Synthesis of heteroaryl substituted α-mercapto acids from thiomalic acid using hexafluoroacetone as protecting and activating reagent

Article abstract of DOI:10.1002/jhet.5570400306

The synthesis of heterocyclic α-mercapto acids starting from (RS)-thiomalic acid using hexafluoroacetone as protecting and activating agent is described. The new compounds are useful building blocks for peptide and depsipeptide modification as well as for drug design.

Full text of DOI:10.1002/jhet.5570400306

435
Synthesis of Heteroaryl Substituted α-Mercapto Acids from Thiomalic
May-Jun 2003
Acid Using Hexafluoroacetone as Protecting and Activating Reagent
*
Ksenia Pumpor, Elisabeth Windeisen and Klaus Burger
Department of Organic Chemistry, University of Leipzig, Johannisalle 29, D-04103 Leipzig, Germany
Received January 10, 2003
The synthesis of heterocyclic α-mercapto acids starting from (RS)-thiomalic acid using hexafluoroacetone
as protecting and activating agent is described. The new compounds are useful building blocks for peptide
and depsipeptide modification as well as for drug design.
J. Heterocyclic Chem., 40, 435 (2003).
Introduction.
Heterocyclic compounds, especially thiazole deriva-
tives, exhibit a broad range of biological activities. The
thiazole substructure is present in numerous natural prod-
ucts, drugs, and pesticides [16]. Some of the natural occur-
ring thiazole derivatives exhibiting antibiotic activity are
amino acids. As the first representative of this class of
compounds 3-amino-3-(thiazol-2-yl)propanoic acid was
isolated from the antibiotic bottromycin (Streptomyces
bottropensis) [17]. Naturally occurring thiazole-substi-
tuted hydroxy acids, like 4-amino-4-(4-carboxythiazol-2-
yl)-2-hydroxybutanoic acid, isolated from the macrocycle
nosiheptide, are rare [18]. Thiazole-substituted mercapto
acids are unknown to the best of our knowledge.
α-Hydroxy acids, besides α-amino acids and carbohy-
drates, belong to the most important and abundant repre-
sentatives of low molecular compounds of the naturally
occurring chiral pool [1]. In contrary, mercapto carboxylic
acids are rare. They were found as constituents of natural
products, for example in biologically active natural pep-
tides [2]. However, mercapto acids as well as acylmer-
capto acids are interesting building blocks for medicinal
chemistry. A β-mercapto acid is a subunit of Captopril, a
classical drug for treating hypertension [3], an α-mercapto
acid subunit is present in Omapatrilat and Gemopatrilat.
Both are vasopeptidase inhibitors that are currently under
clinical evaluation [4]. They all belong to a class of
oligomers called peptide hybrides. Compounds containing
the mercapto or the mercaptoacyl [5] moiety often exhibit
strong inhibitory effects on metal-containing enzymes
(metallozymes) [6], similar to hydroxamic acids [7]. Some
of the zinc-containing angiotensine converting enzymes
(ACE) possess the α-mercaptoacyl substructure [8].
Subsequently, we report on a preparatively simple route to
this class of compounds starting from (RS) thiomalic acid.
Results and Discussion.
We found that a recently described protection/activation
concept for the regioselective derivatization of multifunc-
tional α-amino [19] and α-hydroxy acids [20] can also be
applied to α-mercapto acids. Hexafluoroacetone reacts
readily with α-mercapto acids in DMSO at room tempera-
ture to give 2,2-bis(trifluoromethyl)-1,3-oxathiolan-5-ones
in 80 - 90% yield [21]. In one step, protection of the
α-mercapto and the adjacent carboxy group is achieved.
Concomitantly, the α-carboxy group is activated towards
nucleophiles and can be regioselectively derivatized. A
variety of functional groups present in the side-chain are
tolerated by the above protection/activation procedure and
therefore, can be derivatized regioselectively. On exclu-
sion of moisture 2,2-bis(trifluoromethyl)-1,3-oxathiolan-
5-ones can be stored in a refrigerator over months without
any decomposition.
In this context, compound 2 a derivative of thiomalic
acid is a synthetically useful intermediate, because the car-
boxylic group of the side chain can be regioselectively
functionalized after separate activation. Another advan-
tage, protection and α-activation and on the other hand α-
derivatization and deblocking of the mercapto function
occur in one step. Therefore, the hexafluoroacetone con-
cept saves steps compared to conventional strategies.
On heating 2 with an excess of thionyl chloride, the cor-
responding acid chloride is formed in excellent yields.
A growing number of reports focus on peptidomimetic
compounds built from two or more different types of
monomers [9]. Consequently, the development of new
methodology for the synthesis of new types of amino [10],
hydroxy [11], keto [12] and mercapto acids [13-15] and
their incorporation into peptide and depsipeptide hybrides
is an area of current interest [9].

436
K. Pumpor, E. Windeisen and K. Burger
Vol. 40
nmr spectroscopy. An ir absorption in the region of 1815 -
With an excess of diazomethane (> 2 equivalents) 3 is con-
verted into diazoketone 4, which is a preparatively versa-
tile building block [22]. For example, when 4 is treated
with conc. HBr or conc. HCl at - 78 °C within minutes the
corresponding haloketones 5 are formed in up to 90%
yield, which can be subjected to the Hantzsch reaction
without further purification [23, 24]. Dry acetone proved
to be the best solvent for the reaction of 5 with thioamides,
selenamides and thioureas. When a reaction mixture of 5
and the corresponding thioamide is heated up to 50 °C,
within minutes the HX-salts 6 start to crystallize. On stir-
-1
1800 cm unequivocally reveals the presence of a lactone
13
moiety, whereas the C nmr spectra show resonance sig-
nals of an unchanged 1,3-oxathiolan-5-one and a newly
formed thiazole ring system.
Deprotection of compounds 7 to give the α-mercapto
acids 8 can be achieved by heating up to 50 °C in a
THF/water mixture. In Scheme 4, some synthetically use-
ful reactions are summarized: Esters 9 are obtained on
heating in the presence of an excess of the corresponding
alcohols. Reaction of 7 with amines, hydrazine and
hydroxyl amine at room temperature provides ready
access to a variety of α-mercapto acid derivatives 10 - 14.
Because of their broad spectrum of biological activities,
the development of synthetic routes to new types of
hydroxamic acid derivatives is of current interest [25,26].
Compounds 11 represent a new ligand system to form
metal chelates, having two interesting coordination sites,
namely a mercapto and an N-hydroxyamide moiety.
Reaction of 7 with C-terminal protected amino acids or N-
protected amino acid hydrazides offers a preparatively
simple access to new types of peptide hybrides (15 - 17)
[27]. The option to derivatize the deblocked HS-group
subsequently, increases the synthetic potential of this reac-
tion sequence considerably.
ring in a two-phase system (aqueous NaHCO
3
solution/diethyl ether) the salts 6 were converted into the
thiazoles (6 → 7). After separation of the organic phase
and drying with MgSO , products 7 obtained after evapo-
4
ration of the solvent in vacuo are already analytically pure.
The structure of the new compounds was proved by ir and
Aminolytic ring opening reactions of the lactones 7 occur
efficiently when the resulting products are poorly soluble in

May-Jun 2003
Synthesis of Heteroaryl Substituted α-Mercapto Acids from Thiomalic Acid
437
EXPERIMENTAL
the solvent used and therefore spontaneously crystallize
from the reaction mixture. In most cases the compounds
obtained are already analytically pure. The progress of the
General.
19
reactions can be monitored by F NMR spectroscopy.
