standard deviations were not calculated).
5-[{[3-tert-Butoxycarbonyl-2(R)-butyl-4(R)-thiazolidinyl]-
carbonyl}amino]-5-deoxy-2-O-nitro-1,4:3,6-dianhydro--iditol (19c): 5-
Amino-5-deoxy-1,4:3,6-dianhydro--iditol-2-nitrate (4 g, 21 mmol),
N-tert-butoxycarbonyl-2(R)-n-Butylthiazolidine-4(R)-carboxylic
acid (18c) (6.08 g, 21 mmol), DCC (4.34 g, 21 mmol), and HOBt
(2.84 g, 21 mmol) were stirred at room temp. in 100 ml of dry
dichloromethane for 24 h. After the same treatment as described
for 5a and flash chromatography [ethyl acetate/heptane (3:7 then
1:1)], the solid compound (7.8 g) was recrystallized from ethyl acet-
ate/petroleum ether to give 4.76 g (49%) of 19c; mp 91Ϫ92°C,
20
[α]D ϭ ϩ4 (c ϭ 1.0 in ethanol). Ϫ IR: ν˜ ϭ 3324 cmϪ1, 1670,
1640, 1392, 1276, 1164, 1096, 856. Ϫ 1H NMR: see Table 8. Ϫ
C19H31N3O8S (461): calcd. C 49.44, H 6.77, N 9.11; found C 49.7,
H 6.7, N 9.1.
5-[{[2(RS)-Butyl-4(R)-thiazolidinyl]carbonyl}amino]-5-deoxy-
2-O-nitro-1,4:3,6-dianhydro--iditol Hydrochloride [20c (2R,4R),
21c (2S,4R)]: 3.8 g (8.2 mmol) of 19c was added to 28 ml of 2 
hydrochloric acid in ethyl acetate and the solution was stirred for
16 h at room temp. A precipitate was then filtered and washed with
ether. After recrystallization from methanol, 2.33 g (71%) of 20c
20
and 21c was obtained; mp 198Ϫ200°C (dec.), [α]D ϭ Ϫ34 (c ϭ
1.0 in DMSO). Ϫ IR: ν˜ ϭ 3240 cmϪ1, 2960, 2886, 1692, 1622,
1568, 1326, 1284, 1090, 1038, 960, 888, 862. Ϫ 1H NMR (200 MHz,
C5D5N) (33% 20c, 66% 21c): δ ϭ 9.6 (d, 0.33 H, J ϭ 6.9 Hz, NH
20c), 8.92 (d, 0.66 H, J ϭ 7 Hz, NH 21c), 8.07 (s, 2 H, NH·HCl),
5.53 (m, 1 H, 2-H), 4.97 (m, 2 H, 3-H and 4-H), 4.69 (m, 2.33 H,
9-H, 5-H, and 7-H 20c), 4.54 (dd, 0.66 H, J ϭ 7.2 and 4.5 Hz, 7-
H 21c), 4.01Ϫ4.21 (m, 4 H, 1-H and 6-H), 3.73 (dd, 0.66 H, J ϭ
10.25 and 4.5 Hz, 8-H 21c), 3.46 (dd, 0.33 H, J ϭ 9.9 and 6.8 Hz,
8-H 20c), 3.29 (dd, 0.66 H, J ϭ 10.25 and 7.2 Hz, 8-H 21c), 3.28
(dd, 0.33 H, J ϭ 9.9 and 8 Hz, 8-H 20c), 1.59Ϫ2.05 (m, 2 H,
CH2 nBu), 1.09Ϫ1.44 (m, 4 H, CH2 nBu), 0.76 (m, 3 H, CH3). Ϫ
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942
Eur. J. Org. Chem. 1998, 933Ϫ943

Hexitol and Aminodeoxyhexitol Mononitrate Derivatives Containing a Sulfur Group
FULL PAPER
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