Solvents were purified prior to use. Reagents were used as pur-
chased. Melting points were determined on a Boetius heating
table. For C,H,N analyses a CHNO-Rapid-Elemental-Analyser
(Heraeus) was used. Mass spectra were recorded on a VG 12-250
(Masslab) electron ionization spectrometer (EI = 70 eV). Ir spec-
tra were obtained using a Specord spectrometer (Carl-Zeiss,
Jena) and Genesis Series FTIR ATI Mattson spectrometer. Nmr
1
13
spectra were recorded on Varian GEMINI 200 ( H 199.96;
C
1
13
50.29 MHz), GEMINI 2000 ( H 200.04; C 50.31 MHz) and
1
13
GEMINI 300 ( H 300.08: C 75.46 MHz) instruments.
Chemical shifts are reported in ppm relative to tetramethylsilane.
19
For F nmr spectra, external trifluoroacetic acid is used as refer-
ence. Thin-layer chromatography was performed on Merck
(Darmstadt, Germany) Kieselgel 60F
precoated plates.
254
Reactions were carried out under dry argon.
[2,2-Bis(trifluoromethyl)-5-oxo-1,3-oxathiolan-4-yl]acetic acid (2).
In a closed system, equipped with a dry ice condenser and
sealed with a bubbler, a suspension of racemic thiomalic acid
(15.0 g, 100 mmol) in 50 ml of DMSO was treated with an excess
(> 2 equivalents) of hexafluoroacetone. After the reaction was
complete, the reaction mixture was poured into 300 ml of an
The above described synthetic sequence is well suited
for the generation of libraries of peptide and depsipeptide
surrogates with new sequence motifs, which could be of
interest to pharmaceutical industry. Oxidation on air of the
mercapto group of compounds 8 - 17 is a slow process.
Nevertheless, the experiments should be performed under
inert gas. On further applications of α-mercapto acids for
drug synthesis, including glycosylation and disulfide for-
mation, we report elsewhere.
ice/water mixture and extracted with 200 ml CH Cl . The aque-
2
2
ous phase was extracted with 100 ml of CH Cl (3x) The com-
2
2
.
bined organic phase was washed (3x) with 100 ml portions of an
ice/water mixture, dried with MgSO and evaporated to dryness
4
in vacuo. The solid residue was recrystallized from benzene/
pentane. Yield: 25.6 g (86%) 2, mp 84 °C, white crystals; ir

438
K. Pumpor, E. Windeisen and K. Burger
Vol. 40
-1
1
Hz, J = 10.0 Hz), 3.92 (dd, 1H, J = 19.0 Hz, J = 3.0 Hz), 4.38 (d,
(KBr): ν 3300-2700, 1830, 1720 cm ; H nmr (CDCl ): δ 3.02
3
13
2H, J = 2.0 Hz), 4.87 ppm (dd, 1H, J = 10.0 Hz, J = 3.0 Hz);
C
(dd, 1H, J = 18.0 Hz, J = 10.0 Hz), 3.36 (dd, 1H, J = 18.0 Hz, J =
nmr (acetone-d ): δ 34.8, 41.6, 44.0, 84.0 (sept., J = 34 Hz),
4.0 Hz), 4.51 (dd, 1H, J = 10.0 Hz, J = 4.0 Hz, 1H), 10.63 ppm (s.
6
13
122.1 (q, J = 284 Hz), 122.5 (q, J = 284 Hz), 171.2, 199.2 ppm;
br., 1H); C nmr (CDCl ): δ 37.9, 41.6, 83.5 (sept., J = 35 Hz),
3
19
F nmr (acetone-d ): δ 0.24 (q, J = 10.0 Hz, 3F), 1.14 ppm (q, J
120.8 (q, J = 284 Hz), 121.3 (q, J = 284 Hz), 169.8, 175.6 ppm;
6
+
+
19
= 10.0 Hz, 3F); ms (EI) m/z = 376 [M] , 295 [M - Br] , 281 [M -
CH Br] , 253[M - COCH Br] , 87 [253 - CF COCF ] .
F nmr (CDCl ): δ 0.11 (q, J = 9.0 Hz, 3F), 1.28 ppm (q, J = 9.0
3
+
+
+
+
+
Hz, 3F); ms (EI) m/z = 298 [M] , 280 [M - H O] , 252 [280 -
CO] , 69 [CF ] .
2
2
3
3
2
+
+
Anal. Calcd. for C H BrF O S (375.08): C, 25.61; H, 1.34.
6
5
6 3
3
Found: C, 25.89; H, 1.41.
Anal. Calcd. for C H F O S (298.17): C, 28.19; H, 1.35.
7
4 6 4
Found: C, 28.09; H, 1.42.
4-(3-Chloro-2-oxopropyl)-2,2-bis(trifluoromethyl)-1,3-oxathi-
olan-5-one (5b).
[2,2-Bis(trifluoromethyl)-5-oxo-1,3-oxathiolan-4-yl]acetyl chlo-
ride (3).
To a stirred solution of freshly prepared diazoketone 4 (3.22 g,
10.0 mmol) in 25 ml of THF at - 78 °C, conc. HCl (7 ml) was
added dropwise. After gas formation ceased, the mixture was
warmed up to 0 °C and the solvents and the excess of HCl were
evaporated in vacuo. For working-up procedure see 5a. After
evaporation of the solvent the residue was recrystallized from
Compound 2 (25.0 g, 83.8 mmol) was heated with 20 ml
freshly distilled thionyl chloride under reflux for 6 h. After
removal of the excess of thionyl chloride, the remaining liquid
was distilled in vacuo. Yield: 24.4 g (88%) 3, bp 80 °C/6 torr,
slightly yellow liquid; mp ca. 15 °C; ir (film): ν 1800 br., 1385
-1 1
pentane/CHCl . Yield: 2.68 g (81%) 5b, mp 51 °C, white crys-
cm ; H nmr (CDCl ): δ 3.47 (dd, 1H, J = 19.0 Hz, J = 10.0 Hz),
3
3
-1
1
tals; ir (KBr): ν 1806, 1755 cm ; H nmr (CDCl ): δ 3.22 (dd,
3.86 (dd, 1H, J = 19.0 Hz, J = 4.0 Hz), 4.55 ppm (dd, 1H, J = 10.0
Hz, J = 4.0 Hz); C nmr (CDCl ): δ 41.6, 49.8, 83.9 (sept., J = 35
3
13
1H, J = 19.0 Hz, J = 11.0 Hz), 3.75 (d, 1H, J = 19.0 Hz, J = 3.0
3
13
Hz), 4.21 (s, 2H), 4.49 ppm (dd, 1H, J = 11.0 Hz, J = 3.0 Hz);
C
Hz), 120.9 (q, J = 284 Hz), 121.4 (q, J = 285 Hz), 169.1, 171.5
19
nmr (CDCl ): δ 40.8, 44.3, 47.4, 83.9 (sept., J = 35 Hz), 121.0 (q,
ppm; F nmr (CDCl ): δ 1.60 (q, J = 9.0 Hz, 3F), 2.40 ppm (q, J
3
3
19
+
+
J = 284 Hz), 121.5 (q, J = 285 Hz), 170.8, 199.4 ppm; F nmr
= 9.0 Hz, 3F); ms (EI) m/z = 316/318 [M] , 281 [M - Cl] , 252
[M - CO, - HCl] , 182 [CF CSCF ] , 113 [CF CS] , 87 [281 -
CO, - CF COCF ] , 69 [CF ] .
Anal. Calcd. for C H ClF O S (316.60): C, 26.55; H, 0.95.
+
+
+
(CDCl ): δ 1.65 (q, J = 9.0 Hz, 3F), 2.34 ppm (q, J = 9.0 Hz, 3F);
3
3
3
3
+
+
+
+
+
ms (EI) m/z = 332/330 [M] , 294 [M - HCl] , 281 [M - CH Cl] ,
2
253 [M - COCH Cl] , 87 [253 - CF COCF ] , 79/77
[COCH Cl] .
3
3
3
+
+
2
3
3
7
3
6 3
+
2
Found: C, 26.74; H, 1.09.
Anal. Calcd. for C H ClF O S (330.63): C, 29.06; H, 1.52.
8
5
6 3
4-(3-Diazo-2-oxopropyl)-2,2-bis(trifluoromethyl)-1,3-oxathi-
olan-5-one (4).
Found: C, 29.10; H, 1.08.
4-(Thiazol-4-ylmethyl)-2,2-bis(trifluoromethyl)-1,3-oxathiolan-
5-one (7).
To a stirred solution of diazomethane (100 mmol) in 200 ml of
diethyl ether, 3 (11.78 g, 37.2 mmol) in 50 ml of diethyl ether was
slowly added with cooling (0 °C). After 30 minutes the solvent
was evaporated and the residue was distilled under reduced pres-
sure. Yield: 11.15 g (93%) 4, bp 86 °C/0.1 torr, mp 30 °C, yellow
crystals; ir (CHCl ): ν 2095, 1805, 1635 cm ; H nmr (DCCl ):
δ 2.90 (dd, 1H, J = 17.0 Hz, J = 11.0 Hz), 3.38 (dd, 1H, J = 17.0
Hz, J = 3.0 Hz), 4.51 (dd, 1H, J = 11.0 Hz, J = 3.0 Hz), 5.44 ppm
(s, 1H); C nmr (CDCl ): δ 41.3, 43.8, 55.8, 83.8 (sept, J = 34
General Procedure.
To a stirred solution of 5a (10 mmol) in 10 ml of acetone, the
corresponding thioamide (10 mmol), dissolved in 10 ml of ace-
tone, was added dropwise. Then the reaction mixture was heated
under reflux for 4 hours. The solvent was removed in vacuo, and
the residue was suspended in diethyl ether (100 ml) and washed
-1
1
3
3
13
with ice-cold NaHCO solution. The aqueous phase was
3
3
Hz), 121.0 (q, J = 284 Hz), 121.4 (q, J = 286 Hz), 170.9, 188.9
extracted with diethyl ether (3x 50 ml). The combined organic
layer was washed with ice-cold water (3x 50 ml) and dried with
19
ppm; F nmr (CDCl ): δ 1.60 (q, J = 9.0 Hz, 3F), 2.34 ppm (q, J
3
+
+
= 9.0 Hz, 3F); ms (EI) m/z = 322 [M] , 294 [M - N ] , 252 [M -
CO, - CH N ] , 225 [294 - CF ], 113 [CF CS] , 69 [CF ] , 55
MgSO . After evaporation of the solvent under reduced pressure
2
4
+
+
+
the residue was recrystallized from hexane/CHCl .
2
2
3
3
3
3
+
[CH COCH] .
2
4-[2-(2-Thienyl)-thiazol-4-ylmethyl]-2,2-bis(trifluoromethyl)-
1,3-oxathiolan-5-one (7a).
Anal. Calcd. for C H F N O S (322.18): C, 29.82; H, 1.25; N,
8.69. Found: C, 30.46; H, 1.53; N, 7.60.
8
4 6 2 3
Compound 5a (3.75 g, 10 mmol) was reacted with thiophene
4-(3-Bromo-2-oxopropyl)-2,2-bis(trifluoromethyl)-1,3-oxathi-
olan-5-one (5a).
thioamide (1.43 g, 10 mmol) in 20 ml of acetone. Yield: 3.73 g
-1 1
(89%) 7a, mp 65 °C, white crystals; ir (CHCl ): ν 1815 cm ; H
3
To a stirred solution of freshly prepared diazoketone 4 (10.0 g,
31 mmol) in THF (70 ml) at - 78 °C, conc. HBr (25 ml) was
added dropwise. After gas formation ceased, the mixture was
warmed up to 0 °C and the solvents and the excess of HBr were
distilled off in vacuo. The residue was dissolved in 100 ml of
CHCl , washed with cold NaHCO solution, and dried with
nmr (CDCl ): δ 3.26 (dd, 1H, J = 14.9 Hz, J = 11.1 Hz), 3.77 (dd,
1H, J = 15.0 Hz, J = 3.6 Hz), 4.76 (dd, 1H, J = 10.8 Hz, J = 3.9
3
Hz), 7.05 (s, 1H), 7.13 (m, 1H), 7.46 (m, 1H), 7.56 ppm (m, 1H);
13
C nmr (CDCl ): δ 35.3, 46.1, 83.3 (sept., J = 35 Hz), 114.9,
3
120.9 (q, J = 283 Hz), 121.5 (q, J = 284 Hz), 127.0, 128.0, 128.2,
19
136.8, 151.1, 162.5, 170.5 ppm; F nmr (CDCl ): δ 0.86 (q, J =
3
3
3
MgSO . The solvent was evaporated in vacuo and the remaining
9.0 Hz, 3F), 1.86 ppm (q, J = 9.0 Hz, 3F); ms (EI): m/z = 419
4
+
+
+
liquid was purified by distillation under reduced pressure.
Slightly yellow oil, crystallizing on storage in a refrigerator.
Yield: 9.55 g (82%) 5a, bp 86 °C/0.2 torr, mp 40 °C; ir (KBr): ν
[M] , 253 [M - CF COCF ] , 225 [253 - CO] , 180 [225 -
3
3
+
+
+
CSH] , 71 [C H O ] , 45 [CSH] .
3
3 2
Anal. Calcd. for C H F NO S (419.39): C, 37.23; H, 1.68;
13
7
6
2 3
-1
1
1815, 1735 cm ; H nmr (acetone-d ): δ 3.45 (dd, 1H, J = 19.0
N, 3.34. Found: C, 37.22; H, 1.77; N, 3.39.
6

May-Jun 2003
Synthesis of Heteroaryl Substituted α-Mercapto Acids from Thiomalic Acid
439
4-[2-(4-Fluorophenyl)-thiazol-4-ylmethyl]-2,2-bis(trifluo-
3-[2-(2-Thienyl)-thiazol-4-yl]-(R,S)-2-mercaptopropanoic Acid
romethyl)-1,3-oxathiolan-5-one (7b).
(8a).
Compound 7a (2.10 g, 5 mmol) was heated in a THF/water
mixture. Yield: 1.20 g (88%) 8a, mp 80 °C, white crystals; ir
Compound 5a (3.75 g, 10 mmol) was reacted with 4-fluoroth-
iobenzamide (1.55 g, 10 mmol) in 20 ml of acetone. Yield: 3.03 g
-1 1
-1
(KBr): ν 3580-2930, 1710 cm ; H nmr (CDCl ): δ 3.24 (dd, 1H,
(69%) 7b, mp 75 °C, white crystals; ir (KBr): ν 3400, 1810 cm ;
3
1
J = 15 Hz, J = 6.3 Hz), 3.42 (dd, 1H, J = 14.8 Hz, J = 7.5 Hz), 4.04
(dd, 1H, J = 14.0 Hz, J = 7.0 Hz), 6.95 (s, 1H), 6.99 (m, 1H), 7.32
(d, 1H, J = 5.2 Hz), 7.45 (d, 1H, J = 3.6 Hz), 10.40 ppm (s.br., 2H,
H nmr (CDCl ): δ 3.32 (dd, 1H, J = 15.0 Hz, J = 10.8 Hz), 3.79
3
(dd, 1H, J = 15.3 Hz, J = 3.6 Hz), 4.76 (dd, 1H, J = 10.5 Hz, J =
13
3.6 Hz), 7.11 (s, 1H), 7.19 (m, 2H), 7.96 ppm (m, 2H); C nmr
13
OH, SH); C nmr (CDCl ): δ 32.4, 51.7 (d, J = 61 Hz), 115.7,
(CDCl ): δ 33.5, 45.4, 82.1 (sept., J = 34 Hz), 116.4 (d, J = 22
3
3
127.4, 128.2, 128.3, 136.3, 152.2, 162.4, 175.0 ppm; ms (EI) m/z
Hz), 117.6 (d, J = 8.0 Hz), 120.8 (q, J = 284 Hz), 121.4 (q, J = 285
Hz), 128.3, 129.4 (d, J = 3.0 Hz), 151.3, 163.3 (d, J = 248 Hz),
+
+
+
+
= 271 [M] , 253 [M – H O] , 238 [M - SH] , 226 [M – CO H] ,
2
2
+
+
+
19
220 [253 - SH] , 193 [226 - SH] , 181 [226 - CSH] , 111
166.0, 170.7 ppm; F nmr (CDCl ): δ 0.85 (q, J = 9.3 Hz, CF ),
3
3
+
+
+
+
+
[C H NS] , 83 [C H S] , 71 [C H O ] , 39 [C H ] .
1.91 ppm (q, J = 9.0 Hz, CF ); ms (EI) m/z = 431 [M] , 412 [M -
5
5
4
3
3
3
2
3 3
3
+
+
+
Anal. Calcd. for C H NO S (271.38): C, 44.26; H, 3.34; N,
F] , 265 [M - CF COCF ] , 237 [265 - CO] , 192 [265 -
10
9
2 3
3
3
+
+
5.16. Found: C, 44.20; H, 3.16; N, 4.76.
COCHS] , 122 [FC H CNH] .
6
4
Anal. Calcd. for C H F NO S (431.34): C, 41.77; H, 1.87;
N, 3.35. Found: C, 41.30, H, 2.02; N, 3.35.
15
8
7
2 2
3-[2-(4-Fluorophenyl)-thiazol-4-yl]-(RS)-2-mercaptopropanoic
Acid (8b).
4-[2-(4-Chlorophenyl)-thiazol-4-ylmethyl]-2,2-bis(trifluo-
romethyl)-1,3-oxathiolan-5-one (7c).
Compound 7b (2.16 g, 5 mmol) was heated in a THF/water
mixture. Yield: 1.16 g (82%) 8b, mp 127 °C, white crystals; ir
-1
1
(KBr): ν 3500-2700, 1700, 1605 cm ; H nmr (DMSO-d ): δ
Compound 5a (3.75 g, 10 mmol) was reacted with 4-chloroth-
6
1.01 (d, 1H, J = 5.8 Hz), 3.03 (dd, 1H, J = 15.0 Hz, J = 7.0 Hz),
3.30 (dd, 1H, J = 14.6 Hz, J = 8.0 Hz), 3.79 (m, 1H), 7.30 (m,
iobenzamide (1.72 g, 10 mmol) in 20 ml of acetone. Yield: 2.50 g
-1
1
(56%) 7c, mp 84 °C, white crystals; ir (KBr): ν 1810 cm ; H
13
2H), 7.40 (s, 1H), 7.93 ppm (m, 2H); C nmr (acetone-d ): δ
nmr (acetone-d ): δ 3.44 (dd, 1H, J = 15.0 Hz, J = 10.0 Hz), 3.81
6
6
31.8, 55.0, 116.6 (d, J = 22 Hz), 116.6, 129.1 (d, J = 9.0 Hz),
(dd, 1H, J = 15.0 Hz, J = 4.0 Hz), 5.15 (dd, 1H, J = 10.0 Hz, J =
+
13
130.7, 154.3, 163.0, 166.9, 172.5 ppm; ms (EI) m/z = 283 [M] ,
4.0 Hz), 7.52 (s, 1H), 7.53 (m, 2H), 7.97 ppm (m, 2H); C nmr
+
+
+
250 [M - SH] , 238 [M - CO H] , 193 [238 - CSH] , 71
(acetone-d ): δ 35.2, 46.6, 83.6 (sept., J = 35 Hz), 117.8, 122.0 (q,
2
6
+
+
[C H O ] , 45 [CSH, CO H] .
J = 283 Hz), 122.7 (q, J = 284 Hz), 128.6, 130.1, 132.9, 136.6,
3
3
2
2
19
Anal. Calcd. for C H FNO S (283.35): C, 50.87; H, 3.56;
152.9, 167.5, 181.0 ppm; F nmr (acetone-d ): δ 0.25 (q, J = 9.0
12 10 2 2
6
N, 4.94.Found: C, 50.61; H, 3.79; N, 4.76.
Hz, CF ), 1.41 ppm (q, J = 9.0 Hz, CF ); ms (EI) m/z = 447/449
3
3
+
+
[M] , 281/283 [M - CF COCF ] , 253/255 [M - CF COCF , -
CO] , 208 [M - CF COCF , - COCHS] , 71 [C H O ] .
3
3
3
3
3-[2-(4-Chlorophenyl)-thiazol-4-yl]-(RS)-2-mercaptopropanoic
Acid (8c).
+
+
+
3
3
3 3 2
Anal. Calcd. for C H ClF NO S (447.81): C, 40.23; H,
15
8
6
2 2
Compound 7c (2.24 g, 5 mmol) was heated in a THF/water
mixture. Yield: 1.00 g (67%) 8c; mp 137 °C, yellow crystals; ir
1.80; N, 3.13. Found: C, 40.39; H, 1.86; N, 3.10.
-1
1
4-[2-(4-Methylphenyl)-thiazol-4-ylmethyl]-2,2-bis(trifluo-
romethyl)-1,3- oxathiolan-5-one (7d).
(KBr): ν 3400-2800, 1750-1650 cm ; H nmr (CDCl ): δ 3.28
3
(m, 1H), 3.43 (m, 1H), 4.07 (m, 1H), 7.03 (s, 1H), 7.30 (m, 2H),
13
7.71 ppm (m, 2H); C nmr (CDCl ): δ 32.3, 52.3, 116.4, 127.8,
3
Compound 5a 3.75 g (10 mmol) was reacted with 4-methylth-
iobenzamide (1.51 g, 10 mmol) in 20 ml of acetone. Yield: 2.70 g
129.2, 131.3, 136.2, 152.8, 167.4, 174.9 ppm; ms (EI) m/z =
+
+
+
301/299 [M] , 256/254 [M - CO H] , 211/209 [254 - CSH] , 71
2
(63%) 7d, mp 79 °C, white crystals; ir (KBr): ν 1810, 1790, 1510,
+
+
[C H O ] , 45 [CSH, CO H] .
-1 1
3
3
2
2
1455, 1210 cm ; H nmr (CDCl ): δ 2.39 (s, 3H), 3.25 (dd, 1H, J =
3
Anal. Calcd. for: C H ClNO S (299.80): C, 48.08; H, 3.36;
12 10
2 2
14.8 Hz, J = 10.6 Hz), 3.75 (dd, 1H, J = 15.0 Hz, J = 3.4 Hz), 4.72
(dd, 1H, J = 10.8 Hz, J = 3.2 Hz), 7.03 (s, 1H), 7.24 (d, 2H, J = 8
N, 4.67. Found: C, 48.02, H, 3.46; N, 4.57.
13
Hz), 7.81 ppm (d, 2H, J = 8 Hz); C nmr (CDCl ): δ 21.4, 35.5,
3-[2-(4-Methylphenyl)-thiazol-4-yl]-(RS)-mercaptopropanoic
Acid (8d).
3
46.2, 83.4 (sept., J = 35 Hz), 115.0, 120.9 (q, J = 286 Hz), 121.6 (q,
J = 286 Hz), 126.5, 129.7, 130.6, 140.8, 151.3, 169.1, 170.5 ppm;
Compound 7d (2.14 g, 5 mmol) was heated in a THF/water
mixture. Yield: 1.13 g (81%) 8d, mp 137 °C, white crystals; ir
19
F nmr (CDCl ): δ 1.94 (q, J = 9.0 Hz, CF ), 3.09 ppm (q, J = 9.0
3
3
+
+
Hz, CF ); ms (EI) m/z = 427 [M] , 408 [M - F] , 233 [M -
(CF ) CO, - CO] , 188 [M - C H , - C H NS] , 118 [C H CNH] .
3
-1
1
(KBr) ν 3600-2780, 1705 cm ; H nmr (acetone-d ): δ 2.34 (s,
6
+
+
+
3 2
7
7
4
3
7 7
3H), 3.39 (m, 2H), 4.22 (m, 1H), 7.28 (m, 3H), 7.79 ppm (m,
Anal. Calcd. for C H F NO S (427.37): C, 44.96; H, 2.59;
16 11
6
2 2
13
2H); C nmr (acetone-d ): δ 21.3, 33.6, 53.0, 115.2, 126.9,
6
N, 3.27. Found: C, 45.10; H, 2.78; N, 3.75.
3-[2-(Aryl)-thiazol-4-yl]-(RS)-2-mercapto-propanoic Acid (8).
General Procedure.
130.3, 131.6, 140.8, 154.1, 168.2, 172.3 ppm; ms (EI) m/z = 279
+
+
+
[M] , 246 [M - SH] , 234 [M - CO H] , 188 [M - C H ], 118
2
7 7
+
+
[C H CNH] , 91 [HSCHCO H] .
7
7
2
Anal. Calcd. for C H NO S (279.37): C, 55.89; H, 4.69; N,
13 13
2 2
A solution of 7 (5 mmol) in a 1:1-THF/water mixture (50 ml)
was heated under reflux for 2 days. After evaporation of the sol-
5.01. Found: C, 55.94; H, 4.31; N, 5.19.
Methyl 3-[2-(2-thienyl)-thiazol-4-yl]-(RS)-2-mercaptopropionate
(9).
vents, the residue was dissolved in 100 ml of CH Cl . The
2
2
organic layer was washed with water (3x 50 ml) and dried with
MgSO . After evaporation of the solvent in vacuo the residue
Compound 7a (2.10 g, 5 mmol) was heated in dry methanol
4
was recrystallized from CHCl /hexane.
(25 ml) under reflux for 3 hours. After evaporation of the solvent,
3

440
K. Pumpor, E. Windeisen and K. Burger
Vol. 40
the residue was purified by Kugelrohr distillation in vacuo. Yield:
3-[2-(2-Thienyl)-thiazol-4-yl]-(RS)-2-mercaptopropananilide
(11).
0.75 g (53%) 9; bp 220 °C/1.5 torr; ir (film): ν 3105, 2950, 1730,
-1 1
1510 cm ; H nmr (CDCl ): δ 2.19 (d, 1H, J = 9.0 Hz), 3.16 (dd,
3
Compound 7a (2.10 g, 5 mmol) was treated with aniline (0.93
g, 10 mmol) in 50 ml of diethyl ether. Yield: 1.21 g (70%) 11; mp
158 °C, white crystals; ir (KBr): ν 3545-3285, 1650, 1600, 1540
1H, J = 15.0 Hz, J = 7.0 Hz), 3.40 (dd, 1H, J = 15.0 Hz, J = 8.0
Hz), 3.74 (s, 3H), 3.90 (m, 1H), 6.92 (s, 1H), 7.03 (m, 1H), 7.36
13
(m, 1H), 7.46 ppm (m, 1H); C nmr (CDCl ): δ 37.2, 40.1, 52.6,
3
-1 1
cm ; H nmr (DMSO-d ): δ 3.07 (dd, 1H, J = 14.4 Hz, J = 7.5
6
114.7, 126.5, 127.6, 127.8, 137.2, 153.1, 161.5, 173.2 ppm; ms
Hz), 3.14 (d, 1H, J = 9 Hz), 3.37 (dd, 1H, J = 14.4 Hz, J = 7.5 Hz),
3.97 (m, 1H), 7.05 (m, 1H), 7.14 (m, 1H), 7.30 (m, 2H), 7.34 (m,
+
+
+
(EI) m/z = 285 [M] , 254 [M - OCH ] , 252 [M - SH] , 226 [254
3
+
+
+
+
- CO] , 181 [226 - CSH] , 71 [C H O ] , 45 [CSH] .
3
3 2
1H), 7.57 (m, 1H), 7.60 (m, 1H), 7.61 (m, 1H), 7.69 (m, 1H),
Anal. Calcd. for: C H NO S (285.41): C, 46.29; H, 3.88; N,
13
11 11
2 3
10.18 ppm (s, 1H); C nmr (DMSO-d ): δ 36.6, 41.3, 115.7,
6
4.91. Found: C, 46.04; H, 3.95; N, 5.05.
119.2, 123.4, 127.0, 128,3, 128.5, 128.7, 136.6, 138.9, 153.6,
+
+
160,4, 170.3 ppm; ms (EI) m/z = 346 [M] , 313 [M - SH] , 254
Aminolysis of 4-(thiazol-4-ylmethyl)-2,2-bis(trifluoromethyl)-
1,3-oxathiolan-5-ones (7).
+
+
+
[M – C H N] , 221 [313 - C H N] , 194 [313 - C H N, - CO] ,
6
6
6
6
6 5
+
+
181 [194 - CH] , 128 [181 – C H N] .
3
3
General Procedure.
Anal. Calcd. for C H N OS (346.49): C, 55.46; H, 4.07; N,
16 14
2
3
8.08. Found: C, 55.50; H, 4.30; N, 8.25.
A solution of 7 (5 mmol) in 50 ml of diethyl ether or acetoni-
trile was reacted at room temperature with an excess of the corre-
sponding amine, aniline, hydrazine hydrate, hydroxylamine, (S)-
phenylalanine methyl ester, Z-hydrazide and Z-glycine hydrazide
with stirring. After a few minutes the products began to crystal-
lize. After completion of the reaction ( F NMR analysis) the
precipitate was collected by filtration, washed with diethyl ether
and dried in vacuo.
3-[2-(2-Thienyl)-thiazol-4-yl]-(RS)-2-mercaptopropanhydrazide
(12a).
Compound 7a (2.10 g, 5 mmol) and hydrazine hydrate (1.00 g,
20 mmol) were reacted in 50 ml of diethyl ether. Yield: 1.30 g
(91%) 12a; mp 126 °C, white crystals; ir (KBr): ν 3700-2800,
19
-1
1
3310, 1645, 1535 cm ; H nmr (DMSO-d ): δ 3.02 (dd, 1H, J =
6
14.6 Hz, J = 7.7 Hz), 3.27 (dd, 1H, J = 14.4 Hz, J = 7.7 Hz), 3.73
N-Benzyl 3-[2-(2-thienyl)-thiazol-4yl]-(RS)-2-mercapto-
propanamide (10a).
(t; 1H, J = 7.6 Hz), 4.17 (s, br., 2H, NH ), 7.17 (m, 1H), 7.31 (s,
2
13
1H), 7.63 (m, 1H), 7.71 (m, 1H), 9.29 ppm (s, br., 1H, NH);
C
nmr (DMSO-d ): δ 37.0, 39.0, 115.5, 126.9, 128.2, 128.4, 136.6,
6
Compound 7a (2.10 g, 5 mmol) was treated with benzylamine
+
153.6, 168.6, 170.8 ppm; ms (EI) m/z = 285 [M] , 254 [M -
(1.07 g, 10 mmol) in 50 ml of diethyl ether. Yield: 1.30 g (72%)
+
+
NHNH ] , 226 [254 - CO] .
-
2
10a, mp 131 °C, white crystals; ir (KBr): ν 3290, 2920, 1630 cm
Anal. Calcd. for C H N OS (285.42): C, 42.08; H, 3.88; N,
1
1
10 11
3
3
; H nmr (DMSO-d ): δ 3.06 (dd; 1H, J = 14.0 Hz, J = 7.0 Hz),
6
14.73. Found: C, 41.83; H, 3.64; H, 14.49.
3.32 (dd, 1H, J = 14.0 Hz, J = 8.0 Hz), 3.88 (dd, 1H, J = 8.0 Hz, J
= 7.0 Hz), 4.22 (dd; 1H, J = 15.0, J = 6.0 Hz), 4.36 (dd, 1H, J =
15.0 Hz, J = 6.0 Hz), 7.18 (m, 6H), 7.28 (s, 1H), 7.63 (m, 1H),
3-[2-(4-Fluorophenyl)-thiazol-4-yl]-(RS)-2-mercaptopropanhy-
drazide (12b).
7.63 (m, 1H), 7.69 (m, 1H), 8.63 ppm (t, 1H, NH, J = 6.0 Hz);
Compound 7b (2.16 g, 5 mmol) and hydrazine hydrate (1.00 g,
20 mmol) were reacted in 50 ml of diethyl ether. Yield: 12b; mp
134 °C, white crystals; ir (KBr): ν = 3465-3295, 1650, 1510,
13
C nmr (DMSO-d ): δ 37.4, 40.8, 42.3, 115.9, 126.9, 127.1,
6
127.2, 128.4, 128.5, 128.7, 136.9, 139.3, 154.0, 160.5, 171.7
+
+
ppm; ms (EI) m/z = 360 [M] , 327 [M - SH] , 222 [327 -
-1
1
1230 cm ; H nmr (DMSO-d ): δ 3.06 (dd, 1H, J = 14.3 Hz, J =
6
+
+
+
+
C H N] , 194 [222 - CO] , 181 [194 - CH] , 106 [C H N] , 91
7
7
7 7
7.0 Hz), 3.31 (dd, 1H, J = 14.4, J = 7.8 Hz), 3.78 (t, 1H, J = 7.4
+
[C H ] .
7
7
Hz), 4.31 (s, br., 2H, NH ), 7.33 (s, 1H), 7.37 (m, 2H), 7.99 (m,
2
Anal. Calcd. for: C H N OS (360.54): C, 56.63; H, 4.47; N,
13
17 16
2
3
2H), 9.27 ppm (s, 1H, NH); C nmr (DMSO-d ): δ 39.1, 40.9,
6
7.77. Found: C, 56.65; H, 4.55; N, 7.99.
116.0, 116.3, 116.4, 128.3, 128.4, 129.8 (d, J = 3 Hz), 154.2,
163.1 (d, J = 248 Hz), 165.2, 170.9 ppm; ms (EI): m/z = 298 [M +
N-Benzyl 3-[2-(4-fluorophenyl)-thiazol-4-yl]-(RS)-2-mercapto-
propanamide (10b).
+
+
+
H] , 266 [M - NHNH ] , 238 [M - NHNH , - CO] , 206 [M -
2
2
+
NHNH , - CO, - S] .
2
Compound 7b (2.16 g, 5 mmol) was reacted with benzylamine
(1.07 g, 10 mmol) in 50 ml of diethyl ether. Yield: 1.56 g (84 %)
Anal. Calcd. for C H FN OS (297.38): C, 48.47; H, 4.07;
12 12
3
2
N, 14.13. Found: C, 48.70; H, 4.08; H, 14.40.
10b, mp 147 °C, white crystals; ir (KBr): ν 3540-3360, 3300,
N-Hydroxy 3-[2-(2-thienyl)-thiazol-4-yl]-(RS)-2-mercapto-
propanamide (13).
-1 1
1640, 1540 cm ; H nmr (DMSO-d ): δ 3.04 (d, 1H, J = 9.3 Hz),
6
3.10 (dd, 1H, J = 14.1 Hz, J = 6.3 Hz), 3.35 (dd, 1H, J = 14.1 Hz,
J = 8.7 Hz), 3.93 (m, 1H), 4.19 (dd, 1H, J = 15.6 Hz, J = 5.7 Hz),
4.36 (dd, 1H, J = 15.3 Hz, J = 6.3 Hz), 7.09 (m, 2H), 7.20 (m,
3H), 7.36 (m, 3H), 8.01 (m, 2H), 8.61 ppm (t, 1H, J = 5.9 Hz,
Compound 7a (2.10 g, 5 mmol) was reacted with hydroxyl-
amine (0.50 g, 15 mmol) in 50 ml of diethyl ether. Yield: 1.15 g
(80%) 13; mp 148 °C, white crystals; ir (KBr): ν 3600-2700,
13
-1
1
NH); C nmr (acetone-d ): δ 37.4, 40.5, 42.0, 115.9, 116.3,
3230, 1665, 1535 cm ; H nmr (DMSO-d ): δ 3.02-3.38
6
6
126.6, 126.8, 128.1, 128.2, 128.4, 129.7, 139.0, 154.2, 160.5,
(m, 2H), 3.68/3.86 (m, 1H), 7.18 (m, 1H), 7.31/7.33 (s, 1H), 7.64
(m, 1H), 7.72 (m, 1H), 9.17 (m, 1H, NH), 10.77 ppm (s. br., 1H,
+
165.2, 165.5, 171.4 ppm; ms (EI): m/z = 372 [M] , 339 [M -
+
+
+
+
13
SH] , 234 [339 - C H N] , 206 [234 - CO] , 193 [206 - CH] ,
OH); C nmr (DMSO-d ): δ 32.3, 49.8, 115.5, 126.9, 128.2,
7
7
6
+
+
+
+
139 [193 - C H N] , 122 [F-C H -CNH] , 106 [C H N] , 91
[C H ] , 71 [193 - F-C H -CNH] .
128.4, 136.4, 153.4, 166.1, 168.3 ppm; ms (EI) m/z = 286 [M] ,
253 [M - SH] , 181 [253 - C H O N] .
3
4
6
4
7 8
+
+
+
+
7
7
6 4
2
2 2
Anal. Calcd. for: C H FN OS (372.49): C, 61.27; H, 4.60;
Anal. Calcd. for: C H N O S (286.40): C, 41.94; H, 3.52;
19 17
2
2
10 10
2 2 3
N, 7.52. Found: C, 61.30; H, 4.14; N, 7.67.
N, 9.78: Found: C 42,17; H, 3.58; N, 9.65.

May-Jun 2003
Synthesis of Heteroaryl Substituted α-Mercapto Acids from Thiomalic Acid
441
N-(2-Hydroxyethyl) 3-[2-(2-thienyl)-thiazol-4-yl]-(RS)-2-mer-
captopropanamide (14).
(DMSO-d ): δ 3.09 (dd, J = 14.7 Hz, J = 6.9 Hz, 1H), 3.34 (dd, J =
14.7 Hz, J = 7.5 Hz, 1H), 3.71 (d, J = 6.0 Hz, 2H), 3.93 (t, J = 7.2
Hz, 1H), 5.06 (s, 2H), 7.33 (s, 1H), 7.38 (m, 6H), 7.45 (s, 1H),
6
Compound 7a (2.10 g, 5 mmol) and ethanolamine (0.92 g, 15
mmol) were reacted in 50 ml of diethyl ether. Yield: 1.07 g (68%)
14; mp 94 °C, white crystals; ir (KBr): ν 3435-2930, 1640, 1540
7.55 (t, J = 6.0 Hz, 1H), 8.00 (m, 2H), 10.12 (s br., 1H, NH), 10.25
13
ppm (s br., 1H, NH); C nmr (DMSO-d ): δ 36.9, 38.4, 41.9,
6
65.5, 116.1, 116.4, 116.5, 127.7, 128.4, 129.8, 137.0, 153.9, 156.5,
-1
1
cm ; H nmr (DMSO-d ): δ 2.99 (dd, 1H, J = 14.4 Hz, J = 7.5
6
+
161.5, 164.8, 165.2, 167.8, 170.3 ppm; ms (EI): m/z = 489 [M] ,
Hz), 3.15 (m, 2H), 3.26 (dd, 1H, J = 14.3 Hz, J = 7.5 Hz), 3.39 (m,
+
+
456 [M - SH] , 379 [456 - C H ], 321 [456 - C H CO ] , 264
6
5
7
7
2
2H), 3.78 (t, 1H, J = 7.5 Hz), 7.18 (m, 1H), 7.31 (s, 1H), 7.64 (m,
+
+
+
[321 - COCH NH] , 206 [264 - CON H ] , 193 [206 - CH] .
2
2 2
13
1H), 7.72 (m, 1H), 8.18 ppm (t, 1H, NH); C nmr (DMSO-d ): δ
6
Anal. Calcd. for C H FN O S (488.56): C, 54.09; H, 4.33;
22 21
4 4 2
37.3, 43.7, 47.8, 62.3, 116.7, 128.0, 129.4, 129.6, 139.0, 155.9,
N, 11.47. Found: C, 53.80; H, 4.30; N, 11.30.
+
+
162.2, 173.5 ppm; ms (EI) m/z = 314 [M] , 281 [M - SH] , 253
+
+
[M - NH (CH ) OH] , 226 [M - C(O)NH(CH ) OH] , 193 [226 -
SH] , 181 [226 - CHS] , 143 [253 - C H NS] , 110 [C H NS] ,
Acknowledgements.
2
2 2
2 2
+
+
+
+
5
4
5 4
We are grateful to Volkswagen-Stiftung, Hannover, for finan-
cial support.
+
+
+
83 [C H S] , 71 [181 - C H NS] , 40 [C H ] .
4
3
5
4
3 4
Anal. Calcd. for C H N O S (314.45): C, 45.84; H, 4.49;
12 14
2 2 3
N, 8.91. Found: C 45,80; H, 5.24; N, 8.90.
REFERENCES AND NOTES
N-{3-[2-(4-Fluorophenyl)-thiazol-4-yl]-(RS)-2-mercapto-
propanoyl}-phenylalanine Methylester (15).
[*] Correspondence to: K. Burger. E-mail: burger@organik.
chemie.uni-leipzig.de
Compound 7b (2.16 g, 5 mmol) was reacted with (S)-pheny-
[1] D. Seebach and H. O. Kalinowsky, Nachr. Chem. Techn. Lab.,
24, 415 (1976).
lalanine methyl ester (2.69 g, 15 mmol) in of 50 ml diethyl ether.
Recrystallization from hexane/CHCl . Yield: 1.73 g (78 %) 15;
3
[2a] D. S. Cohen, C. A. Fink, A. J. Trapani, R. L. Webb, P. A. Zane
and R. E. Chatelain, Cardiovasc Drug. Rev., 17, 16 (1999); [b] J. F.
Gaucher, M. Selkti, G. Tiraboschi, T. Prangé, B. P. Roques, A. Thomas
and M. C. Fournié-Zaluski, Biochemistry, 38, 12569 (1999); [c] R.
Bohacek, S. D. Lombaert, C. McMartin, J. Priestle and M. Grütter, J. Am.
Chem. Soc., 118, 8231 (1996).
[3] A. Kleemann and J. Engel, Pharmazeutische Chemie,
Synthesen-Patente-Anwendungen, Georg Thieme, Stuttgart, 1987, p
1104.
[4a] J. A. Robl, Bristol-Meyers Squibb, Patent No. US-5,508,272
(April 16, 1996); Chem. Abstr., 125, 33695h (1996); (b) D. S.
Karanewsky and J. A. Robl, Bristol-Meyers Squibb, Patent No.
US-5,552,397 (September 3, 1996); Chem. Abstr., 125, 328738a (1996).
[5] J. A. Robl, L. M. Simpkins, C.-Q. Sun, N. Murugesun, J. C.
Borrish, M. M. Asad, J. E. Bird, T. Schaeffer, N. C. Trippodo, E. W.
Petrillo and D. S. Karanewsky, Bioorg. Med. Chem. Lett., 4, 1789 (1994).
[6] M. J. Fray and D. Ellis, Tetrahedron, 54, 13825 (1998).
[7a] M. Miller, Acc. Chem. Res., 19, 49 (1986); [b] R. Bihofsky, B.
L. Levinson, R. C. Loewi, P. W. Erhardt and M. A. Polokoff, J. Med.
Chem., 38, 2119 (1995); [c] Y. Ikeda, S. Gomi, K. Yokose, H. Naganawa,
T. Ikeda, M. Manabe, M. Hamada, S. Kondo and H. Umezawa,
J. Antibiotic, 38, 1803 (1985).
mp 148 °C, white crystals; ir (KBr): ν 3290, 1740, 1645, 1550,
-1
1
1510 cm ; H nmr (acetone-d ): δ 2.43 (d, 1H, J = 9.3 Hz), 3.07
6
(dd, 1H, J = 13.7 Hz, J = 7.7 Hz), 3.14 (dd, 1H, J = 9.3 Hz, J = 5.8
Hz), 3.19 (dd, 1H, J = 9.3 Hz, J = 5.8 Hz), 3.43 (dd, 1H, J = 14.5
Hz, J = 7.7 Hz), 3.65 (s, 1H), 4.03 (m, 1H), 4.76 (m, 1H), 7.29
13
(m, 8H), 7.71 (d, 1H, J = 7.8 Hz, NH), 8.05 ppm (m, 2H);
C
nmr (acetone-d ): δ 38.9, 39.0, 42.7, 53.0, 55.3, 117.2, 117.5 (d, J
6
= 26 Hz), 128.2, 129.8, 130.0, 130.9, 131.9, 138.4, 156.1, 162.7,
+
+
167.3, 167.7 ppm; ms (EI) m/z = 444 [M] , 411 [M - SH] , 385
+
+
+
[M - CO CH ] , 265 [385 - C H CHNH ] , 232 [265 - SH] ,
2
3
7
7
2
+
+
205 [385 - C H CHNHCO, - SH] , 121 [FC H CN] .
7
7
6 4
Anal. Calcd. for C H FN O S (444.55): C, 59.44; H, 4.76;
22 21
2 3 2
N, 6.30, Found: C, 58.80; H, 5.19; N, 6.87.
N’-{3-[2-(4-Fluorophenyl)-thiazol-4-yl]-2-mercaptopropanoyl}-
N’’-(benzyloxycarbonyl)-hydrazine (16).
Compound 7b (2.16 g, 5 mmol) was reacted with N-benzyl-
oxycarbonyl-hydrazine (1.32 g, 10 mmol) in 50 ml of diethyl
ether. Yield: 1.60 g (74 %) 17; mp 152 °C, white crystals; ir
-1
1
(KBr): 3240-3220, 1710, 1680, 1510, 1230 cm ; H nmr (ace-
tone-d ): δ 2.50 (d, 1H, J = 8.8 Hz), 3.13 (dd, 1H, J = 14.6 Hz, J
6
[8a] J. A. Robl, C.-G. Sun, J. Stevenson, D. E. Ryono and L. M.
Simpkins, J. Med. Chem., 40, 1570 (1997); (b) R. L. Tolman, W. J.
Greenlee and R. J. Lynch, J. Med. Chem., 35, 2772
= 7.0 Hz), 3.42 (dd, 1H, J = 14.7 Hz, J = 7.0 Hz), 3.94 (dd, 1H, J
= 16.3 Hz, J = 7.2 Hz), 5.11 (s, 2H), 7.20 (s, 1H), 7.27 (d, 2H, J =
8.8 Hz), 7.35 (m, 5H), 8.01 (m, 2H), 8.39 (s, br., 1H, NH), 9.33
(1992).
13
ppm (s, 1H, NH); C nmr (acetone-d ): δ 39.0, 40.9, 68.0, 117.2,
6
[9a] M. J. Soth and J. S. Nowick, Curr. Opin. Chem. Biol., 64, 276
(1999) and references cited therein; [b] J. Aubé (ed), Recent Advances in
Peptidomimetics, Tetrahedron Symposium- in-Print No 83, 56, 9725
(2000).
[10] R. D. Duthaler, Tetrahedron, 50, 1539 (1994) and references
cited therein.
[11] G. M. Coppola and H. F. Schuster, α-Hydroxy Acids in
Enantioselective Syntheses, VCH Weinheim, 1997.
[12] K. Burger and M. Eggersdorfer, Liebigs Ann. Chem., 1547
(1979).
117.5, 117.6, 129.3, 129.9, 130.0, 131.8, 138.3, 155.8, 157.7,
+
+
162.8, 167.3, 173.1 ppm; ms (EI): m/z = 431 [M] , 399 [M - S] ,
+
+
323 [M - PhCH O] , 291 [M - F-C H , -CHS] , 238 [M - F-
3
6 4
+
+
C H -C H NS] , 193 [F-C H -C H NS] .
6
4
4
4
6
4
4 4
Anal. Calcd. for C H FN O S (431.51): C, 55.67; H, 4.20;
20 18
3 3 2
N, 9.74. Found: C, 55.50; H, 3.65; N, 9.77.
N’-{3-[2-(4-Fluorophenyl)-thiazol-4-yl]-2-mercaptopropanoyl}-
N’’-[(N-benzyloxycarbonyl)-glycyl Hydrazine (17).
Compound 7b (2.16 g, 5 mmol) and N-carbobenzoxyglycine
hydrazide (1.67 g, 7.5 mmol) were reacted in 50 ml of acetonitrile.
Yield: 1.83 g (75%) 17; mp 221 °C, white crystals; ir (KBr): ν
[13a] B. Strijtveen and R. M. Kellog, J. Org. Chem., 51, 3664
(1986); [b] S. E. Kelly and T. G. LaCour, Tetrahedron Asymm., 3, 715
(1992); [c] N. J. Hrib, J. G. Jurcak, D. E. Bregna, K. L. Burgher, H. B.
Hartmann, S. Kafka, L. L. Kerman, S. Kongsamut and J. E. Roehr,
-1
1
3510-3320, 1700, 1610, 1510, 1455, 1235, 1155 cm ; H nmr

442
K. Pumpor, E. Windeisen and K. Burger
Vol. 40
J. Med. Chem., 39, 4044 (1996); [d] Japanese Patent, Kokai; Tokyo,
Koho, JP 06,122,671; Chem. Abstr., 121, 179098 (1994); [e] US Patent,
US 5,229,388; Chem Abstr., 120, 270452 (1994); [f] US Patent, US
4,933,453, Chem. Abstr., 114, 81887 (1991); [g] B.-C. Chen, M. S.
Bednarz, O. R. Kocy and J. E. Sundeen, Tetrahedron Asymm., 9, 1641
(1998); [h] H. Schedel, P. J. L. M. Quaedflieg, Q. B. Broxterman, W.
Bisson, A. L. L. Duchateau, I. C. H. Maes, R. Herzschuh and K. Burger,
Tetrahedron Asymm., 11, 2125 (2000); [i] R. L. Harding and T. D. H.
Bugg, Tetrahedron Lett., 41, 2729 (2000); [j] S.-K. Lee, S. Y. Lee and Y.
S. Park, Synlett., 1941 (2001); [k] J. Zhu, L. You, S. X. Zhao, B. White,
J. G. Chen and P. M. Skonezny, Tetrahedron Lett., 43, 7585 (2002);
[l] J. Nam, S.-K. Lee, K. Y. Kim and Y. S. Park, Tetrahedron Lett., 43,
8253 (2002).
[14] For isocysteine see: [a] L. M. Gustavson and A. Srinivasan,
Synth. Commun., 21, 265 (1991); [b] N. Fotouhi, A. Lugo, M. Visnick, L.
Lusch, R. Walsky, J. W. Coffey and A. C. Hanglow, J. Biol. Chem., 48,
30227 (1994); [c] R. Pires and K. Burger, Tetrahedron Lett., 37, 8159
(1996).
[15] For homoisocysteine see: G. Radics, R. Pires, B. Koksch, S.
M. El-Kousy and K. Burger, Tetrahedron Lett., 44, 1059 (2003).
[16] R. Maeda, Chem. Pharm. Bull., 31, 3424 (1983).
[19a] K. Burger, M. Kluge, S. Fehn, B. Koksch, L. Hennig and G.
Müller, Angew. Chem. Int. Ed., 38, 1414 (1999); [b] T. Rühl, L. Hennig,
Y. Hatanaka, K. Burger and P. Welzel, Tetrahedron Lett., 41, 4555
(2000).
[20] K. Burger, E. Windeisen, E. Heistracher, T. Lange and
A. A. H. Abdel-Aleem, Monatsh. Chem., 133, 41 (2002).
[21a] K. Burger, E. Windeisen and R. Pires, J. Org. Chem., 60, 7641
(1995); [b] R. Pires and K. Burger, Synthesis, 1277 (1996).
[22] T. Lange, E. Windeisen, B. Koksch, S. Berger, S. M. El-
Kousey and K. Burger, in preparation.
[23] For Hantzsch reaction see: K. Burger, M. Gold, H. Neuhauser,
M. Rudolph and E. Höß, Synthesis, 1145 (1992).
[24] For Hantzsch reaction see: R. H. Wiley, D. C. England and
L. C. Behr, Org. Reactions, 6, 367 (1951) and references cited therein.
[25a]
A. S. Reddy, M. S. Kumar and G. R. Reddy, Tetrahedron
Lett., 41, 6285 (2000) and lit. cited therein; [b] E. Thouin and
W. D. Lubell, Tetrahedron Lett., 41, 457 (2000) and lit. cited therein;
[c] B. Barlaam, P. Koza and J. Berriot, Tetrahedron, 55, 7221 (1999); [d]
A. Golebiowski and S. Klopfenstein, Tetrahedron Lett., 39, 3397 (1998).
[26] J. J. Chen and A. F. Spatola, Tetrahedron Lett., 38, 1511
(1997).
[17] Y. Seto, K. Torii, K. Bori, K. Inabata, S. Kuwata and H.
Watanabe, Bull. Soc. Chem. Jpn., 47, 151 (1974).
[18] H. Depaire, J. P. Thomas, A. Brun, A. Olesker and G. Lucacs,
Tetrahedron Lett., 18, 1397 (1977).
[27] For first examples of the application of 1,3-oxathiolan-5-ones
for peptide hybride synthesis see: [a] E. Windeisen, PhD Thesis, 1993,
Technical University Munich; [b] G. A. Kraus, J. Bae and
P. K. Choudhury, Synthesis, 19 (2003).